Cancer Drug Interactions from Radboud UMC and University of Liverpool

No Interaction Expected

Selpercatinib

Acarbose

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. After ingestion of acarbose, the majority of active unchanged drug remains in the lumen of the gastrointestinal tract to exert its pharmacological activity and is metabolised by intestinal enzymes and by the microbial flora. Selpercatinib is unlikely to interfere with this metabolic pathway.

Description:

See summary

No Interaction Expected

Selpercatinib

Acenocoumarol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Acenocoumarol is mainly metabolised by CYP2C9 and to a lesser extent by CYP1A2 and CYP2C19. This is not affected by selpercatinib.

Description:

See summary

No Interaction Expected

Selpercatinib

Acetylsalicylic acid (Aspirin)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Aspirin is rapidly deacetylated to form salicylic acid and then further metabolised by glucuronidation (by several UGTs, major UGT1A6), which is not affected by selpercatinib.

Description:

See summary

No Interaction Expected

Selpercatinib

Agomelatine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Agomelatine is metabolised predominantly via CYP1A2 (90%), with a small proportion metabolised by CYP2C9 and CYP2C19 (10%). This is not affected by selpercatinib.

Description:

See summary

No Interaction Expected

Selpercatinib

Alendronic acid

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Alendronic acid is not metabolised and is cleared from the plasma by uptake into bone and elimination via renal excretion. Although no pharmacokinetic interaction is expected, alendronic acid should be separated from food or other medicinal products and patients must wait at least 30 minutes after taking alendronic acid before taking any other oral medicinal product.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Alfentanil

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Alfentanil undergoes extensive CYP3A4 metabolism. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with alfentanil, leading to an increased risk of adverse events of alfentanil. Coadministration should be monitored for alfentanil toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Alfuzosin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Alfuzosin is metabolised by CYP3A. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with alfuzosin, leading to an increased risk of adverse events of alfuzosin. Coadministration should be monitored for alfuzosin toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Aliskiren

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Aliskiren is minimally metabolised and is mainly excreted unchanged in faeces. Aliskiren is also a substrate of P-gp. Selpercatinib is an inhibitor of P-gp in vitro, which might lead to increased plasma concentrations of aliskiren and therefore a higher risk of adverse reactions of aliskiren. However, the relevance of this interaction is unknown. Monitor for aliskiren toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Allopurinol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Allopurinol is converted to oxipurinol by xanthine oxidase and aldehyde oxidase. Selpercatinib is unlikely to interfere with this metabolic pathway. Allopurinol is also an inhibitor of xanthine oxidase, which is not involved in the metabolism of selpercatinib.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Alosetron

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. In vitro data indicate that alosetron is metabolised by CYPs 2C9, 3A4, and 1A2. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with alosetron, leading to an increased risk of adverse events of alosetron. Coadministration should be monitored for alosetron toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Alprazolam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Alprazolam is mainly metabolised by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with alprazolam, leading to an increased risk of adverse events of alprazolam. Coadministration should be monitored for alprazolam toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Aluminium hydroxide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Aluminium hydroxide is not metabolised. However, the bioavailability of selpercatinib is pH-dependent and, thus, an increase in gastric pH by aluminium hydroxide reduces selpercatinib bioavailability. This may reduce the anti-tumor activity of selpercatinib. If coadministration is necessary, selpercatinib should be administered two hours before or four hours after a new dose of aluminium hydroxide.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Ambrisentan

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Ambrisentan is metabolised by glucuronidation via UGT1A3, UGT1A9, and UGT2B7 and to a lesser extent by CYP3A4 and CYP2C19. Ambrisentan is also a substrate of P-gp. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with ambrisentan. Moreover, selpercatinib is an inhibitor of P-gp in vitro, which might also lead to increased plasma concentrations of ambrisentan and therefore a higher risk of adverse reactions of ambrisentan. However, the relevance of this interaction is unknown. Coadministration should be monitored for ambrisentan toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Amikacin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Amikacin is eliminated by glomerular filtration. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Selpercatinib

Amiloride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Amiloride is eliminated unchanged in the kidney. In vitro data indicate that amiloride is a substrate of OCT2. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Do Not Coadminister

Selpercatinib

Amiodarone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Amiodarone is metabolised by CYP3A4 and CYP2C8. Moreover, the major metabolite of amiodarone, desethylamiodarone, is an inhibitor of CYP3A4 (weak), CYP2C9 (moderate), CYP2D6 (moderate), CYP2C19 (weak), CYP1A1 (strong), CYP2B6 (moderate), and P-gp (strong). Selpercatinib is an in vitro substrate of P-gp. No clinically significant differences in selpercatinib pharmacokinetics were observed when coadministered with a single dose of rifampicin, a P-gp inhibitor. Therefore, no relevant effect on selpercatinib exposure is expected due to inhibition of P-gp by desethylamiodarone. However, selpercatinib is metabolised by CYP3A4 and concentrations may increase due to weak inhibition of CYP3A4 by the desethylamiodarone. Selpercatinib is associated with concentration-dependent QTc prolongation and thus, any increase in selpercatinib exposure may result in an increased QTc interval. Since amiodarone also has a risk of QT prolongation, coadministration with amiodarone can lead to an even more prolonged QT interval. Furthermore, concentrations of amiodarone may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with amiodarone, leading to an increased risk of adverse events of amiodarone. Additionally, concentrations may increase due to moderate inhibition of CYP2C8 by selpercatinib. After coadministration with repaglinide, a CYP2C8 substrate, repaglinide exposure increased by 188%. A similar effect may occur after coadministration with amiodarone, leading to an increased risk of adverse events of amiodarone. Therefore, coadministration is contraindicated. Note: due to the long half-life of amiodarone, interactions can be observed for several months after discontinuation of amiodarone.

Description:

See summary

No Interaction Expected

Selpercatinib

Amisulpride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Amisulpride is weakly metabolised and is primarily eliminated renally (possibly via OCT). Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Potential Interaction

Selpercatinib

Amitriptyline

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Amitriptyline is metabolised predominantly by CYP2D6 and CYP2C19, with a small proportion metabolised by CYPs 3A4, 1A2, and 2C9. Selpercatinib is a weak CYP3A4 inhibitor. Since this is a minor pathway, no relevant effect on amitriptyline exposure is expected. However, selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. Therefore, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since amitriptyline also has a risk of QT prolongation, coadministration with amitriptyline can lead to an even more prolonged QTc interval. Coadministration should be avoided. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account. Also monitor for amitriptyline toxicity.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Amlodipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Amlodipine is metabolised by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with amlodipine, leading to an increased risk of adverse events of amlodipine. Coadministration should be monitored for amlodipine toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Amoxicillin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Amoxicillin is mainly excreted in the urine by glomerular filtration and tubular secretion. In vitro data indicate that amoxicillin is a substrate of OAT3. Selpercatinib is unlikely to interfere with these elimination pathways.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Amphotericin B

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Amphotericin B is not appreciably metabolised and is eliminated to a large extent in the bile. Selpercatinib does not interfere with this metabolic or elimination pathway. However, the European SmPC for amphotericin states that concomitant use of amphotericin B and antineoplastic agents can increase the risk of renal toxicity, bronchospasm and hypotension and so monitoring may be required.

Description:

See summary

No Interaction Expected

Selpercatinib

Ampicillin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Renal clearance of ampicillin occurs partly by glomerular filtration and partly by tubular secretion. About 20-40% of an oral dose may be excreted unchanged in the urine in 6 hours. After parenteral use about 60-80% is excreted in the urine within 6 hours. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Selpercatinib

Anidulafungin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Anidulafungin is not metabolised hepatically but undergoes chemical degradation at physiological temperatures. This is not affected by selpercatinib.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Antacids

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Antacids are not metabolised by CYPs. However, the bioavailability of selpercatinib is pH-dependent and, thus, an increase in gastric pH by antacids reduces its bioavailability. This may reduce the anti-tumor activity of selpercatinib. If coadministration is necessary, selpercatinib should be administered two hours before or four hours after a new dose of the antacid.

Description:

See summary

Potential Interaction

Selpercatinib

Apixaban

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Apixaban is a substrate of P-gp and BCRP, and is metabolised by CYP3A4 and to a lesser extent by CYPs 1A2, 2C8, 2C9, and 2C19. Apixaban is metabolised by CYP3A4 and concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with apixaban, leading to an increased risk of adverse events of apixaban. Coadministration should be monitored for anti-Xa activity. A dose reduction of apixaban by 25% is recommended.

Description:

See summary

Potential Interaction

Selpercatinib

Aprepitant

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Aprepitant is mainly metabolised by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C19. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with aprepitant, leading to an increased risk of adverse events of aprepitant. During treatment aprepitant is a moderate inhibitor of CYP3A4. However, after treatment aprepitant is a weak inducer of CYP3A4, CYP2C9, and UGT. Selpercatinib is metabolised by CYP3A4 and concentrations may increase due to moderate inhibition of CYP3A4 by aprepitant. It is predicted that after coadministration with diltiazem/fluconazole/verapamil, moderate CYP3A4 inhibitors, selpercatinib exposure increases by 60 to 99%. A similar effect may occur after coadministration with aprepitant. Selpercatinib is associated with concentration-dependent QTc prolongation and thus, any increase in selpercatinib exposure may result in an increased QTc interval. Therefore, coadministration is not recommended. If coadministration is unavoidable, closely monitor QTc interval and plasma concentrations (if available). Reduce selpercatinib dose by 40 mg. Also monitor closely for aprepitant toxicity.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Aripiprazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Aripiprazole is metabolised by CYP3A4 and CYP2D6. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with aripiprazole, leading to an increased risk of adverse events of aripiprazole. Coadministration should be monitored for aripiprazole toxicity and plasma concentrations (if available). No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Asenapine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Asenapine is metabolised by glucuronidation (UGT1A4) and oxidative metabolism (CYPs 1A2 (major), 3A4 (minor), and 2D6 (minor)). Selpercatinib is a weak CYP3A4 inhibitor. However, since this is a minor pathway, no relevant effect on asenapine exposure is expected. Coadministration should be monitored for asenapine toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Interaction

Selpercatinib

Astemizole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Astemizole is metabolised by CYPs 2D6, 2J2, and 3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with astemizole, leading to an increased risk of adverse events of astemizole. Furthermore, selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. Therefore, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since astemizole also has a risk of QT prolongation, coadministration can lead to an even more prolonged QT interval. Coadministration should be avoided. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account. Also monitor closely for astemizole toxicity.

Description:

See summary

No Interaction Expected

Selpercatinib

Atenolol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Atenolol is mainly eliminated unchanged in the kidney, predominantly by glomerular filtration. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Atorvastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Atorvastatin is metabolised by CYP3A4 and is a substrate of P-gp and OATP1B1. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with atorvastatin. Moreover, selpercatinib is an inhibitor of P-gp in vitro, which might also lead to increased plasma concentrations of atorvastatin and therefore a higher risk of adverse reactions of atorvastatin. However, the relevance of this interaction is unknown. Coadministration should be monitored for atorvastatin toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Azathioprine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Azathioprine is converted to 6-mercaptopurine which is metabolised analogously to natural purines by xanthine oxidase. This is not affected by selpercatinib.

Description:

See summary

Potential Interaction

Selpercatinib

Azithromycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Azithromycin is mainly eliminated via biliary excretion; animal data suggest this may occur via P-gp and MRP2. Azithromycin is also an inhibitor of P-gp. However, the relevance of P-gp inhibition by azithromycin is unknown. Selpercatinib is an in vitro substrate of P-gp. No clinically significant differences in selpercatinib pharmacokinetics were observed when coadministered with a single dose of rifampicin, which acts as a P-gp inhibitor when administered as a single dose. Therefore, no relevant effect on selpercatinib exposure is expected due to inhibition of P-gp by azithromycin. Selpercatinib is an inhibitor of P-gp in vitro, which might lead to increased plasma concentrations of azithromycin and therefore a higher risk of adverse reactions of azithromycin. However, the relevance of this interaction is unknown. Moreover, selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. Therefore, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since azithromycin also has a moderate risk of QT prolongation, coadministration with azithromycin can lead to an even more prolonged QTc interval. Coadministration should be avoided. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account. Monitor also for azithromycin toxicity.

Description:

See summary

No Interaction Expected

Selpercatinib

Beclometasone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Beclometasone is a pro-drug which is not metabolised by CYP450 but is hydrolysed via esterase enzymes to the highly active metabolite beclometasone-17-monopropionate. Selpercatinib is unlikely to interfere with this metabolic pathway.

Description:

See summary

Potential Interaction

Selpercatinib

Bedaquiline

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Bedaquiline is metabolised by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with bedaquiline, leading to an increased risk of adverse events of bedaquiline. Furthermore, selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. So, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since bedaquiline also has a risk of QT prolongation, coadministration with bedaquiline can lead to an even more prolonged QTc interval. Therefore, coadministration is not recommended. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account. Also monitor closely for bedaquiline toxicity.

Description:

See summary

No Interaction Expected

Selpercatinib

Bendroflumethiazide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bendroflumethiazide is mainly eliminated by hepatic metabolism (70%) and excreted unchanged in the urine (30%) via OAT1 and OAT3. In vitro data indicate that bendroflumethiazide inhibits these renal transporters, but a clinically significant interaction is unlikely in the range of observed clinical concentrations. Selpercatinib is unlikely to interfere with these elimination pathways.

Description:

See summary

Potential Interaction

Selpercatinib

Bepridil

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Bepridil is metabolised by CYP2D6 (major) and CYP3A4. Concentrations may increase due to inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with bepridil, leading to an increased risk of adverse events of bepridil. Furthermore, selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. Therefore, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since bepridil also has a risk of QT prolongation, coadministration with bepridil can lead to an even more prolonged QTc interval. Therefore, coadministration is not recommended. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account. Also monitor closely for bepridil toxicity.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Betamethasone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Betamethasone is metabolised by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with betamethasone, leading to an increased risk of adverse events of betamethasone. Coadministration should be monitored for betamethasone toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Bezafibrate

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Half of a bezafibrate dose is eliminated unchanged in the urine. Selpercatinib is unlikely to interfere with this elimination pathway. In vitro data suggest that bezafibrate inhibits the renal transporter OAT1, which is not involved in the elimination of selpercatinib.

Description:

See summary

No Interaction Expected

Selpercatinib

Bisacodyl

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bisacodyl is converted to an active metabolite by intestinal and bacterial enzymes. Absorption from the gastrointestinal tract is minimal and the small amount absorbed is excreted in the urine as the glucuronide. This is not affected by selpercatinib.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Bisoprolol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Bisoprolol is partly metabolised by CYP3A4 and CYP2D6, and partly eliminated unchanged in the urine. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with bisoprolol, leading to an increased risk of adverse events of bisoprolol. Coadministration should be monitored for bisoprolol toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Interaction

Selpercatinib

Bosentan

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Bosentan is a substrate and weak inducer of CYP3A4 and CYP2C9. Selpercatinib is metabolised by CYP3A4. It is predicted that after coadministration with bosentan or efavirenz, selpercatinib exposure decreases by 40-70% due to CYP3A4 induction. This may reduce the anti-tumor activity of selpercatinib. Therefore, coadministration is not recommended. If coadministration is unavoidable, increase the dosage of selpercatinib to a maximum of 240 mg with steps of 40 mg per week alongside close monitoring of QTc interval.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Bromazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Bromazepam undergoes oxidative biotransformation. Interaction studies indicate that CYP3A4 plays a minor role in bromazepam metabolism, but other cytochromes such as CYP2D6 or CYP1A2 may also play a role. Selpercatinib is a weak CYP3A4 inhibitor. However, since this is a minor pathway, no relevant effect on bromazepam exposure is expected. Coadministration should be monitored for bromazepam toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Budesonide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Budesonide is metabolised by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with budesonide, leading to an increased risk of adverse events of budesonide. Coadministration should be monitored for budesonide toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Buprenorphine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Buprenorphine undergoes both N-dealkylation to form norbuprenorphine (via CYP3A4) and glucuronidation (via UGT2B7 and UGT1A1). Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with buprenorphine, leading to an increased risk of adverse events of buprenorphine. Coadministration should be monitored for buprenorphine toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Bupropion

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bupropion is primarily metabolised by CYP2B6 and is a strong inhibitor of CYP2D6. This is not affected by selpercatinib and does not affect selpercatinib.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Buspirone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Buspirone is metabolised by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with buspirone, leading to an increased risk of adverse events of buspirone. Coadministration should be monitored for buspirone toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Calcium

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Calcium is eliminated through faeces, urine, and sweat. Selpercatinib is unlikely to interfere with these elimination pathways.

Description:

See summary

No Interaction Expected

Selpercatinib

Candesartan

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Candesartan is mainly eliminated unchanged via urine and bile. Selpercatinib is unlikely to interfere with these elimination pathways.

Description:

See summary

No Interaction Expected

Selpercatinib

Capreomycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Capreomycin is predominantly excreted via the kidneys as unchanged drug. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Selpercatinib

Captopril

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Captopril is largely excreted in the urine by OAT1. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Do Not Coadminister

Selpercatinib

Carbamazepine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Carbamazepine is primarily metabolised by CYP3A4 and to a lesser extent by CYP2C8. Moreover, carbamazepine is an inducer of CYP2C8 (strong), CYP2C9 (strong), CYP3A4 (strong), CYP1A2 (weak), CYP2B6, UGT1A1, and P-gp (moderate). Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. However, a relevant effect is not expected since carbamazepine is a strong CYP3A4 inducer itself. Additionally, carbamazepine is metabolised by CYP2C8 and concentrations may increase due to moderate inhibition of CYP2C8 by selpercatinib. After coadministration with repaglinide, a CYP2C8 substrate, repaglinide exposure increased by 188%. A similar effect may occur after coadministration with carbamazepine, leading to an increased risk of adverse events of carbamazepine. Selpercatinib is an in vitro substrate of P-gp. Moreover, selpercatinib is metabolised by CYP3A4 and concentrations may decrease due to strong induction of CYP3A4 by phenytoin. After coadministration with rifampicin, a strong CYP3A4 and P-gp inducer, selpercatinib exposure decreased by 87%. This may reduce the anti-tumor activity of selpercatinib. A similar effect may occur after coadministration with carbamazepine, although the magnitude of the effect is unknown. Coadministration is contraindicated.

Description:

See summary

No Interaction Expected

Selpercatinib

Carvedilol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Carvedilol undergoes glucuronidation via UGTs 1A1, 2B4, and 2B7, and additionally metabolism via CYP2D6 and to a lesser extent CYP2C9 and CYP1A2. Selpercatinib is unlikely to interfere with these metabolic pathways. Carvedilol is also an inhibitor of P-gp. However, the relevance of P-gp inhibition by carvedilol is unknown. Selpercatinib is an in vitro substrate of P-gp. No clinically significant differences in selpercatinib pharmacokinetics were observed when coadministered with a single dose of rifampicin, which acts as a P-gp inhibitor when administered as a single dose. Thus, no relevant effect on selpercatinib exposure is expected due to inhibition of P-gp by carvedilol.

Description:

See summary

No Interaction Expected

Selpercatinib

Caspofungin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Caspofungin undergoes spontaneous chemical degradation and metabolism via a non CYP-mediated pathway. This is not affected by selpercatinib.

Description:

See summary

No Interaction Expected

Selpercatinib

Cefalexin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cefalexin is predominantly eliminated unchanged renally by glomerular filtration and tubular secretion via OAT1 and MATE1. Selpercatinib is unlikely to interfere with these elimination pathways.

Description:

See summary

No Interaction Expected

Selpercatinib

Cefazolin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cefazolin is predominantly excreted unchanged in the urine, mainly by glomerular filtration with some renal tubular secretion via OAT3. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Selpercatinib

Cefixime

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cefixime is renally excreted predominantly by glomerular filtration. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Selpercatinib

Cefotaxime

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cefotaxime is partially metabolised by non-specific esterases. Most of a dose of cefotaxime is excreted in the urine - about 60% as unchanged drug and a further 24% as desacetyl-cefotaxime, an active metabolite. In vitro studies indicate that OAT3 participates in the renal elimination of cefotaxime, which is not affected by selpercatinib.

Description:

See summary

No Interaction Expected

Selpercatinib

Ceftazidime

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ceftazidime is excreted predominantly by renal glomerular filtration. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Selpercatinib

Ceftriaxone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ceftriaxone is eliminated mainly as unchanged drug, approximately 60% of the dose being excreted in the urine predominantly by glomerular filtration and the remainder via the biliary and intestinal tracts. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Selpercatinib

Celecoxib

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Celecoxib is primarily metabolised by CYP2C9, which is not affected by selpercatinib.

Description:

See summary

No Interaction Expected

Selpercatinib

Cetirizine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cetirizine is only metabolised to a limited extent and is eliminated unchanged in the urine through both glomerular filtration and tubular secretion. Selpercatinib is unlikely to interfere with these elimination pathways. In vitro data indicate that cetirizine is also an inhibitor of OCT2, which is not involved in the metabolism of selpercatinib.

Description:

See summary

Potential Interaction

Selpercatinib

Chloramphenicol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Chloramphenicol is predominantly glucuronidated. In vitro studies have shown that chloramphenicol can inhibit metabolism mediated by CYP3A4 (strong), CYP2C19 (strong) and CYP2D6 (weak). Selpercatinib is metabolised by CYP3A4, and concentrations may increase due to strong inhibition of CYP3A4 by chloramphenicol. After coadministration with itraconazole, a strong CYP3A4 inhibitor, selpercatinib exposure increased by 133%. A similar effect may occur after coadministration with chloramphenicol. Selpercatinib is associated with concentration-dependent QTc prolongation and thus, any increase in selpercatinib exposure may result in an increased QTc interval. Therefore, coadministration is not recommended. If coadministration is unavoidable, closely monitor QTc interval and plasma concentrations (if available). Reduce selpercatinib dose by 80 mg. Ocular use: Although chloramphenicol is systemically absorbed when used topically in the eye, the absorbed concentrations are unlikely to cause a clinically significant interaction.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Chlordiazepoxide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Chlordiazepoxide is extensively metabolised by CYP3A4 but does not inhibit or induce cytochromes. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with chlordiazepoxide, leading to an increased risk of adverse events of chlordiazepoxide. Coadministration should be monitored for chlordiazepoxide toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Chlorphenamine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Chlorphenamine is predominantly metabolised in the liver via CYP2D6, which is not affected by selpercatinib.

Description:

See summary

Potential Interaction

Selpercatinib

Chlorpromazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Chlorpromazine is metabolised mainly by CYP2D6, but also by CYP1A2, which are not affected by selpercatinib. However, selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. Therefore, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since chlorpromazine also has a risk of QT prolongation, coadministration can lead to an even more prolonged QT interval. Coadministration should be avoided. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account.

Description:

See summary

No Interaction Expected

Selpercatinib

Chlortalidone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Chlortalidone is mainly excreted unchanged in the urine and faeces. OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Selpercatinib is unlikely to interfere with this pathway.

Description:

See summary

Potential Interaction

Selpercatinib

Ciclosporin (Cyclosporine)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Ciclosporin is a substrate of CYP3A4 and P-gp and also inhibits CYP3A4 (moderate) and OATP1B1. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with ciclosporin. Moreover, selpercatinib is an inhibitor of P-gp in vitro, which might also lead to increased plasma concentrations of ciclosporin and therefore a higher risk of adverse reactions of ciclosporin. However, the relevance of this interaction is unknown. Additionally, selpercatinib is metabolised by CYP3A4 and concentrations may increase due to moderate inhibition of CYP3A4 by ciclosporin. It is predicted that after coadministration with diltiazem/fluconazole/verapamil, moderate CYP3A4 inhibitors, selpercatinib exposure increases by 60 to 99%. A similar effect may occur after coadministration with ciclosporin. Selpercatinib is associated with concentration-dependent QTc prolongation and thus, any increase in selpercatinib exposure may result in an increased QTc interval. Therefore, coadministration is not recommended. If coadministration is unavoidable, closely monitor QTc interval and plasma concentrations (if available). Reduce selpercatinib dose by 40 mg. Monitor also ciclosporin toxicity and plasma concentrations (if available).

Description:

See summary

No Interaction Expected

Selpercatinib

Cilazapril

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cilazapril is mainly eliminated unchanged by the kidneys. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Cimetidine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Cimetidine is metabolised by CYP450 enzymes. Concentrations may increase due to moderate inhibition of CYP2C8 by selpercatinib and weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. After coadministration with repaglinide, a CYP2C8 substrate, repaglinide exposure increased by 188%. Similar effects may occur after coadministration with cimetidine, leading to an increased risk of adverse events of cimetidine. In vitro data indicate that cimetidine inhibits OAT1 and OCT2 but at concentrations much higher than the observed clinical concentrations. Cimetidine is also a weak inhibitor of CYPs 3A4, 1A2, 2D6 and 2C19. Selpercatinib is metabolised by CYP3A4 and concentrations may increase due to weak inhibition of CYP3A4 by cimetidine. Selpercatinib is associated with concentration-dependent QTc prolongation and thus, any increase in selpercatinib exposure may result in an increased QTc interval. Furthermore, the bioavailability of selpercatinib is pH-dependent and, thus, an increase in gastric pH by cimetidine reduces selpercatinib bioavailability. This may reduce the anti-tumor activity of selpercatinib. No clinically significant differences in selpercatinib pharmacokinetics (AUC0-INF -7%) were observed when coadministered with multiple daily doses of ranitidine (H2 receptor antagonist) given 10 hours prior to and 2 hours after the selpercatinib dose (administered fasted). If coadministration is necessary, selpercatinib should be administered 10 hours after or 2 hours before a new dose of cimetidine. Monitor also the QTc interval, selpercatinib plasma concentrations (if available) and cimetidine toxicity.

Description:

See summary

Potential Interaction

Selpercatinib

Ciprofloxacin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Ciprofloxacin is primarily eliminated unchanged by the kidneys by glomerular filtration and tubular secretion via OAT3. It is also metabolised and partially cleared through the bile and intestine. Ciprofloxacin is also a weak to moderate inhibitor of CYP3A4 and a strong inhibitor of CYP1A2. Selpercatinib is metabolised by CYP3A4 and concentrations may increase due to weak to moderate inhibition of CYP3A4 by ciprofloxacin. It is predicted that after coadministration with diltiazem/fluconazole/verapamil, moderate CYP3A4 inhibitors, selpercatinib exposure increases by 60 to 99%. A similar effect may occur after coadministration with ciprofloxacin. Selpercatinib is associated with concentration-dependent QTc prolongation and thus, any increase in selpercatinib exposure may result in an increased QTc interval. Moreover, since ciprofloxacin also has a low propensity to increase the QT interval, coadministration with ciprofloxacin can lead to an even more prolonged QTc interval. Therefore, coadministration is not recommended. If coadministration is unavoidable, reduce selpercatinib dose by 40 mg and closely monitor plasma concentrations (if available) and QTc interval, taking risk factors into account.

Description:

See summary

Do Not Coadminister

Selpercatinib

Cisapride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Cisapride is metabolised by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with cisapride, leading to an increased risk of adverse events of cisapride. Moreover, selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. Therefore, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since cisapride has a high risk of QT prolongation, coadministration can lead to an even more prolonged QT interval. Coadministration is contraindicated.

Description:

See summary

Potential Interaction

Selpercatinib

Citalopram

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Citalopram is metabolised by CYPs 2C19 (38%), 2D6 (31%), and 3A4 (31%). Concentrations may increase due to inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with citalopram, leading to an increased risk of adverse events of citalopram. Furthermore, selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. Therefore, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since citalopram also has a risk of QT prolongation, coadministration with citalopram can lead to an even more prolonged QTc interval. Therefore, coadministration is not recommended. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account. Also monitor closely for citalopram toxicity.

Description:

See summary

Potential Interaction

Selpercatinib

Clarithromycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Clarithromycin is metabolised by CYP3A4 and is also an inhibitor of CYP3A4 (strong) and P-gp. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. However, a relevant effect of selpercatinib is not expected since clarithromycin is a strong CYP3A4 inhibitor itself. Selpercatinib is an in vitro substrate of P-gp. No clinically significant differences in selpercatinib pharmacokinetics were observed when coadministered with a single dose of rifampicin, which acts as a P-gp inhibitor when administered as a single dose. No relevant effect on selpercatinib exposure is expected due to inhibition of P-gp by clarithromycin. However, selpercatinib is metabolised by CYP3A4 and concentrations may increase due to strong inhibition of CYP3A4 by clarithromycin. After coadministration with itraconazole, a strong CYP3A4 inhibitor, selpercatinib exposure increased by 133%. A similar effect may occur after coadministration with clarithromycin. Selpercatinib is associated with concentration-dependent QTc prolongation and thus, any increase in selpercatinib exposure may result in an increased QTc interval. Since clarithromycin also has a moderate risk of QT prolongation, coadministration with clarithromycin can lead to an even more prolonged QTc interval. Therefore, coadministration is not recommended. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account.

Description:

See summary

No Interaction Expected

Selpercatinib

Clavulanic acid

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clavulanic acid is extensively metabolised (likely non-CYP mediated pathway) and excreted in the urine by glomerular filtration. Selpercatinib is unlikely to interfere with these elimination pathways.

Description:

See summary

No Interaction Expected

Selpercatinib

Clemastine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clemastine is predominantly metabolised in the liver via CYP2D6, which is not affected by selpercatinib.

Description:

See summary

Potential Interaction

Selpercatinib

Clindamycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Clindamycin is metabolised by CYP3A4 and in vitro data suggest that it is a weak CYP3A4 inhibitor. Clindamycin is metabolised by CYP3A4 and concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with clindamycin, leading to an increased risk of adverse events of clindamycin. Selpercatinib is metabolised by CYP3A4 and concentrations may increase due to weak inhibition of CYP3A4 by clindamycin. Selpercatinib is associated with concentration-dependent QTc prolongation and thus, any increase in selpercatinib exposure may result in an increased QTc interval. Therefore, coadministration is not recommended. If coadministration is unavoidable, closely monitor QTc interval and plasma concentrations (if available). Reduce selpercatinib dose by 40 mg. Also monitor closely for clindamycin toxicity, no a priori dose adjustment is required for clindamycin.

Description:

See summary

No Interaction Expected

Selpercatinib

Clobetasol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely with the topical use of clobetasol.

Description:

See summary

Potential Interaction

Selpercatinib

Clofazimine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Clofazimine is largely excreted unchanged in the faeces. PBPK modelling suggests that clofazimine is a moderate to strong CYP3A4 inhibitor and weak inhibitor of CYPs 2C8 and 2D6. Selpercatinib is metabolised by CYP3A4 and concentrations may increase due to moderate to strong inhibition of CYP3A4 by clofazimine. After coadministration with itraconazole, a strong CYP3A4 inhibitor, selpercatinib exposure increased by 133%. A similar effect may occur after coadministration with clofazimine. Selpercatinib is associated with concentration-dependent QTc prolongation and thus, any increase in selpercatinib exposure may result in an increased QTc interval. Moreover, since clofazimine has a moderate risk of QT prolongation, coadministration with clofazimine can lead to an even more prolonged QTc interval. Coadministration should be avoided. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account. Reduce selpercatinib dose by 80 mg.

Description:

See summary

No Interaction Expected

Selpercatinib

Clofibrate

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clofibrate is hydrolysed to an active metabolite, clofibric acid. Excretion of clofibric acid glucuronide is possibly performed via OAT1. Selpercatinib is unlikely to interfere with this metabolic or elimination pathway.

Description:

See summary

Potential Interaction

Selpercatinib

Clomipramine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Clomipramine is metabolised by CYPs 3A4, 1A2, and 2C19 to desmethylclomipramine, an active metabolite which has a higher activity than the parent drug. In addition, clomipramine and desmethylclomipramine are metabolised by CYP2D6. Concentrations may increase due to inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with clomipramine, which may lead to altered activity/toxicity of clomipramine since the highly active metabolite is formed to a lesser extent. Furthermore, selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. Therefore, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since clomipramine also has a risk of QT prolongation, coadministration with clomipramine can lead to an even more prolonged QTc interval. Therefore, coadministration is not recommended. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account. Also monitor closely for clomipramine efficacy and toxicity.

Description:

See summary

No Interaction Expected

Selpercatinib

Clonidine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Approximately 70% of administered clonidine is excreted in the urine, mainly in form of the unchanged parent drug (40-60% of the dose). Selpercatinib is unlikely to interfere with this elimination pathway. Clonidine is also a weak inhibitor of OCT2, which is not involved in the elimination of selpercatinib.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Clopidogrel

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Clopidogrel is a prodrug and is converted to its active metabolite mainly through CYP2C19 with CYP3A4, 2B6, and 1A2 playing a minor role. Moreover, clopidogrel is an inhibitor of CYP2C8 (strong), CYP2B6 (weak) and in vitro of CYP2C9 at high concentrations. The relevance of CYP2C9 inhibition is unknown. Clopidogrel is metabolised by CYP3A4, and concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with clopidogrel, leading to less efficacy of clopidogrel. Coadministration should be monitored for thrombocytes aggregation test. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Clorazepate

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Clorazepate is rapidly converted to nordiazepam which is then metabolised to oxazepam by CYP3A4. Oxazepam is mainly glucuronidated. Concentrations of the active metabolite may decrease due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with clorazepate, leading to inefficacy of clorazepate. Monitoring of clorazepate efficacy should be considered. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Cloxacillin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cloxacillin is metabolised to a limited extent, and the unchanged drug and metabolites are excreted in the urine by glomerular filtration and renal tubular secretion. Selpercatinib is unlikely to interfere with these elimination pathways.

Description:

See summary

Potential Interaction

Selpercatinib

Clozapine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Clozapine is metabolised mainly by CYP1A2 and CYP3A4, and to a lesser extent by CYP2C19 and CYP2D6. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with clozapine, leading to an increased risk of adverse events of clozapine. Furthermore, selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. Therefore, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since clozapine also has a risk of QT prolongation, coadministration can lead to an even more prolonged QT interval. Coadministration should be avoided. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account. Also monitor closely for clozapine toxicity.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Codeine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Codeine is converted via CYP2D6 to morphine, an active metabolite with analgesic and opioid properties. Morphine is further metabolised by conjugation with glucuronic acid to morphine-3-glucuronide (inactive) and morphine-6-glucuronide (active). Codeine is converted via CYP3A4 to norcodeine, an inactive metabolite. Additionally, the metabolite morphine is a substrate of P-gp. Concentrations of codeine may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with codeine, leading to an increased risk of adverse events of codeine. Furthermore, selpercatinib is an inhibitor of P-gp in vitro, which might lead to increased plasma concentrations of the active metabolite morphine and therefore a higher risk of adverse reactions of codeine. However, the clinical relevance of this interaction is unknown. Coadministration should be monitored for both codeine toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Colchicine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Colchicine is metabolised by CYP3A4 and is a substrate of P-gp. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with colchicine. Moreover, selpercatinib is an inhibitor of P-gp in vitro, which might also lead to increased plasma concentrations of colchicine and therefore a higher risk of adverse reactions of colchicine. However, the relevance of this interaction is unknown. Coadministration should be monitored for colchicine toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Cycloserine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cycloserine is predominantly excreted renally via glomerular filtration. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Potential Interaction

Selpercatinib

Dabigatran

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Dabigatran is transported via P-gp and is renally excreted. Selpercatinib is an inhibitor of P-gp in vitro, which might lead to increased plasma concentrations of dabigatran and therefore a higher risk of adverse reactions of dabigatran. However, the relevance of this interaction is unknown. Coadministration should be monitored for ecarin clotting time (ECT) or diluted thrombin time (dTT) and dabigatran toxicity. Administer dabigatran 2 hours before selpercatinib in fasted state to circumvent the intestinal P-gp interaction.

Description:

See summary

No Interaction Expected

Selpercatinib

Dalteparin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dalteparin is excreted largely unchanged via the kidneys. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Potential Interaction

Selpercatinib

Dapsone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Metabolism of dapsone is mainly by N-acetylation with a component of N-hydroxylation and is via multiple CYP450 enzymes. Dapsone is metabolised by CYP2C8 and concentrations may increase due to moderate inhibition of CYP2C8 by selpercatinib. After coadministration with repaglinide, a CYP2C8 substrate, repaglinide exposure increased by 188%. A similar effect may occur after coadministration with dapsone, leading to an increased risk of adverse events of dapsone. Coadministration should be avoided. If coadministration is unavoidable, monitor for dapsone toxicity and consider reducing the dosage of dapsone.

Description:

See summary

Potential Interaction

Selpercatinib

Desipramine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Desipramine is metabolised by CYP2D6, which is not affected by selpercatinib. However, selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. Therefore, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Coadministration with desipramine can lead to an increased QTc prolongation. Coadministration should be avoided. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Desogestrel

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Desogestrel is a prodrug which is activated to etonogestrel by CYP2C9 (and possibly CYP2C19); the metabolism of etonogestrel is mediated by CYP3A4. Concentrations of the active metabolite etonogestrel may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with desogestrel, leading to an increased risk of adverse events of desogestrel. Coadministration should be monitored for desogestrel toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Dexamethasone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Dexamethasone has been described as a weak inducer of CYP3A4 and could possibly decrease selpercatinib plasma concentrations. However, the relevance of this interaction is not known. Moreover, the induction of CYP3A4 by dexamethasone has not been established yet. It is predicted that after coadministration with modafinil, a weak CYP3A4 inducer, selpercatinib exposure decreased by 33%. This may reduce the anti-tumor activity of selpercatinib. A similar effect may occur after coadministration with dexamethasone. Furthermore, dexamethasone is a substrate of CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with dexamethasone, leading to an increased risk of adverse events of dexamethasone. Coadministration should be monitored for selpercatinib plasma concentrations and dexamethasone toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Interaction

Selpercatinib

Dextropropoxyphene

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Dextropropoxyphene is mainly metabolised by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with dextropropoxyphene, leading to an increased risk of adverse events of dextropropoxyphene. Coadministration should be avoided as dextropropoxyphene toxicity may be increased. Consider reducing the dosage of dextropropoxyphene.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Diamorphine (diacetylmorphine)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Diamorphine is rapidly metabolised by sequential deacetylation to morphine which is then mainly glucuronidated to morphine-3-glucuronide (UGT2B7>UGT1A1) and, to a lesser extent, to the pharmacologically active morphine-6-glucuronide (UGT2B7>UGT1A1). Additionally, morphine is a substrate of P-gp. Selpercatinib is an inhibitor of P-gp in vitro, which might lead to increased plasma concentrations of the active metabolite morphine and therefore a higher risk of adverse reactions of diamorphine. However, the clinical relevance of this interaction is unknown. Monitoring for diamorphine toxicity may be required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Diazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Diazepam is metabolised to nordiazepam (by CYP3A4 and CYP2C19) and to temazepam (mainly by CYP3A4). Temazepam is mainly glucuronidated. Concentrations of the active metabolites may decrease due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with diazepam, leading to inefficacy of diazepam. Monitoring of diazepam efficacy should be considered. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Diclofenac

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Diclofenac is partly glucuronidated by UGT2B7 and partly oxidised by CYP2C9, which are not affected by selpercatinib.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Digoxin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Digoxin is eliminated renally via the renal transporters OATP4C1 and P-gp. Selpercatinib is an inhibitor of P-gp in vitro, which might lead to increased plasma concentrations of digoxin and therefore a higher risk of adverse reactions of digoxin. However, the relevance of this interaction is unknown. Monitor for digoxin toxicity and plasma concentrations of digoxin (if available).

Description:

See summary

Potential Weak Interaction

Selpercatinib

Dihydrocodeine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Dihydrocodeine undergoes predominantly direct glucuronidation, with CYP3A4 mediated metabolism accounting for only 5-10% of the overall metabolism. Selpercatinib is a weak CYP3A4 inhibitor. Since this is a minor pathway, no relevant effect on dihydrocodeine exposure is expected. Coadministration should still be monitored for dihydrocodeine toxicity. No a priori dose adjustment is required .

Description:

See summary

Potential Interaction

Selpercatinib

Diltiazem

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Diltiazem is metabolised by CYP3A4 and CYP2D6. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with diltiazem, leading to an increased risk of adverse events of diltiazem. Diltiazem is also an inhibitor of CYP3A4 (moderate) and P-gp. The relevance of P-gp inhibition by diltiazem is unknown. Selpercatinib is an in vitro substrate of P-gp. No clinically significant differences in selpercatinib pharmacokinetics were observed when coadministered with a single dose of rifampicin, which acts as a P-gp inhibitor when administered as a single dose. Thus, no relevant effect on selpercatinib exposure is expected due to inhibition of P-gp by diltiazem. However, selpercatinib is metabolised by CYP3A4 and it is predicted that after coadministration with diltiazem/fluconazole/verapamil, selpercatinib exposure increases by 60 to 99% due to moderate CYP3A4 inhibition. Selpercatinib is associated with concentration-dependent QTc prolongation and thus, any increase in selpercatinib exposure may result in an increased QTc interval. Therefore, coadministration is not recommended. If coadministration is unavoidable, closely monitor QTc interval and plasma concentrations (if available). Reduce selpercatinib dose by 40 mg. Also monitor closely for diltiazem toxicity.

Description:

See summary

Potential Interaction

Selpercatinib

Diphenhydramine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Diphenhydramine is mainly metabolised by CYP2D6 and to a lesser extent by CYPs 1A2, 2C9, and 2C19, which are not affected by selpercatinib. Moreover, diphenhydramine is a weak inhibitor of CYP2D6, which is not involved in the metabolism of selpercatinib. However, selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. Therefore, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since diphenhydramine also has a risk of QT prolongation, coadministration can lead to an even more prolonged QT interval. Coadministration should be avoided. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account.

Description:

See summary

No Interaction Expected

Selpercatinib

Dipyridamole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dipyridamole is glucuronidated by many UGTs, specifically those of the UGT1A subfamily, which are not affected by selpercatinib.

Description:

See summary

Potential Interaction

Selpercatinib

Disopyramide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Disopyramide is metabolised by CYP3A4 (25%) and 50% of the drug is eliminated unchanged in the urine. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with disopyramide, leading to an increased risk of adverse events of disopyramide. Furthermore, selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. So, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since disopyramide also has a risk of QT prolongation, coadministration with disopyramide can lead to an even more prolonged QTc interval. Therefore, coadministration is not recommended. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account. Also monitor closely for disopyramide toxicity.

Description:

See summary

Potential Interaction

Selpercatinib

Dolasetron

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Dolasetron is converted by carbonyl reductase to its active metabolite, hydrodolasetron, which is mainly glucuronidated (60%) and metabolised by CYP2D6 (10-20%) and CYP3A4 (<1%). Selpercatinib is a weak CYP3A4 inhibitor. However, since this is a minor pathway, no relevant effect on dolasetron exposure is expected. Selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. Therefore, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since dolasetron also has a moderate risk of QT prolongation, coadministration with dolasetron can lead to an even more prolonged QT interval. Coadministration should be avoided. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account. Also monitor closely for dolasetron toxicity.

Description:

See summary

Potential Interaction

Selpercatinib

Domperidone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Domperidone is mainly metabolised by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with domperidone, leading to an increased risk of adverse events of domperidone. Furthermore, selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. Therefore, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since domperidone also has a moderate risk of QT prolongation, coadministration can lead to an even more prolonged QTc interval. Therefore, coadministration is not recommended. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account. Coadministration should also be monitored for domperidone toxicity.

Description:

See summary

No Interaction Expected

Selpercatinib

Dopamine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dopamine is metabolised in the liver, kidneys, and plasma by monoamine oxidase (MAO) and catechol-O-methyltransferase to inactive compounds. About 25% of a dose of dopamine is metabolised to norepinephrine within the adrenergic nerve terminals. There is little potential for dopamine to affect disposition of selpercatinib, or to be affected if co-administered with selpercatinib.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Doxazosin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Doxazosin is metabolised mainly by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with doxazosin, leading to an increased risk of adverse events of doxazosin. Coadministration should be monitored for doxazosin toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Doxepin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Doxepin is metabolised to nordoxepin (a metabolite with comparable pharmacological activity as the parent compound) mainly by CYP2C19. In addition, doxepin and nordoxepin are metabolised by CYP2D6. These are not affected by selpercatinib.

Description:

See summary

No Interaction Expected

Selpercatinib

Doxycycline

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Doxycycline is excreted in the urine and faeces as unchanged active substance. Between 40-60% of an administered dose can be accounted for in the urine. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Dronabinol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Dronabinol is mainly metabolised by CYP2C9 and to a lesser extent by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with dronabinol, leading to an increased risk of adverse events of dronabinol. Coadministration should be monitored for dronabinol toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Drospirenone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Drospirenone is metabolised to a minor extent via CYP3A4. Selpercatinib is a weak CYP3A4 inhibitor. However, since this is a minor pathway, no relevant effect on drospirenone exposure is expected. Coadministration should be monitored for drospirenone toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Dulaglutide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dulaglutide is degraded by endogenous endopeptidases, which are not affected by selpercatinib. Dulaglutide delays gastric emptying and could possibly decrease the absorption rate of concomitantly administered oral drugs. The relevance of delayed absorption is considered to be limited.

Description:

See summary

No Interaction Expected

Selpercatinib

Duloxetine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Duloxetine is metabolised by CYP2D6 and CYP1A2, which are not affected by selpercatinib.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Dutasteride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Dutasteride is mainly metabolised by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with dutasteride, leading to an increased risk of adverse events of dutasteride. Coadministration should be monitored for dutasteride toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Dydrogesterone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Dydrogesterone is metabolised to dihydrodydrogesterone (possibly via CYP3A4). Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with dydrogesterone, leading to an increased risk of adverse events of dydrogesterone. Coadministration should be monitored for dydrogesterone toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Edoxaban

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Edoxaban is partially metabolised by CYP3A4 (<10%) and is transported via P-gp. Selpercatinib is a weak CYP3A4 inhibitor. However, since this is a minor pathway, no relevant effect on edoxaban exposure is expected. Selpercatinib is also an inhibitor of P-gp in vitro, which might lead to increased plasma concentrations of edoxaban and therefore a higher risk of adverse reactions of edoxaban. However, the relevance of this interaction is unknown. Coadministration should be monitored for anti-Xa levels and edoxaban toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Interaction

Selpercatinib

Eltrombopag

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Eltrombopag is metabolised by cleavage conjugation (via UGT1A1 and UGT1A3) and oxidation (via CYP1A2 and CYP2C8). Eltrombopag is metabolised by CYP2C8 and concentrations may increase due to moderate inhibition of CYP2C8 by selpercatinib. After coadministration with repaglinide, a CYP2C8 substrate, repaglinide exposure increased by 188%. A similar effect may occur after coadministration with eltrombopag, leading to an increased risk of adverse events of eltrombopag. Coadministration should be avoided. If coadministration is unavoidable, closely monitor for eltrombopag toxicity and consider reducing the dosage of eltrombopag.

Description:

See summary

No Interaction Expected

Selpercatinib

Enalapril

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Enalapril is hydrolysed to enalaprilat which is eliminated renally (possibly via OATs). Selpercatinib is unlikely to interfere with these metabolic and elimination pathways.

Description:

See summary

No Interaction Expected

Selpercatinib

Enoxaparin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Enoxaparin does not undergo cytochrome metabolism but is desulphated and depolymerised in the liver, and is predominantly renally excreted. Selpercatinib is unlikely to interfere with these elimination pathways.

Description:

See summary

No Interaction Expected

Selpercatinib

Eprosartan

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Eprosartan is largely excreted in bile and urine as unchanged drug. Selpercatinib is unlikely to interfere with these elimination pathways.

Description:

See summary

No Interaction Expected

Selpercatinib

Ertapenem

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ertapenem is mainly eliminated through the kidneys by glomerular filtration with tubular secretion playing a minor role. Selpercatinib is unlikely to interfere with these elimination pathways.

Description:

See summary

Potential Interaction

Selpercatinib

Erythromycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Erythromycin is a substrate of CYP3A4 and P-gp. Moreover, erythromycin is an inhibitor of CYP3A4 (moderate) and P-gp. Selpercatinib is an in vitro substrate of P-gp. No clinically significant differences in selpercatinib pharmacokinetics were observed when coadministered with a single dose of rifampicin, which acts as a P-gp inhibitor when administered as a single dose. No relevant effect on selpercatinib exposure is expected due to inhibition of P-gp by erythromycin. However, selpercatinib is metabolised by CYP3A4 and concentrations may increase due to moderate inhibition of CYP3A4 by erythromycin. It is predicted that after coadministration with diltiazem/fluconazole/verapamil, moderate CYP3A4 inhibitors, selpercatinib exposure increases by 60 to 99%. A similar effect may occur after coadministration with erythromycin. Selpercatinib is associated with concentration-dependent QTc prolongation and thus, any increase in selpercatinib exposure may result in an increased QTc interval. Since erythromycin also has a risk of QT prolongation, coadministration with erythromycin can lead to an even more prolonged QTc interval. Furthermore, concentrations of erythromycin may increase due to inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with erythromycin, leading to an increased risk of adverse events of erythromycin. Additionally, selpercatinib is an inhibitor of P-gp in vitro, which might lead to increased plasma concentrations of erythromycin and therefore a higher risk of adverse reactions of erythromycin. However, the relevance of this interaction is unknown. Coadministration is not recommended. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account. Also monitor closely for erythromycin toxicity.

Description:

See summary

Potential Interaction

Selpercatinib

Escitalopram

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Escitalopram is metabolised by CYPs 2C19 (37%), 2D6 (28%), and 3A4 (35%) to form N-desmethylescitalopram. Concentrations may increase due to inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with escitalopram, leading to an increased risk of adverse events of escitalopram. Furthermore, selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. Therefore, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since escitalopram also has a risk of QT prolongation, coadministration with escitalopram can lead to an even more prolonged QTc interval. Therefore, coadministration is not recommended. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account. Also monitor closely for escitalopram toxicity.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Esomeprazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Esomeprazole is metabolised by CYP2C19 and CYP3A4. Esomeprazole is also an inhibitor of CYP2C19. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with esomeprazole, leading to an increased risk of adverse events of esomeprazole. Furthermore, the bioavailability of selpercatinib is pH-dependent and, thus, an increase in gastric pH by esomeprazole reduces selpercatinib bioavailability. After coadministration with omeprazole, a proton pump inhibitor, selpercatinib exposure decreased by 69%. This may reduce the anti-tumor activity of selpercatinib. A similar effect may occur after coadministration with esomeprazole. If coadministration is necessary, selpercatinib should be administered when acid secretion is the least inhibited, which is just before a new dose of esomeprazole. Furthermore, selpercatinib should be administered concomitantly with food to overcome the decreased bioavailability. Coadministration should also be monitored for esomeprazole toxicity. No a priori dose adjustment of esomeprazole is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Estazolam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Estazolam is metabolised to its major metabolite 4-hydroxyestazolam via CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with estazolam, leading to an increased risk of adverse events of estazolam. Coadministration should be monitored for estazolam toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Estradiol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Estradiol is metabolised by CYP3A4, CYP1A2, and is glucuronidated. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with estradiol, leading to an increased risk of adverse events of estradiol. Coadministration should be monitored for estradiol toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Ethambutol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethambutol is partly metabolised by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and urine (50%). Selpercatinib is unlikely to interfere with these elimination pathways.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Ethinylestradiol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Ethinylestradiol undergoes oxidation (CYP3A4>CYP2C9), sulfation and glucuronidation (UGT1A1). Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with ethinylestradiol, leading to an increased risk of adverse events of ethinylestradiol. Coadministration should be monitored for ethinylestradiol toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Ethionamide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethionamide is extensively metabolised in the liver; animal studies suggest involvement of flavin-containing monooxygenases. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Etonogestrel

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Etonogestrel is metabolised by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with etonogestrel, leading to an increased risk of adverse events of etonogestrel. Coadministration should be monitored for etonogestrel toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Everolimus (Immunosuppressant)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Everolimus is mainly metabolised by CYP3A4 and is a substrate of P-gp. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with everolimus. Moreover, selpercatinib is an inhibitor of P-gp in vitro, which might also lead to increased plasma concentrations of everolimus and therefore a higher risk of adverse reactions of everolimus. However, the relevance of this interaction is unknown. Coadministration should be monitored for everolimus toxicity and plasma concentrations (if available). No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Exenatide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Exenatide is cleared mainly by glomerular filtration. Selpercatinib is unlikely to interfere with this elimination pathway. Exenatide delays gastric emptying and could possibly decrease the absorption rate of concomitantly administered oral drugs. The relevance of delayed absorption is considered to be limited.

Description:

See summary

No Interaction Expected

Selpercatinib

Ezetimibe

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ezetimibe is glucuronidated by UGTs 1A1 and 1A3 and to a lesser extent by UGTs 2B15 and 2B7. These are not affected by selpercatinib.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Famotidine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Famotidine is excreted via OAT1/OAT3, which is not affected by selpercatinib. However, the bioavailability of selpercatinib is pH-dependent and, thus, an increase in gastric pH by famotidine reduces its bioavailability. This may reduce the anti-tumor activity of selpercatinib. No clinically significant differences in selpercatinib pharmacokinetics (AUC0-INF -7%) were observed when coadministered with multiple daily doses of ranitidine (H2 receptor antagonist) given 10 hours prior to and 2 hours after the selpercatinib dose (administered fasted). If coadministration is necessary, selpercatinib should be administered 10 hours after or 2 hours before a new dose of famotidine.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Felodipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Felodipine is metabolised by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with felodipine, leading to an increased risk of adverse events of felodipine. Coadministration should be monitored for felodipine toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Fenofibrate

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fenofibrate is hydrolysed to an active metabolite, fenofibric acid. Selpercatinib is unlikely to interfere with this metabolic pathway. In vitro data suggest that fenofibric acid inhibits OAT3, which is not involved in the elimination of selpercatinib.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Fentanyl

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Fentanyl undergoes extensive CYP3A4 metabolism. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with fentanyl, leading to an increased risk of adverse events of fentanyl. Coadministration should be monitored for fentanyl toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Fexofenadine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Fexofenadine is a substrate of P-gp. Selpercatinib is an inhibitor of P-gp in vitro, which might lead to increased plasma concentrations of fexofenadine and therefore a higher risk of adverse reactions of fexofenadine. However, the relevance of this interaction is unknown. Monitor for fexofenadine toxicity.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Finasteride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Finasteride is metabolised by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with finasteride, leading to an increased risk of adverse events of finasteride. Coadministration should be monitored for finasteride toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Fish oils

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely.

Description:

See summary

Potential Interaction

Selpercatinib

Flecainide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Flecainide is metabolised mainly via CYP2D6, with a proportion (approximately 30%) of the parent drug also eliminated unchanged renally. Selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. Therefore, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since flecainide also has a risk of QT prolongation, coadministration with flecainide can lead to an even more prolonged QTc interval. Therefore, coadministration is not recommended. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Flucloxacillin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Flucloxacillin is mainly renally eliminated partly by glomerular filtration and partly by active secretion via OAT1. Selpercatinib is unlikely to interfere with these elimination pathways. Flucloxacillin is described as a CYP3A4 inducer. However, the mechanism and relevance of this interaction is unknown. Selpercatinib is metabolised by CYP3A4 and concentrations may decrease due to weak induction of CYP3A4 by flucloxacillin. It is predicted that after coadministration with modafinil, a weak CYP3A4 inducer, selpercatinib exposure decreased by 33%. A similar effect may occur after coadministration with flucloxacillin. Monitor selpercatinib plasma concentrations (if available).

Description:

See summary

Potential Interaction

Selpercatinib

Fluconazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Fluconazole is cleared primarily by renal excretion and is also an inhibitor of CYPs 3A4 (moderate), 2C9 (moderate) and 2C19 (strong). Selpercatinib is metabolised by CYP3A4, and concentrations may increase due to moderate inhibition of CYP3A4 by fluconazole. It is predicted that after coadministration with diltiazem/fluconazole/verapamil, selpercatinib exposure increases by 60 to 99% due to moderate CYP3A4 inhibition. Selpercatinib is associated with concentration-dependent QTc prolongation and thus, any increase in selpercatinib exposure may result in an increased QTc interval. Moreover, since fluconazole also has a moderate risk for QT prolongation, coadministration with fluconazole can lead to an even more increased QTc prolongation. Therefore, coadministration is not recommended. If coadministration is unavoidable, reduce selpercatinib dose by 40 mg and monitor plasma concentrations (if available) and QTc interval, taking the risk factors into account.

Description:

See summary

No Interaction Expected

Selpercatinib

Flucytosine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Flucytosine is metabolised to 5-fluorouracil (5-FU). 5-FU is further metabolised by dihydropyrimidine dehydrogenase (DPD) to an inactive metabolite. Selpercatinib does not interfere with flucytosine elimination pathway. However, 5-FU binds to the enzyme thymidylate synthase resulting in DNA damage. This mechanism occurs in all fast-dividing cells including bone marrow cells, resulting in haematological toxicity.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Fludrocortisone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Fludrocortisone is metabolised in the liver to inactive metabolites, possibly via CYP3A. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with fludrocortisone, leading to an increased risk of adverse events of fludrocortisone. Coadministration should be monitored for fludrocortisone toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Flunitrazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Flunitrazepam is metabolised mainly via CYP3A4 and CYP2C19. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with flunitrazepam, leading to an increased risk of adverse events of flunitrazepam. Coadministration should be monitored for flunitrazepam toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Fluoxetine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Fluoxetine is mainly metabolised by CYP2D6 and CYP2C9 and to a lesser extent by CYP2C19 and CYP3A4 to form norfluoxetine. Fluoxetine is a strong inhibitor of CYP2D6 and CYP2C19. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with fluoxetine, leading to an increased risk of adverse events of fluoxetine. Coadministration should be monitored for fluoxetine toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Interaction

Selpercatinib

Fluphenazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Fluphenazine is metabolised by CYP2D6, which is not affected by selpercatinib. However, selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. Therefore, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since fluphenazine also has a risk of QT prolongation, coadministration can lead to an even more prolonged QT interval. Coadministration should be avoided. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Flurazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. The metabolism of flurazepam is most likely CYP-mediated. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with flurazepam, leading to an increased risk of adverse events of flurazepam. Coadministration should be monitored for flurazepam toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Fluticasone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Fluticasone is metabolised by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with fluticasone, leading to an increased risk of adverse events of fluticasone. Coadministration should be monitored for fluticasone toxicity. No a priori dose adjustment is required. Note: A clinically significant interaction is unlikely with the topical use of fluticasone.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Fluvastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Fluvastatin is mainly metabolised by CYP2C9 (75%) and to a lesser extent by CYP3A4 (20%) and CYP2C8 (5%). Moreover, fluvastatin potentially inhibits CYP2C9. However, the relevance of CYP2C9 inhibition is unknown. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with fluvastatin, leading to an increased risk of adverse events of fluvastatin. Coadministration should be monitored for fluvastatin toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Interaction

Selpercatinib

Fluvoxamine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Fluvoxamine is metabolised mainly by CYP2D6 and to a lesser extent by CYP1A2, which are not affected by selpercatinib. Fluvoxamine is also an inhibitor of CYPs 1A2 (strong), 2C19 (strong), 3A4 (moderate), 2C9 (weak-moderate), and CYP2D6 (weak). Selpercatinib is metabolised by CYP3A4, and concentrations may increase due to moderate inhibition of CYP3A4 by fluvoxamine. It is predicted that after coadministration with diltiazem/fluconazole/verapamil, moderate CYP3A4 inhibitors, selpercatinib exposure increases by 60 to 99%. A similar effect may occur after coadministration with fluvoxamine. Selpercatinib is associated with concentration-dependent QTc prolongation and thus, any increase in selpercatinib exposure may result in an increased QTc interval. Therefore, coadministration is not recommended. If coadministration is unavoidable, closely monitor QTc interval and plasma concentrations (if available). Reduce selpercatinib dose by 40 mg.

Description:

See summary

No Interaction Expected

Selpercatinib

Fondaparinux

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fondaparinux does not undergo cytochrome metabolism but is eliminated predominantly renally. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Selpercatinib

Formoterol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Formoterol is eliminated primarily by direct glucuronidation, with O-demethylation (by CYPs 2D6, 2C19, 2C9, and 2A6) followed by further glucuronidation. As multiple CYP450 and UGT enzymes catalyse the transformation the potential for a pharmacokinetic interaction is low.

Description:

See summary

Potential Interaction

Selpercatinib

Fosaprepitant

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Fosaprepitant is rapidly, almost completely, converted to the active metabolite aprepitant. Aprepitant is mainly metabolised by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C19. Concentrations of the active metabolite aprepitant may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with fosaprepitant, leading to an increased risk of adverse events of fosaprepitant. During treatment aprepitant is a moderate inhibitor of CYP3A4. However, after treatment aprepitant is a weak inducer of CYP3A4, CYP2C9, and UGT. Selpercatinib is metabolised by CYP3A4 and concentrations may increase due to moderate inhibition of CYP3A4 by aprepitant. It is predicted that after coadministration with diltiazem/fluconazole/verapamil, moderate CYP3A4 inhibitors, selpercatinib exposure increases by 60 to 99%. A similar effect may occur after coadministration with fosaprepitant. Selpercatinib is associated with concentration-dependent QTc prolongation and thus, any increase in selpercatinib exposure may result in an increased QTc interval. Therefore, coadministration is not recommended. If coadministration is unavoidable, closely monitor QTc interval and plasma concentrations (if available). Reduce selpercatinib dose by 40 mg. Also monitor closely for fosaprepitant toxicity.

Description:

See summary

Do Not Coadminister

Selpercatinib

Fosphenytoin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Fosphenytoin is rapidly converted to the active metabolite phenytoin. Phenytoin is mainly metabolised by CYP2C9 and to a lesser extent by CYP2C19. Phenytoin is a potent inducer of CYP3A4, UGT, and P-gp. Selpercatinib is an in vitro substrate of P-gp. Moreover, selpercatinib is metabolised by CYP3A4 and concentrations may decrease due to strong induction of CYP3A4 by phenytoin. After coadministration with rifampicin, a strong CYP3A4 and P-gp inducer, selpercatinib exposure decreased by 87%. This may reduce the anti-tumor activity of selpercatinib. A similar effect may occur after coadministration with fosphenytoin, although the magnitude of the effect is unknown. Coadministration is contraindicated.

Description:

See summary

No Interaction Expected

Selpercatinib

Furosemide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Furosemide is glucuronidated mainly in the kidney (UGT1A9) and to a lesser extent in the liver (UGT1A1). A large proportion of furosemide is also eliminated unchanged renally (via OATs). OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. In vitro data indicate that furosemide is also an inhibitor of the renal transporters OAT1/OAT3. Selpercatinib is unlikely to interfere with these pathways.

Description:

See summary

No Interaction Expected

Selpercatinib

Gabapentin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Gabapentin is cleared mainly by glomerular filtration. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Selpercatinib

Gemfibrozil

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Gemfibrozil is metabolised by UGT2B7, which is not affected by selpercatinib. Gemfibrozil is an inhibitor of CYP2C8 (strong), OATP1B1 and OAT3. In vitro data indicate gemfibrozil to be a strong inhibitor of CYP2C9, but in vivo data showed no relevant effect on CYP2C9. This does not affect selpercatinib metabolism.

Description:

See summary

No Interaction Expected

Selpercatinib

Gentamicin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Gentamicin is eliminated unchanged predominantly via glomerular filtration. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Gestodene

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Gestodene is metabolised by CYP3A4 and to a lesser extent by CYP2C9 and CYP2C19. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with gestodene, leading to an increased risk of adverse events of gestodene. Coadministration should be monitored for gestodene toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Glibenclamide (Glyburide)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Glibenclamide is mainly metabolised by CYP3A4 and to a lesser extent by CYP2C9. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with glibenclamide, leading to an increased risk of adverse events of glibenclamide. Coadministration should be monitored for glibenclamide toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Gliclazide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Gliclazide is metabolised mainly by CYP2C9 and to a lesser extent by CYP2C19, which are not affected by selpercatinib.

Description:

See summary

No Interaction Expected

Selpercatinib

Glimepiride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Glimepiride is mainly metabolised by CYP2C9, which is not affected by selpercatinib.

Description:

See summary

No Interaction Expected

Selpercatinib

Glipizide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Glipizide is mainly metabolised by CYP2C9, which is not affected by selpercatinib.

Description:

See summary

Potential Interaction

Selpercatinib

Granisetron

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Granisetron is metabolised by CYP3A4 and is a substrate of P-gp. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with granisetron. Moreover, selpercatinib is an inhibitor of P-gp in vitro, which might also lead to increased plasma concentrations of granisetron and therefore a higher risk of adverse reactions of granisetron. However, the relevance of this interaction is unknown. Additionally, selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. Therefore, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since granisetron also has a moderate risk of QT prolongation, coadministration with granisetron can lead to an even more prolonged QT interval. Coadministration should be avoided. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account. Also monitor closely for granisetron toxicity.

Description:

See summary

Do Not Coadminister

Selpercatinib

Grapefruit juice

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Grapefruit juice is known to inhibit CYP3A4 enzymes, potentially increasing selpercatinib concentrations. However, the magnitude of this potential interaction is difficult to predict as the effect of grapefruit juice is concentration, dose and preparation dependent and varies widely across brands. Selpercatinib is associated with concentration-dependent QTc prolongation and thus, any increase in selpercatinib exposure may result in an increased QTc interval. Therefore, coadministration is contraindicated.

Description:

See summary

No Interaction Expected

Selpercatinib

Green tea

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely.

Description:

See summary

Potential Interaction

Selpercatinib

Griseofulvin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Less than 1% of a griseofulvin dose is excreted unchanged via the kidneys. Griseofulvin is also a liver microsomal enzyme inducer and may lower plasma levels, and therefore reduce the efficacy of concomitantly administered medicinal products that are metabolised by CYPs, such as selpercatinib. Griseofulvin is a moderate CYP3A4 inducer in vitro. Selpercatinib is metabolised by CYP3A4, and concentrations may decrease due to moderate induction of CYP3A4 by griseofulvin. It is predicted that after coadministration with bosentan or efavirenz, moderate CYP3A4 inducers, selpercatinib exposure decreases by 40-70%. This may reduce the anti-tumor activity of selpercatinib. A similar effect may occur after coadministration with griseofulvin, although the magnitude of the effect is unknown. Therefore, coadministration is not recommended. If coadministration is unavoidable, increase the dosage of selpercatinib to a maximum of 240 mg with steps of 40 mg per week alongside close monitoring of QTc interval.

Description:

See summary

Potential Interaction

Selpercatinib

Haloperidol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Haloperidol has a complex metabolism as it undergoes glucuronidation (UGTs 2B7>1A4, 1A9), carbonyl reduction as well as oxidative metabolism (CYP3A4 and CYP2D6). Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with haloperidol, leading to an increased risk of adverse events of haloperidol. Furthermore, selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. Therefore, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since haloperidol also has a risk of QT prolongation, coadministration can lead to an even more prolonged QT interval. Coadministration should be avoided. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account. Also monitor closely for haloperidol toxicity.

Description:

See summary

No Interaction Expected

Selpercatinib

Heparin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Heparin is thought to be eliminated via the reticuloendothelial system. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Hydralazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Hydralazine is metabolised via primary oxidative metabolism and acetylation. Selpercatinib is unlikely to interfere with these metabolic pathways. In vitro studies have suggested that hydralazine is a mixed enzyme inhibitor, which may weakly inhibit CYP3A4 and CYP2D6. Selpercatinib is metabolised by CYP3A4 and concentrations may increase due to weak inhibition of CYP3A4 by hydralazine. Selpercatinib is associated with concentration-dependent QTc prolongation and thus, any increase in selpercatinib exposure may result in an increased QTc interval. Monitor QTc interval and plasma concentrations (if available).

Description:

See summary

No Interaction Expected

Selpercatinib

Hydrochlorothiazide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Hydrochlorothiazide is not metabolised and is cleared by the kidneys via OAT1. OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Selpercatinib is unlikely to interfere with this pathway.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Hydrocodone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Hydrocodone is metabolised by CYP2D6 to hydromorphone and by CYP3A4 to norhydrocodone, both of which have analgesic effects. Concentrations of norhydrocodone may decrease due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with hydrocodone, leading to inefficacy of hydrocodone. Coadministration should be monitored for hydrocodone efficacy. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Hydrocortisone (oral)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Hydrocortisone is metabolised by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with hydrocortisone, leading to an increased risk of adverse events of hydrocortisone. Coadministration should be monitored for hydrocortisone toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Hydrocortisone (topical)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely with the topical use of hydrocortisone.

Description:

See summary

No Interaction Expected

Selpercatinib

Hydromorphone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Hydromorphone is eliminated via glucuronidation, mainly by UGT2B7, which is not affected by selpercatinib.

Description:

See summary

No Interaction Expected

Selpercatinib

Hydroxyurea (Hydroxycarbamide)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Hydroxyurea is metabolised in the liver and cleared via the lungs and kidneys. Selpercatinib is unlikely to interfere with these metabolic and elimination pathways.

Description:

See summary

Potential Interaction

Selpercatinib

Hydroxyzine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Hydroxyzine is partly metabolised by alcohol dehydrogenase and partly by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with hydroxyzine, leading to an increased risk of adverse events of hydroxyzine. Furthermore, selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. Therefore, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since hydroxyzine also has a risk of QT prolongation, coadministration can lead to an even more prolonged QT interval. Coadministration should be avoided. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account. Also monitor closely for hydroxyzine toxicity.

Description:

See summary

No Interaction Expected

Selpercatinib

Ibandronic acid

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ibandronic acid is not metabolised and is cleared from the plasma by uptake into bone and elimination via renal excretion. Although no pharmacokinetic interaction is expected, ibandronic acid should be taken after an overnight fast (at least 6 hours) and before the first food or drink of the day. Medicinal products and supplements should be similarly avoided prior to taking ibandronic acid. Fasting should be continued for at least 30 minutes after taking ibandronic acid.

Description:

See summary

Potential Interaction

Selpercatinib

Ibuprofen

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Ibuprofen is metabolised mainly by CYP2C9 and to a lesser extent by CYP2C8 and direct glucuronidation. Concentrations may increase due to moderate inhibition of CYP2C8 by selpercatinib. After coadministration with repaglinide, a CYP2C8 substrate, repaglinide exposure increased by 188%. A similar effect may occur after coadministration with ibuprofen, leading to an increased risk of adverse events of ibuprofen. Coadministration should be avoided. If coadministration is unavoidable, monitor closely for ibuprofen toxicity and consider reducing the dosage of ibuprofen.

Description:

See summary

Potential Interaction

Selpercatinib

Iloperidone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Iloperidone is metabolised by CYP3A4 and CYP2D6. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with iloperidone, leading to an increased risk of adverse events of iloperidone. Furthermore, selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. Therefore, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since iloperidone also has a risk of QT prolongation, coadministration can lead to an even more prolonged QT interval. Coadministration should be avoided. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account. Also monitor closely for iloperidone toxicity.

Description:

See summary

No Interaction Expected

Selpercatinib

Imipenem/Cilastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Imipenem/cilastatin are eliminated by glomerular filtration and to a lesser extent by active tubular secretion. Selpercatinib is unlikely to interfere with these elimination pathways.

Description:

See summary

Potential Interaction

Selpercatinib

Imipramine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Imipramine is metabolised by CYPs 3A4, 2C19, and 1A2 to desipramine. Imipramine and desipramine are both metabolised by CYP2D6. Concentrations may increase due to inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with imipramine, leading to an increased risk of adverse events of imipramine. Furthermore, selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. Therefore, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since imipramine also has a risk of QT prolongation, coadministration with imipramine can lead to an even more prolonged QTc interval. Therefore, coadministration is not recommended. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account. Also monitor closely for imipramine toxicity.

Description:

See summary

Potential Interaction

Selpercatinib

Indapamide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Indapamide is extensively metabolised by CYP450s. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with indapamide, leading to an increased risk of adverse events of indapamide. OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. This is not affected by selpercatinib. However, selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. Therefore, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since indapamide also has a moderate risk of QT prolongation, coadministration can lead to an even more prolonged QT interval. Coadministration should be avoided. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account. Also monitor closely for indapamide toxicity.

Description:

See summary

No Interaction Expected

Selpercatinib

Insulin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely.

Description:

See summary

No Interaction Expected

Selpercatinib

Interferon alpha

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely.

Description:

See summary

No Interaction Expected

Selpercatinib

Interleukin 2 (Aldesleukin)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Interleukin-2 is mainly eliminated by glomerular filtration. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Selpercatinib

Ipratropium bromide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. A small proportion of an inhaled ipratropium dose is systemically absorbed (6.9%). Metabolism is via ester hydrolysis and conjugation. Selpercatinib is unlikely to interfere with these elimination pathways.

Description:

See summary

No Interaction Expected

Selpercatinib

Irbesartan

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Irbesartan is metabolised by glucuronidation and oxidation (mainly CYP2C9). This is not affected by selpercatinib.

Description:

See summary

No Interaction Expected

Selpercatinib

Iron supplements

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Isoniazid

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Isoniazid is acetylated in the liver to form acetylisoniazid which is then hydrolysed to isonicotinic acid and acetylhydrazine. Selpercatinib is unlikely to interfere with this elimination pathway. In vitro data suggest that isoniazid is a weak CYP3A4 inhibitor. Selpercatinib is metabolised by CYP3A4 and concentrations may increase due to weak inhibition of CYP3A4 by isoniazid. Selpercatinib is associated with concentration-dependent QTc prolongation and thus, any increase in selpercatinib exposure may result in an increased QTc interval. Coadministration should be monitored for QTc interval and selpercatinib plasma concentrations (if available).

Description:

See summary

Potential Weak Interaction

Selpercatinib

Isosorbide dinitrate

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. In vitro studies suggest that CYP3A4 has a role in nitric oxide formation from isosorbide dinitrate. Concentrations of nitric oxide may decrease due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with isosorbide dinitrate, leading to decreased efficacy of isosorbide dinitrate. Monitoring of isosorbide dinitrate efficacy should be considered. No a priori dose adjustment is required.

Description:

See summary

Potential Interaction

Selpercatinib

Itraconazole

Quality of Evidence: Low

Summary:

Coadministration has been studied and should be approached with caution. Itraconazole is primarily metabolised by CYP3A4 and is also an inhibitor of CYP3A4 (strong), CYP2C9 (weak), P-gp, and BCRP. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. However, a relevant effect of selpercatinib is not expected since itraconazole is a strong CYP3A4 inhibitor itself. Selpercatinib is metabolized by CYP3A4 and concentrations will increase due to inhibition by itraconazole. In healthy subjects (n=12), coadministration of selpercatinib (160 mg single dose) with itraconazole (200 mg once daily for 7 days) increased selpercatinib exposure increased by 133%. Selpercatinib is associated with concentration-dependent QTc prolongation and thus, any increase in selpercatinib exposure may result in an increased QTc interval. Therefore, coadministration is not recommended. If coadministration is unavoidable, closely monitor QTc interval and plasma concentrations (if available). Reduce selpercatinib dose by 80 mg.

Description:

See summary

Potential Interaction

Selpercatinib

Ivabradine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Ivabradine is metabolised by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with ivabradine, leading to an increased risk of adverse events of ivabradine. Furthermore, selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. Therefore, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since ivabradine also has a moderate risk of QT prolongation, coadministration with ivabradine can lead to an even more prolonged QT interval. Coadministration should be avoided. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account. Also monitor closely for ivabradine toxicity.

Description:

See summary

No Interaction Expected

Selpercatinib

Kanamycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Kanamycin is eliminated unchanged predominantly via glomerular filtration. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Potential Interaction

Selpercatinib

Ketoconazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Ketoconazole is a substrate for CYP3A4. Moreover, ketoconazole is an inhibitor of CYP3A4 (strong) and P-gp. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. However, a relevant effect of selpercatinib is not expected since ketoconazole is a strong CYP3A4 inhibitor itself. Selpercatinib is metabolised by CYP3A4, and concentrations may increase due to strong inhibition of CYP3A4 by ketoconazole. After coadministration with itraconazole, a strong CYP3A4 inhibitor, selpercatinib exposure increased by 133%. A similar effect may occur after coadministration with ketoconazole. Selpercatinib is associated with concentration-dependent QTc prolongation and thus, any increase in selpercatinib exposure may result in an increased QTc interval. Moreover, since ketoconazole also has a moderate risk for QT prolongation, coadministration with ketoconazole can lead to an even more increased QTc prolongation. Therefore, coadministration is not recommended. If coadministration is unavoidable, closely monitor QTc interval and plasma concentrations (if available). Reduce selpercatinib dose by 80 mg.

Description:

See summary

No Interaction Expected

Selpercatinib

Labetalol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Labetalol is mainly glucuronidated (via UGT1A1 and UGT2B7), which is not affected by selpercatinib.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Lacidipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Lacidipine is metabolised by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with lacidipine, leading to an increased risk of adverse events of lacidipine. Coadministration should be monitored for lacidipine toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Lactulose

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metabolism of lactulose to lactic acid occurs via gastro-intestinal microbial flora only. Selpercatinib is unlikely to interfere with this metabolic pathway.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Lansoprazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Lansoprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with lansoprazole, leading to an increased risk of adverse events of lansoprazole. Furthermore, the bioavailability of selpercatinib is pH-dependent and, thus, an increase in gastric pH by lansoprazole reduces selpercatinib bioavailability. After coadministration with omeprazole, a proton pump inhibitor, selpercatinib exposure decreased by 69%. This may reduce the anti-tumor activity of selpercatinib. A similar effect may occur after coadministration with lansoprazole. If coadministration is necessary, selpercatinib should be administered when acid secretion is the least inhibited, which is just before a new dose of lansoprazole. Furthermore, selpercatinib should be administered concomitantly with food to overcome the decreased bioavailability. Coadministration should also be monitored for lansoprazole toxicity. No a priori dose adjustment of lansoprazole is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Lercanidipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Lercanidipine is mainly metabolised by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with lercanidipine, leading to an increased risk of adverse events of lercanidipine. Coadministration should be monitored for lercanidipine toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Levocetirizine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Less than 14% of a dose of levocetirizine is metabolised. Levocetirizine is mainly eliminated unchanged in the urine through both glomerular filtration and tubular secretion. Selpercatinib is unlikely to interfere with these elimination pathways.

Description:

See summary

Potential Interaction

Selpercatinib

Levofloxacin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Levofloxacin is renally eliminated mainly by glomerular filtration and active secretion (possibly OCT2). Selpercatinib is unlikely to interfere with these elimination pathways. However, selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. Therefore, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since levofloxacin also has a risk of QT prolongation, coadministration with levofloxacin can lead to an even more prolonged QTc interval. Coadministration should be avoided. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account.

Description:

See summary

Potential Interaction

Selpercatinib

Levomepromazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Levomepromazine is metabolised by CYP2D6, which is not affected by selpercatinib. However, selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. Therefore, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since levomepromazine also has a risk of QT prolongation, coadministration can lead to an even more prolonged QT interval. Coadministration should be avoided. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Levonorgestrel

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Levonorgestrel mainly is metabolised by CYP3A4 and is glucuronidated to a minor extent. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with levonorgestrel, leading to an increased risk of adverse events of levonorgestrel. Coadministration should be monitored for levonorgestrel toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Levonorgestrel (Emergency Contraception)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Levonorgestrel is mainly metabolised by CYP3A4 and is glucuronidated to a minor extent. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with levonorgestrel, leading to an increased risk of adverse events of levonorgestrel. Coadministration should be monitored for levonorgestrel toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Levothyroxine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Levothyroxine is metabolised by deiodination (by enzymes of deiodinase family) and glucuronidation. Selpercatinib is unlikely to interfere with these metabolic pathways.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Lidocaine (Lignocaine)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. CYP1A2 is the predominant enzyme involved in lidocaine metabolism in the range of therapeutic concentrations with a minor contribution from CYP3A4. Selpercatinib is a weak CYP3A4 inhibitor. However, since this is a minor pathway, no relevant effect on lidocaine exposure is expected. Coadministration should be monitored for lidocaine toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Linagliptin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Linagliptin is mainly eliminated as parent compound in faeces with metabolism by CYP3A4 representing a minor elimination pathway. Linagliptin is also a substrate for P-gp and is a weak inhibitor of CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with linagliptin, leading to an increased risk of adverse events of linagliptin. Moreover, selpercatinib is an inhibitor of P-gp in vitro, which might also lead to increased plasma concentrations of linagliptin and therefore a higher risk of adverse reactions of linagliptin. However, the relevance of this interaction is unknown. Moreover, selpercatinib is metabolised by CYP3A4 and concentrations may increase due to weak inhibition of CYP3A4 by linagliptin. Selpercatinib is associated with concentration-dependent QTc prolongation and thus, any increase in selpercatinib exposure may result in an increased QTc interval. Coadministration should be monitored for QTc interval and selpercatinib plasma concentrations (if available). Also monitor for linagliptin toxicity.

Description:

See summary

No Interaction Expected

Selpercatinib

Linezolid

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Linezolid undergoes non-CYP mediated metabolism. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Selpercatinib

Liraglutide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Liraglutide is degraded by endogenous endopeptidases. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Selpercatinib

Lisinopril

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Lisinopril is eliminated unchanged renally via glomerular filtration. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Potential Interaction

Selpercatinib

Lithium

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Lithium is mainly eliminated unchanged through the kidneys. Lithium is freely filtered at a rate that is dependent upon the glomerular filtration rate therefore no pharmacokinetic interaction is expected. However, selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. Therefore, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since lithium also has a risk of QT prolongation, coadministration with lithium can lead to an even more prolonged QTc interval. Coadministration should be avoided. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account.

Description:

See summary

No Interaction Expected

Selpercatinib

Live vaccines

Quality of Evidence: Very Low

Summary:

Coadministration of live vaccines (such as BCG vaccine; measles, mumps and rubella vaccines; varicella vaccines; typhoid vaccines; rotavirus vaccines; yellow fever vaccines; oral polio vaccine) has not been studied. In patients, who are receiving cytotoxics or other immunosuppressant drugs, use of live vaccines for immunisation is contraindicated. However, since selpercatinib is not an immunosuppressant drug, no additional unwanted effects are expected.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Loperamide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Loperamide is mainly metabolised by CYP3A4 and CYP2C8 and is a substrate of P-gp. Concentrations may increase due to moderate inhibition of CYP2C8 by selpercatinib, weak inhibition of CYP3A4 by selpercatinib and P-gp inhibition by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. After coadministration with repaglinide, a CYP2C8 substrate, repaglinide exposure increased by 188%. Similar effects may occur after coadministration with loperamide, leading to an increased risk of adverse events of loperamide. Coadministration should be monitored for loperamide toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Loratadine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Loratadine is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with loratadine, leading to an increased risk of adverse events of loratadine. Coadministration should be monitored for loratadine toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Lorazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Lorazepam undergoes non-CYP-mediated elimination, which is not affected by selpercatinib.

Description:

See summary

No Interaction Expected

Selpercatinib

Lormetazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Lormetazepam is mainly glucuronidated, which is not affected by selpercatinib.

Description:

See summary

No Interaction Expected

Selpercatinib

Losartan

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Losartan is converted to its active metabolite mainly by CYP2C9 in the range of clinical concentrations, which is not affected by selpercatinib.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Lovastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Lovastatin is metabolised by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with lovastatin, leading to an increased risk of adverse events of lovastatin. Coadministration should be monitored for lovastatin toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Macitentan

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Macitentan is metabolised mainly by CYP3A4 and to a lesser extent by CYPs 2C19, 2C9, and 2C8. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with macitentan, leading to an increased risk of adverse events of macitentan. Coadministration should be monitored for macitentan toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Magnesium

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Magnesium is eliminated in the kidney, mainly by glomerular filtration. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Selpercatinib

Maprotiline

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Maprotiline is mainly metabolised by CYP2D6, which is not affected by selpercatinib.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Medroxyprogesterone (depot)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Medroxyprogesterone is metabolised by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with medroxyprogesterone, leading to an increased risk of adverse events of medroxyprogesterone. Coadministration should be monitored for medroxyprogesterone toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Medroxyprogesterone (non-depot)

Quality of Evidence: Very Low

Summary:

Description:

See summary

No Interaction Expected

Selpercatinib

Mefenamic acid

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Mefenamic acid is metabolised by CYP2C9 and glucuronidated by UGT2B7 and UGT1A9. This is not affected by selpercatinib.

Description:

See summary

No Interaction Expected

Selpercatinib

Megestrol acetate

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Megestrol acetate is mainly eliminated in the urine. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Selpercatinib

Meropenem

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Meropenem is primarily eliminated by the kidney with in vitro data suggesting it is a substrate of the renal transporters OAT3>OAT1. These transporters are not affected by selpercatinib.

Description:

See summary

No Interaction Expected

Selpercatinib

Mesalazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Mesalazine is metabolised to N-acetyl-mesalazine by N-acetyltransferase. Selpercatinib is unlikely to interfere with this metabolic pathway.

Description:

See summary

Do Not Coadminister

Selpercatinib

Metamizole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Metamizole is metabolised by hydrolysis to the active metabolite MAA in the gastrointestinal tract. Metamizole is metabolised in serum and excreted via urine (90%) and faeces (10%). Metamizole is an inducer of CYP3A4 and may decrease selpercatinib concentrations. This may reduce the anti-tumor activity of selpercatinib. However, the relevance of this interaction is unknown. Coadministration is contraindicated.

Description:

See summary

No Interaction Expected

Selpercatinib

Metformin

Quality of Evidence: Low

Summary:

Coadministration has been studied and a clinically significant interaction is unlikely. Metformin is mainly eliminated unchanged in the urine and is substrate for OCT1, OCT2, OCT3, MATE1, and MATE2K. There was no significant change in blood glucose relative to baseline in patients receiving concomitant metformin. Therefore, no relevant effect on metformin is expected after coadministration with selpercatinib.

Description:

See summary

Do Not Coadminister

Selpercatinib

Methadone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Methadone is demethylated by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with methadone, leading to an increased risk of adverse events of methadone. Furthermore, selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. Therefore, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since methadone has a high risk of QT prolongation, coadministration with selpercatinib can lead to an even more prolonged QT interval. Coadministration is contraindicated.

Description:

See summary

No Interaction Expected

Selpercatinib

Methyldopa

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Methyldopa is excreted in urine largely by glomerular filtration, primarily unchanged and as the mono-O-sulfate conjugate. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Selpercatinib

Methylphenidate

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Methylphenidate is not metabolised by CYP450s to a clinically relevant extent and does not inhibit or induce CYP450s. Therefore, there is little potential for methylphenidate to affect disposition of selpercatinib, or to be affected if coadministered with selpercatinib.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Methylprednisolone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Methylprednisolone is metabolised by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with methylprednisolone, leading to an increased risk of adverse events of methylprednisolone. Coadministration should be monitored for methylprednisolone toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Metoclopramide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metoclopramide is partially metabolised by CYP450 system (mainly CYP2D6), which is not affected by selpercatinib.

Description:

See summary

No Interaction Expected

Selpercatinib

Metolazone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metolazone is largely excreted unchanged in the urine. OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Selpercatinib

Metoprolol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metoprolol is mainly metabolised by CYP2D6, which is not affected by selpercatinib.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Metronidazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Metronidazole is eliminated via glomerular filtration. Elevated plasma concentrations have been reported for some CYP3A substrates (e.g. tacrolimus, ciclosporin) with metronidazole. However, metronidazole did not increase concentrations of several CYP3A probe drugs (e.g. midazolam, alprazolam). Since the mechanism of the interaction with CYP3A has not yet been identified, an interaction with selpercatinib cannot be excluded. Selpercatinib is metabolised by CYP3A4, and concentrations may increase due to weak inhibition of CYP3A4 by metronidazole. Selpercatinib is associated with concentration-dependent QTc prolongation and thus, any increase in selpercatinib exposure may result in an increased QTc interval. Monitor QTc interval and plasma concentrations (if available).

Description:

See summary

No Interaction Expected

Selpercatinib

Mexiletine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Mexiletine is metabolised mainly by CYP2D6 and to a lesser extent CYP1A2, which are not affected by selpercatinib.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Mianserin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Mianserin is metabolised by CYPs 2D6 and 1A2, and to a lesser extent by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with mianserin, leading to an increased risk of adverse events of mianserin. Coadministration should be monitored for mianserin toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Interaction

Selpercatinib

Miconazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Miconazole is extensively metabolised by the liver. Moreover, miconazole is an inhibitor of CYP2C9 (moderate) and CYP3A4 (strong). Selpercatinib is metabolised by CYP3A4, and concentrations may increase due to strong inhibition of CYP3A4 by miconazole. After coadministration with itraconazole, a strong CYP3A4 inhibitor, selpercatinib exposure increased by 133%. A similar effect may occur after coadministration with miconazole. Selpercatinib is associated with concentration-dependent QTc prolongation and thus, any increase in selpercatinib exposure may result in an increased QTc interval. Therefore, coadministration is not recommended. If coadministration is unavoidable, closely monitor QTc interval and selpercatinib plasma concentrations (if available). Reduce selpercatinib dose by 80 mg. Note: after dermal application miconazole is only minimally absorbed. Therefore, no clinically relevant interaction is expected.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Midazolam (oral)

Quality of Evidence: Low

Summary:

Coadministration has been studied and care should be taken. Midazolam is metabolised by CYP3A4. In healthy subjects (n=16) coadministration of midazolam (2 mg single dose, oral) and selpercatinib (160 mg twice daily for 10 days) increased midazolam exposure by 54%. This is due to weak inhibition of CYP3A4 by selpercatinib, leading to an increased risk of adverse events of omidazolam. Coadministration should be monitored for midazolam toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Midazolam (parenteral)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Midazolam is metabolised by CYP3A4. Coadministration with oral midazolam increased oral midazolam exposure by 54%. A similar effect may occur after coadministration with parenteral midazolam, leading to an increased risk of adverse events of midazolam. Coadministration should be monitored for midazolam toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Milnacipran

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Milnacipran is mainly eliminated unchanged (50%), and as glucuronides (30%) and oxidative metabolites (20%). Selpercatinib is unlikely to interfere with these elimination pathways.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Mirtazapine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Mirtazapine is metabolised to 8-hydroxymirtazapine by CYP2D6 and CYP1A2, and to N-desmethylmirtazapine mainly by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with mirtazapine, leading to an increased risk of adverse events of mirtazapine. Coadministration should be monitored for mirtazapine toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Mometasone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Mometasone is metabolised by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with mometasone, leading to an increased risk of adverse events of mometasone. Coadministration should be monitored for mometasone toxicity. No a priori dose adjustment is required. Note: No relevant interaction is expected with the topical use of mometasone.

Description:

See summary

Potential Interaction

Selpercatinib

Montelukast

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Montelukast is mainly metabolised by CYP2C8 and to a lesser extent by CYPs 3A4 and 2C9. Concentrations may increase due to moderate inhibition of CYP2C8 by selpercatinib and weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. After coadministration with repaglinide, a CYP2C8 substrate, repaglinide exposure increased by 188%. Similar effects may occur after coadministration with montelukast, leading to an increased risk of adverse events of montelukast. Coadministration should be avoided. If coadministration is unavoidable, monitor for montelukast toxicity and consider reducing the dosage of montelukast.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Morphine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Morphine is mainly glucuronidated to morphine-3-glucuronide (UGT2B7>UGT1A1) and, to a lesser extent, to the pharmacologically active morphine-6-glucuronide (UGT2B7>UGT1A1). Additionally, morphine is a substrate of P-gp. Selpercatinib is an inhibitor of P-gp in vitro, which might lead to increased plasma concentrations of morphine and therefore a higher risk of adverse reactions of morphine. However, the relevance of this interaction is unknown. Monitoring for morphine toxicity may be required.

Description:

See summary

Do Not Coadminister

Selpercatinib

Moxifloxacin

Quality of Evidence: Low

Summary:

Coadministration has not been studied but is contraindicated. Moxifloxacin is predominantly glucuronidated by UGT1A1. However, the product labels for moxifloxacin contraindicate its use in the presence of other drugs that prolong the QT interval, such as selpercatinib. If coadministration is unavoidable, use with caution, including close monitoring of QT interval.

Description:

See summary

No Interaction Expected

Selpercatinib

Mycophenolate

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Mycophenolate is mainly glucuronidated by UGT1A9 and UGT2B7, which are not affected by selpercatinib. The active metabolite of mycophenolate, mycophenolic acid, is an inhibitor of OAT1/OAT3, which are not involved in the elimination of selpercatinib.

Description:

See summary

No Interaction Expected

Selpercatinib

Nadroparin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nadroparin is excreted renally by a nonsaturable mechanism. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Selpercatinib

Nandrolone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nandrolone is metabolised in the liver by alpha-reductase. Selpercatinib is unlikely to interfere with this metabolic pathway.

Description:

See summary

No Interaction Expected

Selpercatinib

Naproxen

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Naproxen is mainly glucuronidated by UGT2B7 (major) and demethylated to desmethylnaproxen by CYP2C9 (major) and CYP1A2. This is not affected by selpercatinib.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Nateglinide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Nateglinide is mainly metabolised by CYP2C9 (70%) and to a lesser extent by CYP3A4 (30%). Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with nateglinide, leading to an increased risk of adverse events of nateglinide. Coadministration should be monitored for nateglinide toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Nebivolol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nebivolol metabolism involves CYP2D6, which is not affected by selpercatinib.

Description:

See summary

Potential Interaction

Selpercatinib

Nefazodone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Nefazodone is metabolised mainly by CYP3A4 and is also a strong inhibitor of CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. However, a relevant effect of selpercatinib is not expected since nefazodone is a strong CYP3A4 inhibitor itself. Selpercatinib is also metabolised by CYP3A4 and concentrations may increase due to strong inhibition of CYP3A4 by nefazodone. After coadministration with itraconazole, a strong CYP3A4 inhibitor, selpercatinib exposure increased by 133%. A similar effect may occur after coadministration with nefazodone. Selpercatinib is associated with concentration-dependent QTc prolongation and thus, any increase in selpercatinib exposure may result in an increased QTc interval. Therefore, coadministration is not recommended. If coadministration is unavoidable, closely monitor QTc interval and plasma concentrations (if available). Reduce selpercatinib dose by 80 mg.

Description:

See summary

Potential Interaction

Selpercatinib

Nicardipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Nicardipine is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6 and CYP2C8. Moreover, nicardipine is a weak inhibitor of CYP3A4. Concentrations may increase due to moderate inhibition of CYP2C8 by selpercatinib and weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. After coadministration with repaglinide, a CYP2C8 substrate, repaglinide exposure increased by 188%. Similar effects may occur after coadministration with nicardipine, leading to an increased risk of adverse events of nicardipine. Furthermore, selpercatinib is metabolised by CYP3A4 and concentrations may increase due to weak inhibition of CYP3A4 by nicardipine. Selpercatinib is associated with concentration-dependent QTc prolongation and thus, any increase in selpercatinib exposure may result in an increased QTc interval. Coadministration should be avoided. If coadministration is unavoidable, closely monitor QTc interval, selpercatinib plasma concentrations (if available) and nicardipine toxicity and consider reducing the dosage of nicardipine.

Description:

See summary

No Interaction Expected

Selpercatinib

Nicotinamide (Niacinamide)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nicotinamide is converted to N-methylnicotinamide by nicotinamide methyltransferase which in turn is metabolised by xanthine oxidase and aldehyde oxidase. Selpercatinib is unlikely to interfere with these metabolic pathways.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Nifedipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Nifedipine is metabolised mainly by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with nifedipine, leading to an increased risk of adverse events of nifedipine. Coadministration should be monitored for nifedipine toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Nimesulide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nimesulide is extensively metabolised in the liver following multiple pathways including CYP2C9, which is not affected by selpercatinib.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Nisoldipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Nisoldipine is metabolised by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with nisoldipine, leading to an increased risk of adverse events of nisoldipine. Coadministration should be monitored for nisoldipine toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Nitrendipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Nitrendipine is extensively metabolised mainly by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with nitrendipine, leading to an increased risk of adverse events of nitrendipine. Coadministration should be monitored for nitrendipine toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Nitrofurantoin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nitrofurantoin is partly metabolised in the liver via glucuronidation and N-acetylation and partly eliminated in the urine as unchanged drug (30-40%). Selpercatinib is unlikely to interfere with these elimination pathways.

Description:

See summary

Do Not Coadminister

Selpercatinib

Norelgestromin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Norelgestromin is metabolised to norgestrel (possibly by CYP3A4). Concentrations of the active metabolite norgestrel may decrease due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with norelgestromin, which may lead to reduced efficacy of norelgestromin. Coadministration is contraindicated.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Norethisterone (Norethindrone)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Norethindrone is extensively biotransformed, first by reduction and then by sulfate and glucuronide conjugation. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with norethisterone, leading to an increased risk of adverse events of norethisterone. Coadministration should be monitored for norethisterone toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Norgestimate

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Norgestimate is rapidly deacetylated to the active metabolite which is further metabolised via CYP450. Concentrations of the active metabolite may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with norgestimate, leading to an increased risk of adverse events of norgestimate. Coadministration should be monitored for norgestimate toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Norgestrel

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Norgestrel is a racemic mixture with levonorgestrel being biologically active. Levonorgestrel is mainly metabolised by CYP3A4 and is glucuronidated to a minor extent. Concentrations of levonorgestrel may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with norgestrel, leading to an increased risk of adverse events of norgestrel. Coadministration should be monitored for norgestrel toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Interaction

Selpercatinib

Nortriptyline

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Nortriptyline is metabolised mainly by CYP2D6, which is not affected by selpercatinib. However, selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. Therefore, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since nortriptyline also has a risk of QT prolongation, coadministration with nortriptyline can lead to an even more prolonged QTc interval. Coadministration should be avoided. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account.

Description:

See summary

No Interaction Expected

Selpercatinib

Nystatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Systemic absorption of nystatin from oral or topical dosage forms is not significant, therefore no drug interactions are expected.

Description:

See summary

Potential Interaction

Selpercatinib

Ofloxacin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Ofloxacin is renally eliminated unchanged by glomerular filtration and active tubular secretion via both cationic and anionic transport systems. Selpercatinib is unlikely to interfere with these elimination pathways. However, selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. Therefore, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since ofloxacin also has a risk of QT prolongation, coadministration with ofloxacin can lead to an even more prolonged QTc interval. Coadministration should be avoided. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account.

Description:

See summary

No Interaction Expected

Selpercatinib

Olanzapine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Olanzapine is metabolised mainly by CYP1A2 (major) and CYP2D6, but also by glucuronidation (UGT1A4). This is not affected by selpercatinib.

Description:

See summary

No Interaction Expected

Selpercatinib

Olmesartan

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Olmesartan medoxomil is de-esterified to the active metabolite olmesartan which is eliminated in the faeces and urine. Selpercatinib is unlikely to interfere with these metabolic or elimination pathways.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Omeprazole

Quality of Evidence: Low

Summary:

Coadministration has been studied and care should be taken. Omeprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYP3A4. Omeprazole is also an inducer of CYP1A2 and an inhibitor of CYP2C19. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with omeprazole, leading to an increased risk of adverse events of omeprazole. Furthermore, the bioavailability of selpercatinib is pH-dependent and, thus, an increase in gastric pH by omeprazole reduces selpercatinib bioavailability. In healthy subjects (n=20), coadministration of selpercatinib (160 mg single dose) and omeprazole (multiple doses) decreased selpercatinib exposure by 69%. This may reduce the anti-tumor activity of selpercatinib. If coadministration is necessary, selpercatinib should be administered when acid secretion is the least inhibited, and that is just before a new dose of omeprazole. Furthermore, selpercatinib should be administered concomitantly with food to overcome the decreased bioavailability. Coadministration should also be monitored for omeprazole toxicity. No a priori dose adjustment of omeprazole is required.

Description:

See summary

Potential Interaction

Selpercatinib

Ondansetron

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Ondansetron is metabolised mainly by CYP1A2 and CYP3A4 and to a lesser extent by CYP2D6. Additionally, ondansetron is a substrate of P-gp. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with ondansetron. Moreover, selpercatinib is an inhibitor of P-gp in vitro, which might also lead to increased plasma concentrations of ondansetron and therefore a higher risk of adverse reactions of ondansetron. However, the relevance of this interaction is unknown. Additionally, selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. Therefore, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since ondansetron also has a moderate risk of QT prolongation, coadministration can lead to an even more prolonged QT interval. Coadministration should be avoided. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account. Also monitor closely for ondansetron toxicity.

Description:

See summary

No Interaction Expected

Selpercatinib

Oxazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Oxazepam is mainly glucuronidated, which is not affected by selpercatinib.

Description:

See summary

Potential Interaction

Selpercatinib

Oxcarbazepine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Oxcarbazepine is extensively metabolised to the active metabolite monohydroxyderivate (MHD) through cytosolic enzymes. Both oxcarbazepine and MHD are inducers of CYP3A4 (moderate) and CYP3A5 and are inhibitors of CYP2C19. Selpercatinib is metabolised by CYP3A4 and concentrations may decrease due to moderate induction of CYP3A4 by oxcarbazepine and its active metabolite. It is predicted that after coadministration with bosentan or efavirenz, moderate CYP3A4 inducers, selpercatinib exposure decreases by 40-70%. This may reduce the anti-tumor activity of selpercatinib. A similar effect may occur after coadministration with oxcarbazepine, although the magnitude of the effect is unknown. Therefore, coadministration is not recommended. If coadministration is unavoidable, increase the dosage of selpercatinib to a maximum of 240 mg with steps of 40 mg per week alongside close monitoring of QTc interval.

Description:

See summary

No Interaction Expected

Selpercatinib

Oxprenolol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Oxprenolol is largely metabolised via glucuronidation, which is not affected by selpercatinib.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Oxycodone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Oxycodone is metabolised principally to noroxycodone via CYP3A and oxymorphone via CYP2D6. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with oxycodone, leading to an increased risk of adverse events of oxycodone. Coadministration should be monitored for oxycodone toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Paliperidone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Paliperidone is primarily eliminated renally (possibly via OCT) with minimal metabolism occurring via CYP2D6 and CYP3A4. Selpercatinib is a weak CYP3A4 inhibitor. However, since this is a minor pathway, no relevant effect on paliperidone exposure is expected. Coadministration should be monitored for paliperidone toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Palonosetron

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Palonosetron is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6 and CYP1A2. Palonosetron is also a substrate of P-gp. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with palonosetron. Moreover, selpercatinib is an inhibitor of P-gp in vitro, which might also lead to increased plasma concentrations of palonosetron and therefore a higher risk of adverse reactions of palonosetron. However, the relevance of this interaction is unknown. Coadministration should be monitored for palonosetron toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Pamidronic acid

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pamidronic acid is not metabolised and is cleared from the plasma by uptake into bone and elimination via renal excretion. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Pantoprazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Pantoprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYPs 3A4, 2D6, and 2C9. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with pantoprazole, leading to an increased risk of adverse events of pantoprazole. Furthermore, the bioavailability of selpercatinib is pH-dependent and, thus, an increase in gastric pH by pantoprazole reduces selpercatinib bioavailability. After coadministration with omeprazole, a proton pump inhibitor, selpercatinib exposure decreased by 69%. This may reduce the anti-tumor activity of selpercatinib. A similar effect may occur after coadministration with pantoprazole. If coadministration is necessary, selpercatinib should be administered when acid secretion is the least inhibited, which is just before a new dose of pantoprazole. Furthermore, selpercatinib should be administered concomitantly with food to overcome the decreased bioavailability. Coadministration should also be monitored for pantoprazole toxicity. No a priori dose adjustment of pantoprazole is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Para-aminosalicylic acid

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Para-aminosalicylic acid and its acetylated metabolite are mainly excreted in the urine by glomerular filtration and tubular secretion. Selpercatinib is unlikely to interfere with these elimination pathways.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Paracetamol (Acetaminophen)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Paracetamol is mainly metabolised by glucuronidation (via UGTs 1A9 (major), 1A6, 1A1, and 2B15) and sulfation and, to a lesser extent, by oxidation (CYPs 2E1 (major), 1A2, 3A4 and 2D6). Selpercatinib is a weak CYP3A4 inhibitor. However, since this is a minor pathway, no relevant effect on paracetamol exposure is expected. Coadministration should be monitored for paracetamol toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Paroxetine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Paroxetine is mainly metabolised by CYP2D6, which is not affected by selpercatinib. Moreover, paroxetine is an inhibitor of CYP2D6 (strong) and CYP2C9, which are not involved in the metabolism of selpercatinib.

Description:

See summary

No Interaction Expected

Selpercatinib

Peginterferon alfa-2a

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely.

Description:

See summary

No Interaction Expected

Selpercatinib

Penicillins

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Penicillins are mainly eliminated in the urine (20% by glomerular filtration and 80% by tubular secretion via OAT). Selpercatinib is unlikely to interfere with these elimination pathways.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Perazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Perazine is mainly metabolised by CYPs 1A2, 3A4 and 2C19, and to a lesser extent by CYPs 2C9, 2D6, and 2E1, with oxidation via FMO3. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with perazine, leading to an increased risk of adverse events of perazine. Coadministration should be monitored for perazine toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Periciazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. The metabolism of periciazine has not been well characterized but is likely to involve CYP2D6, which is not affected by selpercatinib.

Description:

See summary

No Interaction Expected

Selpercatinib

Perindopril

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Perindopril is hydrolysed to the active metabolite perindoprilat and is metabolised to other inactive metabolites. Elimination occurs predominantly via the urine. Selpercatinib is unlikely to interfere with these metabolic or elimination pathways.

Description:

See summary

Potential Interaction

Selpercatinib

Perphenazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Perphenazine is metabolised by CYP2D6, which is not affected by selpercatinib. However, selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. Therefore, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since perphenazine also has a risk of QT prolongation, coadministration can lead to an even more prolonged QT interval. Coadministration should be avoided. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Pethidine (Meperidine)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Pethidine is metabolised mainly by CYP2B6 and to a lesser extent by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with pethidine, leading to an increased risk of adverse events of pethidine. Coadministration should be monitored for pethidine toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Phenelzine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Phenelzine is primarily metabolised by oxidation via monoamine oxidase and to a lesser extent acetylation, which is not affected by selpercatinib.

Description:

See summary

Do Not Coadminister

Selpercatinib

Phenobarbital (Phenobarbitone)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Phenobarbital is metabolised by CYP2C19 and 2C9 (major pathway) and to a lesser extent by CYP2E1. Phenobarbital is a strong inducer of CYP3A4, CYP2C9, CYP2C8 and UGTs. Selpercatinib is metabolised by CYP3A4 and concentrations may decrease due to strong induction of CYP3A4 by phenobarbital. After coadministration with rifampicin, a strong CYP3A4 inducer, selpercatinib exposure decreased by 87%. This may reduce the anti-tumor activity of selpercatinib. A similar effect may occur after coadministration with phenobarbital, although the magnitude of the effect is unknown. Coadministration is contraindicated.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Phenprocoumon

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Phenprocoumon is mainly metabolised by CYP2C9 and CYP3A4 and concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with phenprocoumon, leading to an increased risk of adverse events of phenprocoumon. Coadministration should be monitored for INR/PT and phenprocoumon toxicity. No a priori dose adjustment is required.

Description:

See summary

Do Not Coadminister

Selpercatinib

Phenytoin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Phenytoin is mainly metabolised by CYP2C9 and to a lesser extent by CYP2C19. Phenytoin is a strong inducer of CYP3A4, UGT, and P-gp. Selpercatinib is an in vitro substrate of P-gp. Moreover, selpercatinib is metabolised by CYP3A4 and concentrations may decrease due to strong induction of CYP3A4 by phenytoin. After coadministration with rifampicin, a strong CYP3A4 and P-gp inducer, selpercatinib exposure decreased by 87%. This may reduce the anti-tumor activity of selpercatinib. A similar effect may occur after coadministration with phenytoin, although the magnitude of the effect is unknown. Coadministration is contraindicated.

Description:

See summary

No Interaction Expected

Selpercatinib

Phytomenadione (Vitamin K)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. An in vitro study found that the only CYP450 enzyme involved in phytomenadione metabolism was CYP4F2, which is not affected by selpercatinib.

Description:

See summary

Do Not Coadminister

Selpercatinib

Pimozide

Quality of Evidence: Low

Summary:

Coadministration has not been studied but is contraindicated. Pimozide is mainly metabolised by CYP3A4 and CYP2D6 and to a lesser extent by CYP1A2. However, the product labels for pimozide contraindicate its use in the presence of other drugs that prolong the QT interval, such as selpercatinib.

Description:

See summary

No Interaction Expected

Selpercatinib

Pindolol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pindolol is partly metabolised to hydroxymetabolites (possibly via CYP2D6) and partly eliminated unchanged in the urine. Selpercatinib is unlikely to interfere with these elimination pathways.

Description:

See summary

Potential Interaction

Selpercatinib

Pioglitazone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Pioglitazone is metabolised mainly by CYP2C8 and to a lesser extent by CYPs 3A4, 1A2, and 2C9. Concentrations may increase due to moderate inhibition of CYP2C8 by selpercatinib and weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. After coadministration with repaglinide, a CYP2C8 substrate, repaglinide exposure increased by 188%. Similar effects may occur after coadministration with pioglitazone, leading to an increased risk of adverse events of pioglitazone. Coadministration should be avoided. If coadministration is unavoidable, closely monitor for pioglitazone toxicity and consider reducing the dosage of pioglitazone.

Description:

See summary

Potential Interaction

Selpercatinib

Pipotiazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. The metabolism of pipotiazine has not been well described but may involve CYP2D6, which is not affected by selpercatinib. However, selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. Therefore, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since pipotiazine also has a risk of QT prolongation, coadministration can lead to an even more prolonged QT interval. Coadministration should be avoided. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account.

Description:

See summary

No Interaction Expected

Selpercatinib

Piroxicam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Piroxicam is primarily metabolised by CYP2C9, which is not affected by selpercatinib.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Pitavastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Pitavastatin is metabolised by UGTs 1A3 and 2B7 with minimal metabolism by CYPs 2C9 and 2C8. Moreover, pitavastatin is a substrate of OATP1B1. Concentrations may increase due to moderate inhibition of CYP2C8 by selpercatinib. After coadministration with repaglinide, a CYP2C8 substrate, repaglinide exposure increased by 188%. However, since CYP2C8 is a minor pathway in the metabolism of pitavastatin, no relevant effect on pitavastatin exposure is expected. Coadministration should be monitored for pitavastatin toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Interaction

Selpercatinib

Posaconazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Posaconazole is primarily metabolised by UGTs and is a substrate for P-gp. Moreover, posaconazole is a strong inhibitor of CYP3A4. Selpercatinib is an inhibitor of P-gp in vitro, which might lead to increased plasma concentrations of posaconazole and therefore a higher risk of adverse reactions of posaconazole. However, the relevance of this interaction is unknown. Selpercatinib is metabolised by CYP3A4, and concentrations may increase due to strong inhibition of CYP3A4 by posaconazole. After coadministration with itraconazole, a strong CYP3A4 inhibitor, selpercatinib exposure increased by 133%. A similar effect may occur after coadministration with posaconazole. Selpercatinib is associated with concentration-dependent QTc prolongation and thus, any increase in selpercatinib exposure may result in an increased QTc interval. Since posaconazole also has a moderate risk of QT prolongation, coadministration can lead to an even more prolonged QT interval. Therefore, coadministration is not recommended. If coadministration is unavoidable, closely monitor QTc interval and selpercatinib plasma concentrations (if available). Reduce selpercatinib dose by 80 mg. Also monitor closely for posaconazole toxicity.

Description:

See summary

No Interaction Expected

Selpercatinib

Potassium

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolsim and clearance a clinically significant interaction is unlikely. Potassium is eliminated renally. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Potential Interaction

Selpercatinib

Prasugrel

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Prasugrel is a prodrug and is converted to its active metabolite mainly by CYP3A4 and CYP2B6 and to a lesser extent by CYP2C9 and CYP2C19. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with prasugrel, leading to decreased efficacy of prasugrel. Coadministration should be avoided as prasugrel efficacy may be decreased. If coadministration is unavoidable, monitor on thrombocytes aggregation test and consider increasing the dosage of prasugrel.

Description:

See summary

No Interaction Expected

Selpercatinib

Pravastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pravastatin is minimally metabolised via CYP enzymes and is substrate of OATP1B1. Selpercatinib is unlikely to interfere with these metabolic and elimination pathways.

Description:

See summary

No Interaction Expected

Selpercatinib

Prazosin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Prazosin is extensively metabolised, primarily by demethylation and conjugation. Selpercatinib is unlikely to interfere with these metabolic pathways.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Prednisolone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Prednisolone undergoes hepatic metabolism via CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with prednisolone, leading to an increased risk of adverse events of prednisolone. Coadministration should be monitored for prednisolone toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Prednisone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Prednisone is converted to the active metabolite prednisolone by 11-B-hydroxydehydrogenase. Prednisolone is then metabolised by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with prednisone, leading to an increased risk of adverse events of prednisone. Coadministration should be monitored for prednisone toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Pregabalin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pregabalin is cleared mainly by glomerular filtration (90% as unchanged drug). Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Potential Interaction

Selpercatinib

Prochlorperazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Prochlorperazine is metabolised by CYP2D6 and CYP2C19, which are not affected by selpercatinib. However, selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. Therefore, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since prochlorperazine also has a moderate risk of QT prolongation, coadministration with prochlorperazine can lead to an even more prolonged QT interval. Coadministration should be avoided. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account.

Description:

See summary

Potential Interaction

Selpercatinib

Promethazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Promethazine is metabolised by CYP2D6, which is not affected by selpercatinib. However, selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. Therefore, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since promethazine also has a risk of QT prolongation, coadministration can lead to an even more prolonged QT interval. Coadministration should be avoided. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account.

Description:

See summary

Potential Interaction

Selpercatinib

Propafenone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Propafenone is metabolised mainly by CYP2D6 and to a lesser extent by CYP1A2 and CYP3A4. Concentrations may increase due to inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with propafenone, leading to an increased risk of adverse events of propafenone. Therefore, coadministration is not recommended. If coadministration is unavoidable, closely monitor for propafenone toxicity. Modify the dosage of propafenone when this is recommended in its product labelling.

Description:

See summary

No Interaction Expected

Selpercatinib

Propranolol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Propranolol is metabolised by 3 routes (aromatic hydroxylation by CYP2D6, N-dealkylation followed by side chain hydroxylation via CYPs 1A2, 2C19, 2D6, and direct glucuronidation). This is not affected by selpercatinib.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Prucalopride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Prucalopride is minimally metabolised and mainly eliminated renally, partly by active secretion by renal transporters. Additionally, prucalopride is a substrate of P-gp. Selpercatinib is an inhibitor of P-gp in vitro, which might lead to increased plasma concentrations of prucalopride and therefore a higher risk of adverse reactions of prucalopride. However, the relevance of this interaction is unknown. Monitor for prucalopride toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Pyrazinamide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pyrazinamide is mainly metabolised by xanthine oxidase. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Selpercatinib

Pyridoxine (Vitamin B6)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Quetiapine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Quetiapine is primarily metabolised by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with quetiapine, leading to an increased risk of adverse events of quetiapine. Coadministration should be monitored for quetiapine toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Quinapril

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Quinapril is de-esterified to the active metabolite quinaprilat which is eliminated primarily by renal excretion via OAT3. Selpercatinib is unlikely to interfere with these metabolic or elimination pathways.

Description:

See summary

Potential Interaction

Selpercatinib

Quinidine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Quinidine is mainly metabolised by CYP3A4 and to a lesser extent by CYP2C9 and CYP2E1. Quinidine is a substrate of P-gp. Quinidine is an inhibitor of CYP2D6 (strong), CYP3A4 (weak), and P-gp (moderate). Selpercatinib is an in vitro substrate of P-gp. No clinically significant differences in selpercatinib pharmacokinetics were observed when coadministered with a single dose of rifampicin, a P-gp inhibitor. Therefore, no relevant effect on selpercatinib exposure is expected due to inhibition of P-gp by quinidine. However, selpercatinib is metabolised by CYP3A4 and concentrations may increase due to weak inhibition of CYP3A4 by quinidine. Selpercatinib is associated with concentration-dependent QTc prolongation and thus, any increase in selpercatinib exposure may result in an increased QTc interval. Since quinidine also has a moderate risk of QT prolongation, coadministration with quinidine can lead to an even more prolonged QTc interval. Furthermore, concentrations of quinidine may increase due to inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with quinidine, leading to an increased risk of adverse events of quinidine. Additionally, selpercatinib is an inhibitor of P-gp in vitro, which might lead to increased plasma concentrations of quinidine and therefore a higher risk of adverse reactions of quinidine. However, the relevance of this interaction is unknown. Therefore, coadministration is not recommended. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account, and selpercatinib plasma concentrations (if available). Also monitor closely for quinidine toxicity.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Rabeprazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Rabeprazole is mainly metabolised via non-enzymatic reduction and to a lesser extent by CYP2C19 and CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with rabeprazole, leading to an increased risk of adverse events of rabeprazole. Furthermore, the bioavailability of selpercatinib is pH-dependent and, thus, an increase in gastric pH by rabeprazole reduces selpercatinib bioavailability. After coadministration with omeprazole, a proton pump inhibitor, selpercatinib exposure decreased by 69%. This may reduce the anti-tumor activity of selpercatinib. A similar effect may occur after coadministration with rabeprazole. If coadministration is necessary, selpercatinib should be administered when acid secretion is the least inhibited, which just before a new dose of rabeprazole. Furthermore, selpercatinib should be administered concomitantly with food to overcome the decreased bioavailability. Coadministration should be monitored for rabeprazole toxicity. No a priori dose adjustment of rabeprazole is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Ramipril

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ramipril is hydrolysed to the active metabolite ramiprilat and is metabolised to the diketopiperazine ester, diketopiperazine acid, and the glucuronides of ramipril and ramiprilat. Selpercatinib is unlikely to interfere with these metabolic or elimination pathways.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Ranitidine

Quality of Evidence: Low

Summary:

Coadministration has been studied and care should be taken. Ranitidine is excreted via OAT1/OAT3, which is not affected by selpercatinib. However, the bioavailability of selpercatinib is pH-dependent and, thus, an increase in gastric pH by ranitidine reduces selpercatinib bioavailability. This may reduce the anti-tumor activity of selpercatinib. No clinically significant differences in selpercatinib pharmacokinetics (AUC0-INF -7%) were observed when coadministered with multiple daily doses of ranitidine (H2 receptor antagonist) given 10 hours prior to and 2 hours after the selpercatinib dose (administered fasted). If coadministration is necessary, selpercatinib should be administered 10 hours after or 2 hours before a new dose of ranitidine.

Description:

See summary

Potential Interaction

Selpercatinib

Ranolazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Ranolazine is primarily metabolised by CYP3A4 and to a lesser extent by CYP2D6. Ranolazine is a substrate of P-gp. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with ranolazine. Moreover, selpercatinib is an inhibitor of P-gp in vitro, which might also lead to increased plasma concentrations of ranolazine and therefore a higher risk of adverse reactions of ranolazine. However, the relevance of this interaction is unknown. Additionally, ranolazine is a weak inhibitor of P-gp, CYP3A4, and CYP2D6. Selpercatinib is an in vitro substrate of P-gp. No clinically significant differences in selpercatinib pharmacokinetics were observed when coadministered with a single dose of rifampicin, which acts as a P-gp inhibitor when administered as a single dose. Therefore, no relevant effect on selpercatinib exposure is expected due to inhibition of P-gp by ranolazine. However, selpercatinib is metabolised by CYP3A4 and concentrations may increase due to weak inhibition of CYP3A4 by ranolazine. Selpercatinib is associated with concentration-dependent QTc prolongation and thus, any increase in selpercatinib exposure may result in an increased QTc interval. Since ranolazine also has a moderate risk of QT prolongation, coadministration with ranolazine can lead to an even more prolonged QT interval. Coadministration should be avoided. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account. Monitor also selpercatinib plasma concentrations (if available) and ranolazine toxicity.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Reboxetine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Reboxetine is metabolised by CYP3A4. In vitro data indicate reboxetine to be a weak inhibitor of CYP3A4, but in vivo data showed no inhibitory effect on CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with reboxetine, leading to an increased risk of adverse events of reboxetine. Coadministration should be monitored for reboxetine toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Interaction

Selpercatinib

Repaglinide

Quality of Evidence: Low

Summary:

Coadministration has been studied and should be approached with caution. Repaglinide is metabolised by CYP2C8 and CYP3A4, with clinical data indicating it is a substrate of the hepatic transporter OATP1B1. Concentrations may increase due to moderate inhibition of CYP2C8 by selpercatinib and weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. In healthy subjects (n=16), coadministration of selpercatinib (160 mg twice daily for 10 days) and repaglinide (0.5 mg single dose) increased repaglinide AUC by 87% and Cmax by 70%. This could lead to an increased risk of adverse events of repaglinide. Coadministration should be avoided. If coadministration is unavoidable, closely monitor for repaglinide toxicity and consider reducing the dosage of repaglinide.

Description:

See summary

No Interaction Expected

Selpercatinib

Retinol (Vitamin A)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Vitamin A esters are hydrolysed by pancreatic enzymes to retinol, which is then absorbed and re-esterified. Some retinol is stored in the liver, but retinol not stored in the liver undergoes glucuronide conjugation and subsequent oxidation to retinal and retinoic acid. Selpercatinib is unlikely to interfere with these metabolic pathways.

Description:

See summary

No Interaction Expected

Selpercatinib

Riboflavin (Vitamin B2)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely.

Description:

See summary

Do Not Coadminister

Selpercatinib

Rifabutin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Rifabutin is metabolised by CYP3A and via deacetylation. Rifabutin is also a strong CYP3A4 and P-gp inducer. Rifabutin is metabolised by CYP3A4 and concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. However, a relevant effect is not expected since rifabutin is a strong CYP3A4 inducer itself. Selpercatinib is an in vitro substrate of P-gp. Moreover, selpercatinib is metabolised by CYP3A4 and concentrations may decrease due to strong induction of CYP3A4 by rifabutin. After coadministration with rifampicin, a strong CYP3A4 and P-gp inducer, selpercatinib exposure decreased by 87%. This may reduce the anti-tumor activity of selpercatinib. A similar effect may occur after coadministration with rifabutin, although the magnitude of the effect is unknown. Coadministration is contraindicated.

Description:

See summary

Do Not Coadminister

Selpercatinib

Rifampicin

Quality of Evidence: Low

Summary:

Coadministration has been studied and is contraindicated. Rifampicin is metabolised via deacetylation and is also a strong CYP3A4 and P-gp inducer. Selpercatinib is an in vitro substrate of P-gp. Moreover, selpercatinib is metabolised by CYP3A4 and concentrations will decrease due to induction of P-gp and CYP3A4 by rifampicin. In healthy subjects (n=12), coadministration of selpercatinib (160 mg single dose) and rifampicin (600 mg once daily for 11 days) decreased selpercatinib exposure by 87%. This may reduce the anti-tumor activity of selpercatinib. Coadministration is contraindicated.

Description:

See summary

Do Not Coadminister

Selpercatinib

Rifapentine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Rifapentine is metabolised via deacetylation and is also a strong CYP3A4, CYP2C8, and P-gp inducer. Selpercatinib is an in vitro substrate of P-gp. Moreover, selpercatinib is metabolised by CYP3A4 and concentrations may decrease due to induction of CYP3A4 by rifapentine. After coadministration with rifampicin, a strong CYP3A4 and P-gp inducer, selpercatinib exposure decreased by 87%. This may reduce the anti-tumor activity of selpercatinib. A similar effect may occur after coadministration with rifapentine, although the magnitude of the effect is unknown. Coadministration is contraindicated.

Description:

See summary

No Interaction Expected

Selpercatinib

Rifaximin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Rifaximin is mainly excreted in faeces, almost entirely as unchanged drug. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Risperidone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Risperidone is metabolised by CYP2D6 and to a lesser extent by CYP3A4. Furthermore, risperidone is a substrate of P-gp. Concentrations may increase due to weak inhibition of CYP3A4 and P-gp by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with risperidone, leading to an increased risk of adverse events of risperidone. Coadministration should be monitored for risperidone toxicity.

Description:

See summary

Do Not Coadminister

Selpercatinib

Rivaroxaban

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Rivaroxaban is partly metabolised in the liver (by CYP3A4, CYP2J2, and hydrolytic enzymes) and partly eliminated unchanged in urine. Rivaroxaban is also a substrate of P-gp and BCRP. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with rivaroxaban, leading to an increased risk of adverse events of rivaroxaban. Any increase of exposure to rivaroxaban increases risk of toxicity. Therefore, coadministration is contra-indicated.

Description:

See summary

Potential Interaction

Selpercatinib

Rosiglitazone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Rosiglitazone is metabolised mainly by CYP2C8 and to a lesser extent by CYP2C9. Concentrations may increase due to moderate inhibition of CYP2C8 by selpercatinib. After coadministration with repaglinide, a CYP2C8 substrate, repaglinide exposure increased by 188%. A similar effect may occur after coadministration with rosiglitazone, leading to an increased risk of adverse events of rosiglitazone. Coadministration should be avoided. If coadministration is unavoidable, closely monitor for rosiglitazone toxicity and consider reducing the dosage of rosiglitazone.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Rosuvastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Rosuvastatin is largely excreted unchanged via the faeces via OATP1B1 and is substrate for BCRP. Selpercatinib is an inhibitor of BCRP in vitro, which might lead to increased plasma concentrations of rosuvastatin and therefore a higher risk of adverse reactions of rosuvastatin. However, the relevance of this interaction is unknown. Monitor for rosuvastatin toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Salbutamol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Salbutamol is metabolised to the inactive salbutamol-4’-O-sulphate. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Salmeterol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Salmeterol is metabolised by CYP3A4. The systemic exposure of salmeterol is low. Selpercatinib is a weak CYP3A4 inhibitor. However, since the systemic exposure of salmeterol is low, no relevant effect on salmeterol exposure is expected. Coadministration should be monitored for salmeterol toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Saxagliptin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Saxagliptin is mainly metabolised by CYP3A4 and is a substrate of P-gp. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with saxagliptin, leading to an increased risk of adverse events of saxagliptin. Moreover, selpercatinib is an inhibitor of P-gp in vitro, which might lead to increased plasma concentrations of saxagliptin and therefore a higher risk of adverse reactions of saxagliptin. However, the relevance of this interaction is unknown. Monitor for saxagliptin toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Senna

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Senna glycosides are hydrolysed by colonic bacteria in the intestinal tract and the active anthraquinones liberated into the colon. Excretion occurs in the urine and the faeces and also in other secretions. No clinically significant interactions are known.

Description:

See summary

Do Not Coadminister

Selpercatinib

Sertindole

Quality of Evidence: Low

Summary:

Coadministration has not been studied but is contraindicated. Sertindole is metabolised by CYP2D6 and CYP3A4, which are not affected by selpercatinib. However, the product labels for sertindole contraindicate its use in the presence of other drugs that prolong the QT interval, such as selpercatinib.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Sertraline

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Sertraline is mainly metabolised by CYP2B6 and to a lesser extent by CYPs 2C9, 2C19, 2D6, and 3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with sertraline, leading to an increased risk of adverse events of sertraline. Coadministration should be monitored for sertraline toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Sildenafil (Pulmonary Arterial Hypertension)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Sildenafil is metabolised mainly by CYP3A4 and to a lesser extent by CYP2C9. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with sildenafil, leading to an increased risk of adverse events of sildenafil. Coadministration should be monitored for sildenafil toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Simvastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Simvastatin is metabolised by CYP3A4. Simvastatin is a substrate for BCRP and the active metabolite is a substrate of OATP1B1. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with simvastatin. Additionally, selpercatinib is an inhibitor of BCRP in vitro, which might also lead to increased plasma concentrations of simvastatin and therefore a higher risk of adverse reactions of simvastatin. However, the relevance of this interaction is unknown. Coadministration should be monitored for simvastatin toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Sirolimus

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Sirolimus is metabolised by CYP3A4 and is a substrate of P-gp. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with sirolimus. Moreover, selpercatinib is an inhibitor of P-gp in vitro, which might also lead to increased plasma concentrations of sirolimus and therefore a higher risk of adverse reactions of sirolimus. However, the relevance of this interaction is unknown. Coadministration should be monitored for sirolimus toxicity and plasma concentrations (if available). No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Sitagliptin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Sitagliptin is primarily eliminated in urine as unchanged drug (active secretion by OAT3, OATP4C1, and P-gp) and metabolism by CYP3A4 represents a minor metabolic pathway. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with sitagliptin, leading to an increased risk of adverse events of sitagliptin. Additionally, selpercatinib is an inhibitor of P-gp in vitro, which might lead to increased plasma concentrations of sitagliptin and therefore a higher risk of adverse reactions of sitagliptin. However, the relevance of this interaction is unknown. Monitor for sitagliptin toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Sodium nitroprusside

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Sodium nitroprusside is rapidly metabolised, likely by interaction with sulfhydryl groups in the erythrocytes and tissues. Cyanogen (cyanide radical) is produced which is converted to thiocyanate in the liver by the enzyme thiosulfate sulfurtransferase. Selpercatinib is unlikely to interfere with these metabolic pathways.

Description:

See summary

Do Not Coadminister

Selpercatinib

Sotalol

Quality of Evidence: Low

Summary:

Coadministration has not been studied but is contraindicated. Sotalol is excreted unchanged via renal elimination. Selpercatinib is unlikely to interfere with this elimination pathway. However, the product labels for sotalol advise extreme caution if given with other drugs that prolong the QT interval, such as selpercatinib. Therefore, coadministration is contraindicated.

Description:

See summary

No Interaction Expected

Selpercatinib

Spectinomycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Spectinomycin is predominantly eliminated unchanged in the kidneys via glomerular filtration. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Selpercatinib

Spironolactone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Spironolactone is partly metabolised by the flavin containing monooxygenases. Selpercatinib is unlikely to interfere with this metabolic pathway.

Description:

See summary

No Interaction Expected

Selpercatinib

Stanozolol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Stanozolol undergoes hepatic metabolism. Selpercatinib is unlikely to interfere with this metabolic pathway.

Description:

See summary

Do Not Coadminister

Selpercatinib

St John's Wort

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. St John’s wort is a P-gp and CYP3A4 inducer, potentially causing significant and unpredictable decreases in selpercatinib plasma concentrations. This may reduce the anti-tumor activity of selpercatinib. Therefore, coadministration is contraindicated.

Description:

See summary

No Interaction Expected

Selpercatinib

Streptokinase

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Like other proteins, streptokinase is metabolised proteolytically in the liver and eliminated via the kidneys. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Selpercatinib

Streptomycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Streptomycin is eliminated by glomerular filtration. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Selpercatinib

Sulfadiazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. In vitro studies suggest a role of CYP2C9 in sulfadiazine metabolism, which is not affected by selpercatinib.

Description:

See summary

Potential Interaction

Selpercatinib

Sulpiride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Sulpiride is mainly excreted in the urine and faeces as unchanged drug. Selpercatinib is unlikely to interfere with these elimination pathways. However, selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. Therefore, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since sulpiride also has a risk of QT prolongation, coadministration can lead to an even more prolonged QT interval. Coadministration should be avoided. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account.

Description:

See summary

Potential Interaction

Selpercatinib

Tacrolimus

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Tacrolimus is metabolised mainly by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with tacrolimus, leading to an increased risk of adverse events of tacrolimus. Moreover, tacrolimus is also an inhibitor of CYP3A4 and OATP1B1 in vitro but produced modest inhibition of CYP3A4 and OATP1B1 in the range of clinical concentrations. Selpercatinib is metabolised by CYP3A4 and concentrations may increase due to moderate inhibition of CYP3A4 by tacrolimus. It is predicted that after coadministration with diltiazem/fluconazole/verapamil, moderate CYP3A4 inhibitors, selpercatinib exposure increases by 60 to 99%. A similar effect may occur after coadministration with tacrolimus. Selpercatinib is associated with concentration-dependent QTc prolongation and thus, any increase in selpercatinib exposure may result in an increased QTc interval. Therefore, coadministration is not recommended. If coadministration is unavoidable, closely monitor QTc interval and plasma concentrations (if available). Reduce selpercatinib dose by 40 mg. Monitor also tacrolimus toxicity and plasma concentrations (if available).

Description:

See summary

Potential Weak Interaction

Selpercatinib

Tadalafil (Pulmonary Arterial Hypertension)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Tadalafil is metabolised by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with tadalafil, leading to an increased risk of adverse events of tadalafil. Coadministration should be monitored for tadalafil toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Tamsulosin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Tamsulosin is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with tamsulosin, leading to an increased risk of adverse events of tamsulosin. Coadministration should be monitored for tamsulosin toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Tazobactam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Tazobactam is excreted as unchanged drug (approximately 80%) and inactive metabolite (approximately 20%) in the urine. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Do Not Coadminister

Selpercatinib

Telithromycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Telithromycin is metabolised by CYP3A4 (50%) with the remaining 50% metabolised via non-CYP mediated pathways. Telithromycin is also an inhibitor of CYP3A4 (strong) and P-gp. However, the relevance of P-gp inhibition is unknown. Telithromycin is metabolised by CYP3A4 and concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with telithromycin, leading to an increased risk of adverse events of telithromycin. Selpercatinib is an in vitro substrate of P-gp. No clinically significant differences in selpercatinib pharmacokinetics were observed when coadministered with a single dose of rifampicin, which acts as a P-gp inhibitor when administered as a single dose. Therefore, no relevant effect on selpercatinib exposure is expected due to inhibition of P-gp by telithromycin. Moreover, selpercatinib is metabolised by CYP3A4 and concentrations may decrease due to strong induction of CYP3A4 by telithromycin. After coadministration with rifampicin, a strong CYP3A4 inducer, selpercatinib exposure decreased by 87%. This may reduce the anti-tumor activity of selpercatinib. A similar effect may occur after coadministration with telithromycin, although the magnitude of the effect is unknown. Coadministration is contraindicated.

Description:

See summary

No Interaction Expected

Selpercatinib

Telmisartan

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Telmisartan is mainly glucuronidated by UGT1A3, which is not affected by selpercatinib.

Description:

See summary

No Interaction Expected

Selpercatinib

Temazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Temazepam is mainly glucuronidated, which is not affected by selpercatinib.

Description:

See summary

Potential Interaction

Selpercatinib

Terbinafine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Terbinafine is metabolised by CYPs 1A2, 2C9, 3A4, and to a lesser extent CYP2C8 and CYP2C19. Terbinafine is also a moderate-strong inhibitor of CYP2D6. Concentrations may alter due to weak inhibition of CYP3A4 by selpercatinib and moderate inhibition of CYP2C8 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. After coadministration with repaglinide, a CYP2C8 substrate, repaglinide exposure increased by 188%. Similar effects may occur after coadministration with terbinafine, leading to an increased risk of adverse events of terbinafine. Coadministration should be avoided. If coadministration is unavoidable, monitor for toxicity and consider reducing the dosage of terbinafine.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Testosterone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Testosterone is metabolised by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with testosterone, leading to an increased risk of adverse events of testosterone. Coadministration should be monitored for testosterone toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Tetracycline

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Tetracycline is eliminated unchanged primarily by glomerular filtration. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Selpercatinib

Theophylline

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Theophylline is mainly metabolised by CYP1A2, which is not affected by selpercatinib.

Description:

See summary

No Interaction Expected

Selpercatinib

Thiamine (Vitamin B1)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely.

Description:

See summary

Do Not Coadminister

Selpercatinib

Thioridazine

Quality of Evidence: Low

Summary:

Coadministration has not been studied but is contraindicated. Thioridazine is metabolised by CYP2D6 and to a lesser extent by CYP3A4, which are not affected by selpercatinib. However, the product labels for thioridazine contraindicate its use in the presence of other drugs that prolong the QT interval, such as selpercatinib.

Description:

See summary

Potential Interaction

Selpercatinib

Tiapride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Tiapride is excreted largely unchanged in urine. Selpercatinib is unlikely to interfere with this elimination pathway. However, selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. Therefore, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since tiapride also has a risk of QT prolongation, coadministration can lead to an even more prolonged QT interval. Coadministration should be avoided. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Ticagrelor

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Ticagrelor is a substrate of CYP3A4 and P-gp. Ticagrelor is also a weak inhibitor of CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with ticagrelor, leading to an increased risk of adverse events of ticagrelor. Additionally, selpercatinib is an inhibitor of P-gp in vitro, which might lead to increased plasma concentrations of ticagrelor and therefore a higher risk of adverse reactions of ticagrelor. However, the relevance of this interaction is unknown. Moreover, selpercatinib is metabolised by CYP3A4 and concentrations may increase due to weak inhibition of CYP3A4 by ticagrelor. Selpercatinib is associated with concentration-dependent QTc prolongation and thus, any increase in selpercatinib exposure may result in an increased QTc interval. Coadministration should be monitored for QTc interval and selpercatinib plasma concentrations (if available). In addition, monitor thrombocytes aggregation test and ticagrelor toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Timolol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Timolol is predominantly metabolised in the liver by CYP2D6, which is not affected by selpercatinib. Note: the systemic absorption of timolol after ocular administration is low. Therefore, a relevant interaction via CYP2D6 is unlikely.

Description:

See summary

No Interaction Expected

Selpercatinib

Tinzaparin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Tinzaparin is renally excreted as unchanged or almost unchanged drug. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Potential Interaction

Selpercatinib

Tolbutamide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Tolbutamide is mainly metabolised by CYP2C9 and to a lesser extent by CYPs 2C8 and 2C19. Concentrations may increase due to moderate inhibition of CYP2C8 by selpercatinib. After coadministration with repaglinide, a CYP2C8 substrate, repaglinide exposure increased by 188%. A similar effect may occur after coadministration with tolbutamide, leading to an increased risk of adverse events of tolbutamide. Coadministration should be avoided. If coadministration is unavoidable, closely monitor for toxicity and consider reducing the dosage of tolbutamide.

Description:

See summary

Potential Interaction

Selpercatinib

Tolterodine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Tolterodine is primarily metabolised by CYP2D6 with CYP3A4 playing a minor role. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. However, since this is a minor pathway, no relevant effect on tolterodine exposure is expected. However, selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. Therefore, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since tolterodine also has a risk of QT prolongation, coadministration with tolterodine can lead to an even more prolonged QT interval. Coadministration should be avoided. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account.

Description:

See summary

No Interaction Expected

Selpercatinib

Torasemide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Torasemide is metabolised mainly by CYP2C9, which is not affected by selpercatinib. Furthermore, OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Selpercatinib is unlikely to interfere with this pathway.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Tramadol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Tramadol is metabolised by CYPs 3A4, 2B6, and 2D6. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with tramadol, leading to an increased risk of adverse events of tramadol. Coadministration should be monitored for tramadol toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Trandolapril

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Trandolapril is hydrolysed to trandolaprilat. Selpercatinib is unlikely to interfere with this metabolic pathway.

Description:

See summary

No Interaction Expected

Selpercatinib

Tranexamic acid

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Tranexamic acid is mainly cleared by glomerular filtration. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Selpercatinib

Tranylcypromine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Tranylcypromine is hydroxylated and acetylated. Selpercatinib is unlikely to interfere with these elimination pathways.

Description:

See summary

Potential Interaction

Selpercatinib

Trazodone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Trazodone is primarily metabolised by CYP3A4. Concentrations may increase due to inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with trazodone, leading to an increased risk of adverse events of trazodone. Furthermore, selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. Therefore, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since trazodone also has a risk of QT prolongation, coadministration with trazodone can lead to an even more prolonged QTc interval. Therefore, coadministration is not recommended. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account. Also monitor closely for trazodone toxicity.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Triamcinolone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Triamcinolone is metabolised by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with triamcinolone, leading to an increased risk of adverse events of triamcinolone. Coadministration should be monitored for triamcinolone toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Triazolam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Triazolam is metabolised by CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with triazolam, leading to an increased risk of adverse events of triazolam. Coadministration should be monitored for triazolam toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Trimethoprim/Sulfamethoxazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Trimethoprim is primarily eliminated by the kidneys through glomerular filtration and tubular secretion. To a lesser extent (approximately 30%) trimethoprim is metabolised by CYP enzymes (in vitro data suggest CYP3A4, CYP1A2, and CYP2C9). Sulfamethoxazole is metabolised by CYP2C9. Furthermore, trimethoprim is a weak CYP2C8 inhibitor and in vitro data also suggest that trimethoprim is an inhibitor of OCT2 and MATE1. Sulfamethoxazole is a weak inhibitor of CYP2C9. Trimethoprim concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with trimethoprim, leading to an increased risk of adverse events of trimethoprim. Coadministration should be monitored for trimethoprim plasma concentrations and toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Trimipramine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Trimipramine is metabolised mainly by CYP2D6, which is not affected by selpercatinib.

Description:

See summary

Potential Interaction

Selpercatinib

Tropisetron

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Tropisetron is metabolised mainly by CYP2D6. Tropisetron is also a substrate of P-gp. Selpercatinib is an inhibitor of P-gp in vitro, which might lead to increased plasma concentrations of tropisetron and therefore a higher risk of adverse reactions of tropisetron. However, the relevance of this interaction is unknown. Moreover, selpercatinib is associated with QTc interval prolongation. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state Cmax observed in patients after administration of 160 mg twice daily. Therefore, selpercatinib can be classified as a drug with a moderate QTc prolonging potential (10-60 msec). Since tropisetron also has a moderate risk of QT prolongation, coadministration can lead to an even more prolonged QT interval. Coadministration should be avoided. If coadministration is unavoidable, closely monitor QTc interval, taking risk factors into account. Also monitor closely for tropisetron toxicity.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Ulipristal

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Ulipristal is mainly metabolised by CYP3A4 and to a lesser extent CYP1A2 and CYP2D6. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with ulipristal, leading to an increased risk of adverse events of ulipristal. Coadministration should be monitored for ulipristal toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Valproic acid (Valproate)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Valproic acid is primarily metabolised by glucuronidation (50%) and mitochondrial beta-oxidation (30-40%). Selpercatinib is unlikely to interfere with these elimination pathways. To a lesser extent (10%) valproic acid is metabolised by CYP2C9 and CYP2C19, which are not affected by selpercatinib. In addition, valproic acid is an inhibitor of CYP2C9, which is not involved in the metabolism of selpercatinib.

Description:

See summary

No Interaction Expected

Selpercatinib

Valsartan

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Valsartan is eliminated unchanged mostly through biliary excretion. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Selpercatinib

Vancomycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Vancomycin is excreted unchanged via glomerular filtration. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Venlafaxine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Venlafaxine is mainly metabolised by CYP2D6 and to a lesser extent by CYPs 3A4, 2C19, and 2C9. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with venlafaxine, leading to an increased risk of adverse events of venlafaxine. Coadministration should be monitored for venlafaxine toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Interaction

Selpercatinib

Verapamil

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Verapamil is metabolised mainly by CYP3A4 and to a lesser extent by CYPs 1A2, 2C8, and 2C9. Concentrations may increase due to moderate inhibition of CYP2C8 by selpercatinib and weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. After coadministration with repaglinide, a CYP2C8 substrate, repaglinide exposure increased by 188%. Similar effects may occur after coadministration with verapamil, leading to an increased risk of adverse events of verapamil. Verapamil is also an inhibitor of CYP3A4 (moderate) and P-gp (strong). Selpercatinib is an in vitro substrate of P-gp. No clinically significant differences in selpercatinib pharmacokinetics were observed when coadministered with a single dose of rifampicin, which acts as a P-gp inhibitor when administered as a single dose. Therefore, no relevant effect on selpercatinib exposure is expected due to inhibition of P-gp by verapamil. However, selpercatinib is metabolised by CYP3A4 and it is predicted that after coadministration with diltiazem/fluconazole/verapamil, selpercatinib exposure increases by 60 to 99% due to moderate CYP3A4 inhibition. Selpercatinib is associated with concentration-dependent QTc prolongation and thus, any increase in selpercatinib exposure may result in an increased QTc interval. Therefore, coadministration is not recommended. If coadministration is unavoidable, closely monitor QTc interval and plasma concentrations (if available). Reduce selpercatinib dose by 40 mg. Coadministration should also be monitored for blood pressure and verapamil toxicity and reducing the dosage of verapamil should be considered.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Vildagliptin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Vildagliptin is inactivated via non-CYP mediated hydrolysis and is a substrate of P-gp. Selpercatinib is an inhibitor of P-gp in vitro, which might lead to increased plasma concentrations of vildagliptin and therefore a higher risk of adverse reactions of vildagliptin. However, the relevance of this interaction is unknown. Monitor for vildagliptin toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Vitamin E

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely.

Description:

See summary

Potential Interaction

Selpercatinib

Voriconazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Voriconazole is metabolised by CYP2C19 (major pathway) and to a lesser extent by CYP3A4 and CYP2C9. Voriconazole is also a strong inhibitor of CYP3A4 and a weak inhibitor of CYPs 2C9, 2C19 and 2B6.Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. However, a relevant effect of selpercatinib is not expected since voriconazole is a strong CYP3A4 inhibitor itself. Selpercatinib is metabolised by CYP3A4, and concentrations may increase due to strong inhibition of CYP3A4 by voriconazole. After coadministration with itraconazole, a strong CYP3A4 inhibitor, selpercatinib exposure increased by 133%. A similar effect may occur after coadministration with voriconazole. Selpercatinib is associated with concentration-dependent QTc prolongation and thus, any increase in selpercatinib exposure may result in an increased QTc interval. Since voriconazole also has a moderate risk of QT prolongation, coadministration can lead to an even more prolonged QT interval. Therefore, coadministration is not recommended. If coadministration is unavoidable, closely monitor QTc interval and selpercatinib plasma concentrations (if available). Reduce selpercatinib dose by 80 mg.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Warfarin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Warfarin is a mixture of enantiomers which are metabolised by different cytochromes. R-warfarin is primarily metabolised by CYP1A2 and CYP3A4. S-warfarin (more potent) is metabolised by CYP2C9 . Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with warfarin, leading to an increased risk of adverse events of warfarin. Coadministration should be monitored for INR/PT and warfarin toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Selpercatinib

Xipamide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Approximately 90% of xipamide is excreted in the urine, mainly as unchanged drug (~50%) and glucuronides (30%). Selpercatinib is unlikely to interfere with these elimination pathways. OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Selpercatinib is unlikely to interfere with this pathway.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Zaleplon

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Zaleplon is mainly metabolised by aldehyde oxidase and to a lesser extent CYP3A4. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with zaleplon, leading to an increased risk of adverse events of zaleplon. Coadministration should be monitored for zaleplon toxicity. No a priori dose adjustment is required.

Description:

See summary

Do Not Coadminister

Selpercatinib

Ziprasidone

Quality of Evidence: Low

Summary:

Coadministration has not been studied but is contraindicated. Approximately two thirds of ziprasidone metabolic clearance is by reduction, with less than one third by CYP enzymes (mainly CYP3A4). However, the product labels for ziprasidone contraindicate its use in the presence of other drugs that prolong the QT interval, such as selpercatinib.

Description:

See summary

No Interaction Expected

Selpercatinib

Zoledronic acid

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Zoledronic acid is not metabolised and is cleared from the plasma by uptake into bone and elimination via renal excretion. Selpercatinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Zolpidem

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Zolpidem is metabolised mainly by CYP3A4 and to a lesser extent by CYP2C9, CYP2C19, CYP2D6, and CYP1A2. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with zolpidem, leading to an increased risk of adverse events of zolpidem. Coadministration should be monitored for zolpidem toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Interaction

Selpercatinib

Zopiclone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Zopiclone is metabolised mainly by CYP3A4 and to a lesser extent by CYP2C8. Concentrations may increase due to moderate inhibition of CYP2C8 by selpercatinib and weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. After coadministration with repaglinide, a CYP2C8 substrate, repaglinide exposure increased by 188%. Similar effects may occur after coadministration with zopiclone, leading to an increased risk of adverse events of zopiclone. Coadministration should be avoided. If coadministration is unavoidable, monitor for zopiclone toxicity and consider reducing the dosage of zopiclone.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Zotepine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Zotepine is mainly metabolised by CYP3A4 and to a lesser extent by CYP1A2 and CYP2D6. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with zotepine, leading to an increased risk of adverse events of zotepine. Coadministration should be monitored for zotepine toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Selpercatinib

Zuclopenthixol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Zuclopenthixol is metabolised by sulphoxidation, N-dealkylation (via CYP2D6 and CYP3A4) and glucuronidation. Concentrations may increase due to weak inhibition of CYP3A4 by selpercatinib. After coadministration with midazolam, a CYP3A4 substrate, midazolam exposure increased by 54%. A similar effect may occur after coadministration with zuclopenthixol, leading to an increased risk of adverse events of zuclopenthixol. Coadministration should be monitored for zuclopenthixol toxicity. No a priori dose adjustment is required.

Description:

See summary