Nintedanib

Nintedanib is an oral, intracellular kinase inhibitor that occupies the ATP-binding pocket of multiple receptor and non-receptor tyrosine kinases whose signalling drives the cardinal features of lung fibrosis — fibroblast proliferation and migration, myofibroblast transformation, and aberrant extracellular matrix deposition — and which also support tumour angiogenesis. By disrupting several parallel pro-fibrotic and pro-angiogenic pathways simultaneously, nintedanib slows lung function decline in chronic progressive fibrosing diseases and contributes anti-angiogenic chemotherapy effect in selected tumours.

Mechanism of Action

• Receptor tyrosine kinase inhibition: nintedanib competitively occupies the ATP-binding site of platelet-derived growth factor receptors (PDGFR-α and -β), fibroblast growth factor receptors (FGFR-1, -2, -3), vascular endothelial growth factor receptors (VEGFR-1, -2, -3), and FMS-like tyrosine kinase-3 (FLT3). These receptors mediate the proliferation, migration, and transformation of lung fibroblasts in fibrosing ILDs, and the proliferation and survival of tumour-associated endothelial cells, pericytes, and smooth muscle cells.
• Non-receptor kinase inhibition: also inhibits Src family kinases (Src, Lck, Lyn). Src pathway inhibition contributes specifically to the antifibrotic effect; Lck and Lyn inhibition has unclear therapeutic contribution.
• Net antifibrotic effect: reduces fibroblast-to-myofibroblast transition, attenuates collagen deposition, and slows progressive scarring of lung parenchyma. In clinical trials (INPULSIS, INBUILD, SENSCIS), nintedanib reduced the annual rate of decline in forced vital capacity (FVC) by approximately 50% across IPF, progressive fibrosing ILDs, and SSc-ILD.
• Anti-angiogenic effect: by VEGFR/FGFR/PDGFR inhibition, attenuates tumour angiogenesis — the rationale for the docetaxel combination in NSCLC adenocarcinoma.

Pharmacokinetics

• Absorption: absolute bioavailability ~4.7% (low, owing to first-pass metabolism and P-glycoprotein efflux). Tmax 2 hours fasted, 4 hours fed; a high-fat meal increases Cmax by ~15% and AUC by ~20%, and food administration is required to ensure adequate exposure.
• Volume of distribution: 1,050 L — extensive tissue distribution, with limited CNS penetration.
• Protein binding: 97.8%, primarily to albumin.
• Metabolism: hydrolytic cleavage by esterases is the dominant route — produces the principal metabolite BIBF 1202, which is then glucuronidated by intestinal and hepatic UGT1A1, UGT1A7, UGT1A8, and UGT1A10 to BIBF 1202 glucuronide. CYP-mediated metabolism (predominantly CYP3A4) is minor (~5% of total).
• Half-life: terminal elimination half-life 10–15 hours; effective half-life in IPF patients ~9.5 hours.
• Excretion: predominantly faecal (~93%); renal clearance ~0.65% of total dose.
• Clearance: total plasma clearance 1,390 mL/min; renal clearance 20 mL/min.
• P-gp interaction: nintedanib is both a substrate and inhibitor of P-glycoprotein; clinically relevant interactions with potent P-gp modulators.

• Idiopathic pulmonary fibrosis (IPF) in adults — to slow disease progression.
• Systemic sclerosis-associated interstitial lung disease (SSc-ILD) in adults, adolescents, and children ≥6 years.
• Chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype, of any aetiology, in adults; and in paediatric patients 6–17 years for clinically significant progressive fibrosing ILDs (EU label).
• Non-small cell lung cancer (NSCLC), adenocarcinoma histology (Vargatef brand) — in combination with docetaxel for adult patients with metastatic, locally advanced, or recurrent disease after first-line chemotherapy. (Approved in the EU; the FDA approval focuses on the IPF and ILD indications.)

• Hypersensitivity to nintedanib, peanut or soya (soy lecithin is an excipient), or any other excipient.
• Pregnancy.

Very common (≥1/10): diarrhoea, nausea, vomiting, abdominal pain, decreased appetite, weight loss, transaminase elevations (ALT, AST), GGT elevation.

Common (≥1/100 to <1/10): dehydration, headache, hypertension, bleeding (epistaxis, gastrointestinal, gum), thrombocytopenia, peripheral neuropathy, rash, pruritus.

Uncommon (≥1/1,000 to <1/100): drug-induced liver injury (DILI, sometimes severe), hepatic enzyme elevations >5× ULN, pancreatitis, arterial thromboembolism (including myocardial infarction), venous thromboembolism, gastrointestinal perforation (rare but serious), proteinuria, wound healing complications.

Rare to very rare: severe liver injury including hepatic failure, Stevens-Johnson syndrome, exfoliative dermatitis.

Bleeding risk class effect: VEGFR inhibition predisposes to bleeding and impaired wound healing; cardiovascular event risk modestly elevated.

• Strong P-gp and CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir-boosted antivirals): can increase nintedanib exposure — use with caution and monitor for adverse effects; consider 100 mg dosing.
• Strong P-gp and CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, St John’s Wort): reduce nintedanib exposure — co-administration is not recommended.
• Pirfenidone: combination has been studied; pharmacokinetic interactions are not clinically prohibitive but additive gastrointestinal adverse events are common.
• Anticoagulants and antiplatelet agents: additive bleeding risk; monitor closely.
• NSAIDs: additive bleeding and renal risk.
• No clinically meaningful effect on CYP enzymes by nintedanib itself.

Capsules are swallowed whole with water with food (a main meal). Do not chew, crush, or open. Take morning and evening, approximately 12 hours apart.

Idiopathic Pulmonary Fibrosis, Progressive Fibrosing ILDs, and SSc-ILD (Adults)

• Standard dose: 150 mg twice daily.
• Dose reduction: 100 mg twice daily for tolerability or interactions.
• Treatment duration: indefinite — disease-modifying therapy continued for as long as benefit outweighs harm.

Paediatric (Ages 6–17 Years, Progressive Fibrosing ILDs or SSc-ILD; EU Label)

• Weight-banded dosing: per current product labelling — typically 100 mg twice daily in lighter weight bands and 150 mg twice daily in older/heavier patients.

Non-Small Cell Lung Cancer (Vargatef, in Combination with Docetaxel)

• 200 mg twice daily on days 2–21 of each 21-day cycle (docetaxel administered on day 1 of each cycle).

Renal Impairment

• Mild to moderate: no dose adjustment.
• Severe (CrCl <30 mL/min): pharmacokinetic data limited; use with caution and consider 100 mg twice daily.

Hepatic Impairment

• Mild (Child-Pugh A): consider 100 mg twice daily for IPF/ILD indications.
• Moderate (Child-Pugh B): not recommended.
• Severe (Child-Pugh C): contraindicated.

Dose Adjustment for Adverse Events

• Diarrhoea, nausea, vomiting: optimise supportive therapy (loperamide, antiemetics), maintain hydration. If grade 2 or persistent, interrupt; resume at 100 mg twice daily then re-titrate.
• Transaminase elevations: monitor LFTs at baseline, monthly for 3 months, then every 3 months. For elevations >3× ULN with symptoms or signs of hepatic injury, or >5× ULN without, interrupt; resume at reduced dose once normalised.

Missed Dose

If a dose is missed, take the next scheduled dose at the usual time. Do not take a double dose to make up.

Hepatotoxicity

Drug-induced liver injury, including rare cases of severe and fatal hepatic failure, has been reported. Measure transaminases and bilirubin before initiation, monthly for the first three months, and every three months thereafter and as clinically indicated. Interrupt or reduce dose for significant elevations.

Diarrhoea and Gastrointestinal Tolerability

Diarrhoea is the dose-limiting adverse effect in most patients. Counsel on hydration, dietary modifications, and prompt use of loperamide. Persistent or severe diarrhoea warrants dose reduction or interruption.

Bleeding

VEGFR inhibition increases the risk of bleeding events. Use with caution in patients with known bleeding risk, on full-dose anticoagulation, or with recent surgical intervention. Stop nintedanib at least 1 week before planned surgery; recommence only when wound healing is satisfactory.

Arterial and Venous Thromboembolism

Patients with high cardiovascular risk, prior thromboembolism, or active cardiac disease require careful benefit-risk assessment.

Gastrointestinal Perforation

Rare but serious. Caution in patients with prior abdominal surgery, peptic ulceration, or diverticular disease. Discontinue if perforation occurs.

Wound Healing

VEGFR inhibition impairs wound healing; pause therapy around elective surgery and resume only after wound healing is complete.

Pregnancy and Lactation

• Pregnancy: contraindicated. Effective contraception required for women of childbearing potential during therapy and for at least 3 months after the last dose. Nintedanib may reduce the efficacy of hormonal contraceptives in patients with vomiting or diarrhoea — additional barrier methods are advised.
• Breastfeeding: not recommended.

Soya and Peanut Allergy

The capsule contains soya lecithin; contraindicated in patients with peanut or soya hypersensitivity.

Smoking

Smokers have lower nintedanib exposure; smoking cessation is advised independently and is associated with improved outcomes in fibrosing lung diseases.

Effect on Driving

No specific impairment expected, but symptoms such as fatigue, dizziness, or visual disturbance may transiently affect ability to drive or operate machinery.

Do not store above 25°C. Blister: store in the original package in order to protect from moisture. Bottle: keep the bottle tightly closed in order to protect from moisture.

4 years for the 25 mg soft capsules; 3 years for the 100 mg and 150 mg soft capsules. Do not use after the expiry date printed on the packaging.

Prescription required (Rx). Initiated by specialists in ILD or thoracic oncology and dispensed through specialty pharmacy channels given the price, monitoring requirements, and disease severity.