BINIMETINIB
Clinical safety rating: caution
Comprehensive clinical and safety monograph for BINIMETINIB (BINIMETINIB).
Binimetinib is a reversible, non-ATP-competitive allosteric inhibitor of MEK1 and MEK2, blocking downstream ERK phosphorylation and signaling in the RAS-RAF-MEK-ERK pathway.
| Metabolism | Primarily metabolized by UGT1A1 and UGT1A3 (glucuronidation), with minor contributions from CYP1A2, CYP2C19, and CYP3A4. |
| Excretion | Primarily hepatic metabolism with biliary-fecal elimination; unchanged drug in urine is negligible (<1%). In mass balance studies, ~70-80% of the dose is recovered in feces (mainly as metabolites) and <20% in urine (as metabolites). |
| Half-life | Terminal elimination half-life is approximately 3.5–4 hours at steady state; no significant accumulation observed with twice-daily dosing. |
| Protein binding | Plasma protein binding is approximately 82%, primarily to albumin and alpha-1-acid glycoprotein (AAG). |
| Volume of Distribution | Apparent volume of distribution (Vd/F) is about 27 L (0.4 L/kg for a 70 kg adult), indicating moderate distribution into tissues. |
| Bioavailability | Absolute bioavailability is not determined; relative oral bioavailability is considered high; absorption unaffected by food per FDA labeling. |
| Onset of Action | Peak plasma concentration achieved 1–2 hours after oral administration; clinical effect (e.g., MAPK pathway inhibition) begins within hours, but antitumor response may take weeks. |
| Duration of Action | Plasma levels decline with t1/2 ~3.5–4 h; pharmacodynamic effect (pERK suppression) returns to baseline by 12 hours post-dose, consistent with BID dosing schedule. |
45 mg orally twice daily.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for GFR ≥30 mL/min; not recommended in severe renal impairment (GFR <30 mL/min). |
| Liver impairment | No dose adjustment for Child-Pugh A or B; not recommended in Child-Pugh C. |
| Pediatric use | Not established; safety and efficacy not studied in pediatric patients. |
| Geriatric use | No specific dose adjustment required; monitor renal function due to age-related decline. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for BINIMETINIB (BINIMETINIB).
| Breastfeeding | There are no data on the presence of binimetinib in human milk, its effects on the breastfed infant, or its effects on milk production. Binimetinib is present in the milk of lactating rats at concentrations higher than those in maternal plasma. Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with binimetinib and for at least 3 days after the last dose. The milk-to-plasma (M/P) ratio in humans is unknown. |
| Teratogenic Risk | Binimetinib is an MEK inhibitor with known embryofetal toxicity. Based on animal studies and mechanism of action, it is expected to cause fetal harm when administered to a pregnant woman. In animal reproduction studies, binimetinib was teratogenic and embryotoxic at maternal exposures below the clinical exposure at the recommended dose. There are no adequate and well-controlled studies in pregnant women. Therefore, the drug should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. First trimester exposure carries the highest risk for major congenital malformations. Second and third trimester exposure may affect fetal growth and development, possibly causing low birth weight and developmental delay. |
■ FDA Black Box Warning
No FDA black box warning.
| Serious Effects |
Concomitant use with strong or moderate CYP3A4 inducers (avoid). None known absolute contraindications.
| Precautions | ["Hemorrhage: gastrointestinal and intracranial hemorrhages reported","Venous thromboembolism (VTE): including DVT and PE","Cardiomyopathy: decreased left ventricular ejection fraction","Ocular toxicities: retinal vein occlusion, retinal pigment epithelial detachment","Interstitial lung disease (ILD): including pneumonitis","Hepatotoxicity: monitor liver function","Rhabdomyolysis: monitor CPK levels","Hemolytic uremic syndrome: rare but serious"] |
| Food/Dietary | Avoid grapefruit, grapefruit juice, Seville oranges, and star fruit as they inhibit CYP3A4 and may increase binimetinib exposure. |
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| Fetal Monitoring | In pregnant women exposed to binimetinib, close monitoring of fetal growth and development via serial ultrasound examinations is recommended. Assess for congenital anomalies and fetal growth restriction. Monitor for potential adverse effects such as oligohydramnios, which has been reported with other MEK inhibitors. After birth, monitor the infant for any signs of toxicity or developmental issues. Additionally, monitor maternal liver function, cardiac function (LVEF), and ophthalmologic status as per standard binimetinib monitoring. |
| Fertility Effects | Binimetinib may impair fertility in both males and females. In animal studies, adverse effects on male and female reproductive organs and fertility were observed at clinically relevant exposures. In females, this may include suppression of ovarian function, menstrual cycle disturbances, and premature ovarian failure. In males, it may cause reduced spermatogenesis and testicular degeneration. Reversibility of these effects is uncertain. Women of childbearing potential should be advised to use effective contraception during treatment and for at least 30 days after the last dose. Men with female partners of childbearing potential should use effective contraception during treatment and for at least 90 days after the last dose. |
| Clinical Pearls | Monitor for retinal pigment epithelial detachment (RPED) via ophthalmologic exam before and during therapy. Assess LVEF prior to initiation and periodically thereafter due to risk of left ventricular dysfunction. Do not use with strong or moderate CYP3A4 inducers or inhibitors; adjust dose with concomitant use of strong CYP3A4 inhibitors. Avoid use in patients with severe hepatic impairment (Child-Pugh C). |
| Patient Advice | Take exactly as prescribed. If you vomit after taking a dose, do not take an extra dose; continue with the next scheduled dose. · Notify your healthcare provider immediately if you develop eye pain, blurred vision, or visual disturbances. · Report any new or worsening shortness of breath, chest pain, or swelling in the ankles/feet. · Avoid grapefruit, grapefruit juice, Seville oranges, and star fruit during treatment. · Use effective contraception during treatment and for at least 30 days after the last dose. Do not breastfeed during therapy and for 2 weeks after the last dose. · Avoid sun exposure; wear protective clothing and broad-spectrum SPF ≥30 sunscreen. |