Esbriet

HOS-095896 · has-adverse-reaction-information · PDF-Seite 7

Summary of the safety profile The most frequently reported adverse reactions during clinical study experience with Esbriet at a dose of 2,403 mg/day compared to placebo, respectively, were nausea (32.4% versus 12.2%), rash (26.2% versus 7.7%), diarrhoea (18.8% versus 14.4%), fatigue (18.5% versus 10.4%), dyspepsia (16.1% versus 5.0%), decreased appetite (20.7%% versus 8.0%), headache (10.1% versus 7.7%), and photosensitivity reaction (9.3% versus 1.1%). Tabulated list of adverse reactions The safety of Esbriet has been evaluated in clinical studies including 1,650 volunteers and patients. More than 170 patients have been investigated in open studies for more than five years and some for up to 10 years. Table 1 shows the adverse reactions reported at a frequency of ≥2% in 623 patients receiving Esbriet at the recommended dose of 2,403 mg/day in three pooled pivotal Phase 3 studies. Adverse reactions from post-marketing experience are also listed in Table 1. Adverse reactions are listed by System Organ Class (SOC) and within each frequency grouping [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), not known (cannot be estimated from the available data)] the adverse reactions are presented in order of decreasing seriousness. Table 1 Adverse reactions by SOC and MedDRA frequency Infections and infestations Very Common Upper respiratory tract infection Common Urinary tract infection Blood and lymphatic system disorders Uncommon Agranulocytosis1 Immune system disorders Uncommon Angioedema1 Not known Anaphylaxis1 Metabolism and nutrition disorders Very Common Weight decreased; decreased appetite Uncommon Hyponatraemia1 Psychiatric disorders Very Common Insomnia Nervous system disorders Very Common Headache; dizziness 7  Table 1 Adverse reactions by SOC and MedDRA frequency Common Somnolence; dysgeusia; lethargy Vascular disorders Common Hot flush Respiratory, thoracic and mediastinal disorders Very Common Dyspnoea; cough Common Productive cough Gastrointestinal disorders Very Common Dyspepsia; nausea; diarrhoea; gastroesophageal reflux disease; vomiting; constipation Common Abdominal distensi

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HOS-095892 · has-contraindication-information · PDF-Seite 3

● Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. ● History of angioedema with pirfenidone (see section 4.4). ● Concomitant use of fluvoxamine (see section 4.5). ● Severe hepatic impairment or end stage liver disease (see sections 4.2 and 4.4). ● Severe renal impairment (CrCl <30 ml/min) or end stage renal disease requiring dialysis (see sections 4.2 and 5.2). 3

HOS-095891 · has-indication-information · PDF-Seite 2

Esbriet is indicated in adults for the treatment of idiopathic pulmonary fibrosis (IPF).

HOS-095894 · has-interaction-information · PDF-Seite 5

Approximately 70–80% of pirfenidone is metabolised via CYP1A2 with minor contributions from other CYP isoenzymes including CYP2C9, 2C19, 2D6, and 2E1. Consumption of grapefruit juice is associated with inhibition of CYP1A2 and should be avoided during treatment with pirfenidone. Fluvoxamine and inhibitors of CYP1A2 In a Phase 1 study, the co-administration of Esbriet and fluvoxamine (a strong inhibitor of CYP1A2 with inhibitory effects on other CYP isoenzymes [CYP2C9, 2C19, and 2D6]) resulted in a 4-fold increase in exposure to pirfenidone in non-smokers. Esbriet is contraindicated in patients with concomitant use of fluvoxamine (see section 4.3). Fluvoxamine should be discontinued prior to the initiation of Esbriet therapy and avoided during 5 Esbriet therapy due to the reduced clearance of pirfenidone. Other therapies that are inhibitors of both CYP1A2 and one or more other CYP isoenzymes involved in the metabolism of pirfenidone (e.g. CYP2C9, 2C19, and 2D6) should be avoided during pirfenidone treatment. In vitro and in vivo extrapolations indicate that strong and selective inhibitors of CYP1A2 (e.g. enoxacin) have the potential to increase the exposure to pirfenidone by approximately 2 to 4-fold. If concomitant use of Esbriet with a strong and selective inhibitor of CYP1A2 cannot be avoided, the dose of pirfenidone should be reduced to 801 mg daily (267 mg, three times a day). Patients should be closely monitored for emergence of adverse reactions associated with Esbriet therapy. Discontinue Esbriet if necessary (see sections 4.2 and 4.4). Co-administration of Esbriet and 750 mg of ciprofloxacin (a moderate inhibitor of CYP1A2) increased the exposure to pirfenidone by 81%. If ciprofloxacin at the dose of 750 mg two times a day cannot be avoided, the dose of pirfenidone should be reduced to 1602 mg daily (534 mg, three times a day). Esbriet should be used with caution when ciprofloxacin is used at a dose of 250 mg or 500 mg once or two times a day. Esbriet should be used with caution in patients treated with other moderate inhibitors of CYP1A2 (e.g. amiodarone, propafenone). Special care should also be exercised if CYP1A2 inhibitors are being used concomitantly with potent inhibitors of one or more other CYP isoenzymes involved in the metabolism of pirfenidone such as CYP2C9 (e.g. amiodarone, fluconazole), 2C19 (e.g. chloramphenicol) and 2D6 (e.g. fluoxetine, paroxetine). Cigarette smoking and

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HOS-095895 · has-pregnancy-information · PDF-Seite 6

Pregnancy There are no data from the use of Esbriet in pregnant women. In animals placental transfer of pirfenidone and/or its metabolites occurs with the potential for accumulation of pirfenidone and/or its metabolites in amniotic fluid. At high doses (≥1,000 mg/kg/day) rats exhibited prolongation of gestation and reduction in foetal viability. As a precautionary measure, it is preferable to avoid the use of Esbriet during pregnancy. Breast-feeding It is unknown whether pirfenidone or its metabolites are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of pirfenidone and/or its metabolites in milk 6 with the potential for accumulation of pirfenidone and/or its metabolites in milk (see section 5.3). A risk to the breastfed infant cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue from Esbriet therapy, taking into account the benefit of breast-feeding for the child and the benefit of Esbriet therapy for the mother. Fertility No adverse effects on fertility were observed in preclinical studies (see section 5.3).

HOS-095893 · has-warning-information · PDF-Seite 4

Hepatic function Elevated transaminases have been commonly reported in patients treated with Esbriet. Liver function tests (ALT, AST and bilirubin) should be performed prior to the initiation of treatment with Esbriet, and subsequently at monthly intervals for the first 6 months and then every 3 months thereafter (see section 4.8). If a patient exhibits an aminotransferase elevation >3 to <5 x ULN without bilirubin elevation and without symptoms or signs of drug-induced liver injury after starting Esbriet therapy, other causes should be excluded, and the patient monitored closely. Discontinuation of other medicines associated with liver toxicity should be considered. If clinically appropriate, the dose of Esbriet should be reduced or interrupted. Once liver function tests are within normal limits Esbriet may be re-escalated to the recommended daily dose if tolerated. Drug-induced liver injury Uncommonly, elevations in AST and ALT were associated with concomitant bilirubin increases. Cases of severe drug-induced liver injury, including isolated cases with fatal outcome, have been reported post-marketing (see section 4.8). In addition to the recommended regular monitoring of liver function tests, prompt clinical evaluation and measurement of liver function tests should be performed in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. If a patient exhibits an aminotransferase elevation >3 to <5 x ULN accompanied by hyperbilirubinaemia or clinical signs or symptoms indicative of liver injury, Esbriet should be permanently discontinued and the patient should not be rechallenged. If a patient exhibits an aminotransferase elevation to ≥5 x ULN, Esbriet should be permanently discontinued and the patient should not be rechallenged. Hepatic impairment In subjects with moderate hepatic impairment (i.e. Child-Pugh Class B), pirfenidone exposure was increased by 60%. Esbriet should be used with caution in patients with pre-existing mild to moderate hepatic impairment (i.e. Child-Pugh Class A and B) given the potential for increased pirfenidone exposure. Patients should be monitored closely for signs of toxicity especially if they are concomitantly taking a known CYP1A2 inhibitor (see sections 4.5 and 5.2). Esbriet has not been studied in individuals with severe hepatic impairment and Esbriet must not be used in patients with severe hepatic impairment (see section

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