Drug Formulary information is intended for use by healthcare professionals. It is not intended to be medical advice. Some of the information, including information about funding for cancer drugs, does not apply to all patients. Cancer treatment plans are unique to each patient. If you are a patient, please speak with your healthcare team to understand how this information applies to you.
DABR
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 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma.
Not funded by EAP in patients who have progressed on prior BRAF inhibitor treatment. Treatment beyond third line will not be considered for funding. Brain metastases (if present) should be asymptomatic or stable. Refer to EAP funding criteria details.
daBRAFenib
Exceptional Access Program (daBRAfenib - As monotherapy for the treatment of patients with BRAF V600 mutation-positive unresectable melanoma or metastatic disease, according to specific criteria) (EAP Website)
Minimal – No routine prophylaxis; PRN recommended
Also refer to CCO Antiemetic Recommendations.
Other Supportive Care:
Prophylaxis with antipyretics +/- oral corticosteroids may be required if prior severe febrile reactions with dabrafenib.
Doses should be modified according to the protocol by which the patient is being treated.
A validated test is required to identify BRAF V600 mutation status.
Dosage with toxicity
| Dose Level | Dabrafenib Dose (mg BID) |
| 0 | 150 |
| -1 | 100 |
| -2 | 75 |
| -3 | 50 |
| -4 | Discontinue |
Recommended dose modifications for monotherapy and combination therapy with trametinib:
Toxicity | Dabrafenib Dose |
| ↓ LVEF below LLN and > 20% decrease from baseline | Hold until resolution, then restart at the same or reduced dose level.
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| Symptomatic cardiac failure | Hold until resolution, then restart at the same or reduced dose level.
|
Fever of 38.5-40°C without complications | Hold until resolution; monitor creatinine and for signs and symptoms of infection. Restart at same dose or by ↓ 1 dose level. Prophylaxis with antipyretics +/- oral corticosteroids may be required if prior severe febrile reactions. |
Fever > 40°C or any fever with complications due to rigors, hypotension, dehydration or renal failure | Monitor creatinine and for signs and symptoms of infection. Discontinue. OR Hold until ≤ Grade 1, then restart by ↓ 1 dose level. Prophylaxis with antipyretics +/- oral corticosteroids may be required if prior severe febrile reactions. |
| Intolerable Grade 2 or ≥ Grade 3 rash | Hold until ≤ Grade 1, then restart by ↓ 1 dose level. |
| Intolerable Grade 2 or ≥ Grade 3 rash that does not improve within 3 weeks of holding treatment | Discontinue. |
| Uveitis that responds to local ocular therapies | Continue treatment without dose modifications and monitor. |
| Uveitis that does not improve despite local ocular therapy | Hold until resolved, then restart by ↓ 1 dose level. |
Pancreatitis | Hold until resolved, then restart by ↓ 1 dose level; monitor carefully. |
Cutaneous squamous cell carcinoma or new primary melanoma | No dose modification or interruptions recommended. |
| RAS associated malignancy | Consider risk benefit before making decision to continue treatment. |
| Severe cutaneous adverse reactions (e.g. Stevens-Johnson syndrome, DRESS) | Discontinue. |
Other Grade 1 or tolerable Grade 2 | No change; monitor. |
Other Grade 2 (intolerable) or Grade 3 | Hold until ≤ Grade 1, then restart by ↓ 1 dose level. |
Other Grade 4 or Grade 3 that does not improve to ≤ Grade 1 | Discontinue OR Hold until ≤ Grade 1, then restart by ↓ 1 dose level. |
Hepatic Impairment
Hepatic metabolism and biliary secretion are the main routes of dabrafenib elimination; hepatic impairment may lead to increased exposure and toxicities. Population pharmacokinetics in mild hepatic impairment suggest no dose adjustment is required, but no data are available for moderate to severe hepatic impairment.
| Hepatic Impairment | Dabrafenib Dose |
| Mild | No dose adjustment required. |
| Moderate | No data. |
| Severe | No data. |
Renal Impairment
There are no clinical data in patients with severe renal impairment. With mild to moderate impairment, population pharmacokinetics suggest that no adjustments are required.
| Creatinine Clearance (mL/min) | Dabrafenib Dose |
| 30-89 | No dose adjustment needed. |
| < 30 | No data found. Use with caution. |
Dosage in the Elderly
No dose adjustment required. In unresectable or metastatic melanoma, more serious adverse events were observed in elderly patients (≥ 65 years); peripheral edema and decreased appetite were reported more frequently.
Dosage based on ethnicity:
Dabrafenib clearance is similar in Asian and Caucasian cancer patients with similar liver function.
Children:
Not recommended for use inf children and adolescents < 18 years of age; safety and efficacy have not been established in this population. Adverse growth effects and renal toxicity have been observed in developing animals.
Refer to dabrafenib drug monograph(s) for additional details of adverse effects.
Common (25-49%) | Less common (10-24%) | Uncommon (< 10%), but may be severe or life-threatening |
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Refer to daBRAFenib drug monograph(s) for additional details.
- Avoid strong CYP3A4 & CYP2C8 inducers due to ↓ dabrafenib concentration and/or efficacy.
- Avoid strong CYP3A4 & CYP2C8 inhibitors due to ↑ dabrafenib and metabolite exposure and/or toxicity.
- Avoid hormonal contraceptives as dabrafenib can decrease their efficacy.
- Avoid other drugs that prolong QTc due to increased risk of QT prolongation.
- Dabrafenib can ↓ substrate concentration of CYP2B6, 2C8, 2C9, 2C19, UGTs and Pgp; use alternate medications if possible or monitor for efficacy.
Refer to daBRAFenib drug monograph(s) for additional details.
Administration
- Dabrafenib doses should be given approximately 12 hours apart on an empty stomach, at least 1 hour before or 2 hours after a meal.
- Capsules should be swallowed whole with a full glass of water.
- If a dose is missed and it is less than 6 hours until the next dose, skip it and give the next dose as scheduled. Do not give extra doses to make up for a missed dose.
- Grapefruit, starfruit, Seville oranges, their juices or products should be avoided during treatment.
- Store at room temperature (15-30°C).
Contraindications
- Patients who have a hypersensitivity to this drug or any of its components
Warnings/Precautions
- Dabrafenib should not be used in patients with BRAF wild-type or unknown disease. BRAF mutation must be confirmed using a validated test before starting dabrafenib treatment. Phase II studies reported fewer responses in BRAF V600K patients compared to BRAF V600E patients.
- Dabrafenib monotherapy has not been studied in patients who have had previous treatment with BRAF inhibitors.
- Exercise caution in patients with risk factors for QT prolongation or Torsades de pointes (low potassium/magnesium, congenital QT prolongation, or history of arrhythmia, CHF, anti-arrhythmics, other QTc prolonging agents, prior anthracyclines), diabetes, autonomic neuropathy.
- Patients were excluded from clinical trials if they had abnormal heart valve morphology ≥ grade 2.
- Monitor for hemolytic anemia in patients with G6PD deficiency as dabrafenib contains a sulfonamide moiety.
Pregnancy/Lactation
- Dabrafenib is not recommended for use in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 2 weeks after the last dose when given as monotherapy.
- Efficacy of hormonal contraceptives is likely to be decreased; use effective alternative methods of contraception.
- Breastfeeding is not recommended.
- Fertility effects: Likely
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
Recommended Clinical Monitoring
Liver function tests; Baseline and every 1 to 2 months
Renal function tests and electrolytes, including phosphate; Baseline, every 1 to 2 months, during and after febrile events
Skin examination for cutaneous squamous cell carcinoma and new primary melanoma; Baseline, every 2 months during treatment, continue every 2-3 months for 6 months after the last dose
Non-cutaneous malignancies; Baseline, periodic or as clinically indicated during treatment, up to 6 months after the last dose
Blood glucose; Baseline, every 1 to 2 months, more regularly (at each visit) in patients with diabetes or hyperglycemia
Blood pressure; Baseline and as clinically indicated
Clinical toxicity assessment for febrile events, pancreatitis, musculoskeletal pain, ocular, dermatologic and cardiac effects, hypersensitivity; At each visit
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
Suggested Clinical Monitoring
- INR for patients receiving warfarin; Baseline and as clinically indicated
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Dabrafenib drug monograph. Ontario Health (Cancer Care Ontario).
Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2012 Jul 28;380(9839):358-65.
Long GV, Trefzer U, Davies MA, et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol 2012;13(11):1087-95.
June 2021 Updated rationale and uses, drug administration and special precautions, dose modifications 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.