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Nintedanib is a small molecule, competitive, triple angiokinase inhibitor that targets multiple receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases (nRTKs). Many of these RTKs are implicated in lung fibrosis and tumour angiogenesis, so nintedanib is therefore used in the treatment of proliferative diseases such as idiopathic pulmonary fibrosis, non-small cell lung cancer, and systemic sclerosis-associated interstitial lung disease. The specific RTKs that nintedanib inhibits are platelet-derived growth factor (PDGFR) α and β, fibroblast growth factor receptor (FGFR) 1-3, vascular endothelial growth factor receptor (VEGFR), and Fns-Like tyrosine kinase-3 (FLT3). Nintedanib binds to the ATP-binding pocket of these receptors and inhibits their activity, thereby blocking signalling cascades that result in the proliferation and migration of lung fibroblasts. Nintedanib also inhibits kinase signalling pathways in various cells within tumour tissues, including endothelial cells, pericytes, smooth muscle cells, and cells contributing to angiogenesis, culminating in an inhibition of cell proliferation and apoptosis of affected tumour cells.
In addition to RTK inhibition, nintedanib also prevents the actions of the nRTKs Lck, Lyn, and Src. The contribution of the inhibition of Lck and Lyn towards the therapeutic efficacy of nintedanib is unclear, but inhibition of the Src pathway by nintedanib 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).
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 dedicated drug-drug interaction study. In a drug-drug interaction study with the potent P-gp inducer rifampicin, exposure to Nintedanib decreased to 50.3% based on AUC and to 60.3% based on Cmax upon co-administration with rifampicin compared to administration of Nintedanib alone. If co-administered with Nintedanib, potent P-gp inhibitors (e.g. ketoconazole, erythromycin or cyclosporine) may increase exposure to Nintedanib. In such cases, patients should be monitored closely for tolerability of Nintedanib. Management of side effects may require interruption, dose reduction, or discontinuation of therapy with Nintedanib. Potent P-gp inducers (e.g. rifampicin, carbamazepine, phenytoin, and St. John’s Wort) may decrease exposure to Nintedanib. Selection of an alternate concomitant medicinal product with no or minimal P-gp induction potential should be considered.
Cytochrome (CYP)-enzymes: Only a minor extent of the biotransformation of Nintedanib consisted of CYP pathways. Nintedanib and its metabolites, the free acid moiety BIBF 1202 and its glucuronide BIBF 1202 glucuronide, did not inhibit or induce CYP enzymes in preclinical studies. The likelihood of drug-drug interactions with Nintedanib based on CYP metabolism is therefore considered to be low.
Co-administration with other medicinal products: The potential for interactions of Nintedanib with hormonal contraceptives was not explored.
Hypersensitivity to Nintedanib, to peanut or soya, or to any of the excipients.
Summary of the safety profile: Nintedanib has been studied in clinical trials of 1,529 patients suffering from IPF. The safety data provided in the following are based on the two Phase III, randomized, double-blind, placebo-controlled studies in 1,061 patients comparing treatment with Nintedanib 150 mg twice daily to placebo for 52 weeks (INPULSIS-1 and INPULSIS-2) and based on data observed during the post-marketing period.
The most frequently reported adverse reactions associated with the use of Nintedanib included diarrhea, nausea and vomiting, abdominal pain, decreased appetite, weight decreased and hepatic enzyme increased.
Tabulated list of adverse reactions: The below table provides a summary of the adverse reactions by MedDRA System Organ Class (SOC) and frequency category.
Below table summarizes the frequencies of adverse drug reactions (ADRs) that were reported in the Nintedanib group (638 patients) pooled from the two placebo-controlled Phase III clinical trials of 52 weeks duration or from the post-marketing period.
Frequency categories are defined using the following convention: 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), not known (cannot be estimated from the available data).
Women of childbearing potential/Contraception: Nintedanib may cause foetalharm in humans. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Nintedanib. They should be advised to use adequate contraception during and at least 3 months after the last dose of Nintedanib. Since the effect of Nintedanib on the metabolism and efficacy of hormonal contraceptives has not been investigated, barrier methods should be applied as a second form of contraception, to avoid pregnancy.
Pregnancy: There is no information on the use of Nintedanib in pregnant women, but pre-clinical studies in animals have shown reproductive toxicity of this active substance. As Nintedanib may cause foetal harm also in humans, it must not be used during pregnancy. Female patients should be advised to notify their doctor or pharmacist if they become pregnant during therapy with Nintedanib. If the patient becomes pregnant while receiving Nintedanib, she should be apprised of the potential hazard to the foetus. Termination of the treatment with Nintedanib should be considered.
Lactation: There is no information on the excretion of Nintedanib and its metabolites in human milk. Pre-clinical studies showed that small amounts of Nintedanib and its metabolites (≤ 0.5% of the administered dose) were secreted into milk of lactating rats. A risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with Nintedanib.
Fertility: Based on preclinical investigations there is no evidence for impairment of male fertility. From subchronic and chronic toxicity studies, there is no evidence that female fertility in rats is impaired at a systemic exposure level comparable with that at the maximum recommended human dose (MRHD) of 150 mg twice daily.
Store in a cool and dry place, protected from light. Do not store above 25°C.
Nintedanib 100 mg