Nintedanib is indicated in

• adults for the treatment of Idiopathic Pulmonary Fibrosis (IPF).
• It is also indicated in adults for the treatment of chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype.
• Additionally, it is used in adults for the treatment of systemic sclerosis-associated interstitial lung disease (SSc-ILD).
• In combination with docetaxel, it is indicated for the treatment of adult patients with locally advanced, metastatic, or locally recurrent non-small cell lung cancer (NSCLC) of adenocarcinoma histology after first-line chemotherapy.

Nintedanib is a small-molecule, competitive triple angiokinase inhibitor that targets multiple receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases (nRTKs). These kinases are involved in lung fibrosis and tumor angiogenesis; therefore, Nintedanib is used in proliferative diseases such as idiopathic pulmonary fibrosis, non-small cell lung cancer, and systemic sclerosis-associated interstitial lung disease. It inhibits platelet-derived growth factor receptors (PDGFR α and β), fibroblast growth factor receptors (FGFR 1–3), vascular endothelial growth factor receptors (VEGFR), and FLT3. Nintedanib binds to the ATP-binding site of these receptors and blocks their signaling pathways, thereby reducing proliferation and migration of lung fibroblasts.

In tumor tissues, it inhibits signaling in endothelial cells, pericytes, smooth muscle cells, and other cells involved in angiogenesis, leading to reduced tumor cell growth and increased apoptosis. In addition to RTK inhibition, it also blocks non-receptor tyrosine kinases such as Lck, Lyn, and Src. While the role of Lck and Lyn inhibition is not fully clear, inhibition of the Src pathway has been shown to reduce lung fibrosis.

Treatment with Nintedanib should be initiated by physicians experienced in the diagnosis and treatment of IPF.

Posology: The recommended dose is 150 mg Nintedanib twice daily administered approximately 12 hours apart. The 100 mg twice daily dose is only recommended to be used in patients who do not tolerate the 150 mg twice daily dose. If a dose is missed, administration should resume at the next scheduled time at the recommended dose. If a dose is missed the patient should not take an additional dose. The recommended maximum daily dose of 300 mg should not be exceeded.

For NSCLC:

• The recommended dose of nintedanib is 200 mg twice daily administered approximately 12 hours apart, on days 2 to 21 of a standard 21 day docetaxel treatment cycle.
• Nintedanib must not be taken on the same day of docetaxel chemotherapy administration (= day 1). If a dose of nintedanib is missed, administration should resume at the next scheduled time at the recommended dose. The individual daily doses of nintedanib should not be increased beyond the recommended dose to make up for missed doses. The recommended maximum daily dose of 400 mg should not be exceeded.
• Patients may continue therapy with nintedanib after discontinuation of docetaxel for as long as clinical benefit is observed or until unacceptable toxicity occurs.
• Dose adjustments: In addition to symptomatic treatment if applicable, the management of adverse reactions to Nintedanib could include dose reduction and temporary interruption until the specific adverse reaction has resolved to levels that allow continuation of therapy. Nintedanib treatment may be resumed at the full dose (150 mg twice daily) or a reduced dose (100 mg twice daily). If a patient does not tolerate 100 mg twice daily, treatment with Nintedanib should be discontinued.
• In case of interruptions due to aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevations > 3x upper limit of normal (ULN), once transaminases have returned to baseline values, treatment with Nintedanib may be reintroduced at a reduced dose (100 mg twice daily) which subsequently may be increased to the full dose (150 mg twice daily).

Nintedanib is for oral use. The capsules should be taken with food, swallowed whole with water, and should not be chewed or crushed.

P-glycoprotein (P-gp): Nintedanib is a substrate of P-gp. Co-administration with the potent P-gp inhibitor ketoconazole increased exposure to Nintedanib 1.61-fold based on AUC and 1.83-fold based on Cmax in a drug–drug interaction study. In contrast, co-administration with the potent P-gp inducer rifampicin reduced exposure to 50.3% based on AUC and 60.3% based on Cmax compared to Nintedanib alone. When used with strong P-gp inhibitors (e.g. ketoconazole, erythromycin, cyclosporine), Nintedanib exposure may increase and patients should be closely monitored, with possible dose adjustment, interruption, or discontinuation if needed. Strong P-gp inducers (e.g. rifampicin, carbamazepine, phenytoin, St. John’s Wort) may reduce Nintedanib levels, so alternative medicines should be considered.

Cytochrome (CYP) enzymes: Only a minor portion of Nintedanib metabolism involves CYP pathways. Nintedanib and its metabolites do not inhibit or induce CYP enzymes, so CYP-related drug interaction risk is low.

Co-administration with other medicines: Interaction with hormonal contraceptives has not been evaluated.

Hypersensitivity to Nintedanib, peanut or soya, or to any of the excipients.

Summary of safety profile: Nintedanib has been evaluated in clinical trials involving 1,529 patients with idiopathic pulmonary fibrosis (IPF). The safety data are mainly based on two Phase III randomized, double-blind, placebo-controlled studies (INPULSIS-1 and INPULSIS-2) including 1,061 patients treated with Nintedanib 150 mg twice daily versus placebo for 52 weeks, along with post-marketing experience.

The most commonly reported adverse reactions include diarrhea, nausea, vomiting, abdominal pain, decreased appetite, weight loss, and increased liver enzymes.

Tabulated list of adverse reactions: The following summary presents adverse reactions categorized by MedDRA System Organ Class (SOC) and frequency.

Frequency categories: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), and not known (cannot be estimated from available data).

Women of childbearing potential / Contraception: Nintedanib may cause fetal harm. Women of reproductive potential should avoid pregnancy during treatment and for at least 3 months after the last dose. Effective contraception should be used during treatment. Since the effect of Nintedanib on hormonal contraceptives is unknown, a barrier method should also be used as an additional form of contraception.

Pregnancy: There are no adequate data in pregnant women. Animal studies have shown reproductive toxicity. Therefore, Nintedanib must not be used during pregnancy. If pregnancy occurs during treatment, the patient should be informed about potential fetal risk and discontinuation of therapy should be considered.

Lactation: There is no data on excretion in human breast milk. Animal studies showed minimal excretion in milk. A risk to the infant cannot be excluded; therefore, breastfeeding should be discontinued during treatment.

Fertility: Preclinical studies show no evidence of impaired male fertility. No evidence of impaired female fertility was observed in animal studies at exposures similar to the maximum recommended human dose.

Diarrhoea: In the INPULSIS trials, diarrhoea was the most common gastrointestinal adverse reaction, occurring in 62.4% of patients receiving Nintedanib compared to 18.4% in the placebo group. In most cases, it was mild to moderate and appeared within the first 3 months of treatment. Diarrhoea led to dose reduction in 10.7% of patients and discontinuation in 4.4%. Serious cases associated with dehydration and electrolyte imbalance have been reported post-marketing. Patients should be managed early with adequate hydration and antidiarrhoeal agents (e.g. loperamide). Treatment interruption or dose reduction (100 mg twice daily) may be required. If severe diarrhoea persists despite treatment, Nintedanib should be discontinued.

Nausea and vomiting: Nausea and vomiting are common gastrointestinal adverse reactions, usually mild to moderate in severity. Nausea led to discontinuation in 2.0% of patients and vomiting in 0.8%. If symptoms persist despite supportive therapy (including anti-emetics), dose reduction or temporary interruption may be required. Treatment may be resumed at 100 mg twice daily or 150 mg twice daily. Persistent severe symptoms require discontinuation.

Hepatic function: Nintedanib is not recommended in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment. Patients with mild impairment (Child-Pugh A) require dose reduction due to increased exposure and risk of adverse events. Drug-induced liver injury, including fatal cases, has been reported, mostly within the first 3 months. Liver function tests (ALT, AST, bilirubin, ALP, GGT) should be checked before starting treatment, monthly for the first 3 months, and periodically thereafter. If transaminases rise >3× ULN, dose reduction or interruption is recommended. Treatment may be resumed after normalization. If liver abnormalities occur with clinical signs (e.g. jaundice), treatment should be permanently discontinued. Patients with low body weight (<65 kg), Asian ethnicity, female patients, and elderly patients have higher risk and require closer monitoring.

Renal function: Cases of renal impairment or failure, including fatal outcomes, have been reported. Patients should be monitored, especially those with risk factors. Dose adjustment should be considered if renal dysfunction occurs.

Haemorrhage: VEGFR inhibition may increase bleeding risk. In INPULSIS trials, bleeding events were slightly higher with Nintedanib (10.3%) vs placebo (7.8%). Most were mild epistaxis; serious bleeding occurred at similar rates in both groups. Post-marketing reports include serious and sometimes fatal bleeding (gastrointestinal, respiratory, CNS). Patients with bleeding risk should receive Nintedanib only if benefits outweigh risks.

Arterial thromboembolic events: Patients with recent MI or stroke were excluded from trials. Arterial thromboembolic events were more frequent with Nintedanib (2.5%) than placebo (0.7%), including myocardial infarction (1.6% vs 0.5%). Caution is required in patients with cardiovascular risk. Treatment should be interrupted if signs of acute myocardial ischemia occur.

Venous thromboembolism: No increased risk was observed in trials, but a theoretical risk exists due to mechanism of action.

Gastrointestinal perforation: Rare cases were reported (0.3% vs 0% in placebo), including fatal cases post-marketing. Risk is higher in patients with previous abdominal surgery, peptic ulcer, diverticular disease, or those on corticosteroids/NSAIDs. Treatment should start at least 4 weeks after abdominal surgery and be permanently discontinued if perforation occurs.

Hypertension: Nintedanib may increase blood pressure; regular monitoring is required.

Wound healing complications: Although not increased in trials, Nintedanib may impair wound healing. Treatment should be started or resumed only when adequate healing is confirmed clinically.

Co-administration with Pirfenidone: No significant pharmacokinetic interaction was observed, but increased gastrointestinal and hepatic adverse effects may occur. The safety of combined use is not fully established.

Effect on QT interval: No QT prolongation was observed, but caution is advised in patients at risk of QTc prolongation.

Allergic reaction: Patients allergic to soya or peanut may have increased risk of severe hypersensitivity reactions, including anaphylaxis.

Elderly patients (≥65 years): No overall differences in safety and efficacy have been observed in elderly patients compared to younger adults. No initial dose adjustment is required based on age alone. However, patients aged ≥75 years may have a higher likelihood of requiring dose reduction due to adverse reactions.

Renal impairment: Less than 1% of a single dose of Nintedanib is eliminated via the kidneys. No adjustment of the starting dose is required in patients with mild to moderate renal impairment. The safety, efficacy, and pharmacokinetics of Nintedanib have not been studied in patients with severe renal impairment (creatinine clearance <30 mL/min).

Hepatic impairment: Nintedanib is mainly eliminated through biliary/fecal excretion (>90%). Drug exposure is increased in patients with hepatic impairment (Child-Pugh A and B). In patients with mild hepatic impairment (Child-Pugh A), the recommended dose is 100 mg twice daily, approximately 12 hours apart. Dose interruption or discontinuation may be required for management of adverse reactions. The safety and efficacy of Nintedanib have not been established in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment; therefore, its use is not recommended in these patients.

Paediatric population: The safety and efficacy of Nintedanib in children and adolescents (0–18 years) have not been established. No data are available.

Tyrosine Kinase Inhibitor

Store in a cool, dry place, protected from light. Do not store above 25°C.