REGORAFENIB
Clinical safety rating: avoid
Contraindicated (not allowed)
Regorafenib is a multikinase inhibitor that targets various angiogenic (VEGFR1-3, TIE2), stromal (PDGFR-β, FGFR), and oncogenic kinases (KIT, RET, RAF). It inhibits tumor angiogenesis, growth, and metastasis.
| Metabolism | Primarily metabolized by CYP3A4 and UGT1A9. |
| Excretion | Primarily fecal (approximately 71% of the radiolabeled dose) with renal excretion accounting for 19% (mostly as metabolites). Unchanged regorafenib is minimal in urine. |
| Half-life | Terminal half-life is 14–28 hours (mean approximately 20 hours), supporting twice-daily dosing with a 3-weeks-on/1-week-off schedule to allow washout and reduce toxicity accumulation. |
| Protein binding | Highly bound to plasma proteins (>99.5%), primarily to serum albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Large apparent volume of distribution (approximately 43–100 L), indicating extensive tissue distribution and sequestration, likely due to high lipophilicity and protein binding. |
| Bioavailability | Oral bioavailability is approximately 60–90% (absolute bioavailability not determined in humans due to lack of IV formulation; estimates from animal models and mass balance studies). |
| Onset of Action | For oral administration: clinical response (e.g., disease stabilization) typically observed after 2–8 weeks of continuous dosing; antiangiogenic effects may begin within days of starting therapy. |
| Duration of Action | Duration of pharmacodynamic effect (e.g., VEGF inhibition) persists for approximately 2–3 days after the last dose, correlating with the half-life. Clinical benefit (e.g., progression-free survival) requires sustained dosing cycles. |
| Molecular Weight | 482.82 |
160 mg orally once daily on days 1-21 of a 28-day cycle until disease progression or unacceptable toxicity.
| 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). |
| Liver impairment | Child-Pugh A: No dose adjustment. Child-Pugh B: Reduce initial dose to 80 mg once daily. Child-Pugh C: Not recommended. |
| Pediatric use | Safety and effectiveness not established in pediatric patients. |
| Geriatric use | No specific dose adjustment recommended; monitor for increased toxicity in patients >65 years. |
| 1st trimester | Avoid. Regorafenib is an antiangiogenic tyrosine kinase inhibitor with teratogenic potential. Animal studies show embryofetal toxicity and teratogenicity at exposures below human therapeutic levels. There are no adequate human data; risk cannot be excluded. |
| 2nd trimester | Avoid. Continued risk of fetal harm due to antiangiogenic effects, which may impair fetal organogenesis and growth. No human data available; animal studies confirm adverse effects. |
| 3rd trimester | Avoid. Risk of fetal harm and potential for oligohydramnios, fetal renal impairment, and preterm labor due to VEGF inhibition. Use only if maternal benefit justifies fetal risk; alternative therapy recommended. |
Clinical note
Strong CYP3A4 inhibitors may increase levels and inducers may decrease levels Can cause severe hepatotoxicity and hemorrhage.
| Placental transfer | Animal studies indicate regorafenib and its active metabolites cross the placenta; likely extensive human transfer due to antiangiogenic properties and low molecular weight. |
| Breastfeeding |
■ FDA Black Box Warning
Severe and sometimes fatal hepatotoxicity has occurred. Monitor liver function tests before and during treatment. Interrupt and reduce dose as appropriate.
| Common Effects | GIST |
| Serious Effects |
Hypersensitivity to regorafenib or any excipients
| Precautions | Hepatotoxicity: Severe and fatal liver injury; monitor LFTs., Hemorrhage: Serious bleeding events; monitor for bleeding., Cardiac ischemia/infarction: Increased incidence; monitor for cardiac symptoms., Gastrointestinal perforation or fistula: Discontinue if occurs., Dermatological toxicity: Hand-foot skin reaction and severe rash; manage with dose modification., Hypertension: Monitor blood pressure; treat as needed., Wound healing complications: Withhold for at least 2 weeks before elective surgery., Reversible posterior leukoencephalopathy syndrome (RPLS): Discontinue if diagnosed. |
| Food/Dietary |
Loading safety data…
| No human data on presence in breast milk; based on molecular weight and high protein binding, excretion is likely. Risk of serious adverse effects in nursing infants. Advise discontinue breastfeeding during treatment and for at least 2 weeks after last dose. |
| Lactation Rating | L5 (Contraindicated) |
| Teratogenic Risk | Regorafenib is embryotoxic and teratogenic in animal studies. First trimester: High risk of major congenital malformations based on animal data and its antiangiogenic mechanism. Second and third trimesters: Risk of fetal growth restriction, oligohydramnios, and fetal renal impairment due to VEGF inhibition. Avoid in pregnancy unless no alternative. |
| Fetal Monitoring | If use is unavoidable: Confirm pregnancy status before initiation. Monitor fetal growth via ultrasound every 3-4 weeks. Assess amniotic fluid volume. Monitor maternal blood pressure, renal function (serum creatinine, urinalysis), and liver function tests. Thyroid function monitoring recommended due to risk of hypothyroidism. |
| Fertility Effects | Regorafenib may impair fertility in both males and females. In females, it can cause amenorrhea, ovarian failure, and reduced ovarian reserve. In males, it may cause oligospermia, azoospermia, and testicular atrophy. Advise fertility preservation before treatment. |
| Regorafenib should be taken with a low-fat meal (less than 30% fat) to ensure consistent absorption. Avoid grapefruit and grapefruit juice as they can increase drug levels and toxicity. High-fat meals increase absorption significantly and may lead to increased adverse effects. |
| Clinical Pearls | Regorafenib is a multikinase inhibitor that targets VEGF-R, PDGF-R, RAF, and CSF1-R. Key pearls: 1) Monitor for hand-foot skin reaction (HFSR), which occurs in up to 50% of patients; prophylactic measures include urea-based creams and avoiding friction. 2) Hepatotoxicity: check liver function tests before and during therapy; fatal hepatic failure has occurred. 3) Hypertension: monitor blood pressure weekly for first 6 weeks, then every cycle. 4) Dose modifications: reduce dose for grade 3 HFSR, hypertension, or hepatic impairment. 5) Use with caution in patients with recent bleeding or cardiovascular events. 6) Regorafenib is administered in a 3-weeks-on/1-week-off cycle. |
| Patient Advice | Take regorafenib at the same time each day with a low-fat meal (less than 30% fat). · Swallow tablets whole; do not crush or chew. · Report any new or worsening skin changes, especially on hands and feet (redness, swelling, blisters). · Monitor blood pressure at home and report high readings. · Avoid grapefruit and grapefruit juice during treatment. · Use effective contraception during treatment and for at least 2 months after last dose. · Contact your doctor if you experience severe diarrhea, vomiting, or dehydration. · Avoid direct sunlight; use sunscreen and protective clothing. |