Les renseignements du Formulaire de médicaments s’adressent aux professionnels de la santé. Il ne s’agit pas d’un avis médical. Certains des renseignements, y compris ceux sur le financement des médicaments anticancéreux, ne s’appliquent pas à tous les patients. Les plans de traitement du cancer sont propres à chaque patient. Si vous êtes un patient, veuillez parler avec votre équipe soignante pour comprendre comment ces renseignements s’appliquent à vous.
DABRTRAM
Curative
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 adjuvant treatment of patients with resected Stage III cutaneous melanoma with a BRAF V600 mutation
daBRAFenib
Exceptional Access Program
(daBRAfenib - For the adjuvant treatment of resected Stage III cutaneous melanoma according to clinical criteria)
(EAP Website)
trametinib
Exceptional Access Program
(trametinib - For the adjuvant treatment of resected Stage III cutaneous melanoma according to clinical criteria)
(EAP Website)
CONTINUOUS TREATMENT
For 12 months unless disease progression or unacceptable toxicity occurs
Minimal – No routine prophylaxis; PRN recommended
Other Supportive Care:
- Prophylaxis with antipyretics +/- oral corticosteroids may be required if prior severe febrile reactions with dabrafenib.
- Patients should have a supply of loperamide ready in order to start at the first signs of diarrhea.
- Consider a prophylactic skin regimen; one example is:
- avoidance of unnecessary exposure to sunlight
- an SPF ≥30 broad-spectrum sunscreen (containing titanium dioxide or zinc oxide) applied at least twice daily
- a thick, alcohol-free emollient cream applied to dry areas of the body at least twice daily
- Also consider:
- a mild strength topical steroid (e.g. 1% hydrocortisone) applied twice daily x 6 weeks
- doxycycline 100mg bid or minocycline 100mg bid or topical antibiotic x 6 weeks
Also refer to CCO Antiemetic Recommendations.
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 | Trametinib Dose |
| 0 | 150 mg BID | 2 mg DAILY |
| -1 | 100 mg BID | 1.5 mg DAILY |
| -2 | 75 mg BID | 1 mg DAILY |
| -3 | Discontinue | |
|
Toxicity |
Dabrafenib Dose |
Trametinib Dose |
|
Fever of 38.5 to 40°C |
Hold until resolution (no symptoms for ≥ 24 hours*); monitor creatinine and for infection. Restart at same dose or ↓ 1 dose level if associated with dehydration or hypotension. Prophylaxis with antipyretics +/- oral corticosteroids may be required if prior severe febrile reactions. |
Consider hold until resolution (no symptoms for ≥ 24 hours) and restart at same dose*. |
|
Fever > 40°C or any fever with complications due to rigors, hypotension, dehydration or renal failure |
Monitor creatinine and for infection. Discontinue. OR Hold until ≤ Grade 1 and ↓ 1 dose level. Prophylaxis with antipyretics +/- oral corticosteroids may be required if prior severe febrile reactions. |
Hold until recovery and restart at same dose OR ↓ 1 dose level. |
|
Uveitis that responds to local ocular therapies |
Continue treatment without dose modifications and monitor. | Continue trametinib at the same dose. |
|
Uveitis that does not improve despite local ocular therapy |
Hold until resolved and ↓ 1 dose level. | Hold until resolved and resume trametinib at the same dose or ↓ 1 dose level. |
|
Pancreatitis |
Discontinue OR Hold until resolved and then restart ↓ 1 dose level; monitor carefully. |
Continue at same dose. |
| Severe cutaneous adverse reactions (e.g. Stevens-Johnson syndrome, DRESS) | Discontinue. | |
| 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. | |
|
Grade 1 rash |
No dose modification or interruptions recommended. |
Treat symptomatically and continue with same dose. |
|
Grade 2 rash (tolerable) |
No dose modification or interruptions recommended if tolerable. |
Treat symptomatically and ↓ 1 dose level. If no recovery, hold for up to 3 weeks; if recovers restart with a further reduction. If no recovery within 3 weeks, discontinue. |
|
Intolerable Grade 2 or ≥ Grade 3 rash |
Consider discontinuing if Grade 4. Hold until ≤ Grade 1, restart at ↓ 1 dose level. If no recovery within 3 weeks, discontinue. |
Treat symptomatically. Hold until ≤ Grade 2, restart at ↓ 1 dose level. If no recovery within 3 weeks, discontinue. |
|
Grade 1 or Grade 2 diarrhea (uncomplicated) |
No dose modification or interruptions recommended if tolerable. |
Treat symptomatically; may continue at same dose or hold for up to 3 weeks until improved and then restart at same dose. |
|
≥ Grade 3 diarrhea or intolerable or complicated Grade 2 diarrhea |
Consider discontinuing if Grade 4. Hold until ≤ Grade 1, restart at ↓ 1 dose level. |
Treat symptomatically. Hold until resolves to ≤ Grade 1, restart at ↓ 1 dose level. |
|
Grade 2 or Grade 3 retinal pigment epithelial detachment (RPED) |
No dose modification or interruptions recommended. |
Hold and consult ophthalmologist. If resolves to ≤ Grade 1, restart at ↓ 1 dose level. If does not resolve or recurs, discontinue. |
|
Grade 4 RPED, any grade retinal vein occlusion |
No dose modification or interruptions recommended. |
Discontinue and consult ophthalmologist. |
|
Pneumonitis |
Continue at same dose. |
Hold; investigate and treat as appropriate; discontinue if confirmed. |
| Rhabdomyolysis | Hold until stable. | Hold and treat; carefully consider risk-benefit when deciding whether to restart at a reduced dose after recovery. |
| Other Grade 1 or Grade 2 | No dose modification or interruptions recommended if tolerable. | No dose modification or interruptions recommended if tolerable. |
| Other Grade 3 or intolerable Grade 2 |
Hold until ≤ Grade 1 for up to 3 weeks, then restart at ↓ 1 dose level when recovered. If does not recover, discontinue. |
Hold until ≤ Grade 1 for up to 3 weeks, then restart at ↓ 1 dose level when recovered. If does not recover, discontinue. |
| Other Grade 4 | Discontinue or hold until ≤ Grade 1, restart at ↓ 1 dose level. | Discontinue. |
*CCO melanoma disease site group recommendation; refer to Atkinson et al. 2016 for more information.
|
Left Ventricular Ejection Fraction |
Treatment
|
||
|
Action
|
LVEF at Re-assessment |
Dose
|
|
|
Asymptomatic plus LVEF below LLN AND 10-20% ↓ from baseline |
Hold and repeat MUGA or ECHO in 4 weeks.
|
Improves to normal institutional LVEF limits |
Restart trametinib at ↓ 1 dose level. Restart dabrafenib at previous dose. |
|
Does not improve to normal institutional LVEF limits within 4 weeks OR Symptomatic |
Discontinue trametinib.
Consider restarting dabrafenib monotherapy.
|
||
| Symptomatic OR LVEF below LLN and > 20% ↓ from baseline |
Discontinue treatment and consult cardiologist.
|
If recovers |
Discontinue trametinib. Consider restarting dabrafenib monotherapy. |
Hepatic Impairment
| Hepatic Impairment | Dabrafenib and Trametinib Dose |
| Mild | No dose adjustment required. |
| Moderate | No data. |
| Severe | No data. |
Renal Impairment
| Creatinine Clearance (mL/min) | Dabrafenib and Trametinib Dose |
| 30-89 | No dose adjustment required. |
| < 30 | No data; use with caution. |
Dosage in the Elderly
No dose adjustment required. No overall differences in safety and efficacy were observed in elderly patients (≥ 65 years) compared to younger patients.
Refer to dabrafenib, trametinib 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 dabrafenib, trametinib 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.
- Increased risk of QT or PR interval prolongation; avoid other drugs that prolong QTc and monitor when given with drugs that prolong PR interval.
- Dabrafenib can ↓ substrate concentration of CYP2B6, 2C8, 2C9, 2C19, UGTs and Pgp; use alternate medications if possible or monitor for efficacy.
Refer to dabrafenib, trametinib drug monograph(s) for additional details.
Administration: Dabrafenib
- 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).
Administration: Trametinib
- Give on an empty stomach, at least one hour before or 2 hours after a meal.
- When given in combination, trametinib should be administered once daily with either the morning or evening dose of dabrafenib.
- Tablets should be swallowed whole with a glass of water. Do not crush or chew.
- If a dose is missed and it is less than 12 hours until the next dose, skip it and take the next dose at its scheduled time. Do not give extra doses to make up for a missed dose.
- Keep refrigerated at 2-8°C. Do not freeze and protect from light.
- Once opened, the bottle may be stored for 30 days at no more than 30°C.
Contraindications:
- Dabrafenib and trametinib are contraindicated in patients who have a hypersensitivity to these drugs or any of their components.
Warnings/Precautions:
- Dabrafenib and trametinib should only be used in patients with BRAF V600 mutation. BRAF mutation must be confirmed using a validated test before starting treatment.
- Dabrafenib and trametinib should not be used in patients with BRAF V600 mutation who progressed on a prior BRAF inhibitor.
- The incidence and severity of dabrafenib-associated non-infectious febrile events are increased when used in combination.
- Exercise caution in patients with risk factors for QT prolongation or Torsades de pointes (low potassium/magnesium, congenital QT prolongation, history of arrhythmia, CHF, anti-arrhythmic, other QTc prolonging agents, prior anthracyclines), diabetes, autonomic neuropathy.
- Patients were excluded from dabrafenib 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.
- Use combination therapy with caution in patients at risk of bleeding as severe or fatal events have been reported. The risk may be increased with concomitant use of antiplatelet/anticoagulant therapy or in patients who develop brain metastases while on treatment.
- Use of trametinib is not recommended in patients with decreased LVEF at baseline. Exercise caution in patients with conditions that can impair left ventricular function, with pre-existing conduction disorders, a history of syncope of unknown etiology and medications that can result in PR prolongation.
- Use of trametinib is not recommended in patients with a history of retinal vein occlusion. Exercise caution in patients with risk factors for retinal vein occlusion such as diabetes, hypertension, hypercholesterolemia and glaucoma.
- Use with caution in patients with a history of diverticulitis, metastases to the GI tract and concomitant use of other medications with a risk of GI perforation.
Pregnancy and Lactation:
- Dabrafenib and trametinib are not recommended for use in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 16 weeks after the last dose of treatment.
- 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
-
CBC; Baseline and at each visit
-
Liver function tests; Baseline and every 4 weeks for 6 months, therafter every 1 to 2 months
-
Renal function tests and electrolytes (including phosphate); Baseline, at each visit and during febrile events
-
Blood glucose; Baseline and every 1 to 2 months, more regularly (at each visit) in patients with diabetes or hyperglycemia
-
Blood pressure; Baseline and at each visit.
-
LVEF; Baseline, as indicated within 8 weeks of starting treatment, then as clinically indicated
-
Ophthalmological evaluation; Baseline and as clinically indicated
-
Skin examination for cutaneous squamous cell carcinoma, new primary melanoma; Baseline, every 2 months during treatment, then continue 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
-
Skin, nail toxicity and secondary infections; 2 weeks after initiating treatment, then as clinically indicated
-
Clinical toxicity assessment for fever, diarrhea and other GI effects, pancreatitis, edema, cardiac effects, ocular effects, thromboembolism, bleeding, inflammatory effects, neurologic events, hypersensitivity, rhabdomyolysis, pneumonitis; 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 at each visit
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Atkinson A, Long GV, Menzies AM et al. Optimizing combination dabrafenib and trametinib therapy in BRAF mutation-positive advanced melanoma patients: Guidelines from Australia melanoma medical oncologists. Asia-Pacific Journal of Clinical Oncology. 2016; 12(Suppl.7):5-12.
Dabrafenib and trametinib drug monographs. Ontario Health (Cancer Care Ontario).
Long GV et al. Adjuvant dabrafenib plus trametinib in stage 3 BRAF-mutated melanoma. N Engl J Med 2017;377:1813-23.
June 2021 Expanded to full regimen monograph
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.
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