NINTEDANIB
Clinical safety rating: caution
Comprehensive clinical and safety monograph for NINTEDANIB (NINTEDANIB).
Nintedanib is a small molecule tyrosine kinase inhibitor that inhibits multiple receptor tyrosine kinases, including vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, VEGFR-3), platelet-derived growth factor receptors (PDGFR-α, PDGFR-β), and fibroblast growth factor receptors (FGFR-1, FGFR-2, FGFR-3). It also inhibits RET, FLT3, and Src family kinases. These receptors are involved in angiogenesis, proliferation, and fibrosis.
| Metabolism | Nintedanib is metabolized primarily by esterases (hydrolysis) and to a lesser extent via CYP3A4. The major metabolites are BIBF 1202 (free acid) and its glucuronide conjugate. |
| Excretion | Primarily fecal (85%) as unchanged drug; renal excretion accounts for <1%. |
| Half-life | Terminal half-life: 9.5 hours (range 6-14 hours) in patients with IPF; supports twice-daily dosing. |
| Protein binding | 97.8% bound to plasma proteins, primarily albumin and α1-acid glycoprotein. |
| Volume of Distribution | Vd: 0.6 L/kg (range 0.4-1.0 L/kg), indicating extensive tissue distribution. |
| Bioavailability | Oral: 18-34% (mean 24%); food increases systemic exposure by 20% and reduces variability. |
| Onset of Action | Oral: Steady state achieved within 7 days; clinical effects on FVC decline observed after 12 weeks. |
| Duration of Action | Pharmacodynamic effects persist for 12 hours post-dose; continuous inhibition of tyrosine kinases with twice-daily dosing. |
| Molecular Weight | 649.75 |
150 mg orally twice daily approximately 12 hours apart, taken with food.
| Dosage form | CAPSULE |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (CrCl ≥30 mL/min). Not recommended in severe renal impairment (CrCl <30 mL/min) due to limited data. |
| Liver impairment | Mild hepatic impairment (Child-Pugh A): no dose adjustment. Moderate hepatic impairment (Child-Pugh B): reduce dose to 100 mg orally twice daily. Severe hepatic impairment (Child-Pugh C): not recommended. |
| Pediatric use | Safety and efficacy not established in pediatric patients; no recommended dose. |
| Geriatric use | No specific dose adjustment required based on age alone; monitor tolerability closely due to potential increased risk of gastrointestinal and hepatic adverse effects. |
| 1st trimester | Based on animal studies and its mechanism of action (VEGF receptor inhibitor), there is potential for teratogenicity. Avoid use in first trimester unless benefit outweighs risk. |
| 2nd trimester | Limited human data; animal studies show fetal harm. Use only if clearly needed and benefit outweighs risk. |
| 3rd trimester | Potential for oligohydramnios and fetal renal impairment due to anti-angiogenic effects. Avoid use, especially near term. |
Clinical note
Comprehensive clinical and safety monograph for NINTEDANIB (NINTEDANIB).
| Placental transfer | Based on molecular weight and animal studies, nintedanib is likely to cross the placenta. In rats, fetal plasma levels were approximately 10-20% of maternal levels. |
| Breastfeeding | It is not known whether nintedanib is excreted in human milk. Due to potential for serious adverse reactions in nursing infants, discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother. |
■ FDA Black Box Warning
Nintedanib has a boxed warning for hepatotoxicity, including fatal cases. Liver function tests must be monitored before and during treatment. Dose reduction or interruption may be required.
| Serious Effects |
Hypersensitivity to nintedanib or any excipients
| Precautions | Hepatotoxicity: Monitor liver function tests (ALT, AST, bilirubin) prior to treatment, monthly for 3 months, then every 3 months. Withhold or discontinue if elevations occur., Gastrointestinal adverse events: Diarrhea, nausea, vomiting, abdominal pain. Manage with antidiarrheals, antiemetics, and dose adjustments., Drug-induced liver injury: May present with elevated transaminases and bilirubin; fatal cases reported., Arterial thromboembolic events: Use caution in patients with cardiovascular risk factors; monitor for signs of myocardial infarction or stroke., Hemorrhage: Nintedanib can cause bleeding; avoid in patients with inherited bleeding diatheses or who require full-dose anticoagulation., Gastrointestinal perforation: Rare but serious; discontinue if suspected., Embryo-fetal toxicity: Can cause fetal harm; women of childbearing potential should use effective contraception during and for at least 3 months after treatment. |
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| Lactation Rating | L4 (Possibly Hazardous) |
| Teratogenic Risk | Nintedanib is contraindicated in pregnancy. In animal studies, it caused embryo-fetal toxicity and teratogenic effects at exposures below human therapeutic levels. In humans, it is expected to cause fetal harm if administered during pregnancy. Pregnancy must be ruled out before initiation and avoided during treatment. |
| Fetal Monitoring | Prior to initiating therapy, confirm negative pregnancy test. During treatment, monitor for hepatotoxicity (LFTs), gastrointestinal perforation, bleeding events, hypertension, arterial thromboembolic events, and wound healing complications. In case of unintentional pregnancy exposure, monitor fetal growth via ultrasound and consider consultation with maternal-fetal medicine. |
| Fertility Effects | In animal studies, nintedanib impaired fertility and caused reduced implantation and embryonic survival. In females, it may disrupt menstrual cycles; in males, it may affect spermatogenesis. The impact on human fertility is unknown. Women of reproductive potential should use effective contraception during treatment and for at least 3 months after. |
| Food/Dietary |
| Take with food to reduce gastrointestinal side effects. Avoid grapefruit and grapefruit juice as they inhibit CYP3A4 and may increase nintedanib exposure. Avoid St. John's wort as it may reduce efficacy. No other dietary restrictions. |
| Clinical Pearls | Monitor liver function tests (ALT, AST, bilirubin) before and during treatment; dose reduction or interruption required for moderate hepatic impairment. Check blood pressure regularly due to risk of hypertension and arterial thromboembolic events. Use with caution in patients with bleeding risk or on anticoagulation. Before starting, perform a baseline echocardiogram if history of cardiovascular disease. |
| Patient Advice | Take nintedanib exactly as prescribed, usually twice a day with food. Swallow capsules whole with water; do not crush or chew. · Do not take a missed dose if within 6 hours of the next scheduled dose. Do not double the dose. · Report any signs of liver problems such as yellowing of skin or eyes, dark urine, or severe fatigue. · Monitor for diarrhea and manage with hydration and antidiarrheals; contact your doctor if severe or persistent. · Avoid grapefruit and grapefruit juice during treatment as they may increase nintedanib levels. · Use effective contraception during treatment and for at least 3 months after the last dose; tell your doctor if you become pregnant. · Report any unusual bleeding or bruising, or symptoms of blood clots like sudden chest pain or leg swelling. |