Nintedanib

OFEV is a kinase inhibitor indicated in adults for: Treatment of idiopathic pulmonary fibrosis (IPF). Treatment of chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype. Slowing the rate of decline in pulmonary function in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD)

Nintedanib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases (nRTKs). Nintedanib inhibits the following RTKs: platelet-derived growth factor receptor (PDGFR) α and β, fibroblast growth factor receptor (FGFR) 1-3, vascular endothelial growth factor receptor (VEGFR) 1-3, colony stimulating factor 1 receptor (CSF1R), and Fms-like tyrosine kinase-3 (FLT-3). These kinases except for FLT-3 have been implicated in pathogenesis of interstitial lung diseases (ILD). Nintedanib binds competitively to the adenosine triphosphate (ATP) binding pocket of these kinases and blocks the intracellular signaling cascades, which have been demonstrated to be involved in the pathogenesis of fibrotic tissue remodeling in ILD. Nintedanib also inhibits the following nRTKs: Lck, Lyn and Src kinases.

Recommended dosage: 150 mg taken orally twice daily approximately 12 hours apart taken with food. Recommended dosage in patients with mild hepatic impairment (Child Pugh A): 100 mg taken orally twice daily approximately 12 hours apart taken with food. Consider temporary dose reduction to 100 mg, treatment interruption, or discontinuation for management of adverse reactions. Prior to treatment initiation, conduct liver function tests in all patients and a pregnancy test in females of reproductive potential.

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Hepatic impairment: OFEV is not recommended for use in patients with moderate or severe hepatic impairment. In patients with mild hepatic impairment (Child Pugh A), the recommended dosage is 100 mg twice daily approximately 12 hours apart taken with food. Consider treatment interruption, or discontinuation for management of adverse reactions in these patients. Elevated liver enzymes and drug-induced liver injury: ALT, AST, and bilirubin elevations have occurred with OFEV, including cases of drug-induced liver injury. In the postmarketing period, non-serious and serious cases of drug-induced liver injury, including severe liver injury with fatal outcome, have been reported. The majority of hepatic events occur within the first three months of treatment. Liver enzyme and bilirubin increases were reversible with dose modification or interruption in the majority of cases.

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Elevated Liver Enzymes and Drug-Induced Liver Injury Gastrointestinal Disorders Embryo-Fetal Toxicity Arterial Thromboembolic Events Risk of Bleeding Gastrointestinal Perforation Nephrotic Range Proteinuria Most common adverse reactions (≥5%) are: diarrhea, nausea, abdominal pain, vomiting, liver enzyme elevation, decreased appetite, headache, weight decreased, and hypertension.

Coadministration of P-gp and CYP3A4 inhibitors may increase nintedanib exposure. Monitor patients closely for tolerability of OFEV. P-glycoprotein (P-gp) and CYP3A4 Inhibitors and Inducers Nintedanib is a substrate of P-gp and, to a minor extent, CYP3A4. Coadministration with oral doses of a P-gp and CYP3A4 inhibitor, ketoconazole, increased exposure to nintedanib by 60%. Concomitant use of P-gp and CYP3A4 inhibitors (e.g., erythromycin) with OFEV may increase exposure to nintedanib. In such cases, patients should be monitored closely for tolerability of OFEV. Management of adverse reactions may require interruption, dose reduction, or discontinuation of therapy with OFEV. Coadministration with oral doses of a P-gp and CYP3A4 inducer, rifampicin, decreased exposure to nintedanib by 50%.

Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from exposure to high humidity and avoid excessive heat.