(12.3)]. Exercise caution and consider additional INR monitoring when ZELBORAF is used concomitantly with warfarin.
7.2 Drugs that Inhibit or Induce CYP3A4
Based on in vitro data, vemurafenib is a substrate of CYP3A4, and therefore, concomitant administration of strong CYP3A4 inhibitors or inducers may alter vemurafenib concentrations. Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) and inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) should be used with caution when coadministered with ZELBORAF.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D [see Warnings and Precautions (5.9)].
ZELBORAF may cause fetal harm when administered to a pregnant woman based on its mechanism of action.
Vemurafenib revealed no evidence of teratogenicity in rat embryo/fetuses at doses up to 250 mg/kg/day (approximately 1.3 times the human clinical exposure based on AUC) or rabbit embryo/fetuses at doses up to 450 mg/kg/day (approximately 0.6 times the human clinical exposure based on AUC). Fetal drug levels were 3-5% of maternal levels, indicating that vemurafenib has the potential to be transmitted from the mother to the developing fetus. There are no adequate and well controlled studies in pregnant women. Women of childbearing potential and men should be advised to use appropriate contraceptive measures during ZELBORAF therapy and for at least 2 months after discontinuation of ZELBORAF. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
8.3 Nursing Mothers
It is not known whether vemurafenib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from ZELBORAF in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
8.4 Pediatric Use
Safety and efficacy in pediatric patients below the age of 18 have not been established.
8.5 Geriatric Use
Ninety-four (28%) of 336 patients with unresectable or metastatic melanoma treated with ZELBORAF in Trial 1 were ≥ 65 years. Elderly patients (≥ 65 years) may be more likely to experience some adverse reactions, including cutaneous squamous cell carcinoma, nausea, decreased appetite, peripheral edema, keratoacanthoma and atrial fibrillation. The effects of ZELBORAF on overall survival, progression-free survival and best overall response rate were similar in the elderly as compared to younger patients.
8.6 Gender
The Grade 3 adverse events reported more frequently in females than males were rash, arthralgia, photosensitivity and increased creatinine. The Grade 3 adverse events reported more frequently in males than females were keratoacanthoma, increased alkaline phosphatase and increased total bilirubin.
8.7 Hepatic Impairment
No adjustment to the starting dose is needed for patients with pre-existing mild and moderate hepatic impairment. In the population pharmacokinetic analysis using data from clinical trials in patients with metastatic melanoma, pre-existing mild and moderate hepatic impairment did not influence the apparent clearance of vemurafenib. Clinical and pharmacokinetic data |
