Mekinist Dosage/Direction for Use

Treatment with Mekinist should be initiated by a physician experienced in the use of anticancer therapies.
Mekinist in combination with dabrafenib is not indicated for treatment of patients with colorectal cancer because of known intrinsic resistance to BRAF inhibition (see Pharmacology under Actions).
Confirmation of BRAF V600 (e.g., V600E, V600K, or country specific requirement) mutation status using an approved/validated test is required for selection of patients appropriate for treatment with Mekinist as monotherapy and in combination with dabrafenib (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
When Mekinist is used in combination with dabrafenib, also refer to the full dabrafenib prescribing information.
Dosage regimen: General target population: Adult patients: The recommended dosage for Mekinist tablets in adult patients (either as monotherapy or in combination with dabrafenib) is 2 mg given orally once daily, independent of body weight.
Recommended dose level reductions for Mekinist tablets in adult patients are provided in Table 11. (See Table 11.)

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Pediatric patients: The recommended dosage for Mekinist tablets in pediatric patients who weigh at least 26 kg, is based on body weight (Table 12). A recommended dose for patients who weigh less than 26 kg has not been established. (See Table 12.)

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Recommended dose level reductions for Mekinist tablets in pediatric patients are provided in Table 13. (See Table 13.)

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Duration of treatment: The recommended duration of treatment for patients with unresectable or metastatic melanoma or solid tumors, or metastatic NSCLC is until disease progression or unacceptable toxicity.
In the adjuvant melanoma setting, the treatment duration is limited to a maximum of 1 year.
The recommended duration of treatment for pediatric patients with LGG is until loss of clinical benefit or until unacceptable toxicity. There are limited data in patients older than 18 years of age with LGG who require first systemic therapy. Therefore, continued treatment into adulthood should be based on benefits and risks to the individual patient as assessed by the physician.
Missed dose: If a dose of Mekinist is missed, it should only be taken if it is more than 12 hours until the next scheduled dose.
Dose adjustments: Mekinist as Monotherapy and in combination with dabrafenib: The management of adverse events/adverse drug reactions may require treatment interruption, dose reduction, or treatment discontinuation.
The recommended dose modification schedule is provided in Table 14. 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 Mekinist dose should not exceed 2 mg once daily. (See Table 14.)

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Pyrexia management: Therapy should be interrupted (Mekinist when used as monotherapy, and both Mekinist and Dabrafenib when used in combination) if the patient's temperature is ≥38°C (100.4°F). 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. Patients should be evaluated for signs and symptoms of infection (see Precautions). Mekinist, or both Mekinist and Dabrafenib when used in combination, should be restarted if 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. The use of oral corticosteroids should be considered in those instances in which anti-pyretics are insufficient.
If treatment-related toxicities occur when Mekinist is used in combination with dabrafenib then both treatments should be simultaneously dose reduced, interrupted or discontinued with the exceptions shown as follows.
Exceptions where dose modifications are necessary for Mekinist only: Left ventricular ejection fraction (LVEF) reduction; Retinal vein occlusion (RVO) and retinal pigment epithelial detachment (RPED); Pneumonitis and Interstitial Lung Disease (ILD).
LVEF Reduction/Left Ventricular Dysfunction management: Mekinist should be interrupted in patients who have an asymptomatic, absolute decrease of >10% in LVEF compared to baseline and the ejection fraction below the institution's lower limit of normal (LLN) (see Precautions). If Mekinist is being used in combination with dabrafenib then therapy with dabrafenib may be continued at the same dose. If the LVEF recovers, treatment with Mekinist may be restarted, but the dose should be reduced by one dose level with careful monitoring. Mekinist should be permanently discontinued with Grade 3 or 4 left ventricular cardiac dysfunction or if repeatedly reduced LVEF does not recover.
Retinal vein occlusion (RVO) and retinal pigment epithelial detachment (RPED) management: If RPED is diagnosed, the dose modification schedule (intolerable) in Table 14 as previously shown for Mekinist should be followed and, if Mekinist is being used in combination with dabrafenib, dabrafenib should be continued at the same dose. In patients who experience RVO, treatment with Mekinist should be permanently discontinued (see Precautions).
Pneumonitis and Interstitial Lung Disease (ILD) management: For events of pneumonitis, follow dose modification guidelines in Table 14 for Mekinist only; no modification of dabrafenib is required when taken in combination with Mekinist.
Special populations: Renal impairment: No dosage adjustment is required in patients with mild or moderate renal impairment. Mild or moderate renal impairment had no significant effect on the population pharmacokinetics of Mekinist (see Pharmacology: Pharmacokinetics under Actions). There are no clinical data in patients with severe renal impairment; therefore, the potential need for starting dose adjustment cannot be determined. Mekinist should be used with caution in patients with severe renal impairment.
Hepatic impairment: No dosage adjustment is required in patients with mild hepatic impairment. In a population pharmacokinetic analysis, trametinib oral clearance and thus exposure was not significantly different in patients with mild hepatic impairment compared to patients with normal hepatic function. Available data in patients with moderate or severe hepatic impairment from a clinical pharmacology study indicate a limited impact on trametinib exposure (see Pharmacology: Pharmacokinetics under Actions). Mekinist should be used with caution in patients with moderate or severe hepatic impairment.
Pediatric patients (below 18 years): The safety and efficacy of Mekinist tablets in pediatric patients <6 year of age have not been established. Mekinist is not recommended in this age group.
Geriatric patients (65 years of age or above): No dosage adjustment is required in patients over 65 years of age (see Pharmacology: Pharmacokinetics under Actions).
Method of administration: Mekinist should be taken without food, at least one hour before or two hours after a meal with a full glass of water (see Pharmacology under Actions).
When Mekinist and dabrafenib are taken in combination, the once-daily dose of Mekinist should be taken at the same time each day with either the morning dose or the evening dose of dabrafenib.