FOR IDIOPATHIC PULMONARY FIBROSIS (IPF)
CHANGE THE PATH OF IPF
OFEV® is indicated for the treatment of IPF in adults1,2 Treat your patients with OFEV®
Now accepted for restricted use within NHS Scotland by the Scottish Medicines Consortium (SMC)*
– shown to slow decline in lung function when compared to placebo1,2 OFEV® 100 mg and 150 mg soft capsules
Soft capsules containing 100 mg or 150 mg nintedanib (as esilate). Indication: Ofev is indicated in adults for the treatment of Idiopathic Pulmonary Fibrosis (IPF). Dose and Administration: Treatment with Ofev should be initiated by physicians experienced in the diagnosis and treatment of IPF. 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. Dose adjustments: In addition to symptomatic treatment if applicable, the management of adverse reactions to Ofev could include dose reduction and temporary interruption until the specific adverse reaction has resolved to levels that allow continuation of therapy. Ofev 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 Ofev 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 Ofev may be reintroduced at a reduced dose (100 mg twice daily) which subsequently may be increased to the full dose (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 nintedanib 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 nintedanib have not been studied in patients with severe renal impairment (<30 ml/min creatinine clearance). Hepatic impairment: Nintedanib is predominantly eliminated via biliary/faecal excretion (> 90%). Exposure increased in patients with hepatic impairment (Child Pugh A, Child Pugh B). No adjustment of the starting dose is needed for patients with mild hepatic impairment based on clinical data (Child Pugh A). The safety and efficacy of nintedanib 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 Ofev is not recommended. Paediatric population: The safety and efficacy of Ofev in children aged 0-18 years have not been established. Method of administration: Ofev is for oral use. The capsules should be taken with food, swallowed whole with water, and should not be chewed or crushed. Contraindications: Hypersensitivity to nintedanib, to peanut or soya, or to any of the excipients. Warnings and Precautions: Gastrointestinal disorders: Diarrhoea should be treated at first signs with adequate hydration and anti-diarrhoeal medicinal products, e.g. loperamide, and may require treatment interruption. Ofev 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 Ofev should be discontinued. Nausea and vomiting: 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 Ofev should be discontinued. Hepatic function:
OFEV 23
Treatment with Ofev is not recommended in patients with moderate (Child Pugh B) or severe (Child Pugh C) hepatic impairment. Based on increased exposure, the risk for adverse events may be increased in patients with mild hepatic impairment (Child Pugh A). Administration of nintedanib was associated with elevations of liver enzymes (ALT, AST, alkaline phosphatase (ALKP), gamma-glutamyl-transferase (GGT)) with a potentially higher risk for female patients. Transaminase increases were reversible upon dose reduction or interruption. Administration of nintedanib was also associated with elevations of bilirubin. Hepatic transaminase and bilirubin levels should be investigated before the initiation of treatment with Ofev, and periodically thereafter (e.g. at each patient visit) or as clinically indicated. If transaminase (AST or ALT) elevations > 3x ULN are measured, dose reduction or interruption of the therapy with Ofev is recommended and the patient should be monitored closely. Once transaminases have returned to baseline values, treatment with Ofev 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 Ofev should be permanently discontinued. Alternative causes of the liver enzyme elevations should be investigated. Haemorrhage: Vascular endothelial growth factor receptor (VEGFR) inhibition might be associated with an increased risk of bleeding. Cases of haemorrhage have been reported (including patients with or without anticoagulant therapy or other drugs that could cause bleeding), patients at known risk for bleeding including patients with inherited predisposition to bleeding or patients receiving a full dose of anticoagulative treatment should only be treated with Ofev if the anticipated benefit outweighs the potential risk. Arterial thromboembolic events: 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: Due to the mechanism of action of nintedanib patients might have an increased risk of thromboembolic events. Gastrointestinal perforations: Due to the mechanism of action of nintedanib patients might have an increased risk of gastrointestinal perforation. Particular caution should be exercised when treating patients with previous abdominal surgery. Ofev should only be initiated at least 4 weeks after abdominal surgery. Therapy with Ofev should be permanently discontinued in patients who develop gastrointestinal perforation. Hypertension: Administration of Ofev may increase blood pressure. Systemic blood pressure should be measured periodically and as clinically indicated. Wound healing complication: Based on the mechanism of action nintedanib may impair wound healing. Treatment with Ofev should therefore only be initiated or - in case of perioperative interruption - resumed based on clinical judgement of adequate wound healing. Co-administration with pirfenidone: The benefit/risk of the co-administration of nintedanib with pirfenidone has not been established. Effect on QT interval: Caution should be exercised when administering nintedanib 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. Interactions: P-glycoprotein (P-gp): Nintedanib is a substrate of P-gp. 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 side effects may require interruption, dose reduction, or discontinuation of therapy with Ofev. 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: Likelihood of drug-drug interactions with nintedanib based on CYP metabolism considered to be low. Other medicinal products: The potential for interactions of nintedanib with hormonal contraceptives was not explored. Fertility, Pregnancy and Lactation: Nintedanib may cause foetal harm in humans. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Ofev. They should be advised to use adequate contraception during and at least 3 months after the last dose of Ofev. 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. There is no information on the use of Ofev in pregnant women, but pre-clinical studies in animals have shown reproductive toxicity. 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 Ofev. If the patient becomes pregnant while receiving Ofev, she should be apprised of the potential hazard to the foetus. Termination of the treatment with Ofev should be considered. 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. 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. Undesirable effects: Very common (≥ 1/10): diarrhoea, nausea, abdominal pain, hepatic enzyme increased. Common (≥ 1/100 < 1/10): weight decreased, decreased appetite, epistaxis, vomiting, alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, gamma glutamyl transferase (GGT) increased. Prescribers should consult the Summary of Product Characteristics for further information on side effects. Pack sizes and NHS price: 100 mg x 60 capsules £2151.10; 150 mg x 60 capsules £2151.10. Legal category: POM. MA numbers: 100 mg EU/1/14/979/002; 150 mg EU/1/14/979/004. Marketing Authorisation Holder: Boehringer Ingelheim International GmbH, Binger Strasse 173, 55216 Ingelheim am Rhein, Germany. Prescribers should consult the Summary of Product Characteristics for full prescribing information. Prepared in March 2016
Adverse events should be reported. Reporting forms and information can be found at
www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Boehringer Ingelheim Drug Safety on 0800 328 1627 (freephone).
*For use in patients with a predicted forced vital capacity (FVC) less than or equal to 80%, following assessment and publication by the Scottish Medicines Consortium (SMC) on 12th October 2015. References: 1. OFEV® 100 mg and 150 mg Summary of Product Characteristics. Boehringer Ingelheim UK. Available at:
www.medicines.org.uk/emc. 2. Richeldi L, du Bois RM, Raghu G, et al; for the INPULSIS Trial Investigators. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014; 370(22): 2071–2082.
UK/OFE-141010f Date of preparation: March 2016
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