Vemurafenib (Zelboraf ) BRAF V600 mutation positive Metastatic Melanoma

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1 Vemurafenib (Zelboraf ) BRAF V600 mutation positive Metastatic Melanoma Background: Vemurafenib has been approved by NICE for the treatment of BRAF V600 mutation positive unresectable or metastatic melanoma. Patient Group: Unresectable or metastatic melanoma stage IIIc or IV Positive for BRAF V600 mutation Electrolytes must be corrected prior to treatment QTc < 500 ms at baseline PS 0-2 Pre-treatment Assessment: Weight, FBC, U&E, LFTs and Creatinine clearance BRAF V600E status ECG Electrolyte abnormalities must be corrected prior to treatment with Vemurafenib. Referral and assessment by Dermatologist CT Scan Treatment Threshold WBC 3 x 10 9 /L ANC 1.0 x 10 9 /L Platelets 100 x10 9 /L Regimen Details: Vemurafenib 960mg orally Twice a Day (12 hours apart) continuously Tablets should be swallowed whole with water. Vemurafenib tablets should not be chewed or crushed. To be continued until disease progression or unacceptable toxicity. Administration: Each dose in the morning/evening should always be taken in the same manner i.e. either with or without a meal. Page1

2 Vemurafenib tablets are to be swallowed whole with water. Vemurafenib tablets should not be chewed or crushed. Anti-emetics: Low emetogenicity. Metoclopramide PO 10-20mg TDS PRN. Additional Medication: Sunblock SPF >30 and emollients. Monitoring and Assessment: Physical examination and clinical assessment - every 28 days during treatment and for 6 months after treatment has stopped. FBC, U&E, LFT every 28 days ECG after one month and then after each dose change. Eye examination Dermatological assessment should be assessed regularly and any suspicious lesions excised. Monitoring continued for 6 months after treatment is discontinued. CT scan every 3 months during the treatment and as clinically indicated. Dose Modifications: In the event the patient develops Cutaneous Squamous Cell Carcinoma (cuscc), it is recommended to continue the treatment without modifying the dose of Vemurafenib. Dose modification schedule based on the grade of any Adverse Event Toxicity Grade 1 or 2 (tolerable) Adverse Event (AE) Recommended Dose Maintain dose of Vemurafenib Grade 2 (intolerable) or 3 1 st Occurrence 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). 2 nd occurrence of any grade 2 or 3 AE or persistence after treatment interruption 3 rd occurrence of any grade 2 or 3 AE or persistence after 2 nd dose reduction Interrupt treatment until grade 0 1. Grade 4 1 st occurrence of any grade 4 AE or interrupt vemurafenib treatment until grade 0 1. Page2

3 2 nd occurrence of any grade 4 AE or persistence of any grade 4 AE after 1 st dose reduction Dose modification schedule based on prolongation of the QT interval QTc Value Recommended Dose QTc >500 ms at baseline Treatment not recommended QTc increase meets values of both > 500 ms and >60 ms change from pre-treatment values 1 st occurrence of QTc>500 ms during treatment and change from pre-treatment value remains <60 ms 2 nd occurrence of QTc>500 ms during treatment and change from pre-treatment value remains <60ms 3 rd occurrence of QTc>500 ms during treatment and change from pre-treatment value remains <60ms Temporarily interrupt treatment until QTc decreases below 500 ms. Resume dosing at 720 mg twice daily (or 480 mg twice daily if the dose has already been lowered). Temporarily interrupt treatment until QTc decreases below 500 ms. Renal Impairment Vemurafenib should be used with caution in patients with severe renal impairment and patients should be closely monitored. Hepatic Impairment Limited data are available in patients with hepatic impairment. As Vemurafenib is cleared by the liver, patients with moderate to severe hepatic impairment may have increased exposure and should be closely monitored. Page3

4 Pharmaceutical Care: Supply SPF >30 and loperamide and emollients at first cycle and then as necessary. Patients should be advised to wear protective clothing and use a broad spectrum Ultraviolet A (UVA)/Ultraviolet B (UVB) sunscreen and lip balm (Sun Protection Factor 30) when outdoors to help protect against sunburn. Monitor INR regularly in patients also taking warfarin (and other coumarin-derived anticoagulants). Vemurafenib may decrease the plasma concentration of the combined oral contraceptive pill. Avoid co-prescribing with rifampicin, rifabutin, carbamazepine, phenytoin, St John s wort as these drugs are likely to give rise to markedly reduced plasma concentrations of vemurafenib. Avoid concomitant use of verapamil, clarithromycin, cyclosporine, ritonavir, quinidine, dronedarone, amiodarone, itraconazole, ranolazine. ECG monitoring recommended if the patient is taking medication that is known to prolong the QT interval. 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. 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. Most Common Toxicities: Cutaneous Squamous Cell Carcinoma QT prolongation Serious eye reactions uveitis, iritis and retinal vein occlusion Hypersensitivity reactions Non-cutaneous Squamous Cell Carcinoma Photosensitivity Headache Fatigue Nausea and vomiting Diarrhoea Cough Decreased appetite Arthralgia, myalgia LFTs Page4

5 Rash, pruritus Palmar-plantar erythema Alopecia References: 1. SPC Vemurafenib (Zelboraf). Roche Products LTD. [accessed 18 th September 2012] 2. NICE Technology Appraisal 269. Vemurafenib for treating locally advanced or metastatic BRAF V600 mutation-positive malignant melanoma. [accessed 6 th February 2013] Page5