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Author: Anoma Ranaweera B.V. Sc; PhD (Clinical Biochemistry, University of Liverpool, UK), 2013.
On May 29, 2013, the U. S. Food and Drug Administration (FDA) approved trametinib (MEKINIST™ tablets, GlaxoSmithKline, LLC), as a single agent treatment for patients with non-operable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test, called the THxID™ – BRAF assay from bioMérieux S.A. In November 2015, the FDA approved the combination of dabrafenib and trametinib for the treatment of metastatic melanoma. Trametinib is approved by MedSafe, alone and in combination with dabrafenib, but it is not subsidised by PHARMAC in New Zealand.
BRAF mutations occur in 50% of melanomas. Trametinib targets mutant BRAF protein by inhibiting the MAPK signalling pathway, which mediates cell growth and survival.
The recommended dose of trametinib is 2 mg orally once daily, taken at least 1 hour before or at least 2 hours after a meal. A missed dose must not be taken within 12hours of the next dose.
Dose modification or partial/complete withdrawal of the drug is recommended in the case of severe skin toxicity, cardiomyopathy, ocular and pulmonary abnormalities.
In clinical trials with trametinib, the most common side effects affecting ≥10% patients, and of any grade, were:
Serious adverse reactions (affecting ≥2%), i.e. grades 3 and 4 were:
In clinical trials, the following adverse reactions have also been observed with trametinib.
Trametinib can cause fetal harm when administered to a pregnant woman (pregnancy category D). The patient should be warned of the potential hazard to the fetus, if this drug is used during pregnancy or if the patient becomes pregnant while taking this drug. Female patients should be advised to use highly effective contraceptives during treatment with trametinib and for 4 months after treatment has stopped.
To date studies evaluating trametinib in children have not been conducted.
Clinical studies of trametinib did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects.
No formal clinical study has been conducted to evaluate the effect of renal and hepatic impairment on the pharmacokinetics of trametinib. No dose adjustments are recommended in patients with mild renal or hepatic impairment based on population pharmacokinetic studies.
No formal drug interaction studies have been conducted to evaluate human cytochrome P450 (CYP) enzyme-mediated drug interactions with trametinib.
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