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Rev: [July/2006]
7 DRUG INTERACTIONS
- CYP3A4 Inhibitors: Concurrent administration of sunitinib malate with the strong CYP3A4 inhibitor, ketoconazole, resulted in an increase in exposure after a single dose of sunitinib malate. A dose reduction for SUTENT should be considered when it must be co-administered with strong CYP3A4 inhibitors.
- CYP3A4 Inducers: Concurrent administration of SUTENT with the strong CYP3A4 inducer, rifampin, resulted in a reduction in exposure after a single dose of SUTENT. A dose increase for SUTENT should be considered when it must be co-administered with CYP3A4 inducers.
7.1 In Vitro Studies of CYP Inhibition and Induction
In vitro studies indicated that sunitinib does not induce or inhibit major CYP enzymes. The in vitro studies in human liver microsomes and hepatocytes of the activity of CYP isoforms CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11 indicated that sunitinib and its primary active metabolite are unlikely to have any clinically relevant drug-drug interactions with drugs that may be metabolized by these enzymes.
7.2 CYP3A4 Inhibitors
Concurrent administration of sunitinib malate with the strong CYP3A4 inhibitor, ketoconazole, resulted in 49% and 51% increases in the combined (sunitinib + primary active metabolite) Cmax and AUC0–∞ values, respectively, after a single dose of sunitinib malate in healthy volunteers. Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increase sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. A dose reduction for SUTENT should be considered when it must be co-administered with strong CYP3A4 inhibitors (see 2.2 Dose Modification).
7.3 CYP3A4 Inducers
Concurrent administration of SUTENT with the strong CYP3A4 inducer, rifampin, resulted in a 23% and 46% reduction in the combined (sunitinib + primary active metabolite) Cmax and AUC0–∞ values, respectively, after a single dose of SUTENT in healthy volunteers. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. John's Wort) may decrease sunitinib concentrations. St. John's Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. John's Wort concomitantly. A dose increase for SUTENT should be considered when it must be co-administered with CYP3A4 inducers (see 2.2 Dose Modification).
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10 OVERDOSAGE
No overdose of SUTENT was reported in completed clinical studies. In non-clinical studies mortality was observed following as few as 5 daily doses of 500 mg/kg (3000 mg/m2) in rats. At this dose, signs of toxicity included impaired muscle coordination, head shakes, hypoactivity, ocular discharge, piloerection and gastrointestinal distress. Mortality and similar signs of toxicity were observed at lower doses when administered for longer durations. Treatment of overdose with SUTENT should consist of general supportive measures. There is no specific antidote for overdosage with SUTENT. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage.
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