Nifev100 mg

Nifev 100 mg is indicated in adults for the treatment of Idiopathic Pulmonary Fibrosis (IPF). Nifev 100 mg is indicated in adults for the treatment of chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype. Nifev 100 mg is indicated in adults for the treatment of systemic sclerosis-associated interstitial lung disease (SSc-ILD). ... Read more Nifev 100 mg is indicated in adults for the treatment of Idiopathic Pulmonary Fibrosis (IPF). Nifev 100 mg is indicated in adults for the treatment of chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype. Nifev 100 mg is indicated in adults for the treatment of systemic sclerosis-associated interstitial lung disease (SSc-ILD). Nifev 100 mg is indicated in combination with docetaxel for the treatment of adult patients with locally advanced, metastatic or locally recurrent non-small cell lung cancer (NSCLC) of adenocarcinoma tumor histology after first-line chemotherapy.

Tyrosine Kinase Inhibitor

Nifev 100 mg 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 Nifev 100 mg 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 Nifev 100 mg 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). Nifev 100 mg 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. Nifev 100 mg 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, Nifev 100 mg 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 Nifev 100 mg is unclear, but inhibition of the Src pathway by Nifev 100 mg has been shown to reduce lung fibrosis.

Treatment with Nifev 100 mg should be initiated by physicians experienced in the diagnosis and treatment of IPF.Posology: The recommended dose is 150 mg Nifev 100 mg 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 Nifev 100 mg is 200 mg twice daily administered approximately 12 hours apart, on days 2 to 21 of a standard 21 day docetaxel treatment cycle. Nifev 100 mg must not be taken on the same day of docetaxel chemotherapy administration (= day 1). If a dose of Nifev 100 mg is missed, administration should resume at the next scheduled time at the recommended dose. The individual daily doses of Nifev 100 mg 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 Nifev 100 mg 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 Nifev 100 mg could include dose reduction and temporary interruption until the specific adverse reaction has resolved to levels that allow continuation of therapy. Nifev 100 mg 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 Nifev 100 mg 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 Nifev 100 mg may be reintroduced at a reduced dose (100 mg twice daily) which subsequently may be increased to the full dose (150 mg twice daily).

Nifev 100 mg 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): Nifev 100 mg is a substrate of P-gp. Co-administration with the potent P-gp inhibitor ketoconazole increased exposure to Nifev 100 mg 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 Nifev 100 mg decreased to 50.3% based on AUC and to 60.3% based on Cmax upon co-administration with rifampicin compared to administration of Nifev 100 mg alone. If co-administered with Nifev 100 mg, potent P-gp inhibitors (e.g. ketoconazole, erythromycin or cyclosporine) may increase exposure to Nifev 100 mg. In such cases, patients should be monitored closely for tolerability of Nifev 100 mg. Management of side effects may require interruption, dose reduction, or discontinuation of therapy with Nifev 100 mg. Potent P-gp inducers (e.g. rifampicin, carbamazepine, phenytoin, and St. John’s Wort) may decrease exposure to Nifev 100 mg. 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 Nifev 100 mg consisted of CYP pathways. Nifev 100 mg 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 Nifev 100 mg based on CYP metabolism is therefore considered to be low.Co-administration with other medicinal products: The potential for interactions of Nifev 100 mg with hormonal contraceptives was not explored.

Hypersensitivity to Nifev 100 mg, to peanut or soya, or to any of the excipients.

Summary of the safety profile: Nifev 100 mg 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 Nifev 100 mg 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 Nifev 100 mg 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 Nifev 100 mg 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: Nifev 100 mg may cause foetalharm in humans. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Nifev 100 mg. They should be advised to use adequate contraception during and at least 3 months after the last dose of Nifev 100 mg. Since the effect of Nifev 100 mg 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 Nifev 100 mg in pregnant women, but pre-clinical studies in animals have shown reproductive toxicity of this active substance. As Nifev 100 mg 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 Nifev 100 mg. If the patient becomes pregnant while receiving Nifev 100 mg, she should be apprised of the potential hazard to the foetus. Termination of the treatment with Nifev 100 mg should be considered.Lactation: There is no information on the excretion of Nifev 100 mg and its metabolites in human milk. Pre-clinical studies showed that small amounts of Nifev 100 mg 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 Nifev 100 mg.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.

Diarrhoea: In the INPULSIS trials, diarrhoea was the most frequent gastro-intestinal adverse reaction reported in 62.4% versus 18.4% of patients treated with Nifev 100 mg and placebo, respectively. In most patients the adverse reaction was of mild to moderate intensity and occurred within the first 3 months of treatment. Diarrhoea led to dose reduction in 10.7% of the patients and to discontinuation of Nifev 100 mg in 4.4% of the patients in clinical trials. Serious cases of diarrhoea leading to dehydration and electrolyte disturbances have been reported in the post-marketing. Patients should be treated at first signs with adequate hydration and anti-diarrhoeal medicinal products, e.g. loperamide, and may require treatment interruption. Nifev 100 mg treatment may be resumed at a reduced dose (100 mg twice daily) or at the full dose (150 mg twice daily). In case of persisting severe diarrhoea despite symptomatic treatment, therapy with Nifev 100 mg should be discontinued.Nausea and vomiting: Nausea and vomiting were frequently reported gastrointestinal adverse reactions. In most patients with nausea and vomiting, the event was of mild to moderate intensity. Nausea led to discontinuation of Nifev 100 mg in 2.0% of patients. Vomiting led to discontinuation in 0.8% of the patients. If symptoms persist despite appropriate supportive care (including anti-emetic therapy), dose reduction or treatment interruption may be required. The treatment may be resumed at a reduced dose (100 mg twice daily) or at the full dose (150 mg twice daily). In case of persisting severe symptoms therapy with Nifev 100 mg should be discontinued.Hepatic function: The safety and efficacy of Nifev 100 mg has not been studied  in patients with moderate (Child Pugh B) or severe (Child Pugh C) hepatic impairment. Therefore, treatment with Nifev 100 mg is not recommended in such patients. Based on increased exposure, the risk for adverse events may be increased in patients with mild hepatic impairment (Child Pugh A). Patients with mild hepatic impairment (Child Pugh A) should be treated with a reduced dose of Nifev 100 mg. Cases of drug-induced liver injury have been observed with Nifev 100 mg treatment, including severe liver injury with fatal outcome. The majority of hepatic events occur within the first three months of treatment. Therefore, hepatic transaminase and bilirubin levels should be investigated before treatment initiation and during the first month of treatment with Nifev 100 mg. Patients should then be monitored at regular intervals during the subsequent two months of treatment and periodically thereafter, e.g. at each patient visit or as clinically indicated. Elevations of liver enzymes (ALT, AST, ALKP, gamma-glutamyl-transferase (GGT) and bilirubin were reversible upon dose reduction or interruption in the majority of cases. If transaminase (AST or ALT) elevations > 3x ULN are measured, dose reduction or interruption of the therapy with Nifev 100 mg is recommended and the patient should be monitored closely. Once transaminases have returned to baseline values, treatment with Nifev 100 mg may be resumed at the full dose (150 mg twice daily) or reintroduced at a reduced dose (100 mg twice daily) which subsequently may be increased to the full dose. If any liver test elevations are associated with clinical signs or symptoms of liver injury, e.g. jaundice, treatment with Nifev 100 mg should be permanently discontinued. Alternative causes of the liver enzyme elevations should be investigated.Patients with low body weight (<65 kg), Asian and female patients have a higher risk of elevations of liver enzymes. Nifev 100 mg exposure increased linearly with patient age, which may also result in a higher risk of developing liver enzyme elevations. Close monitoring is recommended in patients with these risk factors.Renal Function: Cases of renal impairment/failure, in some cases with fatal outcome, have been reported with Nifev 100 mg use. Patients should be monitored during Nifev 100 mg therapy, with particular attention to those patients exhibiting risk factors for renal impairment/failure. In case of renal impairment/failure, therapy adjustment should be considered.Haemorrhage: Vascular endothelial growth factor receptor (VEGFR) inhibition might be associated with an increased risk of bleeding. In the INPULSIS trials with Nifev 100 mg, the frequency of patients who experienced bleeding AEs was slightly higher in the Nifev 100 mg arm (10.3%) than in the placebo arm (7.8%). Non-serious epistaxis was the most frequent bleeding event. Serious bleeding events occurred with low and similar frequencies in the 2 treatment groups (placebo: 1.4%; Nifev 100 mg: 1.3%). Patients at known risk for bleeding including patients with inherited predisposition to bleeding or patients receiving a full dose of anti-coagulative treatment were not included in the INPULSIS studies. Non-serious and serious bleeding events, some of which were fatal, have been reported in the post-marketing period (including patients with or without anticoagulant therapy or other drugs that could cause bleeding). Therefore, these patients should only be treated with Nifev 100 mg if the anticipated benefit outweighs the potential risk. Post-marketing bleeding events include but are not limited to gastrointestinal, respiratory and central nervous organ systems, with the most frequent being gastrointestinal.Arterial thromboembolic events: Patients with a recent history of myocardial infarction or stroke were excluded from the INPULSIS trials. Arterial thromboembolic events were infrequently reported: in 0.7% of patients in the placebo and 2.5% in the Nifev 100 mg treated group. While adverse events reflecting ischemic heart disease were balanced between the Nifev 100 mg and placebo groups, a higher percentage of patients experienced myocardial infarctions in the Nifev 100 mg group (1.6%) compared to the placebo group (0.5%). Caution should be used when treating patients at higher cardiovascular risk including known coronary artery disease. Treatment interruption should be considered in patients who develop signs or symptoms of acute myocardial ischemia.Venous thromboembolism: In the INPULSIS trials no increased risk of venous thromboembolism was observed in Nifev 100 mg treated patients. Due to the mechanism of action of Nifev 100 mg patients might have an increased risk of thromboembolic events.Gastrointestinal perforations: In the INPULSIS trials, the frequency of patients with perforation was very low in both treatment groups: 0% placebo, 0.3% Nifev 100 mg (involving two patients). Due to the mechanism of action of Nifev 100 mg patients might have an increased risk of gastrointestinal perforation. Cases of gastrointestinal perforations, some of which were fatal, have been reported in the post-marketing period. Particular caution should be exercised when treating patients with previous abdominal surgery, previous history of peptic ulceration, diverticular disease or receiving concomitant corticosteroids or NSAIDs. Nifev 100 mg should only be initiated at least 4 weeks after abdominal surgery. Therapy with Nifev 100 mg should be permanently discontinued in patients who develop gastrointestinal perforation.Hypertension: Administration of Nifev 100 mg may increase blood pressure. Systemic blood pressure should be measured periodically and as clinically indicated.Wound healing complication: No increased frequency of impaired wound healing was observed in the INPULSIS trials. Based on the mechanism of action Nifev 100 mg may impair wound healing. No dedicated studies investigating the effect of Nifev 100 mg on wound healing were performed. Treatment with Nifev 100 mg should therefore only be initiated or – in case of perioperative interruption – resumed based on clinical judgement of adequate wound healing.Co-administration with Pirfenidone: In a dedicated pharmacokinetic study, concomitant treatment of Nifev 100 mg with Pirfenidone was investigated in patients with IPF. Based on these results, there is no evidence of a relevant pharmacokinetic drug-drug interaction between Nifev 100 mg and Pirfenidone when administered in combination. In view of the limited number of patients, this study detected only the most frequent adverse events and showed an increase in gastrointestinal adverse events and a trend toward increased hepatic adverse events. Given the similarity in safety profiles for both medicinal products, additive adverse events, including gastrointestinal and hepatic adverse events, may be expected. The benefit-risk balance of concomitant treatment with Pirfenidone has not been established.Effect on QT interval: No evidence of QT prolongation was observed for Nifev 100 mg in the clinical trial programme. As some other tyrosine kinase inhibitors are known to exert an effect on QT, caution should be exercised when administered Nifev 100 mg in patients who may develop QTc prolongation.Allergic reaction: Dietary soya products are known to cause allergic reactions including severe anaphylaxis in persons with soya allergy. Patients with known allergy to peanut protein carry an enhanced risk for severe reactions to soya preparations.

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

Elderly patients (≥65 years): No overall differences in safety and efficacy were observed for elderly patients. No a-priori dose adjustment is required on the basis of a patient’s age. Patients ≥75 years may be more likely to require dose reduction to manage adverse effects.Renal impairment: Less than 1% of a single dose of Nifev 100 mg is excreted via the kidney. Adjustment of the starting dose in patients with mild to moderate renal impairment is not required. The safety, efficacy, and pharmacokinetics of Nifev 100 mg have not been studied in patients with severe renal impairment (<30 ml/min creatinine clearance).Hepatic impairment: Nifev 100 mg is predominantly eliminated via biliary/faecal excretion (> 90%). Exposure increased in patients with hepatic impairment (Child Pugh A, Child Pugh B). In patients with mild hepatic impairment (Child Pugh A), the recommended dose of Nifev 100 mg is 100 mg twice daily approximately 12 hours apart. In patients with mild hepatic impairment (Child Pugh A), treatment interruption or discontinuation for management of adverse reactions should be considered. The safety and efficacy of Nifev 100 mg have not been investigated in patients with hepatic impairment classified as Child Pugh B and C. Treatment of patients with moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment with Nifev 100 mg is not recommended.Paediatric population: The safety and efficacy of Nifev 100 mg in children aged 0-18 years have not been established. No data are available.

Tyrosine Kinase Inhibitor

Nifev 100 mg 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 Nifev 100 mg 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 Nifev 100 mg 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). Nifev 100 mg 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. Nifev 100 mg 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, Nifev 100 mg 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 Nifev 100 mg is unclear, but inhibition of the Src pathway by Nifev 100 mg has been shown to reduce lung fibrosis.

Women of childbearing potential/Contraception: Nifev 100 mg may cause foetalharm in humans. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Nifev 100 mg. They should be advised to use adequate contraception during and at least 3 months after the last dose of Nifev 100 mg. Since the effect of Nifev 100 mg 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 Nifev 100 mg in pregnant women, but pre-clinical studies in animals have shown reproductive toxicity of this active substance. As Nifev 100 mg 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 Nifev 100 mg. If the patient becomes pregnant while receiving Nifev 100 mg, she should be apprised of the potential hazard to the foetus. Termination of the treatment with Nifev 100 mg should be considered.Lactation: There is no information on the excretion of Nifev 100 mg and its metabolites in human milk. Pre-clinical studies showed that small amounts of Nifev 100 mg 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 Nifev 100 mg.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.

Elderly patients (≥65 years): No overall differences in safety and efficacy were observed for elderly patients. No a-priori dose adjustment is required on the basis of a patient’s age. Patients ≥75 years may be more likely to require dose reduction to manage adverse effects.Renal impairment: Less than 1% of a single dose of Nifev 100 mg is excreted via the kidney. Adjustment of the starting dose in patients with mild to moderate renal impairment is not required. The safety, efficacy, and pharmacokinetics of Nifev 100 mg have not been studied in patients with severe renal impairment (<30 ml/min creatinine clearance).Hepatic impairment: Nifev 100 mg is predominantly eliminated via biliary/faecal excretion (> 90%). Exposure increased in patients with hepatic impairment (Child Pugh A, Child Pugh B). In patients with mild hepatic impairment (Child Pugh A), the recommended dose of Nifev 100 mg is 100 mg twice daily approximately 12 hours apart. In patients with mild hepatic impairment (Child Pugh A), treatment interruption or discontinuation for management of adverse reactions should be considered. The safety and efficacy of Nifev 100 mg have not been investigated in patients with hepatic impairment classified as Child Pugh B and C. Treatment of patients with moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment with Nifev 100 mg is not recommended.Paediatric population: The safety and efficacy of Nifev 100 mg in children aged 0-18 years have not been established. No data are available.