AXITINIB
Clinical safety rating: caution
Comprehensive clinical and safety monograph for AXITINIB (AXITINIB).
Axitinib is a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, and VEGFR-3). It blocks VEGF-mediated signaling, thereby inhibiting endothelial cell proliferation, migration, and survival, leading to reduced tumor angiogenesis and tumor growth.
| Metabolism | Primarily metabolized by CYP3A4/5 and to a lesser extent by CYP1A2 and CYP2C19. Major metabolite is inactive. |
| Excretion | Fecal (41% unchanged, 23% as metabolites); renal (<1% unchanged, 7% as metabolites) |
| Half-life | Terminal elimination half-life: 2.5-6.1 hours; clinical context: supports twice-daily dosing due to rapid clearance |
| Protein binding | >99% bound to plasma proteins (albumin and alpha-1-acid glycoprotein) |
| Volume of Distribution | Vd: 160 L (approx 2 L/kg); large distribution suggests extensive tissue binding and extravascular localization |
| Bioavailability | Oral bioavailability: 50-58% (fasting); food decreases absorption; avoid food 1 hour before and 2 hours after dose |
| Onset of Action | Oral: maximum plasma concentration reached 2-4 hours post-dose; clinical effect onset within days, but anti-angiogenic effects may take weeks |
| Duration of Action | Duration: half-life ~4 hours supports BID dosing; clinical effect persists with continuous dosing; inhibition of VEGF receptors lasts >12 hours post-dose |
| Molecular Weight | 386.47 |
5 mg orally twice daily (approximately 12 hours apart), with or without food; may increase to 7 mg twice daily or decrease to 3 mg twice daily based on tolerability.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to severe renal impairment (CrCl ≥15 mL/min). Insufficient data for ESRD (CrCl <15 mL/min) or dialysis. |
| Liver impairment | Child-Pugh A: no adjustment. Child-Pugh B: reduce dose by 50% (e.g., start at 2 mg twice daily). Child-Pugh C: not recommended (no data). |
| Pediatric use | Safety and efficacy in pediatric patients (<18 years) have not been established; no recommended dose. |
| Geriatric use | No specific dose adjustment required; monitor blood pressure and manage hypertension closely due to increased incidence of hypertension in elderly. |
| 1st trimester | Axitinib is contraindicated in first trimester due to teratogenic effects observed in animal studies. It should not be used unless there is no safer alternative and patient is fully informed of risks. |
| 2nd trimester | Axitinib is contraindicated in second trimester due to potential fetal harm from VEGF inhibition. |
| 3rd trimester | Axitinib is contraindicated in third trimester due to risk of fetal hemorrhage and potential for oligohydramnios. |
Clinical note
Comprehensive clinical and safety monograph for AXITINIB (AXITINIB).
| Placental transfer | Axitinib is likely to cross the placenta based on its low molecular weight and animal studies showing fetal exposure. |
| Breastfeeding | Axitinib is excreted in rat milk; not studied in humans. Due to potential for serious adverse reactions in nursing infants, breastfeeding is not recommended during therapy and for at least 2 weeks after last dose. |
■ FDA Black Box Warning
No FDA boxed warning exists for axitinib.
| Serious Effects |
Hypersensitivity to axitinib or any excipients
| Precautions | Hypertension: Monitor blood pressure; manage with antihypertensives; interrupt/reduce dose if uncontrolled., Arterial thromboembolic events: Use caution in patients at risk or with history of stroke/MI., Venous thromboembolic events: Discontinue if pulmonary embolism occurs., Hemorrhage: Monitor for bleeding; discontinue if severe., Cardiac failure: Monitor for signs/symptoms; reduce/interrupt dose., Gastrointestinal perforation and fistula: Discontinue if occurs., Hypothyroidism: Monitor thyroid function before and during treatment., Reversible posterior leukoencephalopathy syndrome (RPLS): Discontinue if suspected., Proteinuria: Monitor urine protein; discontinue if nephrotic syndrome., Wound healing complications: Interrupt for at least 24 hours prior to elective surgery., Hepatotoxicity: Monitor liver function tests., Hemolytic uremic syndrome/thrombotic microangiopathy: Discontinue if occurs., Fetal harm: Can cause fetal harm; advise effective contraception. |
| Food/Dietary |
Loading safety data…
| Lactation Rating | L5 |
| Teratogenic Risk | Axitinib is contraindicated in pregnancy. Based on its mechanism of action (VEGF receptor inhibition) and animal studies, axitinib is embryotoxic and teratogenic in rats and rabbits at exposures below human therapeutic levels. Fetal anomalies include skeletal and cardiovascular malformations. First trimester exposure carries highest risk of major malformations. Second and third trimester exposure may cause fetal growth restriction, oligohydramnios, and renal dysfunction. Data in humans are limited but consistent with high risk. |
| Fetal Monitoring | Pregnancy test before initiation and monthly during treatment. Monitor for hypertension (every 2 weeks), proteinuria (urinalysis monthly), thyroid function (every 4 weeks), and liver enzymes (ALT, AST, bilirubin every 4 weeks). Fetal ultrasound for growth and amniotic fluid volume if exposure occurs during pregnancy. Monitor for signs of fetal harm such as intrauterine growth restriction (IUGR) and oligohydramnios. |
| Fertility Effects | Axitinib may impair fertility in humans based on animal studies showing reduced fertility indices (e.g., decreased number of corpora lutea, implantation sites) at clinically relevant doses. Effect is likely reversible after discontinuation. No specific human data available. Females of reproductive potential should use effective contraception during and for 1 week after treatment. Males with female partners of childbearing potential should use condoms during and for 1 week after treatment. |
| Avoid grapefruit and grapefruit juice during therapy as they inhibit CYP3A4 and may increase axitinib concentrations. Axitinib can be taken with or without food. Moderate fat meals do not significantly alter absorption, but high-fat meals may reduce peak concentrations slightly (not clinically relevant). No specific dietary restrictions other than grapefruit. |
| Clinical Pearls | Axitinib is a potent and selective second-generation tyrosine kinase inhibitor targeting VEGFR-1, -2, and -3. It is indicated for second-line treatment of advanced renal cell carcinoma after prior cytokine or anti-angiogenic therapy. Dose adjustments are critical based on tolerability; starting dose is 5 mg twice daily, with up-titration to 7 mg BID or down-titration to 2 mg BID based on blood pressure, liver function, and other adverse events. Monitor blood pressure closely due to dose-dependent hypertension; consider antihypertensives like ACE inhibitors or ARBs. Avoid strong CYP3A4 inducers (e.g., rifampin, phenytoin) or inhibitors (e.g., ketoconazole, clarithromycin) as they significantly alter axitinib exposure. Hemoptysis, gastrointestinal perforation, and fistula formation are rare but serious; discontinue if occurs. Thyroid function should be monitored before and during therapy as hypothyroidism is common. |
| Patient Advice | Take axitinib exactly as prescribed, usually twice daily about 12 hours apart with or without food. · Swallow tablets whole; do not crush or chew. · Do not change dose or stop without consulting your doctor. · Monitor blood pressure regularly at home and report high readings immediately. · Contact your doctor if you experience severe diarrhea, vomiting, or dehydration. · Report any unusual bleeding, coughing up blood, chest pain, or difficulty breathing. · Use effective contraception during treatment and for at least 1 week after the last dose. · Avoid grapefruit or grapefruit juice as it may affect the drug levels. · Tell your doctor about all medications, including over-the-counter drugs and supplements. · Do not breastfeed while taking axitinib and for 2 weeks after last dose. |