Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland
Trametinib as monotherapy or in combination with dabrafenib is indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation (see sections 4.4 and 5.1).
Trametinib monotherapy has not demonstrated clinical activity in patients who have progressed on a prior BRAF inhibitor therapy (see section 5.1).
Trametinib in combination with dabrafenib is indicated for the adjuvant treatment of adult patients with Stage III melanoma with a BRAF V600 mutation, following complete resection.
Trametinib in combination with dabrafenib is indicated for the treatment of adult patients with advanced non-small cell lung cancer with a BRAF V600 mutation.
Treatment with trametinib should only be initiated and supervised by a physician experienced in the administration of anti-cancer medicinal products.
Before taking trametinib, patients must have confirmation of BRAF V600 mutation using a validated test.
The recommended dose of trametinib, either used as monotherapy or in combination with dabrafenib, is 2 mg once daily. The recommended dose of dabrafenib, when used in combination with trametinib, is 150 mg twice daily.
It is recommended that patients continue treatment with trametinib until patients no longer derive benefit or the development of unacceptable toxicity (see Table 2). In the adjuvant melanoma setting, patients should be treated for a period of 12 months unless there is disease recurrence or unacceptable toxicity.
If a dose of trametinib is missed, it should only be taken if it is more than 12 hours until the next scheduled dose.
If a dose of dabrafenib is missed, when trametinib is given in combination with dabrafenib, the dose of dabrafenib should only be taken if it is more than 6 hours until the next scheduled dose.
The management of adverse reactions may require dose reduction, treatment interruption or treatment discontinuation (see Tables 1 and 2).
Dose modifications are not recommended for adverse reactions of cutaneous squamous cell carcinoma (cuSCC) or new primary melanoma (see dabrafenib SmPC for further details).
Table 1. Recommended dose level reductions:
| Dose level | Trametinib dose Used as monotherapy or in combination with dabrafenib | Dabrafenib dose* Only when used in combination with trametinib |
|---|---|---|
| Starting dose | 2 mg once daily | 150 mg twice daily |
| 1st dose reduction | 1.5 mg once daily | 100 mg twice daily |
| 2nd dose reduction | 1 mg once daily | 75 mg twice daily |
| 3rd dose reduction (combination only) | 1 mg once daily | 50 mg twice daily |
Dose adjustment for trametinib below 1 mg once daily is not recommended, whether used as monotherapy or in combination with dabrafenib. Dose adjustment for dabrafenib below 50 mg twice daily is not recommended when used in combination with trametinib.
* Please refer to the dabrafenib SmPC, Posology and method of administration, for dosing instructions for treatment with dabrafenib monotherapy.
Table 2. Dose modification schedule based on the grade of any adverse reactions (excluding pyrexia):
| Grade (CTC-AE)* | Recommended trametinib dose modifications Used as monotherapy or in combination with dabrafenib |
|---|---|
| Grade 1 or Grade 2 (Tolerable) | Continue treatment and monitor as clinically indicated. |
| Grade 2 (Intolerable) or Grade 3 | Interrupt therapy until toxicity is Grade 0 to 1 and reduce by one dose level when resuming therapy. |
| Grade 4 | Discontinue permanently, or interrupt therapy until Grade 0 to 1 and reduce by one dose level when resuming therapy. |
* The intensity of clinical adverse reactions graded by the Common Terminology Criteria for Adverse Events v4.0 (CTC-AE)
When an individual’s adverse reactions are under effective management, dose re-escalation following the same dosing steps as de-escalation may be considered. The trametinib dose should not exceed 2 mg once daily.
If a patient’s temperature is ≥38°C, therapy should be interrupted (trametinib when used as monotherapy, and both trametinib and dabrafenib when used in combination). In case of recurrence, therapy can also be interrupted at the first symptom of pyrexia. Treatment with anti-pyretics such as ibuprofen or acetaminophen/paracetamol should be initiated. The use of oral corticosteroids should be considered in those instances in which anti-pyretics are insufficient. Patients should be evaluated for signs and symptoms of infection and if necessary treated in line with local practice (see section 4.4). Trametinib, or both trametinib and dabrafenib when used in combination, should be restarted if the patient is symptom free for at least 24 hours either (1) at the same dose level, or (2) reduced by one dose level, if pyrexia is recurrent and/or was accompanied by other severe symptoms including
dehydration, hypotension or renal failure.
If treatment-related toxicities occur when trametinib is used in combination with dabrafenib, then both treatments should be simultaneously dose reduced, interrupted or discontinued. Exceptions where dose modifications are necessary for only one of the two treatments are detailed below for uveitis, RAS mutation positive non-cutaneous malignancies (primarily related to dabrafenib), left ventricular ejection fraction (LVEF) reduction, retinal vein occlusion (RVO), retinal pigment epithelial detachment (RPED) and interstitial lung disease (ILD)/pneumonitis (primarily related to trametinib).
No dose modifications are required for uveitis as long as effective local therapies can control ocular inflammation. If uveitis does not respond to local ocular therapy, dabrafenib should be withheld until resolution of ocular inflammation and then dabrafenib should be restarted reduced by one dose level. No dose modification of trametinib is required when taken in combination with dabrafenib (see section 4.4).
The benefits and risks must be considered before continuing treatment with dabrafenib in patients with a non-cutaneous malignancy that has a RAS mutation. No dose modification of trametinib is required when taken in combination with dabrafenib.
Trametinib should be interrupted in patients who have an asymptomatic, absolute decrease of >10% in LVEF compared to baseline and the ejection fraction is below the institution’s lower limit of normal (LLN) (see section 4.4). No dose modification of dabrafenib is required when trametinib is taken in combination with dabrafenib. If the LVEF recovers, treatment with trametinib may be restarted, but the dose should be reduced by one dose level with careful monitoring (see section 4.4).
Trametinib should be permanently discontinued in patients with Grade 3 or 4 left ventricular cardiac dysfunction or clinically significant LVEF reduction which does not recover within 4 weeks (see section 4.4).
If patients report new visual disturbances such as diminished central vision, blurred vision, or loss of vision at any time while on trametinib therapy, a prompt ophthalmological assessment is recommended. In patients who are diagnosed with RVO, treatment with trametinib, whether given as monotherapy or in combination with dabrafenib, should be permanently discontinued. No dose modification of dabrafenib is required when trametinib is taken in combination with dabrafenib. If RPED is diagnosed, follow the dose modification schedule in Table 3 below for trametinib (see section 4.4).
Table 3. Recommended dose modifications for trametinib for RPED:
| Grade 1 RPED | Continue treatment with retinal evaluation monthly until resolution. If RPED worsens follow instructions below and withhold trametinib for up to 3 weeks. |
| Grade 2-3 RPED | Withhold trametinib for up to 3 weeks. |
| Grade 2-3 RPED that improves to Grade 0-1 within 3 weeks | Resume trametinib at a lower dose (reduced by 0.5 mg) or discontinue trametinib in patients taking trametinib 1 mg daily. |
| Grade 2-3 RPED that does not improve to at least Grade 1 within 3 weeks | Permanently discontinue trametinib. |
Trametinib must be withheld in patients with suspected ILD or pneumonitis, including patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnoea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Trametinib must be permanently discontinued in patients diagnosed with treatment-related ILD or pneumonitis. No dose modification of dabrafenib is required when trametinib is taken in combination with dabrafenib for cases of ILD or pneumonitis.
No dosage adjustment is required in patients with mild or moderate renal impairment (see section 5.2). There are no data with trametinib in patients with severe renal impairment; therefore, the potential need for starting dose adjustment cannot be determined. Trametinib should be used with caution in patients with severe renal impairment when administered as monotherapy or in combination with dabrafenib.
No dosage adjustment is required in patients with mild hepatic impairment. Available data from a clinical pharmacology study indicate a limited impact of moderate to severe hepatic impairment on trametinib exposure (see section 5.2). Trametinib should be used with caution in patients with moderate or severe hepatic impairment when administered as monotherapy or in combination with dabrafenib.
The safety and efficacy of trametinib in non-Caucasian patients have not been established. No data are available.
No initial dose adjustment is required in patients >65 years of age. More frequent dose adjustments (see Tables 1 and 2 above) may be required in patients >65 years of age (see section 4.8).
The safety and efficacy of trametinib in children and adolescents (<18 years) have not been established. No data are available. Studies in juvenile animals have shown adverse effects of trametinib which were not observed in adult animals (see section 5.3).
Trametinib should be taken orally with a full glass of water. The tablets should not be chewed or crushed and they should be taken without food, at least 1 hour before or 2 hours after a meal.
It is recommended that the dose of trametinib is taken at a similar time every day. When trametinib and dabrafenib are taken in combination, the once-daily dose of trametinib should be taken at the same time each day with either the morning dose or the evening dose of dabrafenib.
If a patient vomits after taking trametinib, the patient should not retake the dose and should take the next scheduled dose.
Please refer to dabrafenib SmPC for information on method of administration when given in combination with trametinib.
In clinical trials with trametinib monotherapy one case of accidental overdose was reported; a single dose of 4 mg. No AEs were reported following this event of trametinib overdose. In clinical trials with the combination of trametinib and dabrafenib 11 patients reported trametinib overdose (4 mg); no SAEs were reported. There is no specific treatment for overdose. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary.
Unopened bottle: 3 years.
Opened bottle: 30 days at no more than 30°C.
This medicinal product does not require any special temperature storage conditions.
Store in the original package in order to protect from light and moisture.
Keep the bottle tightly closed.
For storage conditions after first opening of the medicinal product, see section 6.3.
High-density polyethylene (HDPE) bottle with child-resistant polypropylene closure. The bottle contains a desiccant.
Pack sizes: One bottle contains either 7 or 30 tablets.
Not all pack sizes may be marketed.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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