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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Aluminium hydroxide is not metabolised. Panobinostat does not interact with this pathway. Furthermore, the aqueous solubility of panobinostat is pH dependent, with higher pH resulting in lower solubility. Coadministration of panobinostat with drugs that elevate the gastric pH has not been evaluated in vitro or in a clinical trial. However, based on PBPK simulations, a clinical relevant effect on panobinostat absorption after coadministration with aluminium hydroxide is not expected.

Coadministration has not been studied but is not recommended. Amiodarone is metabolised by CYP3A4 and CYP2C8. Panobinostat is an inhibitor of CYP3A4 in vitro but a clinically relevant effect on amiodarone exposure is not expected in vivo. However, the major metabolite of amiodarone, desethylamiodarone, is an inhibitor of CYPs 3A4 (weak), 2C9 (moderate), 2D6 (moderate), 2C19 (weak), 1A1 (strong) and 2B6 (moderate) and P-gp (strong). Concentrations of panobinostat may increase due to inhibition of CYP3A4. As the clinical relevance of this interaction is unknown, monitoring for panobinostat toxicity may be required. Due to the long half-life of amiodarone, interactions can be observed for several months after discontinuation of amiodarone. Furthermore, panobinostat and amiodarone may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, monitor ECG.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Amphotericin B is not appreciably metabolised but is eliminated to a large extent in the bile. Panobinostat does not interfere with this elimination pathway. However, the European SPC 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.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Antacids are not metabolised by CYPs. Panobinostat is unlikely to interfere with this metabolic pathway. Furthermore, the aqueous solubility of panobinostat is pH dependent, with higher pH resulting in lower solubility. Coadministration of panobinostat with drugs that elevate the gastric pH has not been evaluated in vitro or in a clinical trial. However, based on PBPK simulations, a clinical relevant effect on panobinostat absorption after coadministration with antacids is not expected.

Coadministration has not been studied but is not recommended. Astemizole is metabolised by CYPs 2D6, 2J2 and 3A4. Panobinostat is an inhibitor of CYP2D6 (weak) and CYP3A4 (in vitro) and may increase concentrations of astemizole. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, monitor closely for astemizole toxicity. Furthermore, panobinostat and astemizole may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, monitor ECG.

Coadministration has not been studied. Chloramphenicol is predominantly glucuronidated. Panobinostat does not inhibit or induce UGTs. However, in vitro studies have shown that chloramphenicol can inhibit metabolism mediated by CYPs 3A4 (strong), 2C19 (strong) and 2D6 (weak). Concentrations of panobinostat may increase due to inhibition of CYP3A4. As the clinical relevance of this interaction is unknown, monitoring for panobinostat toxicity may be required. Ocular use: Although chloramphenicol is systemically absorbed when used topically in the eye, the absorbed concentrations are unlikely to cause a clinically significant interaction.

Coadministration has not been studied. Ciclosporin is a substrate of CYP3A4 and P-gp. Panobinostat is an inhibitor of CYP3A4 in vitro but a clinically relevant effect on ciclosporin exposure is not expected in vivo. However, ciclosporin is an inhibitor of CYP3A4 and OATP1B1. Concentrations of panobinostat may increase due to inhibition of CYP3A4. As the clinical relevance of this interaction is unknown, monitoring for panobinostat toxicity may be required.

Coadministration has not been studied. Cimetidine is a weak inhibitor of several CYP-enzymes (CYPs 3A4, 1A2, 2D6 and 2C19, among others). Concentrations of panobinostat may increase due to inhibition of CYP3A4. As the clinical relevance of this interaction is unknown, monitoring for panobinostat toxicity may be required. Cimetidine may also decrease the renal excretion of drugs due to competition for the active tubular secretion. In vitro data indicate that cimetidine also inhibits OAT1 and OCT2 but at concentrations much higher than the observed clinical concentrations. Panobinostat does not interact with this pathway. Furthermore, the aqueous solubility of panobinostat is pH dependent, with higher pH resulting in lower solubility. Coadministration of panobinostat with drugs that elevate the gastric pH has not been evaluated in vitro or in a clinical trial. However, based on PBPK simulations, a clinical relevant effect on panobinostat absorption after coadministration with cimetidine is not expected.

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. Panobinostat is unlikely to interfere with this elimination pathway.

Coadministration has not been studied but is not recommended. Desipramine is metabolised by CYP2D6. Panobinostat is a weak inhibitor of CYP2D6 and may increase concentrations of desipramine. Coadministration of panobinostat and dextromethorphan, a CYP2D6 substrate, increased dextromethorphan AUC and Cmax by 1.64-fold and 1.83-fold, respectively. A similar effect may occur with desipramine. Monitoring for desipramine toxicity may be required. Furthermore, panobinostat and desipramine may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, monitor ECG.

Coadministration has not been studied but is not recommended. Escitalopram is metabolised by CYPs 2C19 (37%), 2D6 (28%) and 3A4 (35%) to form N-desmethylescitalopram. Panobinostat is an inhibitor of CYP2D6 (weak) and CYP3A4 (in vitro), and may increase concentrations of escitalopram. Monitoring for escitalopram toxicity may be required. Furthermore, panobinostat and escitalopram may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, monitor ECG.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Esomeprazole is metabolised by CYP2C19 and CYP3A4. Panobinostat is an inhibitor of CYP3A4 in vitro but a clinically relevant effect on esomeprazole exposure is not expected in vivo. Esomeprazole is also an inhibitor of CYP2C19. Panobinostat is not metabolised by CYP2C19. Furthermore, the aqueous solubility of panobinostat is pH dependent, with higher pH resulting in lower solubility. Coadministration of panobinostat with drugs that elevate the gastric pH has not been evaluated in vitro or in a clinical trial. However, based on a PBPK simulation, a clinical relevant effect on panobinostat absorption after coadministration with esomeprazole is not expected.

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. Panobinostat does not inhibit or induce UGTs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Famotidine is excreted via OAT1/OAT3. Panobinostat is an inhibitor of OAT3 in vitro but a clinically relevant effect on famotidine exposure is not expected in vivo. Furthermore, the aqueous solubility of panobinostat is pH dependent, with higher pH resulting in lower solubility. Coadministration of panobinostat with drugs that elevate the gastric pH has not been evaluated in vitro or in a clinical trial. However, based on PBPK simulations, a clinical relevant effect on panobinostat absorption after coadministration with famotidine is not expected.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Heparin is thought to be eliminated via the reticuloendothelial system. Panobinostat does not interact with this metabolic pathway. However, panobinostat in combination with heparin increases the risk of haemorrhage due to the thrombocytopenic effect of panobinostat. If coadministration is unavoidable, monitor closely for signs of bleeding.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Ibandronic acid is not metabolised but 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.

Coadministration has been studied but should be approached with caution. Ketoconazole is metabolised by CYP3A4. Panobinostat is an inhibitor of CYP3A4 in vitro but a clinically relevant effect on ketoconazole exposure is not expected in vivo. However, ketoconazole is an inhibitor of CYP3A4 (strong) and P-gp and may increase concentrations of panobinostat. Coadministration of ketoconazole, a strong CYP3A4 inhibitor, and panobinostat increased panobinostat AUC and Cmax by 1.6-fold and 1.8-fold, respectively. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, reduce the panobinostat starting dose to 10 mg. Monitor closely for panobinostat toxicity. Monitor panobinostat plasma concentrations, if available. If continuous treatment with a strong CYP3A4 inhibitor is required, a dose escalation from 10 mg to 15 mg panobinostat may be considered based on patient tolerability.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Lansoprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYP3A4. Panobinostat is an inhibitor of CYP3A4 in vitro but a clinically relevant effect on lansoprazole exposure is not expected in vivo. Furthermore, the aqueous solubility of panobinostat is pH dependent, with higher pH resulting in lower solubility. Coadministration of panobinostat with drugs that elevate the gastric pH has not been evaluated in vitro or in a clinical trial. However, based on PBPK simulations, a clinical relevant effect on panobinostat absorption after coadministration with lansoprazole is not expected.

Coadministration has not been studied. Maprotiline is mainly metabolised by CYP2D6. Panobinostat is a weak inhibitor of CYP2D6 and may increase concentrations of maprotiline. Coadministration of panobinostat and dextromethorphan, a CYP2D6 substrate, increased dextromethorphan AUC and Cmax by 1.64-fold and 1.83-fold, respectively. A similar effect may occur with maprotiline. Therefore, care should be taken. Monitoring for maprotiline toxicity may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metformin is mainly eliminated unchanged in the urine and is a substrate of OCT1/2/3, MATE1 and MATE2K. Panobinostat is an inhibitor of OCT1/2 in vitro but a clinically relevant effect on metformin exposure is not expected in vivo.

Coadministration has not been studied but care should be taken. Nebivolol metabolism involves CYP2D6. Panobinostat is a weak inhibitor of CYP2D6 and may increase concentrations of nebivolol. Coadministration of panobinostat and dextromethorphan, a CYP2D6 substrate, increased dextromethorphan AUC and Cmax by 1.64-fold and 1.83-fold, respectively. A similar effect may occur with nebivolol. Therefore, care should be taken when nebivolol is coadministered with panobinostat. Monitoring for blood pressure may be required

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%). Panobinostat does not inhibit or induce UGTs and is unlikely to interfere with the renal elimination of nitrofurantoin.

Coadministration has not been studied. Norethisterone is extensively biotransformed, first by reduction and then by sulfate and glucuronide conjugation. Panobinostat does not interact with this metabolic pathway. However, the effect of oral contraceptives can be reduced by the registered comedication dexamethasone. Therefore, women using hormonal contraceptives should add a barrier method as a second form of contraception while taking panobinostat in combination with dexamethasone and bortezomib.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Ofloxacin is renally eliminated unchanged by glomerular filtration and active tubular secretion via both cationic and anionic transport systems. Panobinostat is unlikely to interfere with this elimination pathway. However, panobinostat and ofloxacin may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, monitor ECG.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Omeprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYP3A4. Panobinostat is an inhibitor of CYP3A4 in vitro but a clinically relevant effect on omeprazole exposure is not expected in vivo. Omeprazole is also an inducer of CYP1A2 and an inhibitor of CYP2C19. Panobinostat is not metabolised by CYP1A2 or CYP2C19. Furthermore, the aqueous solubility of panobinostat is pH dependent, with higher pH resulting in lower solubility. Coadministration of panobinostat with drugs that elevate the gastric pH has not been evaluated in vitro or in a clinical trial. However, based on PBPK simulations, a clinical relevant effect on panobinostat absorption after coadministration with omeprazole is not expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Palonosetron is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6 and CYP1A2. Palonosetron is also a substrate of P-gp. Panobinostat is an inhibitor of CYP3A4 (in vitro) and CYP2D6 (weak) but a clinically relevant effect on palonosetron exposure is not expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pantoprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYPs 3A4, 2D6 and 2C9. Panobinostat is an inhibitor of CYP2D6 (weak) and CYP3A4 (in vitro) but since CYP3A4 and CYP2D6 mediated metabolism are minor pathways, a clinically relevant effect on pantoprazole exposure is not expected. Furthermore, the aqueous solubility of panobinostat is pH dependent, with higher pH resulting in lower solubility. Coadministration of panobinostat with drugs that elevate the gastric pH has not been evaluated in vitro or in a clinical trial. However, based on PBPK simulations, a clinical relevant effect on panobinostat absorption after coadministration with pantoprazole is not expected.

Coadministration has not been studied but is contraindicated. Pimozide is mainly metabolised by CYP3A4 and CYP2D6, and to a lesser extent by CYP1A2. Panobinostat is an inhibitor of CYP3A4 (in vitro) and CYP2D6 (weak) and may increase pimozide exposure. Furthermore, the product labels for pimozide contraindicate its use in the presence of other drugs that prolong the QT interval, such as panobinostat.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Rabeprazole is mainly metabolised via non-enzymatic reduction and to a lesser extent by CYP2C19 and CYP3A4. Panobinostat is an inhibitor of CYP3A4 in vitro but a clinically relevant effect on rabeprazole exposure is not expected in vivo. Furthermore, the aqueous solubility of panobinostat is pH dependent, with higher pH resulting in lower solubility. Coadministration of panobinostat with drugs that elevate the gastric pH has not been evaluated in vitro or in a clinical trial. However, based on PBPK simulations, a clinical relevant effect on panobinostat absorption after coadministration with rabeprazole is not expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ranitidine is excreted via OAT1/OAT3. Panobinostat is an inhibitor of OAT3 in vitro but a clinically relevant effect on ranitidine exposure is not expected in vivo. Furthermore, the aqueous solubility of panobinostat is pH dependent, with higher pH resulting in lower solubility. Coadministration of panobinostat with drugs that elevate the gastric pH has not been evaluated in vitro or in a clinical trial. However, based on PBPK simulations, a clinical relevant effect on panobinostat absorption after coadministration with aluminium hydroxide is not expected.

Coadministration has not been studied but should be avoided. Rifabutin is metabolised by CYP3A and via deacetylation. Panobinostat is an inhibitor of CYP3A4 in vitro but a clinically relevant effect on rifabutin exposure is not expected in vivo. Rifabutin is also a strong CYP3A4 and P-gp inducer. Concentrations of panobinostat may decrease due to strong induction of CYP3A4. No clinical interaction studies with CYP3A inducers have been performed and so the clinical relevance of this interaction is unknown. In a PBPK simulation, coadministration of rifampicin, a strong CYP3A4 inducer, and panobinostat decreased panobinostat exposure by ~ 60%. A similar effect may occur with rifabutin and a decrease in exposure may lead to a decreased efficacy. Therefore, coadministration should be avoided.

Coadministration has not been studied but should be avoided. Rifampicin is metabolised via deacetylation. Panobinostat does not interact with this metabolic pathway. Rifampicin is also a strong CYP3A4 and P-gp inducer. Concentrations of panobinostat may decrease due to strong induction of CYP3A4. No clinical interaction studies with CYP3A inducers have been performed and so the clinical relevance of this interaction is unknown. In a PBPK simulation, coadministration of rifampicin and panobinostat decreased panobinostat exposure by ~ 60%. A decrease in exposure may lead to a decreased efficacy. Therefore, coadministration should be avoided.

Coadministration has not been studied but should be avoided. Rifapentine is metabolised via deacetylation. Panobinostat does not interact with this metabolic pathway. Rifapentine is also a strong CYP3A4, CYP2C8 and P-gp inducer. Concentrations of panobinostat may decrease due to strong induction of CYP3A4. No clinical interaction studies with CYP3A inducers have been performed and so the clinical relevance of this interaction is unknown. In a PBPK simulation, coadministration of rifampicin, a strong CYP3A4 inducer, and panobinostat decreased panobinostat exposure by ~ 60%. A similar effect may occur with rifapentine and a decrease in exposure may lead to a decreased efficacy. Therefore, coadministration should be avoided.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Rosuvastatin is largely excreted unchanged via the faeces via OATP1B1 and is a substrate of BCRP. Panobinostat is an inhibitor of OATP1B1 in vitro but a clinically relevant effect on rosuvastatin exposure is not expected in vivo.

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 but also in other secretions. No clinically significant interactions are known.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Sirolimus is metabolised by CYP3A4 and is a substrate of P-gp. Panobinostat is an inhibitor of CYP3A4 in vitro but a clinically relevant effect on sirolimus exposure is not expected in vivo. However, due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

Coadministration has not been studied but should be avoided. St John’s wort is a P-gp and CYP3A4 inducer. Concentrations of panobinostat may decrease due to CYP3A4 induction. A decrease in exposure may lead to decreased efficacy. Therefore, coadministration should be avoided.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Terbinafine is metabolised by CYPs 1A2, 2C9, 3A4 and to a lesser extent by CYP2C8 and CYP2C19. Panobinostat is an inhibitor of CYP3A4 in vitro but a clinically relevant effect on terbinafine exposure is not expected in vivo.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 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 CYPs 3A4, 1A2 and 2C9). Panobinostat is an inhibitor of CYP3A4 in vitro but a clinically relevant effect on trimethoprim exposure is not expected. Furthermore, trimethoprim is a weak CYP2C8 inhibitor and in vitro data also suggest that trimethoprim is an inhibitor of OCT2 and MATE1. Panobinostat does not interact with this pathway. In addition, sulfamethoxazole is metabolised via and is a weak inhibitor of CYP2C9. Panobinostat does not interact with these pathways.

Coadministration has not been studied but care should be taken. Trimipramine is metabolised mainly by CYP2D6. Panobinostat is a weak inhibitor of CYP2D6 and may increase concentrations of trimipramine. Coadministration of panobinostat and dextromethorphan, a CYP2D6 substrate, increased dextromethorphan AUC and Cmax by 1.64-fold and 1.83-fold, respectively. A similar effect may occur with trimipramine. Therefore, care should be taken when trimipramine is coadministered with panobinostat. Monitoring for trimipramine toxicity may be required.