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VEMU
Regimen is considered appropriate as part of the standard care of patients; meaningfully improves outcomes (survival, quality of life), tolerability or costs compared to alternatives (recommended by the Disease Site Team and national consensus body e.g. pan-Canadian Oncology Drug Review, pCODR). Recommendation is based on an appropriately conducted phase III clinical trial relevant to the Canadian context OR (where phase III trials are not feasible) an appropriately sized phase II trial. Regimens where one or more drugs are not approved by Health Canada for any indication will be identified under Rationale and Use.
For the treatment of BRAF V600 mutation-positive unresectable Stage 3 or 4 melanoma. Brain metastases, if present, should be asymptomatic or stable
Data supporting use with BRAF mutations other than V600E are limited.
vemURAFenib
Exceptional Access Program
(vemURAFenib - Monotherapy in patients with BRAF V600 mutation-positive unresectable stage Ill or stage IV melanoma, with specific criteria)
(EAP Website)
CONTINUOUS TREATMENT
Until disease progression, no evidence of further response, or unacceptable toxicity.
Minimal – No routine prophylaxis; PRN recommended
- Also refer to CCO Antiemetic Recommendations.
Screen for hepatitis B virus in all cancer patients starting systemic treatment. Refer to the hepatitis B virus screening and management guideline.
Other Supportive Care:
- Patients should be advised to avoid sun exposure and use sunscreen.
Doses should be modified according to the protocol by which the patient is being treated.
Only patients with BRAF V600 mutations identified by a validated test should be treated. Data supporting effectiveness in patients with BRAF mutations other than V600E are limited.
Patients with QTc > 500 ms at baseline should not be treated.
Dosage with toxicity
Dose levels:
| Dose Level | Vemurafenib Dose |
| 0 | 960 mg BID |
| -1 | 720 mg BID |
| -2 | 480 mg BID |
| -3 | Discontinue |
Dose modifications are not recommended for cutaneous squamous cell carcinoma.
Table A
|
Toxicity / Grade* |
Occurrence |
Recommendation |
|
Grade 1 or Grade 2 (tolerable) |
Any |
No change |
|
Grade 2 (Intolerable) or Grade 3, including photosensitivity |
1st |
Hold until ≤ grade 1, then restart with 1 dose level ↓ |
| 2nd |
Hold until ≤ grade 1, then restart with 1 additional dose level ↓ |
|
| 3rd |
Discontinue |
|
| Grade 4 | 1st |
Discontinue permanently for skin reactions or hypersensitivity or other life-threatening organ toxicity. If other toxicity, discontinue OR hold until ≤ grade 1, then restart with 2 dose level ↓ |
| 2nd |
Discontinue |
|
| Hepatotoxicity** | Any | Consider temporary hold, dose reduction or discontinuation |
| Pancreatitis | Any | Hold, then consider restart with 1 dose level ↓ |
| DRESS syndrome, Stevens-Johnson syndrome, Toxic epidermal necrolysis | Any | Discontinue permanently |
* Graded by the Common Terminology Criteria for Adverse Events v4.0 (CTC-AE)
** Defined as ALT ≥ 3 x ULN plus bilirubin ≥ 2 x ULN, or ALT ≥ 5 x ULN, or ALP ≥ 2 x ULN (without bone pathology)
Table B:
QT Prolongation:
|
Criteria |
Occurrence |
Action |
|
QTc > 500 ms and > 60 ms increase from baseline |
Any |
Discontinue permanently |
| QTc > 500 ms during treatment and ≤ 60 ms increase from baseline | 1st | Hold until QTc < 500 ms. Resume with 1 dose level ↓ |
| 2nd | Hold until QTc < 500 ms. Resume with 1 additional dose level ↓ | |
| 3rd | Discontinue permanently |
Hepatic Impairment
Hepatic impairment may result in higher vemurafenib exposure and related adverse effects. Refer to Table A for management of hepatic impairment during treatment.
|
Hepatic Impairment |
Bilirubin |
Starting Dose |
|
Mild |
> 1 to 1.5 x ULN |
100%, caution |
|
Moderate |
> 1.5 to 3 x ULN |
100%, caution |
|
Severe |
> 3 x ULN |
No data |
Renal Impairment
The appropriate dose has not been established in severe renal impairment. Refer to Table A for dose modifications with renal toxicity.
Dosage in the Elderly
Elderly patients (≥ 65 years) are at greater risk of experiencing side effects such as cuSCC, decreased appetite and cardiac effects. No adjustment to starting dose is indicated.
Refer to vemurafenib drug monograph(s) for additional details of adverse effects.
|
Very common (≥ 50%) |
Common (25-49%) |
Less common (10-24%) |
Uncommon (< 10%), but may be severe or life-threatening |
|
|
|
|
Refer to vemurafenib drug monograph(s) for additional details.
- Avoid strong CYP3A4 inducers or inhibitors, if possible. If vemurafenib is co-administered with strong CYP3A4 inhibitors, vemurafenib dose reduction may be required.
- Avoid concurrent use with CYP1A2 substrates with a narrow therapeutic range, and consider dose modification if they must be used together.
- Drugs that have been associated with QTc interval prolongation and/or torsade de pointes should not be administered with vemurafenib, if possible.
Refer to vemurafenib drug monograph(s) for additional details
Administration:
- The daily doses should be given in the morning and in the evening, around 12 hours apart.
- May be administered with or without food (but administration in relation to food should be consistent).
- Film-coated tablet should be swallowed whole with a glass of water; do not crush or split.
- Avoid grapefruit, starfruit, Seville oranges, their juices or products during treatment.
- Avoid excessive caffeine as this may increase side effects (refer to interactions).
- If vomiting occurs after taking a dose, do not take an additional dose. Continue to take the next dose as scheduled.
- If a dose is missed, it may be given if there are more than 4 hours before the next dose. Otherwise, skip this dose and give the next one as scheduled. Never give both doses at the same time.
- Store between 15-30°C, in the original package; protect from moisture.
Contraindications:
- Patients who have a hypersensitivity to this drug or any of its components
Warnings/Precautions:
- Vemurafenib should not be used in patients with baseline QTc > 500 ms, with wild-type BRAF tumours or where the BRAF mutation status is unknown.
- Consider benefits vs risks of starting vemurafenib in these patients:
- Patients with uncontrolled hypertension (excluded from clinical trials)
- Concurrent use with radiation therapy (possible severe/fatal radiation sensitization and radiation recall reaction).
- Caution in patients with increased QT interval or who are at risk (low potassium/magnesium, congenital QT prolongation, or history of arrhythmia, CHF, anti-arrhythmics, other QTc prolonging agents, prior anthracyclines), diabetes, autonomic neuropathy.
- Caution in patients with prior or concurrent cancers, especially those associated with RAS mutation.
- The concurrent use of ipilimumab and vemurafenib is not recommended since hepatotoxicity was observed in a clinical trial.
- Secondary malignancies (cutaneous squamous cell carcinoma, non-cutaneous squamous cell carcinoma, primary melanoma) are common - patients must be closely monitored and treated appropriately.
- Caution should be exercised when driving or operating a vehicle or potentially dangerous machinery due to vision problems.
Pregnancy/Lactation
- This regimen is not recommended for use in pregnancy. Adequate contraception should be used by patients and their partners while on treatment and after the last treatment dose. Recommended methods and duration of contraception may differ depending on the treatment. Refer to the drug monograph(s) for more information.
- Breastfeeding is not recommended during this treatment and after the last treatment dose. Refer to the drug monograph(s) for recommendations after the last treatment dose (if available).
- Fertility effects: Unknown
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
Refer to the hepatitis B virus screening and management guideline for monitoring during and after treatment.
Recommended Clinical Monitoring
-
ECG and electrolytes (including potassium, magnesium and calcium, especially in patients with risk factors for QT prolongation); baseline and after dose modification, Day 15, monthly for first 3 months then every 3 months, or more often as clinically indicated
-
Liver function tests; baseline and periodic, monitor closely if abnormal
-
Renal function tests; baseline and periodic, monitor closely if abnormal
-
Blood pressure; baseline and periodic during treatment
-
INR in patients taking warfarin; during initiation of vemurafenib and after dose modification or discontinuation
-
Dermatologic evaluation; baseline and regular, until 6 months after the last dose
-
Chest CT scan (for NCuSCC); baseline and every 6 months, until 6 months after the last dose
-
Head and neck examination (at least a visual inspection of oral mucosa and lymph node palpation, for NCuSCC); baseline and every 3 months, until 6 months after the last dose
-
Pelvic (females) / anal examinations (for NCuSCC); baseline, end of treatment and when clinically indicated, until 6 months after the last dose
-
Clinical toxicity assessment for musculoskeletal, skin, ocular, GI toxicity; At each visit
-
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
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Chapman PB et al. Phase III randomized, open-label, multicenter trial (BRIM3) comparing BRAF inhibitor vemurafenib with dacarbazine (DTIC) in patients with V600EBRAF-mutated melanoma. J Clin Oncol 2011; 29 (suppl; abstr LBA4).
August 2023 Modified Dose Modifications, Dosage in hepatic impairment, Adverse effects, Interactions, Warnings/Precautions, and Monitoring sections
Regimen Abstracts
A Regimen Abstract is an abbreviated version of a Regimen Monograph and contains only top level information on usage, dosing, schedule, cycle length and special notes (if available). It is intended for healthcare providers and is to be used for informational purposes only. It is not intended to constitute or be a substitute for medical advice, and all uses of the Regimen Abstract are subject to clinical judgment. Such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability, and Cancer Care Ontario disclaims all liability for the use of this information, and for any claims, actions, demands or suits that arise from such use.
Information in regimen abstracts is accurate to the extent of the ST-QBP regimen master listings, and has not undergone the full review process of a regimen monograph. Full regimen monographs will be published for each ST-QBP regimen as they are developed.
Regimen Monographs
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.
The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.
Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.
While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.
CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.