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. |
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 | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for NINTEDANIB (NINTEDANIB).
| Breastfeeding | It is unknown whether nintedanib is excreted in human breast milk. Due to potential adverse effects in the nursing infant, breastfeeding is not recommended during treatment and for at least 3 months after the last dose. M/P ratio is not established. |
| 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. |
■ 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 |
["Known hypersensitivity to nintedanib, peanut, or soya (due to capsule excipients containing lecithin from soybean oil)","Severe hepatic impairment (Child-Pugh class C)","Pregnancy (based on animal studies showing embryofetal toxicity)"]
| 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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| 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. |