STIVARGA
Clinical safety rating: caution
Comprehensive clinical and safety monograph for STIVARGA (STIVARGA).
Multikinase inhibitor that inhibits VEGFR-1, -2, -3, PDGFR-α, PDGFR-β, FGFR-1, -2, TIE2, KIT, RET, RAF-1, and B-RAF.
| Metabolism | Primarily metabolized by CYP3A4 and UGT1A9. |
| Excretion | Approximately 51% fecal (as unchanged drug and metabolites), 19% renal (as metabolites, <1% unchanged). |
| Half-life | Terminal elimination half-life is approximately 30 hours (range 15-42 h) for regorafenib and 25-60 h for its active metabolites M-2 and M-5. Steady-state is reached within 2-3 weeks. |
| Protein binding | Regorafenib is 99% bound to plasma proteins (mainly albumin). |
| Volume of Distribution | Volume of distribution is 3.9 L/kg (range 1.8-6.6 L/kg) indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability is approximately 69% (with high-fat meal). Administration with a low-fat meal reduces AUC by 42% and Cmax by 60%. |
| Onset of Action | Oral: Clinical effects (tumor response) observed after 2-4 weeks of continuous dosing; maximum plasma concentrations occur at 3-6 hours post-dose. |
| Duration of Action | Oral: Duration of action is continuous with daily dosing; recommended cycle is 3 weeks on/1 week off due to cumulative toxicity. |
| Molecular Weight | 482.82 |
160 mg orally once daily for 3 weeks, followed by 1 week off (28-day cycle).
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (CrCl ≥30 mL/min). Not studied in severe renal impairment (CrCl <30 mL/min) or end-stage renal disease. |
| Liver impairment | Child-Pugh A: No adjustment. Child-Pugh B: Use reduced dose of 120 mg orally once daily. Child-Pugh C: Not recommended. |
| Pediatric use | Safety and efficacy not established in pediatric patients. No specific weight-based guidelines available. |
| Geriatric use | No specific dose adjustment required based on age alone; monitor for adverse events more frequently due to potential age-related comorbidities and reduced organ function. |
| 1st trimester | Avoid due to embryofetal toxicity (FDA Pregnancy Category D). |
| 2nd trimester | Avoid due to embryo-fetal harm risk. |
| 3rd trimester | Avoid due to potential fetal harm and maternal toxicity. |
Clinical note
Comprehensive clinical and safety monograph for STIVARGA (STIVARGA).
| Placental transfer | Highly likely; molecular weight <500 Da and animal studies show placental transfer. |
| Breastfeeding | No human data; based on molecular weight and animal studies, likely excreted. Discontinue breastfeeding or drug due to potential serious adverse reactions. |
| Lactation Rating | L5 |
■ FDA Black Box Warning
WARNING: HEMORRHAGE. Severe and sometimes fatal hemorrhages have occurred. Stivarga should be permanently discontinued in patients with severe hemorrhage.
| Serious Effects |
Hypersensitivity to regorafenib or any excipientsSevere hepatic impairment (Child-Pugh C)
| Precautions | Hemorrhage, Hepatic toxicity: monitor liver function tests, Gastrointestinal perforation or fistula, Dermatological toxicity: hand-foot skin reaction, severe rash, Hypertension, Cardiac ischemia and infarction, Reversible posterior leukoencephalopathy syndrome (RPLS), Wound healing complications: interrupt therapy at least 2 weeks prior to elective surgery, Thyroid dysfunction: monitor TSH levels, Risk of infection |
| Food/Dietary | Take STIVARGA with a low-fat meal (less than 30% fat) to standardize absorption. Avoid grapefruit, grapefruit juice, and Seville oranges as they may increase drug levels. Avoid St. John's wort as it decreases drug exposure. High-fat meals increase Cmax and AUC, potentially increasing toxicity. |
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| Teratogenic Risk | FDA Pregnancy Category D. First trimester: Risk of structural anomalies based on animal studies showing embryofetal toxicity (e.g., cardiovascular, skeletal malformations). Second/third trimester: Risk of fetal growth restriction, oligohydramnios, and potential for fetal hemorrhage due to VEGF inhibition. Safety data in human pregnancy are lacking; use only if benefit outweighs risk. |
| Fetal Monitoring | Monitor maternal blood pressure (risk of hypertension), liver function tests (hepatotoxicity), thyroid function, and renal function. Fetal monitoring: serial ultrasound for fetal growth and amniotic fluid volume. Consider fetal echocardiography due to potential cardiovascular effects. |
| Fertility Effects | Based on animal studies, regorafenib may impair male and female fertility (reduced sperm count, ovulation, and reproductive organ weights). Reversible in some studies. Human data are lacking. |
| Clinical Pearls | Regorafenib (STIVARGA) is a multikinase inhibitor with a black box warning for hepatotoxicity requiring monitoring of liver function every 2 weeks during the first 2 months then monthly. Dose reductions are indicated for hand-foot skin reaction (HFSR) and hypertension. Monitor for thyroid dysfunction and ensure effective contraception. Adjust dose for moderate hepatic impairment (Child-Pugh B) to 80 mg once daily. |
| Patient Advice | Take exactly as prescribed, usually 4 tablets (160 mg) once daily for 3 weeks followed by 1 week off. · Swallow tablets whole with water after a low-fat meal to reduce absorption variability. · Report any new or worsening yellowing of skin/eyes, dark urine, or abdominal pain immediately. · Call your doctor if you develop severe skin rash, blisters, or peeling on hands/feet. · Use effective non-hormonal birth control during treatment and for at least 2 months after last dose. · Avoid grapefruit, grapefruit juice, Seville oranges, and St. John's wort during therapy. · You may experience voice changes, diarrhea, nausea, fatigue, and mouth sores; report severe symptoms. |