MEKINIST
Clinical safety rating: caution
Comprehensive clinical and safety monograph for MEKINIST (MEKINIST).
Reversible, selective inhibitor of MEK1 and MEK2, which are downstream kinases in the RAS/RAF/MEK/ERK signaling pathway. Inhibition prevents phosphorylation and activation of ERK, thereby reducing cell proliferation in BRAF V600 mutant tumors.
| Metabolism | Primarily metabolized by CYP3A4 and UGT1A9, with minor contributions from CYP2C8 and CYP2C19. |
| Excretion | Fecal (80% as unchanged drug and metabolites), renal (<1% unchanged) |
| Half-life | Terminal half-life of 3.9 days (93.6 hours) in patients; supports once-daily dosing and steady-state achieved in ~19 days |
| Protein binding | ~99% bound to plasma proteins (primarily albumin) |
| Volume of Distribution | 638 L (extensive tissue distribution, not volume of distribution per kg; based on population PK, ~9.1 L/kg for a 70 kg individual) |
| Bioavailability | Oral: ~52% (range 26–80%) |
| Onset of Action | Oral: 2–3 hours for plasma levels to reach therapeutic concentrations; clinical response observed within weeks |
| Duration of Action | Pharmacodynamic effect persists for several days due to long half-life; dosing is once daily for continuous MEK inhibition |
2 mg orally once daily, at least 1 hour before or 2 hours after a meal.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (CrCl ≥30 mL/min). Safety and efficacy not established in severe renal impairment (CrCl <30 mL/min); use with caution. |
| Liver impairment | Mild (Child-Pugh A): no adjustment. Moderate (Child-Pugh B): reduce to 1.5 mg orally once daily. Severe (Child-Pugh C): not recommended. |
| Pediatric use | For children ≥6 years: 0.025 mg/kg (max 2 mg) orally once daily; for children ≥2 to <6 years: 0.032 mg/kg (max 1 mg) orally once daily; administer on empty stomach. |
| Geriatric use | No specific dose adjustment; monitor for adverse events due to potential age-related renal and hepatic decline. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for MEKINIST (MEKINIST).
| Breastfeeding | No data available on trametinib excretion in human breast milk or its effects on the nursing infant. Due to potential for serious adverse reactions in breastfed infants (e.g., diarrhea, rash, ocular toxicity), advise women not to breastfeed during treatment and for 4 months after the last dose. M/P ratio unknown. |
| Teratogenic Risk | Based on its mechanism of action (MEK inhibitor) and animal studies, MEKINIST (trametinib) is teratogenic and embryotoxic. In pregnant rats and rabbits, trametinib caused embryofetal death, reduced fetal weight, and structural abnormalities including cardiovascular and skeletal malformations at exposures below the clinical exposure at the recommended human dose. There are no adequate and well-controlled studies in pregnant women. Risk cannot be ruled out; avoid use in pregnancy unless benefit outweighs risk. First trimester exposure carries highest risk for major malformations. |
■ FDA Black Box Warning
None.
| Serious Effects |
["None known based on FDA label."]
| Precautions | ["Cardiomyopathy: Left ventricular ejection fraction (LVEF) reduction; monitor LVEF before and during treatment.","Venous thromboembolism (VTE): Increased risk of DVT and PE; monitor for symptoms and treat as appropriate.","Hemorrhage: Major hemorrhagic events can occur; monitor for signs of bleeding.","Serious febrile reactions: Fever may be severe with or without infection; withhold or discontinue if high fever persists.","Interstitial lung disease (ILD): Evaluate for pneumonitis; permanently discontinue if ILD is confirmed.","Ocular toxicities: Retinal events including retinal detachment and RPE detachment; perform ophthalmic evaluations.","Colitis and gastrointestinal perforation: Can occur; monitor for symptoms and discontinue if required.","Skin toxicities: Rash, dermatitis, and Stevens-Johnson syndrome; manage with supportive care.","Rhabdomyolysis: Monitor CK levels in patients with muscle symptoms.","Embryo-fetal toxicity: Can cause fetal harm; advise effective contraception."] |
Loading safety data…
| Fetal Monitoring | If used in pregnancy, monitor fetal growth and development with serial ultrasounds. Assess for oligohydramnios, as MEK inhibitors can cause oligohydramnios via inhibition of fetal renal development. Monitor maternal renal function and electrolytes. No specific fetal monitoring required outside of standard prenatal care. |
| Fertility Effects | In animal studies, trametinib impaired male and female fertility. In female rats, it caused reduced corpora lutea, decrease in implantation sites, and increased pre- and post-implantation loss. In male rats, it caused decreased sperm motility and concentration, and testicular degeneration. Human fertility effects unknown; may impair fertility in both males and females. |