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). |
| Molecular Weight | 649.76 |
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 | Avoid use. Teratogenic effects observed in animal studies; inhibits VEGF signaling critical for embryofetal development. |
| 2nd trimester | Avoid use. Potential fetal harm due to antiangiogenic effects. |
| 3rd trimester | Avoid use. Risk of fetal hemorrhage and impaired renal development. |
Clinical note
Comprehensive clinical and safety monograph for NINTEDANIB ESYLATE (NINTEDANIB ESYLATE).
| Placental transfer | Evidence of placental transfer in animals; expected in humans due to low molecular weight and lipophilicity. |
| Breastfeeding | No human data; potential for serious adverse reactions in breastfed infants due to molecular weight and animal toxicity. Advise against breastfeeding during treatment and for at least 3 weeks after last dose. |
■ FDA Black Box Warning
None (no FDA black box warning)
| Serious Effects |
Hypersensitivity to nintedanib or excipientsSevere hepatic impairment (Child-Pugh C)Pregnancy
| 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. |
| Food/Dietary | Avoid grapefruit and grapefruit juice; they may inhibit CYP3A4 and increase nintedanib plasma concentrations. Nintedanib should be taken with food to reduce gastrointestinal adverse effects. |
Loading safety data…
| Lactation Rating |
| L5 (Contraindicated) |
| 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. |
| 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. |
| Clinical Pearls | Monitor liver function tests before and during treatment; dose reduction or interruption may be required for hepatotoxicity. Antiemetic prophylaxis is recommended due to high incidence of nausea, vomiting, and diarrhea. Nintedanib is associated with an increased risk of bleeding; avoid in patients with recent hemorrhagic events or requiring anticoagulation. Check for drug interactions with P-glycoprotein inhibitors (e.g., verapamil, ketoconazole) and CYP3A4 inducers (e.g., rifampin), which may alter nintedanib exposure. Use with caution in patients with renal impairment (CrCl <30 mL/min) as safety data are limited. |
| Patient Advice | Take capsules with food and swallow whole with water; do not open, crush, or chew. · Do not take a double dose; if a dose is missed, skip it and take the next dose at the scheduled time. · Contact your healthcare provider immediately if you experience signs of liver problems (yellowing of skin or eyes, dark urine, abdominal pain), bleeding (unusual bruising, black tarry stools), or severe diarrhea. · Use effective contraception during treatment and for at least 3 months after the last dose; nintedanib may cause fetal harm. · Avoid grapefruit and grapefruit juice during treatment as they may increase drug levels and risk of side effects. · Report any new or worsening shortness of breath, as drug-induced interstitial lung disease has been reported (though rare). |