In vitro studies have demonstrated that vemurafenib is a substrate of the efflux transporters P-gp and BCRP. The effects of P-gp and BCRP inducers and inhibitors on vemurafenib exposure are unknown. It cannot be excluded that vemurafenib pharmacokinetics could be affected by medicines that influence P-gp (e.g. verapamil, cyclosporine, ritonavir, quinidine, itraconazole) or BCRP (e.g. cyclosporine, gefitinib).

It is currently unknown whether vemurafenib is a substrate also to other transport proteins.
4.6 Fertility, pregnancy and lactation
 
Women of childbearing potential / Contraception in females

Women of childbearing potential have to use effective contraception during treatment and for at least 6 months after treatment.

Vemurafenib might decrease the efficacy of hormonal contraceptives (see section 4.5).

Pregnancy

There are no data regarding the use of vemurafenib in pregnant women.

Vemurafenib revealed no evidence of teratogenicity in rat or rabbit embryo/foetuses (see section 5.3). In animal studies, vemurafenib was found to cross the placenta. Vemurafenib should not be administered to pregnant women unless the possible benefit to the mother outweighs the possible risk to the foetus.

Breast-feeding

It is not known whether vemurafenib is excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue vemurafenib therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

No specific studies with vemurafenib have been conducted in animals to eva luate the effect on fertility. However, in repeat-dose toxicity studies in rats and dogs, no histopathological findings were noted on reproductive organs (see section 5.3).
4.7 Effects on ability to drive and use machines
 The effects of vemurafenib on the ability to drive and use machines have not been studied. Patients should be made aware of the potential fatigue or eye problems that could be a reason for not driving.

4.8 Undesirable effects
 Summary of the safety profile

The most common adverse drug reactions (ADR) (> 30%) reported with vemurafenib include arthralgia, fatigue, rash, photosensitivity reaction, nausea, alopecia and pruritus. CuSCC was very commonly reported and was most commonly treated by local excision.

Tabulated summary of adverse reactions

ADRs which were reported in melanoma patients are listed below by MedDRA body system organ class, frequency and grade of severity. The following convention has been used for the classification of frequency:

Very common ≥ 1/10

Common ≥ 1/100 to < 1/10

Uncommon ≥ 1/1,000 to < 1/100

Rare ≥ 1/10,000 to < 1/1,000

Very rare < 1/10,000

In this section, ADRs are based on results in 468 patients from a phase III randomised open label study in adult patients with BRAF V600 mutation-positive unresectable or stage IV melanoma, as well as a phase II single-arm study in patients with BRAF V600 mutation-positive stage IV melanoma who had previously failed at least one prior systemic therapy (see section 5.1). In addition ADRs originating from safety reports across all clinical trials and post-marketing sources are reported. All terms included are based on the highest pe