TRAMETINIB DIMETHYL SULFOXIDE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for TRAMETINIB DIMETHYL SULFOXIDE (TRAMETINIB DIMETHYL SULFOXIDE).
Trametinib is a reversible, selective inhibitor of MEK1 and MEK2, downstream effectors of the RAS/RAF/MEK/ERK signaling pathway, thereby inhibiting cell proliferation.
| Metabolism | Primarily metabolized via deacetylation to form hydroxylamine and desmethyl metabolites. Metabolized by CYP3A4, UGT1A1, UGT1A3, UGT2B1, and UGT1A7 in vitro. Excreted mainly in feces (80%) and urine (19%). |
| Excretion | Primarily fecal (80%), with 20% excreted in urine; less than 0.1% recovered unchanged in urine. |
| Half-life | Terminal elimination half-life approximately 5.3 days (127 hours); supports once-daily dosing with steady-state achieved in ~21 days. |
| Protein binding | 97% bound to plasma proteins, primarily albumin and alpha-1 acid glycoprotein. |
| Volume of Distribution | 143 L (approximately 2.0 L/kg), indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability is 72% (under fasted conditions); administration with high-fat meal reduces Cmax and AUC by 70% and 24%, respectively. |
| Onset of Action | Oral: Initial pathway inhibition within hours; maximal pharmacodynamic effect on ERK phosphorylation observed by day 15. |
| Duration of Action | Duration of MEK inhibition persists for at least 7 days after last dose; clinically, continuous daily dosing is required for sustained antitumor effect. |
2 mg orally once daily.
| Dosage form | TABLET |
| Renal impairment | No dosage adjustment required for GFR ≥30 mL/min. For GFR <30 mL/min, no recommendation available. |
| Liver impairment | Child-Pugh A: 2 mg once daily. Child-Pugh B: 1.5 mg once daily. Child-Pugh C: 1 mg once daily. |
| Pediatric use | Safety and efficacy not established in pediatric patients. |
| Geriatric use | No specific dose adjustment; monitor for adverse effects 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 TRAMETINIB DIMETHYL SULFOXIDE (TRAMETINIB DIMETHYL SULFOXIDE).
| Breastfeeding | No human data available. Trametinib and its active metabolite are excreted in rat milk. M/P ratio unknown. Due to potential for serious adverse reactions in nursing infants, breastfeeding is contraindicated during therapy and for at least 4 months after the last dose. |
| Teratogenic Risk | FDA Pregnancy Category D. Trametinib is embryotoxic and teratogenic in animals. First trimester exposure is associated with increased risk of major congenital malformations, including cardiovascular and skeletal anomalies. Second and third trimester exposure may cause fetal growth restriction, oligohydramnios, and potential late-onset adverse effects similar to those seen in adults (e.g., cutaneous, gastrointestinal, ocular toxicities). |
■ FDA Black Box Warning
WARNING: NEW PRIMARY MALIGNANCIES, HEMORRHAGE, VENOUS THROMBOEMBOLISM, CARDIOMYOPATHY, SERIOUS FEBRILE REACTIONS, and VISUAL DISTURBANCES. New primary malignancies (cutaneous and non-cutaneous) can occur when trametinib is used in combination with dabrafenib. Serious hemorrhagic events, including fatal hemorrhage, can occur. Venous thromboembolism (including fatal pulmonary embolism) can occur. Cardiomyopathy (including symptomatic left ventricular dysfunction) can occur. Serious febrile reactions (including febrile neutropenia) can occur. Visual disturbances (including retinal vein occlusion, retinal pigment epithelial detachment) can occur.
| Serious Effects |
["None known (no absolute contraindications listed in labeling) Note: Avoid use in patients with known severe hypersensitivity to trametinib or any component of the formulation."]
| Precautions | ["New primary malignancies (cutaneous and non-cutaneous) when used in combination with dabrafenib","Hemorrhage (including fatal events)","Venous thromboembolism","Cardiomyopathy (left ventricular ejection fraction reduction)","Serious febrile reactions (including febrile neutropenia)","Visual disturbances (including retinal vein occlusion, serous chorioretinopathy)","Interstitial lung disease / pneumonitis","Serious skin toxicities (including Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms)","Hyperglycemia","Embryo-fetal toxicity","Impairment of fertility"] |
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| Fetal Monitoring | Monitor for left ventricular ejection fraction (LVEF) reduction by echocardiogram at baseline and every 3 months during pregnancy; fetal ultrasound for growth and anatomy at 18-22 weeks, with follow-up for growth every 4 weeks; monitor for oligohydramnios if used in second/third trimester; monitor maternal liver function, renal function, and electrolytes monthly. |
| Fertility Effects | Trametinib may impair male and female fertility. In animal studies, it caused reduced spermatogenesis, testicular atrophy, and altered estrous cycles. Human data are limited; reversible impairment is possible but not confirmed. Advise patients of potential impact on fertility preservations. |