Ofev · 4.5 Interaction with other medicinal products and other forms of interaction · 1

HOS-097159 · has-adverse-reaction-information · PDF-Seite 10

Summary of the safety profile In clinical trials and during the post-marketing experience, the most frequently reported adverse reactions associated with the use of nintedanib included diarrhoea, nausea and vomiting, abdominal pain, decreased appetite, weight decreased and hepatic enzyme increased. For the management of selected adverse reactions see section 4.4. Tabulated list of adverse reactions Table 2 provides a summary of the adverse drug reactions (ADRs) by MedDRA System Organ Class (SOC) and frequency category 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). Table 2: Summary of ADRs per frequency category Frequency Other chronic Systemic sclerosis System Organ Class Idiopathic pulmonary fibrosing ILDs with a associated interstitial preferred term fibrosis progressive phenotype lung disease Blood and lymphatic system disorders Thrombocytopenia Uncommon Uncommon Uncommon Metabolism and nutrition disorders Weight decreased Common Common Common Decreased appetite Common Very common Common Dehydration Uncommon Uncommon Not known Nervous system disorders Headache Common Common Common Posterior reversible Not known Not known Not known encephalopathy syndrome Cardiac disorders Myocardial infarction Uncommon Uncommon Not known Vascular disorders Bleeding (see Common Common Common section 4.4) Hypertension Uncommon Common Common Aneurysms and artery Not known Not known Not known dissections Gastrointestinal disorder Diarrhoea Very common Very common Very common Nausea Very common Very commo

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HOS-097155 · has-contraindication-information · PDF-Seite 5

• Pregnancy (see section 4.6) • Hypersensitivity to nintedanib, to peanut or soya, or to any of the excipients listed in section 6.1.

HOS-097154 · has-indication-information · PDF-Seite 2

Ofev is indicated in adults for the treatment of idiopathic pulmonary fibrosis (IPF). Ofev is also indicated in adults for the treatment of other chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype (see section 5.1). Ofev is indicated in children and adolescents from 6 to 17 years old for the treatment of clinically significant, progressive fibrosing interstitial lung diseases (ILDs) (see section 4.2 and 5.1). Ofev is indicated in adults, adolescents and children aged 6 years and older for the treatment of 2 systemic sclerosis associated interstitial lung disease (SSc-ILD).

HOS-097157 · has-interaction-information · PDF-Seite 8

P-glycoprotein (P-gp) Nintedanib is a substrate of P-gp (see section 5.2). 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 Ofev, 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 adverse reactions may require interruption, dose reduction, or discontinuation of therapy with Ofev (see section 4.2). Potent P-gp inducers (e.g. rifampicin, carbamazepine, phenytoin, and St. John’s Wort) may decrease 8 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 (see section 5.2). The likelihood of drug-drug interactions with nintedanib based on CYP metabolism is therefore considered to be low. Co-administration with other medicinal products Co-administration of nintedanib with oral hormonal contraceptives did not alter the pharmacokinetics of oral hormonal contraceptives to a relevant extent (see section 5.2). Co-administration of nintedanib with bosentan did not alter the pharmacokinetics of nintedanib (see section 5.2). Paediatric population Interaction studies have only been performed in adults.

HOS-097158 · has-pregnancy-information · PDF-Seite 9

Women of childbearing potential / Contraception Nintedanib may cause foetal harm in humans (see section 5.3). Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Ofev and to use highly effective contraceptive methods at initiation of, during and at least 3 months after the last dose of Ofev. Nintedanib does not relevantly affect the plasma exposure of ethinylestradiol and levonorgestrel (see section 5.2). The efficacy of oral hormonal contraceptives may be compromised by vomiting and/or diarrhoea or other conditions where the absorption may be affected. Women taking oral hormonal contraceptives experiencing these conditions should be advised to use an alternative highly effective contraceptive measure. Pregnancy There is no information on the use of Ofev in pregnant women, but pre-clinical studies in animals have shown reproductive toxicity of this active substance (see section 5.3). As nintedanib may cause foetal harm also in humans, it must not be used during pregnancy (see section 4.3) and pregnancy testing must be conducted prior to treatment with Ofev and during treatment as appropriate. Female patients should be advised to notify their doctor or pharmacist if they become pregnant during therapy with Ofev. If the patient becomes pregnant while receiving Ofev, treatment must be discontinued and she should be apprised of the potential hazard to the foetus. Breast-feeding 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 Ofev. Fertility Based on preclinical investigations there is no evidence for impairment of male fertility (see section 5.3). 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 (see section 5.3). 9

HOS-097156 · has-warning-information · PDF-Seite 5

Gastrointestinal disorders Diarrhoea In the clinical trials, diarrhoea was the most frequent gastro-intestinal adverse reaction reported (see section 4.8). In most patients, the adverse reaction was of mild to moderate intensity and occurred within the first 3 months of treatment. 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 dose reduction or treatment interruption. Ofev treatment may be resumed at a reduced dose or at the full dose (see section 4.2). In case of persisting severe diarrhoea despite symptomatic treatment, therapy with Ofev should be discontinued. Nausea and vomiting Nausea and vomiting were frequently reported gastrointestinal adverse reactions (see section 4.8). In most patients with nausea and vomiting, the event was of mild to moderate intensity. In clinical trials, nausea led to discontinuation of Ofev in up to 2.1% of patients and vomiting led to discontinuation of Ofev in up to 1.4% of 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 or at the full dose (see section 4.2 Dose adjustments). In case of persisting severe symptoms therapy with Ofev should be discontinued. Hepatic function The safety and efficacy of Ofev has not been studied in patients with moderate (Child Pugh B) or severe (Child Pugh C) hepatic impairment. Therefore, treatment with Ofev is not recommended in such patients (see section 4.2). Based on increased exposure, the risk for adverse reactions may be increased in patients with mild hepatic impairment (Child Pugh A). Adult patients with mild hepatic impairment (Child Pugh A) should be treated with a reduced dose of Ofev (see sections 4.2 and 5.2). Cases of drug-induced liver injury have been observed with nintedanib 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 Ofev. Patients should then be monitored at regular intervals during the subsequent two months of treatment and periodically thereafter, e.g. at each p

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