Interactions : אינטראקציות

4.5    Interaction with other medicinal products and other forms of interaction

Sonidegib undergoes metabolism primarily by CYP3A4, and concomitant administration of strong inhibitors or inducers of CYP3A4 can increase or decrease sonidegib concentrations significantly.

Agents that may increase sonidegib plasma concentration

In healthy subjects, co-administration of a single 800 mg dose of sonidegib with ketoconazole (200 mg twice daily for 14 days), a strong CYP3A inhibitor, resulted in a 2.25-fold and a 1.49-fold increase in sonidegib AUC and Cmax, respectively, compared with sonidegib alone.
Longer duration of concomitant use of CYP3A4 strong inhibitors (e.g. more than 14 days) will lead to a larger fold change in sonidegib exposure based on simulation. If concomitant use of a strong CYP3A inhibitor is required, the sonidegib dose should be reduced to 200 mg every other day. Strong CYP3A inhibitors include, but are not limited to, ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole and nefazodone. Patients should be carefully monitored for adverse events if one of these agents is used together with sonidegib.

Agents that may decrease sonidegib plasma concentration

In healthy subjects, co-administration of a single dose of 800 mg sonidegib with rifampicin (600 mg daily for 14 days), a strong CYP3A inducer, resulted in 72% and 54% decreases in sonidegib AUC and Cmax respectively, compared with when sonidegib was given alone.
Co-administration of sonidegib with strong CYP3A inducers decreases sonidegib plasma concentration. Concomitant use of strong CYP3A inducers should be avoided; this includes, but is not limited to, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin and St John’s Wort (Hypericum perforatum). If a strong CYP3A4 inducer must be used 
concomitantly with sonidegib, consideration should be given to increasing the daily dose of sonidegib to 400-800 mg. This dose of sonidegib is predicted to adjust the AUC to the range observed without inducers based on pharmacokinetic data when the concomitant treatment with the inducer is no longer than 14 days. Longer concomitant treatment with inducer is not recommended because sonidegib exposure will be decreased and this may compromise efficacy. The dose of sonidegib used prior to initiation of the strong inducer should be resumed if the strong inducer is discontinued.

Results from a clinical study demonstrated a change in sonidegib exposure (32% and 38% decrease in AUC and Cmax) after co-administration of a single dose of Odomzo 200 mg with esomeprazole (a proton pump inhibitor) at 40 mg daily for 6 days in healthy subjects. This interaction is not expected to be clinically significant.

Effects of sonidegib on other medicinal products

Sonidegib is a competitive inhibitor of CYP2B6 and CYP2C9 in. However, results of a drug- drug interaction study in cancer patients demonstrate that the systemic exposure of bupropion (a CYP2B6 substrate) and warfarin (a CYP2C9 substrate) is not altered when co-administered with sonidegib. Sonidegib is also a breast cancer resistance protein (BCRP) inhibitor (IC50 ~1.5µM). Patients concomitantly using substrates of BCRP transporters, should be carefully monitored for adverse drug reactions. Substances that are BCRP substrates with narrow therapeutic range (e.g. methotrexate, mitoxantrone, irinotecan, topotecan) should be avoided.

Agents that may increase muscle-related adverse reactions

Due to overlapping toxicities, patients taking Odomzo who are also taking medicinal products known to increase the risk of muscle-related toxicity may be at increased risk of developing muscle-related adverse reactions. Patients should be closely monitored and dose adjustments should be considered if muscle symptoms develop.

In the phase II pivotal trial, 12 (15.2%) patients treated with Odomzo 200 mg took concomitant HMG-CoA reductase inhibitors (9 took pravastatin, 3 took non-pravastatin HMG-CoA reductase inhibitors including rosuvastatin and simvastatin). Of these patients, 7 (58.3%) had up to grade 1 muscle symptoms while 43 (64.1%) patients not taking HMG-CoA reductase inhibitors experienced up to grade 3 symptoms. No patient taking HMG-CoA reductase inhibitors experienced grade 3/4 CK elevations, as opposed to 6 (9.0%) patients not taking HMG-CoA reductase inhibitors.

Food interaction

The bioavailability of sonidegib is increased in the presence of food (see section 5.2).
Odomzo must be taken at least two hours after a meal and at least one hour before the following meal.