Ofev (Nintedanib)
nintedanib — multi-targeted tyrosine kinase inhibitor (anti-fibrotic)
Indications
Nintedanib is one of only two anti-fibrotic oral therapies available for interstitial lung diseases. It works by inhibiting multiple receptor tyrosine kinases involved in fibrotic tissue remodelling, including the PDGF, FGF, and VEGF receptor families. Its FDA approval spans three distinct ILD populations, making it the broadest-indicated anti-fibrotic agent for lung fibrosis.
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Idiopathic pulmonary fibrosis (IPF) | Adults | Monotherapy or with pirfenidone | FDA Approved |
| Chronic fibrosing ILDs with a progressive phenotype (PPF) | Adults | Monotherapy | FDA Approved |
| Systemic sclerosis-associated ILD (SSc-ILD) | Adults | Monotherapy or with mycophenolate | FDA Approved |
Nintedanib slows the rate of FVC decline across all three indications; it is not a cure for fibrosis and does not reverse established lung scarring. The primary clinical benefit is delaying disease progression. Nintedanib is also approved in the EU as Vargatef in combination with docetaxel for adenocarcinoma NSCLC (not covered in this monograph).
Chronic hypersensitivity pneumonitis (progressive) — Patients with progressive fibrosing HP were included in the INBUILD trial and showed benefit consistent with the overall PPF population. Evidence quality: high (subgroup of phase 3 trial).
Unclassifiable ILD with progressive fibrosis — Included in INBUILD. Evidence quality: high.
Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| IPF — standard dosing | 150 mg PO BID | 150 mg PO BID | 300 mg/day | Take with food ~12 hours apart; swallow whole Capsules must not be chewed, crushed, or opened |
| PPF — chronic fibrosing ILD with progressive phenotype | 150 mg PO BID | 150 mg PO BID | 300 mg/day | Same dose regardless of underlying ILD type INBUILD trial included HP, autoimmune ILDs, unclassifiable ILD |
| SSc-ILD — slowing FVC decline | 150 mg PO BID | 150 mg PO BID | 300 mg/day | Can be used with stable-dose mycophenolate 49% of SENSCIS patients were on concomitant mycophenolate |
| Mild hepatic impairment (Child-Pugh A) | 100 mg PO BID | 100 mg PO BID | 200 mg/day | Reduced dose; consider interruption or discontinuation for AEs Child-Pugh B/C: NOT recommended |
| Adverse reaction management — dose reduction | 100 mg PO BID | 100 mg PO BID (may re-escalate) | 300 mg/day | Reduce to 100 mg BID for GI/hepatic AEs; if not tolerated at 100 mg BID, discontinue May re-escalate to 150 mg BID once AE resolves |
Diarrhea affects 62–76% of patients depending on indication. Proactive counselling is essential: start anti-diarrheal therapy (loperamide) at first signs, ensure adequate hydration, and take nintedanib with food. Many patients will require dose reduction to 100 mg BID (16–34% across trials), but this is preferable to discontinuation. The diarrhea is typically worst in the first 3 months and may improve with continued therapy. Unlike pirfenidone, nintedanib does not cause photosensitivity, and the two agents can be co-administered without PK interaction.
Pharmacology
Mechanism of Action
Nintedanib is a small molecule that competitively binds to the ATP-binding pocket of multiple receptor tyrosine kinases (RTKs) involved in the pathogenesis of pulmonary fibrosis. It inhibits platelet-derived growth factor receptors (PDGFR-α and -β), fibroblast growth factor receptors (FGFR 1–3), and vascular endothelial growth factor receptors (VEGFR 1–3), as well as colony stimulating factor 1 receptor (CSF1R) and Fms-like tyrosine kinase-3 (FLT-3). Nintedanib also inhibits non-receptor tyrosine kinases Lck, Lyn, and Src. By blocking these kinase-mediated signalling cascades, nintedanib inhibits fibroblast proliferation, migration, and differentiation into myofibroblasts, reduces extracellular matrix deposition, and attenuates angiogenesis within the lungs. The net effect is a slowing of the fibrotic remodelling process that underlies progressive lung function decline in IPF, PPF, and SSc-ILD. Nintedanib does not reverse established fibrosis.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Bioavailability ~4.7% (limited by P-gp efflux and extensive first-pass metabolism); Tmax 2–4 hours; food increases exposure by ~20%; linear PK across 50–450 mg QD and 150–300 mg BID range | Must be taken with food to maximize absorption; very low bioavailability is inherent to the drug and already accounted for in dosing; P-gp substrate status drives key drug interactions |
| Distribution | Vss ~1050 L; protein binding ~97.8% (albumin); extensive tissue distribution; low CNS penetration | Very large Vd indicates extensive peripheral tissue distribution; high protein binding means hemodialysis is not effective for overdose |
| Metabolism | Primarily by ester hydrolysis (esterases) to BIBF 1202 (free acid metabolite), then glucuronidation (UGT1A1 and others) to BIBF 1202 glucuronide; CYP3A4 accounts for only ~5% of metabolism; no CYP inhibition or clinically relevant CYP induction | Ester cleavage (not CYP) is the primary metabolic pathway, reducing traditional CYP-mediated drug interaction risk; however, P-gp interactions remain clinically relevant |
| Elimination | t½ ~10–15 hours; >93% fecal excretion; <1% renal; clearance ~1390 mL/min (IV); steady state within 1 week; accumulation ratio 1.76-fold (negligible) | Predominantly biliary/fecal elimination; no renal dose adjustment needed; steady state reached rapidly; twice-daily dosing appropriate given 10–15 h half-life |
Side Effects
| Adverse Effect | Incidence (IPF / SSc-ILD) | Clinical Note |
|---|---|---|
| Diarrhea | 62% / 76% vs 18% / 32% placebo | Most common AE; usually mild-moderate; occurs in first 3 months; treat early with loperamide and hydration; led to dose reduction in 11–22% and discontinuation in 5–7% |
| Nausea | 24% / 32% vs 7% / 14% placebo | Often accompanies diarrhea; anti-emetics may help; led to discontinuation in 2% |
| Abdominal pain | 15% / 18% vs 6% / 11% placebo | Includes upper and lower abdominal pain and GI pain |
| Liver enzyme elevation | 14% / 13% vs 3% / 3% placebo | ALT/AST ≥3× ULN in 4.9% (SSc-ILD); majority <5× ULN; reversible with dose modification; monitor per protocol |
| Vomiting | 12% / 25% vs 3% / 10% placebo | More common in SSc-ILD; may compromise oral contraceptive efficacy |
| Decreased appetite | 11% / 9% vs 5% / 4% placebo | Contributes to weight loss; monitor nutritional status |
| Weight decreased | 10% / 12% vs 3% / 4% placebo | Monitor weight regularly; consider nutritional support |
| Adverse Effect | Incidence (IPF / SSc-ILD) | Clinical Note |
|---|---|---|
| Headache | 8% / 9% vs 5% / 8% placebo | Generally mild; marginally above placebo |
| Hypertension | 5% / 5% vs 4% / 2% placebo | Includes hypertensive crisis (rare); VEGFR inhibition is the mechanism; monitor blood pressure |
| Fatigue | — / 11% vs — / 7% placebo | SSc-ILD specific; may be disease-related |
| Pyrexia | — / 6% vs — / 5% placebo | SSc-ILD specific |
| Back pain / Dizziness | — / 6% each vs — / 4% each placebo | SSc-ILD specific; marginally above placebo |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Drug-induced liver injury (DILI) | ALT/AST ≥3× ULN: ~5%; fatal cases reported postmarketing | Majority within first 3 months | Monitor LFTs at baseline, regularly × 3 months, then periodically; >5× ULN or >3× ULN with symptoms: discontinue; 3–5× ULN without symptoms: interrupt or reduce to 100 mg BID |
| Arterial thromboembolic events (MI, stroke) | 2.5% vs <1% placebo (IPF); MI 1.5% vs <1% | Any time during treatment | Use caution in patients with coronary artery disease or high CV risk; consider treatment interruption for signs of acute MI |
| Bleeding events | 10–11% vs 7–13% placebo; fatal cases postmarketing | Any time | Use only if benefit outweighs risk in patients with known bleeding risk; monitor patients on anticoagulants closely |
| Gastrointestinal perforation | <1% (IPF); fatal cases postmarketing | Variable | Discontinue nintedanib; use with caution in patients with recent abdominal surgery, diverticular disease, or concurrent corticosteroids/NSAIDs |
| Embryo-fetal toxicity | Teratogenic in animals at <MRHD | Throughout pregnancy | Verify pregnancy status before treatment; use highly effective contraception during and for ≥3 months after last dose; if vomiting/diarrhea may reduce OC absorption, use alternative contraception |
| Nephrotic-range proteinuria | Rare (postmarketing) | Variable | Consider treatment interruption for new or worsening proteinuria; improvement observed after discontinuation in some cases |
Diarrhea affects the majority of patients (62–76%) and is the primary driver of dose reduction (up to 22%) and discontinuation (up to 7%). Proactive management is critical: counsel patients before starting therapy that diarrhea is expected, provide loperamide for early use, advise adequate hydration, take nintedanib with food, and consider dose reduction to 100 mg BID before resorting to discontinuation. Most diarrhea events are mild to moderate, peak in the first 3 months, and do not recur after the initial period.
Drug Interactions
Nintedanib is primarily a substrate of P-glycoprotein (P-gp) and, to a minor extent, CYP3A4. Its metabolism is predominantly via ester hydrolysis (not CYP), so traditional CYP-mediated drug interactions are minimal. Nintedanib does not inhibit or induce CYP enzymes at therapeutic concentrations. The key interaction pathway is P-gp transport, which governs intestinal absorption and exposure levels.
Monitoring
-
Liver Function Tests
Baseline; regular × 3 months; then periodically
Routine ALT, AST, and bilirubin prior to initiation, at regular intervals during the first 3 months, and periodically thereafter. Majority of hepatic events occur in the first 3 months. Higher risk in low body weight (<65 kg), Asian, female, and elderly patients. Discontinue if >3× ULN with symptoms or >5× ULN. -
Pregnancy Testing
Before initiation; during treatment as appropriate
Routine Verify pregnancy status in females of reproductive potential before starting and during therapy. Nintedanib is teratogenic. Ensure highly effective contraception during and for at least 3 months after last dose. -
GI Tolerability
Each visit; proactively in first 3 months
Routine Assess for diarrhea (62–76%), nausea (24–32%), vomiting (12–25%), and abdominal pain (15–18%). Initiate loperamide and hydration early. Dose reduce to 100 mg BID if needed. Discontinue if intolerable at 100 mg BID. -
Blood Pressure
Baseline; each visit
Routine Hypertension reported in 5% vs 2–4% placebo (VEGFR inhibition mechanism). Monitor and manage with standard anti-hypertensives. -
Cardiovascular Risk
Baseline assessment
Trigger-based Arterial thromboembolic events including MI reported in 2.5% vs <1% in IPF trials. Use caution in patients with known CAD. Monitor for signs of acute ischemia. -
Pulmonary Function
Q3–6 months
Routine Serial FVC measurements to assess treatment effect. Nintedanib slows FVC decline but does not improve or stabilize FVC in all patients. Consider continuing treatment if decline rate has slowed relative to pre-treatment trajectory. -
Weight
Each visit
Routine Weight loss reported in 10–12% vs 3–4% placebo. Combined with decreased appetite (9–11%) and GI symptoms, nutritional status should be monitored, especially in underweight patients.
Contraindications & Cautions
Absolute Contraindications
- None formally listed in the FDA PI. However, moderate-to-severe hepatic impairment is effectively a contraindication as the PI states treatment is “not recommended” in Child-Pugh B/C patients.
Relative Contraindications (Specialist Input Recommended)
- Moderate or severe hepatic impairment (Child-Pugh B or C) — nintedanib is predominantly eliminated via biliary/fecal excretion (>90%). Exposure is increased in hepatic impairment. Treatment is not recommended.
- Pregnancy — nintedanib is teratogenic (embryo-fetal deaths and structural abnormalities in animals at <MRHD in rats). Can cause fetal harm. Females of reproductive potential must use highly effective contraception during and for ≥3 months after the last dose.
- Known risk of GI perforation — recent abdominal surgery, diverticular disease, concurrent corticosteroids/NSAIDs. Use only if benefit outweighs risk.
Use with Caution
- Mild hepatic impairment (Child-Pugh A) — reduce dose to 100 mg BID. Monitor closely; consider interruption or discontinuation for adverse reactions.
- Higher cardiovascular risk (known CAD) — arterial thromboembolic events (MI 1.5%) were more frequent with nintedanib in IPF trials. Consider treatment interruption for signs of acute myocardial ischemia.
- Patients on full anticoagulation — VEGFR inhibition may increase bleeding risk. Monitor closely and adjust anticoagulation as necessary.
- Lactation — not recommended; nintedanib and metabolites present in rat milk at concentrations similar to plasma.
- Smokers — smoking decreases nintedanib exposure, which may alter efficacy. Encourage smoking cessation before and during treatment.
- Low body weight (<65 kg), Asian, and female patients — higher risk of liver enzyme elevations. Monitor LFTs more closely.
Nintedanib does not carry a formal FDA Boxed Warning. However, the PI prominently warns about embryo-fetal toxicity (teratogenic in animals at sub-MRHD exposures; pregnancy must be excluded before treatment and highly effective contraception used) and drug-induced liver injury (DILI with fatal outcomes reported in the postmarketing period; LFT monitoring is mandatory). Clinicians should verify pregnancy status and liver function before every initiation of therapy.
Patient Counselling
Purpose of Therapy
Nintedanib is an oral anti-fibrotic medication that works by blocking the growth factors that drive scar tissue formation in the lungs. It slows the rate at which your lung function declines but does not cure the disease or reverse existing scarring. You will need regular blood tests and lung function assessments throughout treatment.
How to Take
Take one capsule twice daily, approximately 12 hours apart, with food. Swallow the capsule whole with liquid. Do not chew, crush, or open the capsule as it has a bitter taste. If you miss a dose, take the next dose at your regular scheduled time; do not double the dose. Do not exceed 300 mg per day.
Sources
- Ofev (nintedanib capsules), for oral use. Full Prescribing Information. Boehringer Ingelheim Pharmaceuticals, Inc. Revised 06/2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/205832s027lbl.pdf Primary source for all dosing, indications, adverse reactions, warnings, PK data, drug interactions, and clinical trial summaries.
- Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2071-2082. doi:10.1056/NEJMoa1402584 INPULSIS-1 and INPULSIS-2 pivotal phase 3 trials for IPF; primary source for IPF adverse reaction rates (Table 1) and FVC decline data.
- Distler O, Highland KB, Gahlemann M, et al. Nintedanib for systemic sclerosis-associated interstitial lung disease. N Engl J Med. 2019;380(26):2518-2528. doi:10.1056/NEJMoa1903076 SENSCIS trial; established nintedanib efficacy in SSc-ILD; source for SSc-ILD-specific adverse reaction rates (Table 2).
- Flaherty KR, Wells AU, Cottin V, et al. Nintedanib in progressive fibrosing interstitial lung diseases. N Engl J Med. 2019;381(18):1718-1727. doi:10.1056/NEJMoa1908681 INBUILD trial; extended nintedanib approval to progressive fibrosing ILDs beyond IPF; included HP, autoimmune ILDs, and unclassifiable ILD.
- Richeldi L, Costabel U, Selman M, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med. 2011;365(12):1079-1087. doi:10.1056/NEJMoa1103690 TOMORROW phase 2 dose-finding trial for IPF; established the 150 mg BID dose and proof of concept.
- Vancheri C, Kreuter M, Richeldi L, et al. Nintedanib with add-on pirfenidone in IPF: results of the INJOURNEY trial. Am J Respir Crit Care Med. 2018;197(3):356-363. doi:10.1164/rccm.201706-1301OC INJOURNEY open-label trial assessing nintedanib + pirfenidone combination; source for GI tolerability data of dual anti-fibrotic therapy.
- Raghu G, Remy-Jardin M, Richeldi L, et al. Idiopathic pulmonary fibrosis (an update) and progressive pulmonary fibrosis in adults: an official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med. 2022;205(9):e18-e47. doi:10.1164/rccm.202202-0399ST Joint ATS/ERS/JRS/ALAT guideline providing conditional recommendation for nintedanib in IPF and PPF.
- Wollin L, Wex E, Pautsch A, et al. Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis. Eur Respir J. 2015;45(5):1434-1445. doi:10.1183/09031936.00174914 Comprehensive preclinical review of nintedanib’s multi-kinase inhibition, anti-fibrotic and anti-angiogenic effects in lung fibrosis models.
- Roth GJ, Binder R, Colbatzky F, et al. Nintedanib: from discovery to the clinic. J Med Chem. 2015;58(3):1053-1063. doi:10.1021/jm501562a Drug discovery story of nintedanib covering SAR, preclinical pharmacology, and early PK characterization.
- Wind S, Schmid U, Freiwald M, et al. Clinical pharmacokinetics and pharmacodynamics of nintedanib. Clin Pharmacokinet. 2019;58(9):1131-1147. doi:10.1007/s40262-019-00766-0 Comprehensive PK review covering bioavailability (~5%), P-gp substrate status, ester hydrolysis metabolism, and covariate effects (weight, age, smoking, ethnicity).
- Stopfer P, Rathgen K, Bischoff D, et al. Pharmacokinetic properties of nintedanib in healthy volunteers and patients with advanced cancer. J Clin Pharmacol. 2016;56(11):1387-1394. doi:10.1002/jcph.752 Phase 1 PK study establishing absolute bioavailability (~5%), Vss (~1050 L), clearance, and half-life in healthy volunteers and cancer patients.