Vemurafenib

Dermatologic reactions have been observed, including case reports of Stevens-Johnson syndrome and toxic epidermal necrolysis. Discontinue (permanently) for severe dermatologic toxicity.

Cases of Dupuytren contracture and plantar fascial fibromatosis have been reported with vemurafenib use (Chan 2015; Perez 2017; Vandersleyen 2016). In June of 2017, the vemurafenib manufacturer issued a “Dear Healthcare Provider” letter stating that the majority of cases reported were mild to moderate, although disabling Dupuytren contracture cases have been observed. The median time to onset was 224 days from therapy initiation; the majority of patients experienced symptom resolution or improvement with interruption or discontinuation of vemurafenib (Perez 2017). Per the manufacturer, fibromatoses may require therapy interruption or treatment discontinuation.

Liver injury has been reported with use, and may cause functional impairment such as coagulopathy or other organ dysfunction. Monitor transaminases, alkaline phosphatase, and bilirubin at baseline and monthly during therapy, or as clinically necessary. May require dosage reduction, therapy interruption, or discontinuation.

Anaphylaxis and severe hypersensitivity may occur during treatment or upon reinitiation. Serious reactions have included generalized rash, erythema, hypotension, and drug rash with eosinophilia and systemic symptoms (DRESS syndrome). Discontinue (permanently) with severe hypersensitivity reaction.

Cutaneous squamous cell carcinomas (cuSCC), keratoacanthomas, and melanoma have been reported (at a higher rate in patients receiving vemurafenib compared to control). Cutaneous SCC generally occurs early in the treatment course (median onset: 7 to 8 weeks in melanoma patients and ~12 weeks in Erdheim Chester disease [ECD] patients) and is managed with excision (while continuing vemurafenib treatment). Approximately one-third of melanoma patients experienced >1 cuSCC occurrence and the median time between occurrences was 6 weeks. Potential risk factors for cuSCC include age ≥65 years, history of skin cancer, or chronic sun exposure. Monitor for skin lesions (with dermatology evaluation) at baseline and every 2 months during treatment; consider continued monitoring for 6 months after treatment. In patients receiving vemurafenib for the treatment of melanoma, new primary malignant melanomas have been reported (rare). Noncutaneous squamous cell carcinomas (non-cuSCC) of the head and neck have also been observed; monitor closely for signs/symptoms. Vemurafenib may promote malignancies correlated with RAS activation; monitor for signs/symptoms of other malignancies. Myeloid malignancies in patients with ECD have been reported, including patients receiving vemurafenib; monitor CBC in patients with ECD and co-existing myeloid malignancies.

Acute kidney injury, including interstitial nephritis, acute tubular necrosis, and serum creatinine elevations (grades 1 to 4) have been reported. Monitor serum creatinine.

Uveitis (including iritis), blurred vision, and photophobia may occur; monitor for signs and symptoms. Uveitis may be managed with corticosteroid and mydriatic eye drops. Retinal vein occlusion has been reported in clinical trials.

Pancreatitis has been reported (rare). Onset occurs within 2 weeks after initiation, with exacerbation occurring upon rechallenge at a reduced dose (Muluneh 2013). Consider evaluating unexplained abdominal pain for pancreatitis (eg, serum lipase and amylase; abdominal CT) as clinically indicated.

Photosensitivity ranging from mild to severe has been reported. Advise patients to avoid sun exposure and wear protective clothing and use effective UVA/UVB sunscreen and lip balm (SPF ≥30) when outdoors. Dosage modifications are recommended for intolerable photosensitivity consisting of erythema ≥10% to 30% of body surface area.

QT prolongation (dose-dependent) has been observed; may lead to increased risk for ventricular arrhythmia, including torsade de pointes. Monitor electrolytes (calcium, magnesium and potassium) at baseline and with dosage adjustments. Monitor ECG at baseline, 15 days after initiation, then monthly for 3 months, then every 3 months thereafter (more frequently if clinically appropriate); also monitor with dosage adjustments. Do not initiate treatment if baseline QTc >500 msec. During treatment, if QTc >500 msec, temporarily interrupt treatment; correct electrolytes and control other risk factors for QT prolongation. May reinitiate with a dose reduction once QTc falls to 500 msec and there is >60 msec change above baseline. Do not initiate treatment in patients with electrolyte abnormalities which are not correctable, long QT syndrome, or taking concomitant medication known to prolong the QT interval.

Radiation sensitization and recall (some cases may be severe or involve cutaneous and visceral organs) have been reported in patients treated with radiation prior to, during, or after treatment with vemurafenib; fatal cases have been reported in patients with visceral organ involvement. Monitor closely when vemurafenib is administered concomitantly or sequentially with radiation treatment. Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Special populations:

May be at increased risk for adverse effects; in clinical trials, there was an increased incidence of cuSCC and keratoacanthoma, atrial fibrillation, peripheral edema, and nausea/decreased appetite in patients ≥65 years. Other warnings/precautions:

Only patients with a BRAF V600 mutation-positive melanoma (including BRAF V600E) will benefit from treatment; mutation must be detected and confirmed by an approved test prior to treatment. The cobas 4800 BRAF V600 Mutation Test was used in clinical trials and is FDA-approved to detect BRAF V600E mutation.