NINTEDANIB ESYLATE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for NINTEDANIB ESYLATE (NINTEDANIB ESYLATE).
Nintedanib esylate is a tyrosine kinase inhibitor that binds competitively to the ATP-binding pocket of 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). This inhibition blocks downstream signaling pathways involved in angiogenesis and fibrosis.
| Metabolism | Primarily metabolized via ester cleavage by esterases to the free acid moiety BIBF 1202; minor metabolism via CYP3A4; the free acid is further glucuronidated (UGT1A1, UGT1A7, UGT1A8, UGT1A10) and excreted in feces. |
| Excretion | Biliary/fecal: >90% (unchanged and metabolites); Renal: <1% |
| Half-life | Terminal elimination half-life is approximately 10 hours in patients with IPF; steady state reached within 7 days. |
| Protein binding | 98%, primarily to albumin and alpha-1 acid glycoprotein |
| Volume of Distribution | Vd/F: 770 L (approximately 11 L/kg, indicating extensive tissue distribution) |
| Bioavailability | Oral: 4.7% due to first-pass metabolism; food increases AUC by approximately 20% |
| Onset of Action | Oral: Clinical effects observed after approximately 2-4 weeks of continuous dosing; maximal effects may take several months. |
| Duration of Action | Duration of action is sustained with continuous twice-daily dosing; effects on FVC decline are maintained over long-term therapy (up to 52 weeks in trials). |
150 mg orally twice daily, 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 for severe renal impairment (CrCl <30 mL/min). |
| Liver impairment | Mild hepatic impairment (Child-Pugh A): 100 mg twice daily. Moderate hepatic impairment (Child-Pugh B): 100 mg twice daily with caution; contraindicated in severe hepatic impairment (Child-Pugh C). |
| Pediatric use | Not established; safety and efficacy not studied in pediatric patients. |
| Geriatric use | No specific dose adjustment recommended based on age alone; monitor for adverse events more frequently due to possible renal or hepatic function decline. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for NINTEDANIB ESYLATE (NINTEDANIB ESYLATE).
| Breastfeeding | It is unknown if nintedanib or its metabolites are excreted in human milk. No data on M/P ratio available. Due to potential serious adverse reactions in the breastfed infant, including tumorigenicity and reproductive toxicity, breastfeeding is not recommended during treatment and for at least 2 weeks after the last dose. |
| Teratogenic Risk | Nintedanib esylate is contraindicated in pregnancy. Based on its mechanism of action (VEGFR, FGFR, and PDGFR inhibition) and animal studies, it is teratogenic and embryotoxic. Use in pregnancy caused fetal malformations and death. First trimester exposure carries the highest risk of structural anomalies. Second and third trimester exposure may impair fetal growth and cause oligohydramnios due to antiangiogenic effects. |
■ FDA Black Box Warning
None (no FDA black box warning)
| Serious Effects |
["Hypersensitivity to nintedanib or any excipients"]
| Precautions | ["Hepatic impairment: risk of elevated liver enzymes and drug-induced liver injury; monitor liver function tests before and during treatment.","Gastrointestinal perforation: occurs in <1% of patients; discontinue if perforation occurs.","Hemorrhage: risk of bleeding; avoid use in patients with a known risk of bleeding.","Arterial thromboembolic events: increased risk in patients with cardiovascular risk factors.","Venous thromboembolism: increased risk; monitor for symptoms.","Hypertension: monitor blood pressure regularly.","Diarrhea, nausea, vomiting: common; manage with antiemetics and antidiarrheals; reduce dose if severe.","Embryofetal toxicity: can cause fetal harm; advise females of reproductive potential to use effective contraception."] |
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| Fetal Monitoring | Before initiating therapy, exclude pregnancy. Conduct pregnancy test in women of childbearing potential prior to treatment and monthly during therapy. Monitor for signs of hepatotoxicity (liver function tests), bleeding, gastrointestinal perforation, hypertension, and arterial thromboembolic events. Fetal monitoring: ultrasound for growth and amniotic fluid volume if accidental exposure occurs. Monitor for oligohydramnios. |
| Fertility Effects | Nintedanib may impair fertility in females of childbearing potential. Animal studies showed reduced fertility and increased preimplantation loss. In males, no effects on fertility were observed in rats, but potential effects on spermatogenesis cannot be excluded. Reversible infertility may occur. |