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.
TRAM
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.
trametinib
Exceptional Access Program (trametinib - As monotherapy in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma, according to specific criteria) (EAP Website)
Minimal – No routine prophylaxis; PRN recommended
Other Supportive Care:
- 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)
- a thick, alcohol-free emollient cream applied on dry areas of the body daily
- Also consider:
- a mild strength topical steroid (e.g. 1% hydrocortisone) applied daily
- doxycycline 100mg bid or minocycline 100mg bid or topical antibiotic for the first 2-3 weeks of treatment
Also refer to CCO Antiemetic Recommendations.
A validated test is required to identify BRAF V600 mutation status.
Dosage with toxicity
| Dose Level | Trametinib Dose (mg/day) |
| 0 | 2 |
| -1 | 1.5 |
| -2 | 1 |
| -3 | Discontinue |
| Toxicity | Trametinib Dose |
| Grade 2 rash (tolerable) | Continue treatment with 1 dose level reduction. If does not improve with reduced dose, hold for up to 3 weeks until improves and then restart with a further 1 dose level reduction. Discontinue if no improvement after 3 weeks. |
| Intolerable grade 2 or ≥ grade 3 rash | Hold up to 3 weeks until ≤ grade 1 then ↓ 1 dose level. Discontinue if no recovery within 3 weeks. |
Severe cutaneous adverse reactions (e.g. Stevens-Johnson syndrome, DRESS) | Discontinue. |
| Fever of 38.5 to 40○C (no complications) | Continue at same dose. |
| Fever >40○C or any fever with complications (rigors, hypotension, dehydration, renal failure) | Hold until resolved, then resume at the same dose, or ↓ by one dose level. |
| Grade 1 or uncomplicated grade 2 diarrhea | May continue with same dose. OR Hold up to 3 weeks until improved then restart with the same dose. |
| Grade 3 or 4 diarrhea or complicated Grade 1 or 2 diarrhea | Hold up to 3 weeks until ≤ grade 1 and restart by ↓ 1 dose level. |
| Grade 2 or 3 retinal pigment epithelial detachments (RPED) | Hold up to 3 weeks until ≤ grade 1, then restart by ↓ 1 dose level. Discontinue if no improvement or if it recurs. |
| Grade 4 RPED, Any grade retinal vein occlusion | Discontinue. |
| Uveitis | Use local ocular therapy; if responds, continue dose. If does not improve, hold until resolves then restart at same dose or consider a 1 dose level decrease. |
| Rhabdomyolysis | Hold and manage appropriately. When recovers consider risk – benefit before restarting at a reduced dose; otherwise, discontinue. |
| Pneumonitis | Hold and investigate; if confirmed, discontinue. |
| Other grade 1 and 2 (tolerable) | Continue at the same dose. |
| Other grade 3 or intolerable grade 2 related organ | Hold up to 3 weeks until ≤ grade 1 then ↓1 dose level. Discontinue if no improvement. |
| Other grade 4 related organ | Discontinue. |
Cardiotoxicity:
| Left Ventricular Ejection Fraction | Trametinib | ||
| Action | LVEF at Re-assessment | Dose | |
| Asymptomatic plus LVEF below LLN AND 10-20% ↓ from baseline | Hold and repeat MUGA in 4 weeks | Improves to normal institutional LVEF limits | Restart with ↓ 1 dose level |
Does not improve to normal institutional LVEF limits within 4 weeks OR Symptomatic | Discontinue | ||
| Symptomatic OR LVEF below LLN and > 20% ↓ from baseline | Discontinue | Not applicable | Not applicable |
*LLN = Lower limit of normal
Hepatic Impairment
No formal studies have been conducted. Population pharmacokinetics in patients with mild hepatic impairment showed no significant effects.
| Hepatic Impairment | Bilirubin | AST | Trametinib Dose | |
| Mild | and | > ULN | No dose adjustment required | |
| >1 - 1.5 x ULN | and | Any | ||
| Moderate or Severe | >1.5 x ULN | and | Any | No data |
Renal Impairment
No formal studies have been conducted. Due to the low renal excretion of trametinib, renal impairment is unlikely to have a clinically relevant effect on trametinib pharmacokinetics.
| Creatinine Clearance (mL/min) | Trametinib Dose |
| ≥ 30 | No dose adjustment required |
| < 30 | No data |
Dosage in the Elderly
Elderly patients (≥ 65 years) experienced higher rates of severe events, discontinuation and dose interruptions / reductions than younger patients. No prospective dose adjustment is required. Peripheral edema and decreased appetite were reported more frequently in elderly patients (for both monotherapy and combination treatment).
Refer to 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 |
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Refer to trametinib drug monograph(s) for additional details.
- Trametinib prolongs PR interval and caution should be taken when it is administered with other PR interval-prolonging agents (antiarrhythmics, beta-blockers, non-dihydropyridine Ca channel blockers, digoxin, some HIV protease inhibitors, sphingosine-1 phosphate receptor modulators).
Refer to trametinib drug monograph(s) for additional details.
Administration:
- Give on an empty stomach, at least one hour before or 2 hours after a meal.
- Tablets should be swallowed whole with a glass of water and not crushed or chewed.
- 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:
- Patients who have a hypersensitivity to this drug or any of its components
Warnings/Precautions:
- BRAF mutation must be confirmed using a validated test before starting trametinib treatment.
- Trametinib should not be used in patients with BRAF V600 mutation who progressed on a prior BRAF inhibitor.
- 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:
- Trametinib is 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.
- Breastfeeding is not recommended.
- Fertility effects: Probable
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
Blood pressure; Baseline and at each visit
LVEF; Baseline, periodic within 8 weeks of starting treatment, then as clinically indicated
Ophthalmological evaluation; Baseline and as clinically indicated
Skin, nail toxicity and secondary infections; 2 weeks after initiating treatment and then as clinically indicated
Clinical toxicity assessment for diarrhea and other GI effects, edema, arrhythmia, thromboembolism, hypersensitivity, pneumonitis, bleeding, rhabdomyolysis and neurologic events; At each visit
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
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Flaherty KT, Robert C, Hersey P, et al; METRIC Study Group. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012 Jul 12;367(2):107-14.
Trametinib drug monograph. Ontario Health (Cancer Care Ontario).
June 2021 Updated rationale, dose modifications, drug administration and special precautions 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.
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