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Nintedanib

Nintedanib is an oral small-molecule tyrosine kinase inhibitor indicated for the treatment of idiopathic pulmonary fibrosis (IPF) and other progressive fibrosing interstitial lung diseases in adults, as well as systemic sclerosis-associated interstitial lung disease (SSc-ILD).^[1] Developed by Boehringer Ingelheim and marketed under the brand name Ofev, it was first approved by the U.S. Food and Drug Administration (FDA) in October 2014 for IPF, marking it as one of the first therapies to slow disease progression in this condition.^[2] Subsequent approvals expanded its use to SSc-ILD in 2019 and chronic fibrosing ILDs with a progressive phenotype in 2020.^[1] In Europe, the European Medicines Agency (EMA) authorized it in January 2015, with similar expansions for adult use and pediatric indications (ages 6 and older) approved in March 2025 for progressive fibrosing ILDs and SSc-ILD.^[3] The drug's mechanism of action involves competitive binding to the ATP-binding pocket of multiple receptor tyrosine kinases, including vascular endothelial growth factor receptors (VEGFR 1-3), platelet-derived growth factor receptors (PDGFR α/β), and fibroblast growth factor receptors (FGFR 1-3), as well as non-receptor tyrosine kinases like FLT3 and Src family kinases.^[4] This inhibition disrupts downstream signaling pathways that promote fibroblast proliferation, migration, and extracellular matrix deposition, thereby reducing fibrotic remodeling in the lungs and exhibiting anti-angiogenic effects.^[1] Preclinical studies have demonstrated its ability to attenuate bleomycin-induced lung fibrosis in animal models, supporting its antifibrotic properties.^[2] Nintedanib is administered as soft capsules (100 mg or 150 mg) taken twice daily with food to enhance bioavailability, which is approximately 4.7% under fed conditions.^[4] The recommended adult dose is 150 mg every 12 hours, with reductions to 100 mg for intolerance or mild hepatic impairment (Child-Pugh Class A); it is contraindicated in moderate or severe hepatic impairment.^[1] For pediatric patients (6-17 years), dosing is weight-based, starting at 50 mg twice daily for those weighing 13.5-22.9 kg and scaling up to 150 mg for those 57.5 kg or more.^[3] Pharmacokinetically, it exhibits linear absorption with a half-life of 9.5-15 hours, high plasma protein binding (97.8%), and primary elimination via biliary/fecal excretion (>93%), with minimal renal clearance (<1%).^[1] Beyond its primary indications, nintedanib has been approved in combination with docetaxel for second-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) of adenocarcinoma histology in adults previously treated with chemotherapy, under the brand name Vargatef in Europe since 2014.^[4] Clinical trials, such as the INPULSIS studies for IPF and SENSCIS for SSc-ILD, demonstrated statistically significant reductions in the rate of forced vital capacity (FVC) decline, confirming its efficacy in slowing lung function deterioration.^[2] However, common adverse effects include diarrhea (62-76% of patients), nausea, vomiting, and elevated liver enzymes, often requiring dose interruptions or reductions, while serious risks encompass arterial thromboembolism, bleeding, gastrointestinal perforation, and embryo-fetal toxicity, necessitating careful monitoring and contraception in patients of reproductive potential.^[1]

Medical uses

Idiopathic pulmonary fibrosis

Nintedanib was approved by the U.S. Food and Drug Administration (FDA) in October 2014 for the treatment of idiopathic pulmonary fibrosis (IPF) in adults, marking it as one of the first antifibrotic therapies specifically indicated to slow lung function decline in this condition.^[5] This approval stemmed from the pivotal phase 3 INPULSIS trials, which enrolled over 1,000 patients with IPF and demonstrated that nintedanib significantly reduced the annual rate of decline in forced vital capacity (FVC) by approximately 50% compared to placebo over 52 weeks (adjusted mean difference of 125 ml/year in INPULSIS-01 and 90 ml/year in INPULSIS-02).^[6] These trials established nintedanib's role in mitigating disease progression, with the primary endpoint met in both studies, supporting its use as a standard therapy for eligible patients.^[6] The recommended dosing regimen for nintedanib in IPF is 150 mg taken orally twice daily, approximately 12 hours apart and following meals to improve tolerability.^[7] Dose reductions to 100 mg twice daily or temporary interruptions are advised for managing common adverse effects like diarrhea, allowing most patients to continue treatment long-term.^[7] Patient selection criteria from the INPULSIS trials focus on adults aged 40 years or older with mild to moderate IPF, typically those having an FVC of at least 50% predicted and a diffusing capacity of the lung for carbon monoxide (DLCO) between 30% and 79% predicted, ensuring the therapy targets individuals with sufficient lung function to benefit from antifibrotic intervention.^[6] Long-term efficacy has been substantiated through the INPULSIS-ON open-label extension study, involving over 1,200 patients from the original trials who continued nintedanib for up to 5.5 years.^[8] This extension demonstrated sustained slowing of FVC decline (annual rate of approximately -100 to -120 ml/year) and a reduced risk of investigator-reported acute exacerbations (hazard ratio 0.32 compared to placebo lead-in), with benefits persisting beyond 4 years in those adherent to therapy.^[8] Compared to pirfenidone, the other primary antifibrotic approved for IPF, nintedanib shows comparable efficacy in reducing FVC decline over 52 weeks (both achieving around 50% reduction relative to placebo in respective trials), though real-world and post-hoc analyses indicate similar overall slowing of disease progression but with differing tolerability profiles—nintedanib more often associated with gastrointestinal issues versus pirfenidone's higher rates of photosensitivity and nausea.^[9]

Systemic sclerosis-associated interstitial lung disease

In September 2019, the U.S. Food and Drug Administration (FDA) approved nintedanib (Ofev) for the treatment of systemic sclerosis-associated interstitial lung disease (SSc-ILD) in adults, marking it as the first therapy specifically indicated to slow the rate of decline in pulmonary function in this condition. This approval was based on the results of the phase III SENSCIS trial, a randomized, double-blind, placebo-controlled study involving 576 patients with SSc-ILD, of whom approximately 52% had diffuse cutaneous systemic sclerosis and 48% were receiving mycophenolate at baseline.^[10] The trial demonstrated that nintedanib reduced the annual rate of forced vital capacity (FVC) decline by 44%, with an adjusted mean decline of -52.4 mL/year in the nintedanib group compared to -93.3 mL/year in the placebo group (difference of 40.9 mL/year; 95% CI, 2.9 to 78.8; P=0.04).^[10] The SENSCIS trial's primary endpoint focused on the change in FVC over 52 weeks, confirming nintedanib's antifibrotic benefit in preserving lung function specific to SSc-ILD. Secondary endpoints included the modified Rodnan skin score (mRSS), which showed no significant difference between groups (adjusted mean change of -2.17 with nintedanib vs. -1.96 with placebo; difference -0.21; 95% CI, -0.94 to 0.53; P=0.58), indicating no impact on skin fibrosis. Additionally, the St. George's Respiratory Questionnaire (SGRQ) total score, a measure of health-related quality of life, exhibited no significant improvement (adjusted mean change of 0.81 with nintedanib vs. -0.88 with placebo; difference 1.69; 95% CI, -0.73 to 4.12). These findings underscore nintedanib's targeted role in mitigating lung function deterioration while integrating with standard SSc management, such as immunosuppressive therapies.^[10] Nintedanib is administered at a dose of 150 mg twice daily, approximately 12 hours apart, with capsules taken whole and with food to enhance gastrointestinal tolerability and increase systemic exposure by about 20%, which is particularly relevant for SSc patients who often experience gastrointestinal involvement that may affect drug absorption.^[7] In the SENSCIS trial, gastrointestinal adverse events, primarily diarrhea (75.7% vs. 31.6% with placebo), were common but mostly mild to moderate, necessitating dose interruptions or reductions in about 25% of patients; this profile highlights the need for proactive management of gastrointestinal symptoms in the context of SSc's multisystem effects.^[10] In March 2025, the European Commission extended approval of nintedanib to children and adolescents aged 6 to 17 years with SSc-ILD, based on pharmacokinetic, safety, and efficacy extrapolation data from adult studies and the InPedILD trial; dosing is weight-based (50-150 mg twice daily). This pediatric indication is not yet approved by the FDA.^[11] Post-approval real-world studies have supported these trial outcomes, showing sustained slowing of FVC decline and a significant reduction in hospitalizations for respiratory issues after 12 months of nintedanib therapy in patients with connective tissue disease-associated ILD, including SSc-ILD (p<0.0001).^[12]

Progressive fibrosing interstitial lung diseases

Nintedanib is approved for the treatment of adults with chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype, excluding idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated ILD (SSc-ILD).^[7] The European Commission granted approval on July 15, 2020, based on results from the INBUILD trial demonstrating slowed lung function decline in this patient population.^[13] Similarly, the U.S. Food and Drug Administration (FDA) approved nintedanib on March 9, 2020, for the same indication.^[14] This approval targets heterogeneous chronic fibrosing ILDs, such as hypersensitivity pneumonitis and rheumatoid arthritis-associated ILD, in patients exhibiting evidence of disease progression.^[7] The progressive phenotype in chronic fibrosing ILDs is diagnosed through a multidisciplinary evaluation confirming worsening despite standard care.^[15] Key criteria include at least two of the following within the previous 24 months: a relative decline in forced vital capacity (FVC) of ≥10%; a relative FVC decline of 5% to <10% accompanied by worsening symptoms or imaging; or worsening respiratory symptoms or high-resolution computed tomography (HRCT) findings of fibrosis progression, irrespective of FVC stability.^[16] Patients typically show a ≥2% absolute decline in FVC or persistent worsening symptoms, prompting consideration for antifibrotic therapy like nintedanib, which shares a tyrosine kinase inhibition mechanism to target fibrotic pathways observed in IPF.^[7] The pivotal INBUILD trial, a randomized, double-blind, placebo-controlled phase 3 study, evaluated nintedanib (150 mg twice daily) in 663 adults with progressive fibrosing ILDs across 13 countries.^[16] Over 52 weeks, nintedanib reduced the adjusted annual rate of FVC decline by 57% compared to placebo (−80.8 mL/year versus −187.8 mL/year; rate ratio 0.43, 95% CI 0.34–0.53; P<0.001), indicating slowed disease progression.^[16] This benefit was observed without increased risk of acute exacerbations or death, though gastrointestinal adverse events were common and managed with dose adjustments.^[16] Subgroup analyses from INBUILD demonstrated consistent FVC benefits across underlying ILD etiologies, including hypersensitivity pneumonitis (rate ratio 0.34), rheumatoid arthritis-ILD (rate ratio 0.47), and unclassifiable ILD (rate ratio 0.45), supporting broad applicability in non-IPF progressive fibrosing ILDs.^[16] Treatment requires a confirmed progressive diagnosis via multidisciplinary review, including pulmonologists, radiologists, and pathologists. The recommended dose is 150 mg orally twice daily, approximately 12 hours apart, with or without food; permanent discontinuation is advised for moderate hepatic impairment, and dose reduction to 100 mg twice daily may be needed for tolerability issues.^[7] Ongoing monitoring includes regular FVC assessments and liver function tests to optimize safety.^[7] In March 2025, the European Commission extended approval of nintedanib to children and adolescents aged 6 to 17 years with chronic fibrosing ILDs with a progressive phenotype (excluding IPF), based on safety data from the InPedILD trial and extrapolation from adult efficacy; dosing is weight-based (50-150 mg twice daily). This pediatric indication is not approved by the FDA, where effectiveness has not been established in patients under 18 years.^[11]

Non-small cell lung cancer

Nintedanib, marketed as Vargatef in oncology settings, is authorized in the European Union for use in combination with docetaxel as second-line therapy for adults with locally advanced, metastatic, or locally recurrent non-small cell lung cancer (NSCLC) of adenocarcinoma histology following failure of first-line chemotherapy.^[17] This conditional approval was granted by the European Commission on 21 November 2014, based on data from the pivotal phase 3 LUME-Lung 1 trial, which evaluated nintedanib plus docetaxel versus placebo plus docetaxel in patients with advanced NSCLC progressing after platinum-based first-line therapy.^[18] The indication is specifically limited to adenocarcinoma due to the observed benefits being most pronounced in this histological subgroup, reflecting nintedanib's targeted inhibition of angiogenic pathways that may be more relevant in this tumor type.^[19] In the LUME-Lung 1 trial, a double-blind, randomized, placebo-controlled study involving 1,314 patients, the addition of nintedanib to docetaxel significantly prolonged progression-free survival (PFS), the primary endpoint, with a median of 3.4 months (95% CI 2.9-3.9) compared to 2.7 months (95% CI 2.6-2.9) in the placebo arm (hazard ratio [HR] 0.79; 95% CI 0.68-0.92; p=0.0019).^[19] Overall survival (OS) showed a numerical improvement of 1.0 month (median 10.1 months vs. 9.1 months; HR 0.94; 95% CI 0.83-1.07; p=0.37), but achieved statistical significance in the prespecified adenocarcinoma subgroup, where median OS was 12.6 months versus 10.6 months (HR 0.83; 95% CI 0.70-0.99; p=0.0359).^[19] These results established nintedanib's role as an adjunctive agent enhancing the efficacy of docetaxel, particularly in adenocarcinoma, though benefits were less evident in squamous histology. Post-approval analyses and real-world studies have confirmed modest PFS gains but highlighted challenges in broader adoption due to the absence of confirmatory trials replicating OS benefits across diverse populations and the lack of approval in major markets like the United States.^[20] The recommended dosing regimen for nintedanib in NSCLC is 200 mg administered orally twice daily on days 2-21 of each 21-day cycle, alongside docetaxel 75 mg/m² intravenously on day 1; this represents a higher exposure than the 150 mg twice-daily dose used in interstitial lung disease indications to optimize antitumor activity while managing tolerability.^[18] Nintedanib's mechanism involves triple kinase inhibition of vascular endothelial growth factor receptors (VEGFR 1-3), fibroblast growth factor receptors (FGFR 1-3), and platelet-derived growth factor receptors (PDGFR α/β), thereby disrupting tumor angiogenesis and stromal interactions critical in NSCLC progression.^[21] The combination's safety profile is characterized by additive gastrointestinal and hematologic toxicities, with diarrhea (any grade: 75% vs. 44% with placebo plus docetaxel; grade ≥3: 8% vs. <1%), nausea, and vomiting more common with nintedanib, alongside docetaxel-related events like neutropenia (72% vs. 63%; grade ≥3: 45% vs. 40%) and fatigue.^[19] Adverse event management emphasizes proactive monitoring and dose modifications: nintedanib interruptions for up to 3 weeks followed by reductions to 150 mg or 100 mg twice daily for persistent grade 3 diarrhea or liver enzyme elevations (ALT/AST >5× upper limit of normal), with permanent discontinuation if unresolved; docetaxel dose reductions (to 60 mg/m²) address neutropenia or neuropathy, supported by antiemetics, antidiarrheals (e.g., loperamide), and growth factors as needed.^[22] Overall discontinuation rates due to adverse events were similar between arms (18% vs. 16%), indicating a tolerable profile when managed appropriately.^[19]

Pharmacology

Mechanism of action

Nintedanib is a small-molecule kinase inhibitor that targets receptor tyrosine kinases including vascular endothelial growth factor receptors (VEGFR 1-3), fibroblast growth factor receptors (FGFR 1-3), platelet-derived growth factor receptors (PDGFR α/β), colony-stimulating factor 1 receptor (CSF1R), and FMS-like tyrosine kinase 3 (FLT3), as well as non-receptor tyrosine kinases such as Lck, Lyn, and Src family kinases.^[1] By competitively binding to the ATP-binding pocket of these kinases, nintedanib inhibits their autophosphorylation and activation, with representative IC₅₀ values of 13-34 nM for VEGFR, 37-108 nM for FGFR, and 59-65 nM for PDGFR.^[23] This multi-targeted approach disrupts key signaling involved in pathological fibrosis and angiogenesis. The inhibition of VEGFR, FGFR, and PDGFR by nintedanib blocks downstream intracellular pathways, including the PI3K/Akt and MAPK cascades, which are critical for cell survival, proliferation, and migration. Consequently, nintedanib reduces fibroblast proliferation, prevents myofibroblast transformation, and limits extracellular matrix deposition, thereby attenuating fibrotic processes in the lung.^[24] Additionally, VEGFR blockade confers potent anti-angiogenic effects by suppressing endothelial cell proliferation and vascular remodeling, mechanisms relevant to both interstitial lung diseases and tumor progression.^[25] Nintedanib demonstrates high selectivity for its primary targets, showing minimal inhibitory activity against other kinases such as the epidermal growth factor receptor (EGFR) or insulin-like growth factor receptor (IGFR), which helps mitigate off-target effects.^[23] In preclinical studies using bleomycin-induced lung fibrosis models in mice and rats, nintedanib administration significantly reduced collagen accumulation, inflammatory cell infiltration, and overall fibrotic burden in the lungs.^[23]

Pharmacokinetics

Nintedanib exhibits low oral bioavailability of approximately 5%, primarily attributed to extensive first-pass metabolism in the liver and gut wall.^[26] Following oral administration, peak plasma concentrations are achieved within 2–4 hours, with the pharmacokinetics demonstrating time-independent characteristics across single and multiple doses.^[27] Steady-state plasma concentrations are reached after about 1 week of twice-daily dosing, accompanied by a 1.4-fold accumulation.^[26] The drug is highly bound to plasma proteins, at 97.8%, mainly to albumin, and has a large volume of distribution of approximately 1050 L, indicating extensive tissue distribution.^[27] Nintedanib is primarily metabolized by non-cytochrome P450-mediated hydrolysis via esterases to the inactive carboxylic acid metabolite BIBF 1202, which undergoes subsequent glucuronidation; a minor pathway involves CYP3A4-mediated O-demethylation to BIBF 1053.^[26] The effective half-life is approximately 9.5 hours, supporting twice-daily administration, while the terminal half-life ranges from 10 to 15 hours.^[27] Elimination occurs predominantly via biliary and fecal routes, with 93.4% of the dose recovered in feces and less than 1% in urine, reflecting minimal renal clearance.^[26] Administration with food increases systemic exposure by about 20% (AUC) and 15% (C_max), though it is recommended to take nintedanib with food to improve gastrointestinal tolerability despite this effect.^[27] In special populations, hepatic impairment reduces clearance; in patients with mild hepatic impairment (Child-Pugh Class A), the recommended dose is 100 mg twice daily with monitoring, while treatment is not recommended in moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment.^[1] No dose adjustments are needed for mild to moderate renal impairment due to the negligible urinary excretion.^[27]

Drug interactions

Nintedanib is metabolized primarily by non-CYP pathways, with minor involvement of CYP3A4, which forms the basis for potential interactions with strong CYP3A4 inhibitors.^[1] Coadministration of nintedanib with strong CYP3A4 inhibitors, such as ketoconazole, increases nintedanib exposure approximately 1.6-fold based on AUC and 1.8-fold based on C_max.^[1]^[28] Patients receiving concomitant strong CYP3A4 inhibitors should be monitored closely for tolerability, with management of adverse reactions potentially requiring dose interruption, reduction to 100 mg twice daily, or discontinuation.^[1] Inhibitors of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), such as ritonavir, may elevate nintedanib plasma levels by reducing efflux.^[1] Concomitant use requires close monitoring for signs of toxicity, with dose adjustments as needed based on tolerability.^[29] Proton pump inhibitors (PPIs), such as omeprazole, do not significantly alter nintedanib exposure despite its pH-dependent solubility, as shown in clinical studies where coadministration had no effect on trough concentrations or overall pharmacokinetics.^[1] Although some guidelines suggest potential minor reductions in absorption (up to 25% in isolated reports), official recommendations do not require dose adjustments, but spacing administration or alternatives may be considered if concerns arise.^[3] Antacids, such as those containing aluminum and magnesium hydroxide (e.g., Maalox TC), have minimal impact on nintedanib pharmacokinetics when administered at least 2 hours after nintedanib dosing.^[1] No significant pharmacokinetic interactions occur between nintedanib and pirfenidone when coadministered in patients with idiopathic pulmonary fibrosis, with exposure to neither agent altered.^[30] Similarly, combination therapy with docetaxel shows no apparent pharmacokinetic interactions, supporting its use in non-small cell lung cancer regimens without dose modifications for this reason.^[31]

Safety and administration

Contraindications

Nintedanib is contraindicated in patients with hypersensitivity to the active substance, peanut, soya, or any of the excipients.^[3] It is also contraindicated during pregnancy, as animal studies have demonstrated teratogenic effects and embryotoxicity, and there are no adequate data in humans to confirm safety, posing a significant risk of fetal harm.^[1]^[3] Treatment with nintedanib is not recommended in patients with moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment due to substantially increased drug exposure and limited safety data.^[1]^[3] Breastfeeding is not recommended during treatment and for at least 3 months afterward, as nintedanib and its metabolites may be excreted in breast milk, potentially harming the infant.^[3] Concomitant administration with strong P-glycoprotein or CYP3A4 inducers, such as rifampicin, is not recommended, as it significantly reduces nintedanib plasma concentrations and may compromise efficacy.^[1]^[18] Caution is advised in patients with active or recent peptic ulcer disease, as nintedanib increases the risk of gastrointestinal perforation.^[3] Similarly, use in patients with cardiovascular risk factors or a history of bleeding requires weighing benefits against risks, with close monitoring for arterial thromboembolism or hemorrhage.^[1]^[18]

Adverse effects

Nintedanib is associated with a range of adverse effects, primarily gastrointestinal and hepatic, observed across its indications for idiopathic pulmonary fibrosis (IPF), systemic sclerosis-associated interstitial lung disease (SSc-ILD), progressive fibrosing interstitial lung diseases (PF-ILD), and non-small cell lung cancer (NSCLC). The most common adverse effects, occurring in more than 20% of patients in ILD indications, include diarrhea (62-76%), which is typically mild to moderate and managed with antidiarrheal agents such as loperamide along with adequate hydration. Nausea affects approximately 24-32% of patients in these settings, often resolving with supportive care. Elevations in liver enzymes (ALT/AST) occur in 13-23% of cases, usually transient and reversible upon dose adjustment. In pediatric patients (ages 6-17 years) treated under EMA approval for fibrosing ILDs and SSc-ILD, the adverse effect profile is similar to adults, with common events including diarrhea, nausea, and elevated liver enzymes; additional monitoring for growth, dental health, and long-term effects is recommended.^[7]^[3]^[32] Serious adverse effects, reported in at least 1% of patients, include arterial thromboembolism (1-3%), manifesting as myocardial infarction or stroke, and drug-induced liver injury, which can be severe and requires prompt monitoring. Gastrointestinal perforation is rare, occurring in less than 1% of cases, but necessitates immediate discontinuation of therapy. These events are monitored through regular clinical assessments, with incidence rates derived from pooled clinical trial data.^[7]^[6]^[3] Incidence of gastrointestinal effects is notably higher in ILD indications (diarrhea 62-76%) compared to NSCLC (diarrhea approximately 42% when combined with docetaxel), reflecting differences in patient populations and concomitant therapies. Overall, 15-21% of patients discontinue nintedanib due to adverse effects, predominantly gastrointestinal. Certain drug interactions, such as with potent CYP3A4 inducers, may exacerbate gastrointestinal or hepatic effects.^[7]^[3]^[33] Management strategies emphasize dose interruption or reduction (from 150 mg to 100 mg twice daily) for grade 3 or higher events, with resumption at the full dose once resolved. Liver function should be monitored monthly for the first three months, then periodically thereafter. In long-term use, tolerability improves over time, with approximately 70% of patients maintaining the full dose at one year in extended follow-up studies, and no new safety signals emerging beyond the initial profile.^[7]^[3]^[34]

Dosage and administration

Nintedanib is administered orally, with the standard recommended dose varying by indication. For idiopathic pulmonary fibrosis (IPF), systemic sclerosis-associated interstitial lung disease (SSc-ILD), and other progressive fibrosing interstitial lung diseases (PF-ILDs), the dose is 150 mg twice daily, approximately 12 hours apart, taken with food. For non-small cell lung cancer (NSCLC) in combination with docetaxel, the dose is 200 mg twice daily on days 2 through 21 of a standard 21-day docetaxel cycle, also taken with food and not on day 1 of docetaxel administration. The twice-daily regimen is selected based on nintedanib's pharmacokinetic profile, which achieves effective steady-state plasma concentrations with this schedule.^[1]^[18]^[1] Under EMA approval (as of March 2025), for pediatric patients (ages 6-17 years) with PF-ILDs or SSc-ILD, dosing is weight-based twice daily with food: 50 mg for 13.5-22.9 kg, 75 mg for 23.0-33.4 kg, 100 mg for 33.5-57.4 kg, and 150 mg for ≥57.5 kg. For mild hepatic impairment (Child-Pugh A), reduce starting dose proportionally (e.g., 100 mg for adults). Effectiveness has not been established in pediatrics per FDA labeling.^[3]^[32] Capsules should be swallowed whole with liquid and not chewed or crushed; if a dose is missed, the next dose should be taken at the regularly scheduled time without doubling up.^[1] Dose adjustments may be necessary for tolerability. In patients experiencing intolerable adverse events, the dose can be reduced to 100 mg twice daily (for ILD indications) or in 50 mg decrements (e.g., to 150 mg twice daily for NSCLC), with further interruption or discontinuation if symptoms persist or worsen.^[1]^[18] For mild hepatic impairment (Child-Pugh class A), the starting dose is reduced to 100 mg twice daily for ILD indications; treatment is not recommended for moderate or severe hepatic impairment in any indication.^[1]^[18] Monitoring is essential to ensure safe use. Liver function tests, including ALT, AST, and total bilirubin, should be performed prior to initiation, monthly for the first 3 months, and then every 3 months thereafter, or more frequently if elevations occur.^[1] For ILD indications, forced vital capacity (FVC) assessments are recommended every 3 to 6 months to monitor disease progression.^[1] No dose adjustment is required for mild to moderate renal impairment (creatinine clearance ≥30 mL/min), but nintedanib has not been studied in severe renal impairment or end-stage renal disease, where use is not recommended.^[1]^[18]

Chemistry

Chemical structure

Nintedanib has the molecular formula C₃₁H₃₃N₅O₄ and a molecular weight of 539.63 g/mol.^[35] Its IUPAC name is 3-Z-[1-(4-(N-((4-methylpiperazin-1-yl)acetyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone.^[25] Nintedanib is an indolinone derivative characterized by a central 2-indolinone (oxindole) ring system, which serves as the core scaffold common to several tyrosine kinase inhibitors. This core is substituted at the 6-position with a methoxycarbonyl (methyl ester) group, enhancing its binding affinity to kinase domains. At the 3-position, it features a (Z)-configured methylidene bridge [=C(phenyl)-] connected to an N-(4-substituted phenyl)amino group, where the phenyl ring bears a methyl[2-(4-methylpiperazin-1-yl)acetyl]amino substituent at the para position; this side chain contributes to the molecule's solubility and specific interactions with target kinases.^[25]^[35] Structurally, nintedanib belongs to the class of 3-substituted indolin-2-ones and shares the indolinone core with other multi-kinase inhibitors like sunitinib, though it demonstrates enhanced selectivity for vascular endothelial growth factor receptors (VEGFR), fibroblast growth factor receptors (FGFR), and platelet-derived growth factor receptors (PDGFR).^[25]

Physical and chemical properties

Nintedanib esylate, the active pharmaceutical ingredient, appears as a pale yellow to bright greenish-yellow, non-hygroscopic powder.^[36] The commercial formulation is presented as soft gelatin capsules in 100 mg (peach-colored, opaque, oblong) and 150 mg (brown-colored, opaque, oblong) strengths, imprinted with the Boehringer Ingelheim logo and dosage identifier.^[7] These capsules contain the drug substance suspended in a fill material comprising medium-chain triglycerides, lauroyl macrogol glycerides (a polyethylene glycol derivative), and lecithin, encapsulated in a shell of gelatin, glycerol, titanium dioxide, and iron oxides.^[7]^[36] Nintedanib esylate exhibits poor aqueous solubility at neutral and higher pH values, classifying it as BCS Class II, with solubility increasing markedly at acidic pH below 3 due to protonation.^[36]^[37] Its lipophilicity is indicated by a logP value of 3.0, reflecting favorable partitioning into lipid environments.^[25] The pKa of approximately 7.23 corresponds to a basic site, contributing to the pH-dependent ionization and solubility profile.^[38] This physicochemical behavior underpins the drug's oral bioavailability, as gastric pH influences absorption.^[37] The compound demonstrates high stability, remaining unchanged under thermal, acidic, basic, oxidative, and humidity stress conditions, with no polymorphic transitions observed.^[36] It is not photosensitive and supports a shelf life of up to 60 months when stored at or below 25°C and 60% relative humidity.^[36] Recommended storage for the formulated capsules is at controlled room temperature (20–25°C), with protection from excessive heat and high humidity to maintain integrity.^[7]

History

Development and initial approvals

Nintedanib, originally designated as BIBF 1120, was discovered by Boehringer Ingelheim in the early 2000s as part of a research program initiated in 1998 to develop small-molecule angiogenesis inhibitors for cancer therapy.^[25] The lead optimization efforts culminated in 2001 with the selection of BIBF 1120 for preclinical development, targeting key receptors such as vascular endothelial growth factor receptors (VEGFR), platelet-derived growth factor receptors (PDGFR), and fibroblast growth factor receptors (FGFR) to inhibit tumor angiogenesis and stromal support.^[25] Early clinical evaluation focused on oncology, with phase I trials for advanced solid tumors, including non-small cell lung cancer (NSCLC), commencing in 2006 to assess safety, pharmacokinetics, and maximum tolerated dose.^[39] A phase II double-blind study in patients with relapsed advanced NSCLC followed in 2007, evaluating two doses of BIBF 1120 versus placebo, which demonstrated preliminary antitumor activity and tolerability up to 250 mg twice daily.^[40] Concurrently, exploratory phase II investigations in idiopathic pulmonary fibrosis (IPF) began around 2007 with the TOMORROW trial (NCT00514683), revealing initial antifibrotic signals through reduced decline in forced vital capacity after 12 months of treatment at 150 mg twice daily compared to placebo.^[41] In 2013, nintedanib received orphan drug designation from the European Medicines Agency for the treatment of IPF, recognizing the unmet need in this rare disease.^[42] The compound's shift toward IPF was supported by pivotal phase III INPULSIS-1 and INPULSIS-2 trials (NCT01335464 and NCT01335477), which enrolled over 1,000 patients and demonstrated that nintedanib at 150 mg twice daily reduced the annual rate of forced vital capacity decline by approximately 50% versus placebo.^[6] These results led to the first regulatory approval for IPF by the European Medicines Agency in January 2015 (positive Committee for Medicinal Products for Human Use opinion in November 2014), marketed as Ofev, followed shortly by U.S. Food and Drug Administration approval on October 15, 2014.^[43]^[23] For NSCLC, phase III LUME-Lung 1 trial data supported initial approval in Europe in November 2014 for use in combination with docetaxel in adults with locally advanced, metastatic, or recurrent adenocarcinoma of the NSCLC subtype after first-line chemotherapy, marketed as Vargatef.^[17]

Expansions to additional indications

Following its initial approvals for idiopathic pulmonary fibrosis (IPF) and non-small cell lung cancer (NSCLC), nintedanib received regulatory expansions to address additional interstitial lung disease (ILD) indications, reflecting evidence from pivotal clinical trials demonstrating its antifibrotic effects in broader fibrosing phenotypes. In 2019, the U.S. Food and Drug Administration (FDA) approved nintedanib for the treatment of systemic sclerosis-associated ILD (SSc-ILD) in adults, based on the phase 3 SENSCIS trial, which enrolled 576 patients and showed that nintedanib reduced the annual rate of forced vital capacity (FVC) decline by 44% compared to placebo over 52 weeks, with a favorable risk-benefit profile.^[44] The European Medicines Agency (EMA) followed with approval for SSc-ILD in adults in April 2020.^[45] Nintedanib's label was further expanded to chronic fibrosing ILDs with a progressive phenotype, encompassing conditions beyond IPF and SSc-ILD, such as hypersensitivity pneumonitis and autoimmune ILDs exhibiting progressive fibrosis. The EMA granted approval for this indication in adults in July 2020, supported by the phase 3 INBUILD trial involving 663 patients with heterogeneous progressive fibrosing ILDs, where nintedanib slowed the FVC decline by 47% relative to placebo over 52 weeks, irrespective of underlying ILD diagnosis.^[32]^[13] The FDA approved the same indication in March 2020, marking nintedanib as the first therapy for this group of progressive fibrosing ILDs.^[14] These expansions were informed by post-marketing data and subgroup analyses from INBUILD, which supported broader application to ILD phenotypes showing progressive fibrosis despite standard care, without altering the established 150 mg twice-daily dosing regimen across indications. In the NSCLC domain, nintedanib's use post-initial launch was refined to focus on adenocarcinoma histology following confirmatory trial outcomes. Approved in the EU in 2014 in combination with docetaxel for second-line treatment of locally advanced or metastatic adenocarcinoma NSCLC after first-line chemotherapy, based on the phase 3 LUME-Lung 1 trial showing improved overall survival (median 10.3 months vs. 7.9 months with placebo plus docetaxel), the indication remained limited to this subtype due to negative results in squamous NSCLC from the LUME-Lung 3 trial, which failed to meet its primary endpoint of progression-free survival.^[17]70586-4/fulltext) In 2021, the EMA implemented a partial withdrawal of marketing authorization for Vargatef (nintedanib's oncology brand) in certain contexts, reflecting ongoing evaluation of confirmatory data from LUME-Lung 2 (nonsquamous NSCLC with pemetrexed), which demonstrated progression-free survival benefit but no overall survival improvement, leading to no further broadening beyond adenocarcinoma.^[18] Globally, these expansions aligned with regional regulatory timelines; in Japan, nintedanib was approved for IPF in July 2015 by the Pharmaceuticals and Medical Devices Agency (PMDA), followed by SSc-ILD in 2019 and progressive fibrosing ILDs in May 2020, based on the same international trial data adapted to local evidence, enabling access for patients with diverse fibrotic lung conditions.^[46]

Recent developments

In the European Union, generic formulations of nintedanib have gained authorization, marking significant post-2020 advancements in accessibility. Nintedanib Accord received marketing approval on April 19, 2024, for indications including idiopathic pulmonary fibrosis (IPF) and other chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype in adults.^[36] Subsequently, Nintedanib Viatris was authorized on August 22, 2025, extending availability for similar adult indications, as well as systemic sclerosis-associated ILD.^[47] These approvals facilitate broader patient access while maintaining bioequivalence to the originator Ofev. In the United States, patents protecting nintedanib (marketed as Ofev) extend protection until December 2029, implying that generic entry is not anticipated before early 2030, despite ongoing challenges from generic manufacturers seeking to accelerate market access through litigation.^[48] This timeline underscores continued exclusivity for Boehringer Ingelheim amid efforts by competitors to contest formulation and method-of-use patents. Regulatory label updates have refined clinical guidance. In June 2024, the FDA approved revisions to Ofev's prescribing information, emphasizing enhanced hepatic monitoring due to risks of drug-induced liver injury and reinforcing warnings on embryo-fetal toxicity, advising effective contraception for patients of reproductive potential.^[1] These changes aim to mitigate serious adverse events observed in postmarketing surveillance. Market expansions for progressive fibrosing ILDs have progressed internationally. Additional approvals in countries across Latin America and Asia occurred between 2023 and 2024, increasing global reach to over 80 nations for this indication.^[49] In December 2024, the EMA approved nintedanib for use in children and adolescents aged 6 years and older with progressive fibrosing ILDs and SSc-ILD, based on data from the phase III InPedILD trial (NCT03856847), which demonstrated an acceptable safety profile consistent with adult use.^[50] Patent litigation has shaped the landscape. In 2024, the Federal Court of Canada ruled in favor of Boehringer Ingelheim, upholding a treatment patent and granting an injunction against Jamp Pharma's generic nintedanib capsules for IPF, preventing premature market entry.^[51] More recently, in August 2025, the Unified Patent Court of Appeal affirmed a preliminary injunction across 17 European territories, blocking Zentiva's generic nintedanib ahead of the relevant patent's expiry in December 2025.^[52] These resolutions reinforce Boehringer's intellectual property protections.

Society and culture

Legal status

Nintedanib is classified as a prescription-only medication (Rx) in the United States, the European Union, and Japan, requiring a physician's prescription for dispensing. It is not subject to any controlled substance scheduling, as it does not have abuse potential or meet criteria for regulation under narcotic or psychotropic substance laws in these jurisdictions.^[53]^[32]^[46] In the United States, the Food and Drug Administration (FDA) has approved nintedanib for idiopathic pulmonary fibrosis (IPF) in October 2014, systemic sclerosis-associated interstitial lung disease (SSc-ILD) in September 2019, and chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype in March 2020, with extensions in 2024 for progressive fibrosing ILDs and SSc-ILD in pediatric patients aged 6 years and older. Approval for non-small cell lung cancer (NSCLC) has been limited, with no broad authorization granted for this indication. In the European Union, the European Medicines Agency (EMA) has authorized nintedanib for the treatment of various ILDs, including IPF since January 2015, SSc-ILD since April 2020, and other progressive fibrosing ILDs since June 2020, with an extension in March 2025 for use in children and adolescents aged 6 to 17 years for progressive fibrosing ILDs and SSc-ILD. It is also authorized in combination with docetaxel for second-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) of adenocarcinoma histology in adults (marketed as Vargatef).^[44]^[54]^[32]^[17]^[11] Globally, nintedanib is approved for IPF in more than 80 countries, including major markets such as Canada, Brazil, Switzerland, and others, with similar authorizations for SSc-ILD and progressive ILDs in many of these regions. Access varies, with restrictions in some lower-income countries primarily due to high treatment costs and limited healthcare reimbursement frameworks. In the United States, nintedanib is covered under Medicare Part D prescription drug plans, with nearly all plans providing reimbursement subject to formulary and copayment terms. Boehringer Ingelheim, the manufacturer, offers patient assistance programs through the Boehringer Ingelheim Cares Foundation to support eligible uninsured or underinsured patients with access to the medication at reduced or no cost.^[11]^[55]^[56]^[57]

Brand names and generics

Nintedanib is primarily marketed under the brand name Ofev by Boehringer Ingelheim, available as soft capsules in 100 mg and 150 mg strengths for the treatment of idiopathic pulmonary fibrosis and other chronic fibrosing interstitial lung diseases. In some regions, nintedanib is also sold under the brand name Vargatef, developed by Boehringer Ingelheim specifically for use in combination with docetaxel for non-small cell lung cancer of adenocarcinoma histology following first-line chemotherapy.^[18]^[4] Generic versions of nintedanib have been authorized in the European Union, including Nintedanib Accord, approved as a reference to Ofev for idiopathic pulmonary fibrosis and other progressive fibrosing interstitial lung diseases, and Nintedanib Viatris, which received marketing authorization on August 22, 2025, for similar indications.^[58]^[59] As of November 2025, no generic versions of nintedanib are available in the United States due to ongoing patent protections.^[60]^[61] All branded and generic formulations of nintedanib contain the active ingredient as the esilate salt (nintedanib esilate), ensuring consistency in the chemical composition across products.^[62]^[23] Ofev maintains a dominant market position globally for nintedanib-based therapies, though the emergence of generics in Europe is beginning to enhance accessibility and potentially lower costs for patients in those markets.^[63]^[64]

Research

Inhaled formulations

Inhaled formulations of nintedanib are under investigation to enable targeted delivery to the lungs, potentially enhancing efficacy in pulmonary fibrosis while minimizing systemic exposure.^[65] These approaches aim to achieve higher drug concentrations in lung tissue compared to oral administration, coupled with lower plasma levels to reduce off-target effects.^[66] Preclinical studies in fibrosis models have demonstrated that inhaled nintedanib improves lung exposure and antifibrotic activity, supporting its potential for diseases like idiopathic pulmonary fibrosis (IPF).^[66] Avalyn Pharma's AP02 is an investigational inhaled solution of nintedanib delivered via a handheld PARI eFlow nebulizer.^[67] The company completed two Phase 1 studies in 2024, evaluating safety, tolerability, and pharmacokinetics in healthy volunteers and IPF patients, which showed favorable lung delivery and reduced systemic exposure.^[68] In September 2025, Avalyn presented the design of the Phase 2 AURA-IPF trial at the European Respiratory Society International Congress, a randomized study assessing AP02's impact on lung function and fibrosis markers in adults with IPF. The AURA-IPF trial (NCT07194382) was initiated on September 26, 2025, and as of November 2025, is not yet recruiting participants.^[69]^[70] This formulation seeks to mitigate gastrointestinal side effects associated with the oral version by limiting systemic absorption.^[71] MannKind Corporation's MNKD-201 is a dry powder inhaler (DPI) version of nintedanib, designed for pulmonary fibrotic diseases including IPF.^[72] A Phase 1 trial completed in November 2024 confirmed its safety and tolerability in healthy volunteers, with pharmacokinetic data indicating effective lung deposition and low systemic levels.^[73] Following a Phase 1 trial completed in November 2024, MannKind plans to initiate a Phase 2 trial (INFLO study) for MNKD-201 in IPF in the first quarter of 2026.^[74] Developing inhaled nintedanib presents challenges such as ensuring formulation stability, particularly for dry powders or aqueous solutions prone to degradation over time, and optimizing device usability for consistent patient delivery.^[75] Despite these hurdles, potential advantages include improved long-term tolerability for IPF patients, as inhalation may lower the incidence of systemic adverse events like gastrointestinal issues that limit oral therapy adherence.^[76]

Combination therapies

Nintedanib has been investigated in combination with pirfenidone for the treatment of idiopathic pulmonary fibrosis (IPF), with 2025 long-term studies demonstrating comparable preservation of forced vital capacity (FVC) over five years between the two agents, though the dual therapy did not confirm additive synergistic benefits beyond monotherapy.^[77] In a retrospective five-year analysis, patients on combination therapy experienced similar rates of FVC decline to those on pirfenidone alone, but required higher rates of nintedanib dose reductions due to tolerability issues.^[78] A multicenter observational study further supported these findings, noting that while the combination reduced FVC decline potential, it did not outperform individual antifibrotics in efficacy endpoints.^[79] In acute interstitial lung disease (ILD), a 2025 European Respiratory Society (ERS) phase 2 study evaluated upfront combination therapy with nintedanib, tacrolimus, and prednisolone, showing improved lung function preservation without excess toxicity compared to historical controls.^[80] This multicenter, single-arm trial (TOP-ILD) reported enhanced functional outcomes, such as stabilized FVC and reduced progression, in patients with progressive pulmonary fibrosis, attributing benefits to the synergistic anti-inflammatory and antifibrotic mechanisms.^[81] The regimen was well-tolerated, with no significant increase in severe adverse events beyond those expected from immunosuppressants alone. For systemic sclerosis-associated ILD (SSc-ILD), ongoing trials explore nintedanib combined with anti-inflammatory biologics like rituximab or tocilizumab to address both fibrotic and inflammatory components for broader disease control.^[82] A 2025 network meta-analysis highlighted tocilizumab and rituximab as optimal partners for nintedanib, improving FVC and skin scores in early diffuse cutaneous SSc with elevated inflammatory markers.^[83] ERS/EULAR guidelines endorse this approach, recommending tocilizumab addition in select SSc-ILD cases, while retrospective data from connective tissue disease cohorts confirm the safety and efficacy of dual or triple regimens including nintedanib.^[84] These combinations target progressive fibrosis while mitigating systemic autoimmunity, with trials showing reduced ILD progression rates. In oncology, beyond established use with docetaxel in non-small cell lung cancer (NSCLC), exploratory phase I/II trials have assessed nintedanib with PD-1 inhibitors like nivolumab, often combined with ipilimumab, for advanced NSCLC post-immunotherapy failure.^[85] These studies report meaningful efficacy in terms of progression-free survival, with the triple regimen demonstrating acceptable tolerability in pretreated patients.^[86] Across these combinations, safety profiles indicate increased gastrointestinal (GI) events, primarily diarrhea and nausea, but these remain manageable with dose adjustments and supportive care, without emerging new contraindications.^[80] Real-world data from 2025 analyses confirm that GI adverse events occur at rates consistent with nintedanib monotherapy (around 60-75%), with no excess serious toxicities in multi-agent regimens for fibrotic or oncologic indications.^[87]

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MannKind Successfully Completes Phase 1 Trial of Nintedanib DPI ...
Nov 4, 2024 · Expect to meet with the FDA in 1H 2025 to advance MNKD-201 into the next phase of development. DANBURY, Conn. and WESTLAKE VILLAGE, Calif., Nov.
[75]
Inhaled nintedanib dry powder formulation for the treatment of ...
... devices. Additionally, aqueous formulations pose challenges in terms of physicochemical stability, particularly under long-term storage conditions (Ye et al ...Missing: usability | Show results with:usability
[76]
Inhaled nintedanib is well-tolerated and delivers key ...
Aug 1, 2020 · While oral nintedanib meaningfully slows IPF disease progression, nintedanib treatment induces well-described adverse effects (AE), most ...
[77]
Long-term treatment with nintedanib and pirfenidone in idiopathic ...
Oct 7, 2025 · Importantly, we identified a 4-fold higher risk of dosage reduction for patients starting nintedanib as compared to those starting pirfenidone.
[78]
[PDF] Comparative Long-term Effects of Nintedanib and Pirfenidone in ...
This five-year, real-life retrospective study compared the clinical, radiological, and functional outcomes of idiopathic pulmonary fibrosis (IPF) patients ...Missing: preservation | Show results with:preservation
[79]
(PDF) Efficacy and safety of combination therapy with pirfenidone ...
Aug 7, 2025 · Conclusion: The combination of pirfenidone and nintedanib in patients with IPF has the potential to reduce the rate of FVC decline. However, in ...Missing: preservation | Show results with:preservation
[80]
Upfront combination therapy with nintedanib and anti-inflammatory ...
Sep 11, 2025 · The present study was therefore performed to evaluate the efficacy and safety of concurrent treatment with tacrolimus, prednisolone, and ...
[81]
a multicenter, single-arm phase 2 study (TOP-ILD) | Request PDF
Sep 21, 2025 · Conclusion Early combination therapy with tacrolimus, prednisolone, and nintedanib ... 2025 for studies investigating CV disease in IPF patients.Missing: ERS | Show results with:ERS
[82]
Study of the Efficacy of Nintedanib+Tocilizumab in Patients With ...
The study includes adult patients with systemic sclerosis (SSc) with interstitial lung disease (ILD) to evaluate the efficacy and safety of nintedanib plus ...
[83]
Treatment of Systemic Sclerosis-Associated Interstitial Lung Disease
Sep 1, 2025 · Conclusion: Tocilizumab and rituximab may be the optimal interventions. Still, further direct head-to-head trials are necessary to substantiate ...
[84]
ERS/EULAR clinical practice guidelines for connective tissue ...
Sep 4, 2025 · We recommend using tocilizumab in SSc-ILD patients with early diffuse cutaneous SSc and increased inflammatory markers or recent skin fibrosis ...
[85]
NCT03377023 | Phase I/II Study of Nivolumab and Ipilimumab ...
The main purpose of this study is to see if the combination of nivolumab, ipilimumab and nintedanib is effective in people with non- small cell lung cancer.
[86]
The final analysis of a phase I/II study of nivolumab, ipilimumab ...
May 31, 2023 · We initiated a phase Ib/II trial to evaluate the combination of NT, nivolumab (N) and ipilimumab (I) in advanced (a)NSCLC. Based on the phase IB ...Missing: ongoing | Show results with:ongoing
[87]
Risk and Association of Specific HLA Alleles With Nintedanib ...
Sep 29, 2025 · The most common adverse effect of nintedanib was gastrointestinal issues, particularly diarrhea, occurring in 12 out of 16 patients (75%). Among ...