Cases of cuSCC have been reported in patients treated with vemurafenib. The incidence of cuSCC in vemurafenib-treated patients across studies was approximately 20%. The majority of the excised lesions reviewed by an independent central dermatopathology laboratory were classified as SCC-keratoacanthoma subtype or with mixed-keratoacanthoma features (52%). Most lesions classified as “other” (43%) were benign skin lesions (e.g. verruca vulgaris, actinic keratosis, benign keratosis, cyst/benign cyst). CuSCC usually occurred early in the course of treatment with a median time to the first appearance of 7 to 8 weeks. Of the patients who experienced cuSCC, approximately 33% experienced > 1 occurrence with median time between occurrences of 6 weeks. Cases of cuSCC were typically managed with simple excision, and patients generally continued on treatment without dose modification (see sections 4.2 and 4.4).

Non-cutaneous squamous cell carcinoma (non-cuSCC)

Cases of non-cuSCC have been reported in patients receiving vemurafenib while enrolled in clinical trials. Surveillance for non-cuSCC should occur as outlined in section 4.4.

New primary melanoma

New primary melanomas have been reported in clinical trials. These cases were managed with excision, and patients continued treatment without dose adjustment. Monitoring for skin lesions should occur as outlined in section 4.4.

Hypersensitivity reactions (d)

Serious hypersensitivity reactions, including anaphylaxis have been reported in association with vemurafenib. Severe hypersensitivity reactions may include Stevens-Johnson syndrome, generalised rash, erythema or hypotension. In patients who experience severe hypersensitivity reactions, vemurafenib treatment should be permanently discontinued (see section 4.4).

Dermatologic Reactions (e)

Severe dermatologic reactions have been reported in patients receiving vemurafenib, including rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis in the pivotal clinical trial. In patients who experience a severe dermatologic reaction, vemurafenib treatment should be permanently discontinued.

QT prolongation

Analysis of centralised ECG data from an open-label uncontrolled phase II QT sub-study in 132 patients dosed with vemurafenib 960 mg twice daily (NP22657) showed an exposure-dependent QTc prolongation. The mean QTc effect remained stable between 12-15 ms beyond the first month of treatment, with the largest mean QTc prolongation (15.1 ms; upper 95% CI: 17.7 ms) observed within the first 6 months (n=90 patients). Two patients (1.5%) developed treatment-emergent absolute QTc values >500 ms (CTC Grade 3), and only one patient (0.8%) exhibited a QTc change from baseline of >60 ms (see section 4.4).

Special populations

Older people

In the phase III study, ninety-four (28%) of 336 patients with unresectable or metastatic melanoma treated with vemurafenib were ≥ 65 years. Older patients (≥ 65 years) may be more likely to experience adverse reactions, including cuSCC, decreased appetite, and cardiac disorders.

Gender

During clinical trials with vemurafenib, grade 3 adverse reactions reported more frequently in females than males were rash, arthralgia and photosensitivity.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicina