Posology : מינונים

4.2   Posology and method of administration

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. In ATC, solid tumors and Low-Grade Glioma, confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with trametinib and dabrafenib (see section 5.1) 
Posology

The recommended dose of trametinib in adult patients, 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.

The recommended dose for trametinib in pediatric patients who weigh at least 26 kg is based on body weight (Table 1). A recommended dose has not been established in patients who weigh less than 26 kg.

Table 1. Dosing in Pediatric Patients from 6 to 17 Years Old (Weight-Based Dose)* Body Weight                            Recommended Dose
26 to 37 kg             1 mg (two 0.5 mg tablets) orally once daily
38 to 50 kg             1.5 mg (three 0.5 mg tablets) orally once daily 51 kg or greater        2 mg orally once daily
* Refer to the dabrafenib prescribing information for recommended dabrafenib dosing information.

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 4). In the adjuvant melanoma setting, patients should be treated for a period of 12 months unless there is disease recurrence or unacceptable toxicity. In ATC and solid tumors, treatment should continue until disease progression or unacceptable toxicity.
The optimal duration of combination therapy in the paediatric LGG population is not defined.
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 2, 3 and 4).

Dose modifications are not recommended for adverse reactions of cutaneous squamous cell carcinoma (cuSCC) or new primary melanoma (see dabrafenib Prescribing Information for further details).

Table 2. Recommended dose level reductions in Adult Patients

Dose level                        Trametinib dose                          Dabrafenib dose* Used as monotherapy or in             Only when used in combination with combination with dabrafenib                       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               1 mg once daily                    50 mg twice daily (combination only)
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 Prescribing Information, Posology and method of administration, for dosing instructions for treatment with dabrafenib monotherapy.

Table 3. Recommended Dose Reductions for trametinib for Adverse Reactions in Pediatric Patients (6 to 17 Years Old)

Action                                               Recommended Dosage (See Table 1) 
1 mg                        1.5 mg
2 mg
(two 0.5 mg tablets)         (three 0.5 mg tablets) orally once daily orally once daily            orally once daily
1 mg                        1.5 mg
First Dose Reduction        0.5 mg orally once daily     (two 0.5 mg tablets) orally   (three 0.5 mg tablets) once daily               orally once daily
1 mg
Second Dose Reduction                 -                 0.5 mg orally once daily    (two 0.5 mg tablets) orally once daily
Subsequent Modification    Permanently discontinue if unable to tolerate a maximum of two trametinib dose reductions



Table 4. Dose modification schedule based on the grade of any adverse reactions (excluding pyrexia)

Grade (CTCAE)*              Recommended trametinib dose modifications Used as monotherapy or in combination with dabrafenib
Grade 1 or Grade 2          Continue treatment and monitor as clinically indicated.
(Tolerable)
Grade 2 (Intolerable) or    Interrupt therapy until toxicity is Grade 0 to 1 and reduce by one dose Grade 3                     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 (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 dose.

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 5 below for trametinib (see section 4.4).

Table 5. 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            Resume trametinib at a lower dose level (see Tables 2 Grade 0-1 within 3 weeks                   and 3) or discontinue trametinib in patients on the lowest dose level.
Grade 2-3 RPED that does not improve       Permanently discontinue trametinib.
to at least Grade 1 within 3 weeks

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.

Non-Caucasian patients
The safety and efficacy of trametinib in non-Caucasian patients have not been established. No data are 
available.

Elderly
No initial dose adjustment is required in patients >65 years of age. More frequent dose adjustments (see Tables 2 and 4 above) may be required in patients >65 years of age (see section 4.8).

Paediatric population
BRAF V600E Mutation-Positive Unresectable or Metastatic Solid Tumors and LGG The safety and effectiveness of trametinib tablets in combination with dabrafenib have been established in pediatric patients 6 years of age and older that weigh at least 26 kg with unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options; or with LGG with BRAF V600E mutation who require systemic therapy. Use of trametinib in combination with dabrafenib for these indications is supported by evidence from studies X2101 and G2201 that enrolled 171 patients (1 to < 18 years) with BRAF V600 mutation-positive advanced solid tumors, of which 4 (2.3%) patients were 1 to < 2 years of age, 39 (23%) patients were 2 to < 6 years of age, 54 (32%) patients were 6 to < 12 years of age, and 74 (43%) patients were 12 to < 18 years of age. (see sections 4.8, 5.1 and 5.2).
The safety and effectiveness of trametinib tablets in combination with dabrafenib have not been established for these indications in pediatric patients less than 6 years old.
The safety and effectiveness of trametinib as a single agent in pediatric patients have not been established.

There are no adequate data on the safety and efficacy of combination therapy for long-term paediatric use in LGG.

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 Prescribing Information for information on method of administration when given in combination with trametinib.