COTELLIC
Clinical safety rating: caution
Comprehensive clinical and safety monograph for COTELLIC (COTELLIC).
Cotellic (cobimetinib) is a reversible, selective inhibitor of mitogen-activated protein kinase kinase 1 (MEK1) and MEK2. It inhibits MEK1/2 activity, blocking phosphorylation of extracellular signal-regulated kinase 1 (ERK1) and ERK2, thereby inhibiting the MAPK signaling pathway, which is often dysregulated in cancers with BRAF mutations.
| Metabolism | Primarily metabolized by CYP3A4, with minor contributions from CYP2D6 and other enzymes. |
| Excretion | Primarily fecal (88%) with unchanged drug accounting for 1.6%; renal excretion of unchanged drug is minimal (<0.2% of dose). |
| Half-life | Terminal elimination half-life is approximately 44 hours (range 33–55 hours) in patients with advanced melanoma, supporting twice-daily dosing. |
| Protein binding | Approximately 97% bound to human plasma proteins, primarily to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Apparent volume of distribution (Vd/F) is approximately 72 L (0.94 L/kg for a 77 kg patient), indicating extensive tissue distribution. |
| Bioavailability | Absolute oral bioavailability is not determined; relative bioavailability compared to oral solution is approximately 41% for the tablet formulation. Food does not significantly affect absorption (AUC reduction <15%). |
| Onset of Action | Pharmacodynamic effects (e.g., reduction in pERK) observed within 4 hours of oral administration; clinical response (tumor shrinkage) typically assessed after 6–8 weeks of continuous dosing. |
| Duration of Action | Sustained target inhibition for the full dosing interval (12 hours) with twice-daily dosing; continuous daily dosing recommended for clinical effect. |
60 mg orally once daily with or without food.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (CrCl ≥30 mL/min). Not recommended in severe renal impairment (CrCl <30 mL/min) due to lack of data. |
| Liver impairment | Child-Pugh A: No adjustment. Child-Pugh B: Reduce dose to 40 mg orally once daily. Child-Pugh C: Not recommended. |
| Pediatric use | Safety and efficacy not established in pediatric patients; no specific dosing guidelines available. |
| Geriatric use | No specific dose adjustment recommended; monitor for increased toxicity due to age-related renal and hepatic function decline. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for COTELLIC (COTELLIC).
| Breastfeeding | No data exist on the presence of cobimetinib in human milk, its effects on the breastfed infant, or milk production. Cobimetinib and its metabolites are excreted in rat milk. Due to potential for serious adverse reactions in nursing infants, breastfeeding is not recommended during treatment and for 2 weeks after the last dose. M/P ratio is unknown. |
| Teratogenic Risk | Based on animal studies and its mechanism of action (MEK inhibitor), COTELIC (cobimetinib) is embryotoxic and fetotoxic. In rats and rabbits, administration during organogenesis resulted in increased post-implantation loss, reduced fetal body weights, and increased incidences of cardiovascular and skeletal malformations. Human data are absent; however, MEK inhibitors are known to be teratogenic. Use is contraindicated in pregnancy. First trimester exposure carries highest risk of major congenital malformations. Second and third trimester exposure may cause fetal growth restriction, oligohydramnios, and embryofetal death. |
■ FDA Black Box Warning
None.
| Serious Effects |
["None."]
| Precautions | ["New primary malignancies (cutaneous and non-cutaneous)","Hemorrhage","Cardiomyopathy","Vemurafenib-associated photosensitivity and hepatotoxicity when used in combination","Severe cutaneous adverse reactions (e.g., Stevens-Johnson syndrome)","Uveitis and other ocular toxicities","Interstitial lung disease","Rhabdomyolysis","Embryo-fetal toxicity","Impairment of fertility"] |
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| Fetal Monitoring | If unintentional exposure occurs during pregnancy, immediate obstetrical consultation is required. Monitor fetal growth and amniotic fluid volume via ultrasound every 3-4 weeks due to risk of growth restriction and oligohydramnios. Assess for fetal cardiac function and structural anomalies with detailed fetal echocardiography. Postnatally, monitor for toxicity in neonates (e.g., gastrointestinal, dermatologic, ocular). Maternal monitoring includes liver function tests, renal function, cardiac function (LVEF via echocardiogram), and dermatologic evaluation for rash and photosensitivity. Serial blood pressure monitoring is recommended. |
| Fertility Effects | Cobimetinib may impair fertility in both males and females based on animal studies. In female rats, ovarian and uterine atrophy and disrupted estrous cycles occurred. In male rats, testicular degeneration and decreased sperm motility were observed. Human data are limited; recommend fertility counseling prior to treatment. |