SUNITINIB MALATE
Clinical safety rating: avoid
Contraindicated (not allowed)
Sunitinib is a multitargeted tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, VEGFR-3), platelet-derived growth factor receptors (PDGFR-α, PDGFR-β), stem cell factor receptor (c-KIT), FMS-like tyrosine kinase 3 (FLT3), colony-stimulating factor receptor type 1 (CSF-1R), and glial cell line-derived neurotrophic factor receptor (RET). It exerts antiangiogenic and antitumor activity by blocking signaling pathways involved in tumor growth and angiogenesis.
| Metabolism | Primarily metabolized by CYP3A4 to its active metabolite, N-desethyl sunitinib, which is further metabolized by CYP3A4. Sunitinib and its major metabolite are also substrates of P-glycoprotein (P-gp). |
| Excretion | Fecal (61%), renal (16%) as unchanged drug and metabolites. |
| Half-life | 40-60 hours for sunitinib; 80-110 hours for active metabolite SU12662. Clinical context: supports once-daily dosing with 2 weeks on/1 week off schedule. |
| Protein binding | 95% bound to albumin and alpha-1 acid glycoprotein for sunitinib; 90% for SU12662. |
| Volume of Distribution | 2230 L (oral) indicating extensive tissue distribution; not standardized to L/kg, but approximate 31 L/kg assuming 70 kg. |
| Bioavailability | Oral: 50% (range 40-70%) with no food effect. |
| Onset of Action | Oral: 2-4 weeks for antitumor response; maximal at 4-6 weeks. |
| Duration of Action | Prolonged; drug is present for ~2 weeks after discontinuation due to long half-life. Clinical note: monitor for adverse effects during washout. |
50 mg orally once daily for 4 weeks, followed by 2 weeks off (4/2 schedule). Alternatively, 37.5 mg orally once daily on a continuous daily dosing schedule for gastrointestinal stromal tumors (GIST) after tyrosine kinase inhibitor failure.
| Dosage form | CAPSULE |
| Renal impairment | No dosage adjustment required for mild to moderate renal impairment (CrCl ≥30 mL/min). For severe renal impairment (CrCl <30 mL/min), consider dose reduction to 37.5 mg once daily; pharmacokinetics have not been studied in patients on dialysis. |
| Liver impairment | Child-Pugh Class A and B: no dosage adjustment recommended. Child-Pugh Class C: pharmacokinetics not studied; use with caution and consider dose reduction to 37.5 mg once daily. |
| Pediatric use | Safety and efficacy in pediatric patients have not been established. In clinical studies for solid tumors, a dose of 25 mg/m² orally once daily (maximum 50 mg) on a 4/2 schedule was explored but not approved. |
| Geriatric use | No specific dose adjustment based on age alone. Monitor renal function and tolerability closely, as elderly patients may have decreased renal function and increased sensitivity to adverse effects (e.g., fatigue, hypertension, cardiotoxicity). |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Strong CYP3A4 inhibitors may increase levels and inducers may decrease levels Can cause hepatotoxicity and left ventricular dysfunction.
| Breastfeeding | Excretion into human milk unknown; M/P ratio not established. Due to potential for serious adverse reactions in nursing infants, discontinue breastfeeding during therapy and for at least 4 weeks after last dose. |
| Teratogenic Risk | Sunitinib malate is teratogenic in animal studies. First trimester exposure is associated with increased risk of congenital malformations (cardiovascular, skeletal). Second and third trimester use may cause fetal growth restriction, oligohydramnios, and spontaneous abortion. Category D. |
■ FDA Black Box Warning
Hepatotoxicity: Severe and sometimes fatal hepatotoxicity has been observed. Monitor liver function tests before and during treatment. Interrupt or discontinue sunitinib based on severity of hepatic impairment.
| Common Effects | GIST |
| Serious Effects |
["None absolute; however, sunitinib should not be used in patients with known severe hypersensitivity to sunitinib or any component of the formulation"]
| Precautions | ["Hepatotoxicity (including fatal hepatic failure)","Left ventricular dysfunction and QT prolongation","Hemorrhagic events (including tumor hemorrhage and pulmonary hemorrhage)","Hypertension (including hypertensive crisis)","Adrenal insufficiency (with or without adrenal hemorrhage)","Thyroid dysfunction (hypothyroidism and hyperthyroidism)","Impaired wound healing and risk of fistula formation","Thrombotic microangiopathy (including thrombotic thrombocytopenic purpura)","Pancreatitis and elevated lipase/amylase","Proteinuria and nephrotic syndrome","Osteonecrosis of the jaw (ONJ) (especially with concurrent bisphosphonates)","Tumor lysis syndrome (TLS)"] |
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| Fetal Monitoring | Monitor maternal blood pressure, thyroid function, left ventricular ejection fraction, complete blood count, serum electrolytes and urinalysis. Fetal ultrasound for growth restriction and oligohydramnios during second and third trimesters. |
| Fertility Effects | Sunitinib malate may impair male and female fertility. Azoospermia and menstrual cycle irregularities reported. Reversible upon discontinuation in some cases; however, long-term effects on fertility unknown. |