Leitlinien & Arzneimittelsicherheit

HOS-216586 · has-adverse-reaction-information · PDF-Seite 10

Summary of the safety profile The pharmacodynamically predictable and most commonly reported adverse reactions are thirst, polyuria, nocturia, and pollakiuria occurring in approximately 55 %, 38 %, 29 % and 23 % of patients, respectively. Furthermore, tolvaptan has been associated with idiosyncratic elevations of blood alanine aminotransferase (ALT; 4.4 %) and aspartate aminotransferases (AST; 3.1 %) with infrequent cases of concomitant elevations in bilirubin-total (BT; 0.2 %). Tabulated list of adverse reactions The incidences of the adverse drug reactions (ADRs) associated with tolvaptan therapy are tabulated below. The table is based on adverse reactions reported during clinical trials and/or post-marketing use. All ADRs are listed by system organ class and frequency; 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) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The frequency of adverse reactions reported during post-marketing use cannot be determined as they are derived from spontaneous reports. Consequently, the frequency of these adverse reactions is qualified as "not known". Very common Common Uncommon Not known Immune system Anaphylactic disorders shock, Generalised rash Metabolism and Polydipsia Dehydration, nutrition Hypernatraemia, disorders Decreased appetite, Hyperuricaemia, Hyperglycaemia, Gout Psychiatric Insomnia disorders Nervous system Headache, Dysgeusia, disorders Dizziness Syncope Cardiac Palpitations disorders Respiratory, Dyspnoea thoracic and mediastinal disorders 10  Very common Common Uncommon Not known Gastrointestinal D

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HOS-216582 · has-contraindication-information · PDF-Seite 5

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or to benzazepine or benzazepine derivatives (see section 4.4) • Elevated liver enzymes and/or signs or symptoms of liver injury prior to initiation of treatment that meet the requirements for permanent discontinuation of tolvaptan (see section 4.4) • Anuria • Volume depletion • Hypernatraemia • Patients who cannot perceive or respond to thirst • Pregnancy (see section 4.6) • Breast-feeding (see section 4.6)

HOS-216581 · has-indication-information · PDF-Seite 3

Jinarc is indicated to slow the progression of cyst development and renal insufficiency of autosomal dominant polycystic kidney disease (ADPKD) in adults with chronic kidney disease (CKD) stage 1 to 4 at initiation of treatment with evidence of rapidly progressing disease (see section 5.1).

HOS-216584 · has-interaction-information · PDF-Seite 8

Effect of other medicinal products on the pharmacokinetics of tolvaptan CYP3A inhibitors Concomitant use of medicinal products that are moderate CYP3A inhibitors (e.g. amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, verapamil) or strong CYP3A inhibitors (e.g. itraconazole, ketoconazole, ritonavir, clarithromycin) increase tolvaptan exposure. Co-administration of tolvaptan and ketoconazole resulted in a 440 % increase in area under time- concentration curve (AUC) and 248 % increase in maximum observed plasma concentration (Cmax) for tolvaptan. Co-administration of tolvaptan and fluconazole, a moderate CYP3A inhibitor, produced a 200 % and 80 % increase in tolvaptan AUC and Cmax, respectively. Co-administration of tolvaptan with grapefruit juice, a moderate to strong CYP3A inhibitor, produced a doubling of peak tolvaptan concentrations (Cmax). Dose reduction of tolvaptan is recommended for patients while taking moderate or strong CYP3A inhibitors (see section 4.2). Patients taking moderate or strong CYP3A inhibitors must be managed cautiously, in particular if the inhibitors are taken more frequently than once a day. CYP3A inducers Concomitant use of medicinal products that are potent CYP3A inducers (e.g. rifampicin) will decrease tolvaptan exposure and efficacy. Co-administration of tolvaptan with rifampicin reduces Cmax and AUC for tolvaptan by about 85 %. Therefore, concomitant administration of tolvaptan with potent CYP3A inducers (e.g. rifampicin, rifabutin, rifapentine, phenytoin, carbamazepine, and St. John’s Wort) is to be avoided. Co-administration with medicinal products that increase serum sodium concentration There is no experience from controlled clinical trials with concomitant use of tolvaptan and hypertonic sodium chloride solution, oral sodium formulations, and medicinal products that increase serum sodium concentration. Medicinal products with high sodium content such as effervescent analgesic preparations and certain sodium containing treatments for dyspepsia may also increase serum sodium concentration. Concomitant use of tolvaptan with medicinal products that increase serum sodium concentration may result in a higher risk for developing hypernatraemia (see section 4.4) and is therefore not recommended. Diuretics Tolvaptan has not been extensively studied in ADPKD in combination with diuretics. While there does not appear to be a syn

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HOS-216585 · has-pregnancy-information · PDF-Seite 9

Pregnancy There are no or limited amount of data from the use of tolvaptan in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Jinarc is not recommended in women of childbearing potential not using contraception. Jinarc is contraindicated during pregnancy (see section 4.3). Breast-feeding It is unknown whether tolvaptan is excreted in human breast milk. Studies in rats have shown excretion of tolvaptan in milk. A risk for the newborns/infants cannot be excluded. Jinarc is contraindicated during breast-feeding (see section 4.3). 9 Fertility Studies in animals showed effects on fertility (see section 5.3). The potential risk for humans is unknown.

HOS-216583 · has-warning-information · PDF-Seite 5

Idiosyncratic hepatic toxicity Tolvaptan has been associated with idiosyncratic elevations of blood alanine and aspartate aminotransferases (ALT and AST) with infrequent cases of concomitant elevations in bilirubin-total (BT). In post-marketing experience with tolvaptan in ADPKD, acute liver failure requiring liver transplantation has been reported. In a double-blind, placebo-controlled trial in patients with ADPKD, the period of onset of hepatocellular injury (by ALT elevations > 3 × ULN) was within 3 to 14 months after initiating treatment and these increases were reversible, with ALT returning to < 3 × ULN within 1 to 4 months. While these concomitant elevations were reversible with prompt discontinuation of tolvaptan, they represent a potential for significant liver injury. Similar changes with other medicinal products have been associated with the potential to cause irreversible and potentially life-threatening liver injury (see section 4.8). Prescribing physicians must comply fully with the safety measures required below. To mitigate the risk of significant and/or irreversible liver injury, blood testing for hepatic transaminases and bilirubin is required prior to initiation of Jinarc, continuing monthly for 18 months and at regular 3- monthly intervals thereafter. Concurrent monitoring for symptoms that may indicate liver injury (such as fatigue, anorexia, nausea, right upper abdominal discomfort, vomiting, fever, rash, pruritus, dark urine or jaundice) is recommended. If a patient shows abnormal ALT, AST or BT levels prior to initiation of treatment which fulfil the criteria for permanent discontinuation (see below), the use of tolvaptan is contraindicated (see section 4.3). In case of abnormal baseline levels below the limits for permanent discontinuation treatment can only be initiated if the potential benefits of treatment outweigh the potential risks and liver function testing must continue at increased time frequency. The advice of a hepatologist is recommended. During the first 18 months of treatment, Jinarc can only be supplied to patients whose physician has determined that liver function supports continued therapy. At the onset of symptoms or signs consistent with hepatic injury or if clinically significant abnormal ALT or AST increases are detected during treatment, Jinarc administration must be immediately interrupted and repeat tests including ALT, AST, BT and alkaline phosphatase (AP) must be obtained as soon as possible (ideal

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