MEKINIST FILM-COATED TABLETS 0.5MG [SIN15181P]

Product Info

MEKINIST FILM-COATED TABLETS 0.5MG

[SIN15181P]

3 Indications

Unresectable or metastatic melanoma

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 section 6 Warnings and Precautions and section 12 Clinical studies – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Trametinib monotherapy has not demonstrated clinical activity in patients who have progressed on a prior BRAF inhibitor therapy (see section 12 Clinical studies – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Adjuvant treatment of melanoma

Trametinib in combination with dabrafenib is indicated for the adjuvant treatment of patients with melanoma with BRAF V600 mutation and involvement of lymph node(s), following complete resection.

Advanced non-small cell lung cancer

Trametinib in combination with dabrafenib is indicated for the treatment of adult patients with advanced non-small cell lung cancer (NSCLC) with a BRAF V600 mutation.

Locally advanced or metastatic anaplastic thyroid cancer

Trametinib in combination with dabrafenib is indicated for the treatment of patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) with a BRAF V600 mutation and with no satisfactory locoregional treatment options (see section 12 Clinical studies – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Low-grade glioma

Trametinib in combination with dabrafenib is indicated for the treatment of pediatric patients 1 year of age and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy (see section 12 Clinical studies – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

4 Dosage regimen and administration

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

Mekinist is available in two dosage forms, film-coated tablet and powder for oral solution.

Before taking Mekinist, patients must have confirmation of BRAF V600 (e.g., V600E, V600K, or country specific requirement) mutation status using a validated test.

When Mekinist is used in combination with Tafinlar, please also refer to the full Tafinlar Package Insert.

Note: trametinib tablets and powder for oral solution are not fully bioequivalent/interchangeable; caution is advised when consideration is given to changing formulations due to any difficulty in swallowing solid forms.

Dosage regimen

General target population

Film-coated Tablets

Adult patients

The recommended dosage for Mekinist tablets in adult patients (either as monotherapy or in combination with Tafinlar) 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 4-1.

Pediatric patients

The recommended dosage for Mekinist tablets in pediatric patients who weigh at least 26 kg, is based on body weight (Table 4-2). A recommended dose for patients who weigh less than 26 kg has not been established for Mekinist tablets.

Recommended dose level reductions for Mekinist tablets in pediatric patients are provided in Table 4-3.

Powder for Oral Solution

The recommended dosage and dose level reductions for Mekinist powder for oral solution are based on body weight (Table 4-4).

Duration of treatment

The recommended duration of treatment for patients with unresectable or metastatic melanoma or solid tumors, metastatic NSCLC, or locally advanced or metastatic anaplastic thyroid cancer 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 doses

If a dose of Mekinist is missed, it should only be taken if it is more than 12 hours until the next scheduled dose.

If a dose of Tafinlar is missed, when Mekinist is given in combination with Tafinlar, the dose of Tafinlar should only be taken if it is more than 6 hours until the next scheduled dose.

Dose adjustments

Mekinist as monotherapy and in combination with Tafinlar

The management of adverse events/adverse drug reactions may require treatment interruption, dose reduction, or treatment discontinuation.

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

The recommended dose modification schedule is provided in Table 4-5. 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.

If treatment-related toxicities occur when Mekinist is used in combination with Tafinlar, 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 pyrexia, 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

Pyrexia

Therapy should be interrupted (Mekinist when used as monotherapy, and both Mekinist and Tafinlar 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 section 6 Warnings and precautions – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information). Mekinist, or both Mekinist and Tafinlar 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.

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, Tafinlar should be withheld until resolution of ocular inflammation and then Tafinlar should be restarted reduced by one dose level. No dose modification of Mekinist is required when taken in combination with Tafinlar (see section Warnings and Precautions – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

RAS-mutation-positive non-cutaneous malignancies

Consider the benefits and risks before continuing treatment with Tafinlar in patients with a non-cutaneous malignancy that has a RAS mutation. No dose modification of Mekinist is required when taken in combination with Tafinlar.

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

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 section Warnings and Precautions – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information). No dose modification of Tafinlar is required when Mekinist is taken in combination with Tafinlar. If the LVEF recovers, treatment with Mekinist may be restarted, but the dose should be reduced by one dose level with careful monitoring (see section Warnings and Precautions – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Mekinist 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 Warnings and Precautions – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

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 Mekinist therapy, a prompt ophthalmological assessment is recommended. In patients who are diagnosed with RVO, treatment with Mekinist, whether given as monotherapy or in combination with Tafinlar, should be permanently discontinued. No dose modification of Tafinlar is required when Mekinist is taken in combination with Tafinlar. If RPED is diagnosed, follow the dose modification schedule in Table 4-6 below for Mekinist (see section Warnings and Precautions – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Interstitial lung disease (ILD)/Pneumonitis

Withhold Mekinist 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. Permanently discontinue Mekinist for patients diagnosed with treatment-related ILD or pneumonitis. No dose modification of Tafinlar is required when Mekinist is taken in combination with Tafinlar for cases of ILD or pneumonitis.

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 section Clinical pharmacology, Pharmacokinetics – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information). 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 when administered as monotherapy or in combination with Tafinlar.

Hepatic impairment

No dosage adjustment is required in patients with mild hepatic impairment. In a population pharmacokinetic analysis, Mekinist 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 Mekinist exposure (see section Clinical pharmacology, Pharmacokinetics – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information). Mekinist should be used with caution in patients with moderate or severe hepatic impairment when administered as monotherapy or in combination with Tafinlar.

Non-Caucasian patients

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

Geriatric patients (65 years of age or above)

No dose adjustment is required in patients 65 years of age or older (see section Clinical pharmacology, Pharmacokinetics – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information). More frequent dose adjustments (see Tables 4-1 and 4-2 above) may be required in patients 65 years of age or older (see section Adverse Drug Reactions – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Pediatric patients

The safety and efficacy of trametinib in combination with dabrafenib in pediatric patients with low-grade glioma younger than 1 year old and/or < 8 kg have not been established. Mekinist is not recommended in this age group. No data are available. Studies in juvenile animals have shown adverse effects of trametinib which had not been observed in adult animals (see section Non-clinical safety data – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

MEKINIST is not indicated for pediatric patients (<18 years old) with melanoma, NSCLC or anaplastic thyroid cancer.

Method of administration

It is recommended that the dose of Mekinist is taken at a similar time every day. When Mekinist and Tafinlar 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 Tafinlar.

If a patient vomits after taking Mekinist, the patient should not retake the dose and should take the next scheduled dose.

Please refer to Tafinlar Package Insert for information on method of administration when given in combination with Mekinist.

Film-coated Tablets

The tablets should be taken without food, at least one hour before or two hours after a meal with a full glass of water (see section 11 Clinical pharmacology – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information). Mekinist tablets should not be chewed or crushed.

Powder for Oral Solution

The solution can be taken with a low-fat meal or on an empty stomach (see section 11 Clinical pharmacology – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

When coadministering with dabrafenib, the Mekinist solution should be taken without food, at least one hour before or two hours after a meal. Breast-feeding and/or baby formula may be given on demand if a patient is unable to tolerate the fasting conditions (see section 11 Clinical pharmacology – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Mekinist powder for oral solution is a bottle containing powder (to be reconstituted with 90 mL water) for the patient or caregiver(s) to prepare the solution or as a ready-to-use solution. After the solution has been prepared, it must be used within 35 days. Discard any unused solution 35 days after reconstitution.

When using Mekinist powder for oral solution, physicians should review and discuss with the patient or caregiver(s) the Patient Information and instructions for mixing and administering trametinib. Physicians should confirm that caregiver(s) understand how to mix trametinib powder for oral solution with water and administer the correct daily dose.

A complete and illustrated set of instructions for the powder for oral solution is in section 14 Pharmaceutical information – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information.

5 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed.