Introduction
Ofev (nintedanib) is an oral triple angiokinase inhibitor approved for the treatment of idiopathic pulmonary fibrosis (IPF) and other progressive fibrotic interstitial lung diseases. Developed by Boehringer Ingelheim, it represents a significant advancement in managing these chronic, debilitating conditions characterized by progressive scarring of lung tissue.
Mechanism of Action
Nintedanib is a small molecule inhibitor that targets multiple receptor tyrosine kinases. It specifically inhibits:
- Vascular endothelial growth factor receptors (VEGFR 1-3)
- Platelet-derived growth factor receptors (PDGFR α and β)
- Fibroblast growth factor receptors (FGFR 1-3)
These pathways are implicated in the pathogenesis of pulmonary fibrosis by promoting fibroblast proliferation, migration, and differentiation into myofibroblasts, which excessively produce extracellular matrix components. By blocking these signaling pathways, nintedanib reduces the progression of fibrosis and slows decline in lung function.
Indications
- Treatment of idiopathic pulmonary fibrosis (IPF)
- Slowing the rate of decline in pulmonary function in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD)
- Treatment of chronic fibrosing interstitial lung diseases with a progressive phenotype
Dosage and Administration
Standard dosing: 150 mg twice daily taken approximately 12 hours apart with food Dose modification:- For patients unable to tolerate 150 mg twice daily: Reduce to 100 mg twice daily
- For hepatic impairment (Child-Pugh B): 100 mg twice daily
- For hepatic impairment (Child-Pugh C): Not recommended
- No dose adjustment required for renal impairment
- Swallow capsules whole with fluid
- Take with food to reduce gastrointestinal adverse effects
- If a dose is missed, the next dose should be taken at the regular time
Pharmacokinetics
Absorption: Bioavailability is approximately 4.7% in fasted state; high-fat meal increases bioavailability to 20.3% Distribution: Volume of distribution is 1050 L; plasma protein binding >97% Metabolism: Primarily hydrolyzed by esterases; minor CYP3A4 metabolism Elimination: Half-life is 10-15 hours; primarily fecal excretion (93.4%), with renal excretion accounting for only 0.65% of administered doseContraindications
- Hypersensitivity to nintedanib or any component of the formulation
- Moderate to severe hepatic impairment (Child-Pugh B or C)
- Pregnancy
Warnings and Precautions
Hepatic toxicity: Elevations in liver enzymes may occur; monitor ALT, AST, and bilirubin before initiation, during the first 3 months, and periodically thereafter Gastrointestinal disorders: Diarrhea, nausea, and vomiting are common; may require symptomatic treatment, dose reduction, or interruption Arterial thromboembolic events: Increased risk of myocardial infarction and stroke Bleeding risk: May increase risk of bleeding; monitor patients at higher risk Gastrointestinal perforation: Use with caution in patients at risk Embryo-fetal toxicity: Can cause fetal harm; advise females of reproductive potential of potential risk and need for effective contraceptionDrug Interactions
Strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir): May increase nintedanib exposure; consider dose reduction to 100 mg twice daily P-gp inhibitors (e.g., erythromycin, cyclosporine): May increase nintedanib exposure; monitor for adverse effects Anticoagulants: May increase bleeding risk; monitor closely P-glycoprotein substrates: Nintedanib may increase concentrations of P-gp substratesAdverse Effects
Very common (≥10%):- Diarrhea (62%)
- Nausea (24%)
- Abdominal pain (15%)
- Vomiting (12%)
- Liver enzyme elevation (14%)
- Decreased appetite (11%)
- Weight decrease
- Headache
- Hypertension
- Bleeding events
- Rash
- Hepatic impairment
- Gastrointestinal perforation
- Arterial thromboembolic events
- Severe diarrhea requiring hospitalization
Monitoring Parameters
Baseline:- Complete pulmonary function tests (FVC, DLCO)
- Liver function tests (ALT, AST, bilirubin)
- Pregnancy test in women of childbearing potential
- Assessment of bleeding risk
- Liver function tests: monthly for first 3 months, then every 3 months
- Pulmonary function tests: every 3-6 months
- Monitoring for gastrointestinal symptoms
- Weight monitoring
- Signs of bleeding
- Blood pressure monitoring
Patient Education
- Take Ofev exactly as prescribed with food
- Report any new or worsening symptoms, especially diarrhea, nausea, vomiting, or abdominal pain
- Notify your healthcare provider if you experience yellowing of skin/eyes, dark urine, or unusual bleeding/bruising
- Use effective contraception during treatment and for at least 3 months after discontinuation
- Inform all healthcare providers about Ofev use before starting new medications
- Do not stop taking Ofev without discussing with your healthcare provider
- Keep all scheduled appointments for monitoring tests
- Report any planned surgeries or procedures to your healthcare provider
References
1. 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. 2. Ofev [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2020. 3. 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. 4. Flaherty KR, Wells AU, Cottin V, et al. Nintedanib in progressive fibrosing interstitial lung diseases. N Engl J Med. 2019;381(18):1718-1727. 5. National Institute for Health and Care Excellence (NICE). Nintedanib for treating idiopathic pulmonary fibrosis. TA379. London: NICE; 2016.