Loading…
Zelboraf is a brand name for Vemurafenib. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: Vemurafenib is indicated in monotherapy for the treatment of adult patients with BRAF V600 mutation- positive unresectable or metastatic melanoma (see section 5.1).
Verbatim from this product's EMA label. Tap a section to expand.
Treatment with vemurafenib should be initiated and supervised by a qualified physician experienced in the use of anticancer medicinal products. 1). Posology The recommended dose of vemurafenib is 960 mg (4 tablets of 240 mg) twice daily (equivalent to a total daily dose of 1,920 mg).
2). Duration of treatment Treatment with vemurafenib should continue until disease progression or the development of unacceptable toxicity (see tables 1 and 2 below). Missed doses If a dose is missed, it can be taken up to 4 hours prior to the next dose to maintain the twice daily regimen.
Both doses should not be taken at the same time. Vomiting In case of vomiting after vemurafenib administration the patient should not take an additional dose of the medicinal product but the treatment should be continued as usual. 3 Posology adjustments Management of adverse drug reactions or QTc prolongation may require dose reduction, temporary interruption and/or treatment discontinuation (see tables 1 and 2).
Posology adjustments resulting in a dose below 480 mg twice daily are not recommended. 8).
Table 1:
Dose modification schedule based on the grade of any Adverse Events (AEs) Grade (CTC-AE) (a) Recommended dose modification Grade 1 or Grade 2 (tolerable) Maintain vemurafenib at a dose of 960 mg twice daily. Grade 2 (intolerable) or Grade 3 1st occurrence of any grade 2 or 3 AE Interrupt treatment until grade 0 – 1.
Resume dosing at 720 mg twice daily (or 480 mg twice daily if the dose has already been lowered). 2nd occurrence of any grade 2 or 3 AE or persistence after treatment interruption Interrupt treatment until grade 0 – 1. Resume dosing at 480 mg twice daily (or discontinue permanently if the dose has already been lowered to 480 mg twice daily).
3rd occurrence of any grade 2 or 3 AE or persistence after 2nd dose reduction Discontinue permanently. Grade 4 1st occurrence of any grade 4 AE Discontinue permanently or interrupt vemurafenib treatment until grade 0 – 1. Resume dosing at 480 mg twice daily (or discontinue permanently if the dose has already been lowered to 480 mg twice daily).
2nd occurrence of any grade 4 AE or persistence of any grade 4 AE after 1st dose reduction Discontinue permanently. 0 (CTC-AE). Exposure-dependent QT prolongation was observed in an uncontrolled, open-label phase II study in previously treated patients with metastatic melanoma.
Summary of the safety profile The most common adverse drug reactions (ADR) of any grade (> 30%) reported with vemurafenib include arthralgia, fatigue, rash, photosensitivity reaction, alopecia, nausea diarrhea, headache, pruritus, vomiting, skin papilloma and hyperkeratosis.
The most common (≥ 5%) Grade 3 ADRs were cuSCC, keratoacanthoma, rash, arthralgia and gamma-glutamyltransferase (GGT) increased. CuSCC 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.
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 percentage observed among phase II and phase III clinical trials. 0 (common toxicity criteria) for assessment of toxicity.
11 Table 3: ADRs occurring in patients treated with vemurafenib in the phase II or phase III studyand events originating from safety reports across all trials(1) and post-marketing sources(2). System organ class Very Common Common Uncommon Rare Infections and infestations Folliculitis Neoplasms benign, malignant and unspecified (including cysts and polyps) SCC of the skin(d), keratoacanthoma, seborrhoeic keratosis, skin papilloma Basal cell carcinoma, new primary melanoma(3) Non-cuSCC(1)(3) Chronic myelomonocytic leukaemia(2)(4), pancreatic adenocarcinoma( 5) Blood and lymphatic system disorders Neutropenia, thrombocytopenia (6) Immune System Disorders Sarcoidosis(1)(2)(j) Metabolism and nutrition disorders Decreased appetite Nervous system disorders Headache, dysgeusia, dizziness 7th nerve paralysis, neuropathy peripheral Eye disorders Uveitis, Retinal vein occlusion, iridocyclitis Vascular disorders Vasculitis Respiratory, thoracic and mediastinal disorders Cough Gastrointestinal disorders Diarrhoea, vomiting, nausea, constipation Stomatitis Pancreatitis(2) Hepatobiliary disorders Liver injury(1)(2)(g) Skin and subcutaneous tissue disorders Photosensitivity reaction, actinic keratosis, rash, rash maculo- papular, pruritus, hyperkeratosis, erythema, palmar- plantar erythrodysaesthesi a syndrome, alopecia, dry skin, sunburn Rash papular, panniculitis (including erythema nodosum), keratosis pilaris Toxic epidermal necrolysis(e), Stevens-Johnson syndrome(f) Drug reaction with eosinophilia and systemic symptoms(1)(2) 12 System organ class Very Common Common Uncommon Rare Musculoskeletal and connective tissue disorders Arthralgia, myalgia, pain in extremity, musculoskeletal pain, back pain Arthritis, Plantar fascial fibromatosis(1)(2) Dupuytren’s contracture(1)(2) Renal and urinary disorders Acute interstitial nephritis(1)(2)(h), acute tubular necrosis(1)(2)(h) General disorders and administration site conditions Fatigue, pyrexia, oedema peripheral, asthenia Investigations ALT increased(c), alkaline phosphatase increased(c), AST increased(c), bilirubin increased(c) GGT increased(c), weight decreased, electrocardiogram QT prolonged, blood creatinine increased(1)(2)(h) Injury, Poisoning, and Procedural Complications Potentiation of Radiation toxicity (1)(2)(i) (1) Events originating from safety reports across all trials (2) Events originating from post-marketing sources.
4. Resume dosing at 720 mg twice daily (or 480 mg twice daily if the dose has already been lowered). 2nd occurrence of QTc>500 ms during treatment and change from pre-treatment value remains <60 ms Temporarily interrupt treatment until QTc decreases below 500 ms.
4. Resume dosing at 480 mg twice daily (or discontinue permanently if the dose has already been lowered to 480 mg twice daily). 3rd occurrence of QTc>500 ms during treatment and change from pre-treatment value remains <60 ms Discontinue permanently.
Special population Elderly No special dose adjustment is required in patients aged > 65 years old. Renal impairment Limited data are available in patients with renal impairment. A risk for increased exposure in patients with severe renal impairment cannot be excluded.
2). Hepatic impairment Limited data are available in patients with hepatic impairment. 2). Paediatric population The safety and efficacy of vemurafenib in children less than 18 years old have not been established. 2, but no recommendation on a posology can be made.
Non-Caucasian patients The safety and efficacy of vemurafenib has not been established in non-Caucasian patients. No data are available. Method of administration Vemurafenib is for oral use. The tablets are to be swallowed whole with water.
They should not be chewed or crushed. 1. 4 Special warnings and precautions for use Before taking vemurafenib, patients must have BRAF V600 mutation-positive tumour status confirmed by a validated test. 1). Vemurafenib should not be used in patients with wild type BRAF malignant melanoma.
8). 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.
Dermatologic reactions 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. 8). In patients who experience a severe dermatologic reaction, vemurafenib treatment should be permanently discontinued.
1. 5
Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
Know a brand we are missing in European Union? Suggest a brand →
Brand names are compiled from public regulatory records for active-ingredient mapping only. Drugvu is not affiliated with any manufacturer. This is not medical advice.
4). 4 Table 2: Dose modification schedule based on prolongation of the QT interval QTc value Recommended dose modification QTc>500 ms at baseline Treatment not recommended. QTc increase meets values of both >500 ms and >60 ms change from pre-treatment values Discontinue permanently.
1st occurrence of QTc>500 ms during treatment and change from pre-treatment value remains <60 ms Temporarily interrupt treatment until QTc decreases below 500 ms. See monitoring measures in section
(3) A causal relationship between the medicinal product and the adverse event is at least a reasonable possibility. (4) Progression of pre-existing chronic myelomonocytic leukaemia with NRAS mutation. (5) Progression of pre-existing pancreatic adenocarcinoma with KRAS mutation.
(6) Calculated based on phase II and phase III studies. Description of selected adverse reactions Hepatic enzyme increase (c) Liver enzyme abnormalities reported in the phase III clinical study are expressed below as the proportion of patients who experienced a shift from baseline to a grade 3 or 4 liver enzyme abnormalities: ● Very common: GGT ● Common: ALT, alkaline phosphatase, bilirubin ● Uncommon: AST There were no increases to Grade 4 ALT, alkaline phosphatase or bilirubin.
Liver injury (g) Based on the criteria for drug induced liver injury developed by an international expert working group of clinicians and scientists, liver injury was defined as any one of the following laboratory abnormalities: ● ≥ 5x ULN ALT ● ≥ 2x ULN ALP (without other cause for ALP elevation) ● ≥ 3x ULN ALT with simultaneous elevation of bilirubin concentration > 2x ULN 13 Cutaneous squamous cell carcinoma (d) (cuSCC) 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%).
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 […]
Potentiation of radiation toxicity Cases of radiation recall and radiation sensitization have been reported in patients treated with radiation either prior, during, or subsequent to vemurafenib treatment. 8). Vemurafenib should be used with caution when given concomitantly or sequentially with radiation treatment.
8). QT prolongation may lead to an increased risk of ventricular arrhythmias including Torsade de Pointes. Treatment with vemurafenib is not recommended in patients with uncorrectable electrolyte abnormalities (including magnesium), long QT syndrome or who are taking medicinal products known to prolong the QT interval.
Electrocardiogram (ECG) and electrolytes (including magnesium) must be monitored in all patients before treatment with vemurafenib, after one month of treatment and after dose modification. Further monitoring is recommended in particular in patients with moderate to severe hepatic impairment monthly during the first 3 months of treatment followed by every 3 months thereafter or more often as clinically indicated.
Initiation of treatment with vemurafenib is not recommended in patients with QTc>500 milliseconds (ms). g. congestive heart failure, bradyarrhythmias) should be controlled. Re-initiation of treatment should occur once the QTc decreases below 500 ms and at a lower dose as described in table 2.
Permanent discontinuation of vemurafenib treatment is recommended if the QTc increase meets values of both >500 ms and >60 ms change from pre-treatment values. Ophthalmologic reactions Serious ophthalmologic reactions, including uveitis, iritis and retinal vein occlusion, have been reported.
Monitor patients routinely for ophthalmologic reactions. 8). 6 It is recommended that all patients receive a dermatologic evaluation prior to initiation of therapy and be monitored routinely while on therapy. Any suspicious skin lesions should be excised, sent for dermatopathologic evaluation and treated as per local standard of care.
The prescriber should examine the patient monthly during and up to six months after treatment for cuSCC. In patients who develop cuSCC, it is […]