MEKINIST Film-coated tablet Ref.[8867] Active ingredients: Trametinib

Treatment with trametinib should only be initiated and supervised by a physician experienced in the administration of anti-cancer medicinal products.

Patient selection

Before taking trametinib, patients must have confirmation of tumour BRAF V600 mutation assessed by a CE-marked in vitro diagnostic (IVD) medical device with the corresponding intended purpose. If no CE-marked IVD is available, an alternative validated test should be used.

Posology

In adults, the recommended dose of trametinib is 2 mg once daily, regardless of body weight.

In adolescents (aged 12 to <18 years) with melanoma, the recommended dose of trametinib is based on body weight (see also Table 1):

• 1 mg trametinib once daily for a body weight of 26 to 37 kg
• 1.5 mg trametinib once daily for a body weight of 38 to 50 kg
• 2 mg trametinib once daily for a body weight of 51 kg or more

The recommended dose of trametinib film-coated tablets for patients with a body weight less than 26 kg has not been established.

Please refer to the dabrafenib summary of product characteristics (SmPC) for information on the recommended dose of dabrafenib, when used in combination with trametinib.

Duration of treatment

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.

Missed doses

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.

Dose modification

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:

NA = Not applicable
Dose adjustment for trametinib below 1 mg once daily is not recommended for adults and adolescents with a body weight ≥51 kg.

Table 2. Dose modification schedule based on the grade of any adverse reactions (excluding pyrexia):

^* The intensity of clinical adverse reactions graded by the Common Terminology Criteria for Adverse Events (CTCAE)

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 the recommended starting dose indicated in Table 1.

Pyrexia

If a patient's temperature is ≥38ºC, 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).

Dose modification exceptions (where only one of the two therapies is dose reduced) for selected adverse reactions

Uveitis

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).

RAS mutation-positive non-cutaneous malignancies

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.

Left ventricular ejection fraction (LVEF) reduction/Left ventricular dysfunction

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).

Retinal vein occlusion (RVO) and retinal pigment epithelial detachment (RPED)

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:

Interstitial lung disease (ILD)/Pneumonitis

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.

Special populations

Renal impairment

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.

Hepatic impairment

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.

Race

Limited safety and efficacy data have been collected on trametinib in non-Caucasian patients. The population pharmacokinetic analysis showed no significant differences in the pharmacokinetics of trametinib between Asian and Caucasian patients. No trametinib dose adjustment is needed in Asian patients.

Elderly

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).

Paediatric population

The safety and efficacy of trametinib film-coated tablets in children and adolescents (<18 years) have not been established, except in adolescents aged 12 years and older with melanoma. No clinical data are available. Studies in juvenile animals have shown adverse effects of trametinib which were not observed in adult animals (see section 5.3).

Method of administration

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 studies 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 studies 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: After opening, store at not more than 30ºC and use within 30 days.

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.