Nifev

Approved Indications:

• Idiopathic Pulmonary Fibrosis (IPF):
  Treatment of adults with IPF to slow the rate of decline in pulmonary function.
• Systemic Sclerosis-Associated Interstitial Lung Disease (SSc-ILD):
  To slow the rate of decline in pulmonary function in patients with systemic sclerosis-associated ILD.
• Chronic Fibrosing Interstitial Lung Diseases (ILDs) with a Progressive Phenotype:
  Approved to reduce the rate of decline in lung function in adults with other fibrosing ILDs showing progression.
• Non-Small Cell Lung Cancer (NSCLC):
  In combination with docetaxel for the treatment of adults with locally advanced, metastatic, or recurrent NSCLC of adenocarcinoma histology after first-line chemotherapy failure.

Important Off-Label/Investigational Uses:

• Other progressive pulmonary fibrosing diseases not classified under current approved indications (e.g., chronic hypersensitivity pneumonitis, rheumatoid arthritis-associated ILD)
• Under study in various fibrotic disorders

Formulation: Oral capsules (100 mg and 150 mg)

Idiopathic Pulmonary Fibrosis / SSc-ILD / Progressive Fibrosing ILDs:

• Adults: 150 mg orally twice daily (every 12 hours)
• Administration: With food; swallow whole with water
• Duration: Chronic, long-term treatment unless contraindicated due to adverse effects

NSCLC (with docetaxel):

• Adults: 200 mg orally twice daily (every 12 hours)
• Docetaxel co-administration: Administered on Day 1 of each 21-day cycle at 75 mg/m² IV over 1 hour after premedication

Renal Impairment:

• Mild to moderate: No adjustment needed
• Severe impairment: Use with caution due to lack of sufficient data

Hepatic Impairment:

• Mild (Child-Pugh A): 100 mg twice daily recommended
• Moderate to severe (Child-Pugh B or C): Not recommended

Elderly:

• No dosage adjustment required

Pediatrics:

• Safety and efficacy not established in patients <18 years

Missed Dose:

• Skip missed dose if >12 hours have passed; do not double doses

Nintedanib is a tyrosine kinase inhibitor (TKI) that targets multiple growth factor receptors involved in fibrogenesis and tumor angiogenesis. It selectively inhibits the intracellular ATP-binding sites of:

• Fibroblast growth factor receptors (FGFR 1–3)
• Platelet-derived growth factor receptors (PDGFR α and β)
• Vascular endothelial growth factor receptors (VEGFR 1–3)

By blocking these pathways, nintedanib interferes with the proliferation, migration, and transformation of fibroblasts, which are central to the fibrotic process in ILDs and to angiogenesis in NSCLC. This results in attenuation of fibrotic tissue remodeling in the lungs and reduced tumor vascularization in cancer.

• Absorption: Peak plasma concentration ~2–4 hours after oral administration
• Bioavailability: Approximately 4.7% (high first-pass metabolism)
• Distribution: Highly protein bound (~98%); volume of distribution ~1,050 L
• Metabolism: Predominantly via esterase hydrolysis (to BIBF 1202) followed by glucuronidation; minor role of CYP3A4
• Half-life: ~10–15 hours
• Elimination: ~93% via feces (biliary), ~1% in urine
• Steady State: Reached within 1–2 days

Pregnancy:

• FDA Pregnancy Category D
  Based on animal data and mechanism of action, nintedanib can cause fetal harm. Not recommended during pregnancy.

Lactation:

• Unknown whether nintedanib is excreted into human milk.
  Due to potential serious adverse effects in breastfed infants, either discontinue drug or stop breastfeeding.

Contraception:

• Effective contraception is required during treatment and for at least 3 months after the last dose.

• Class: Antifibrotic Agent / Tyrosine Kinase Inhibitor
• Subclass: Multi-targeted receptor tyrosine kinase inhibitor (angiokinase inhibitor)

• Known hypersensitivity to nintedanib or any excipients
• Moderate to severe hepatic impairment (Child-Pugh B or C)
• Pregnancy
• History of significant bleeding disorders

• Gastrointestinal toxicity: High risk of diarrhea, nausea, vomiting—monitor hydration and consider antidiarrheal prophylaxis
• Hepatic impairment: Elevated liver enzymes; monitor LFTs regularly
• Bleeding risk: Use with caution in patients with bleeding disorders or on anticoagulants
• Arterial thromboembolic events: Risk of myocardial infarction and other cardiovascular events
• Gastrointestinal perforation: Rare but serious; discontinue if suspected
• Embryo-fetal toxicity: Confirm negative pregnancy status before initiation
• Smoking: Reduces drug exposure; patients should stop smoking

Common Adverse Effects:

• Gastrointestinal: Diarrhea, nausea, vomiting, abdominal pain, decreased appetite
• Hepatic: Elevated ALT/AST
• Skin: Rash
• General: Weight loss, fatigue

Serious Adverse Effects:

• Liver enzyme elevations and hepatotoxicity
• Bleeding (e.g., epistaxis, GI bleeding)
• Arterial thromboembolic events (MI, stroke)
• GI perforation
• Hypersensitivity reactions including anaphylaxis (rare)

Enzyme System Involvement: Minor substrate of CYP3A4, major metabolism via esterases

Major Interactions:

• P-gp and CYP3A4 inhibitors (e.g., ketoconazole, erythromycin): May increase plasma concentration → use with caution
• CYP3A4 inducers (e.g., rifampin, phenytoin): May reduce efficacy → avoid if possible
• Anticoagulants (e.g., warfarin): Increased bleeding risk → monitor INR/bleeding signs
• NSAIDs and antiplatelets: Increased risk of GI bleeding

Food Interaction:

• Must be taken with food to improve tolerability and reduce GI side effects.

·         2023 ATS/ERS/JRS/ALAT guidelines reaffirmed nintedanib as first-line antifibrotic therapy in IPF and progressive ILDs

·         EMA Safety Update (2024): Emphasis on liver function monitoring and bleeding risk

·         Expanded indication (2020): Inclusion of progressive fibrosing ILDs beyond IPF

·         Ongoing trials: Investigating efficacy in COVID-related lung fibrosis and other fibrotic disorders

• Temperature: Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C
• Humidity: Store in a dry environment; avoid high humidity
• Light Protection: Store in original packaging to protect from light
• Handling Precautions:
• Swallow capsules whole; do not chew or crush
• Keep out of reach of children
• Do not use expired medication