Leitlinien & Arzneimittelsicherheit

HOS-098861 · has-adverse-reaction-information · PDF-Seite 10

Summary of the safety profile The safety of Evrenzo was evaluated in 3542 non-dialysis dependent (NDD) and 3353 dialysis dependent (DD) patients with anaemia and CKD who have received at least one dose of roxadustat. The most frequent (≥ 10%) adverse reactions associated with roxadustat are hypertension (13.9%), vascular access thrombosis (12.8%), diarrhoea (11.8%), peripheral oedema (11.7%), hyperkalaemia (10.9%) and nausea (10.2%). The most frequent (≥ 1%) serious adverse reactions associated with roxadustat were sepsis (3.4%), hyperkalaemia (2.5%), hypertension (1.4%) and deep vein thrombosis (1.2%). Tabulated list of adverse reactions Adverse reactions observed during clinical studies and/or in post-marketing experience are listed in this section by frequency category. Frequency categories are defined as follows: 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 3. Adverse reactions MedDRA System organ class Frequency category Adverse reaction (SOC) Infections and infestations Common Sepsis Blood and lymphatic system Common Thrombocytopenia disorders Endocrine disorders Not known Secondary hypothyroidism Metabolism and nutrition Very common Hyperkalaemia disorders Psychiatric disorders Common Insomnia Nervous system disorders Common Seizures, headache Uncommon Cerebral infarction Vascular disorders Very common Hypertension, vascular access thrombosis (VAT)1 Common Deep vein thrombosis (DVT) Respiratory, thoracic, Uncommon Pulmonary embolism mediastinal disorders Gastrointestinal disorders Very common Nausea, diarrhoea Common Constipation, vomiting Hepatobiliary disorders Uncommon Hyperbilirubinaemia Skin and subcutaneous tissue Not known

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HOS-098857 · has-contraindication-information · PDF-Seite 6

• Hypersensitivity to the active substance, peanut, soya or to any of the excipients listed in section 6.1. • Third trimester of pregnancy (see sections 4.4 and 4.6). • Breast-feeding (see section 4.6).

HOS-098856 · has-indication-information · PDF-Seite 3

Evrenzo is indicated for treatment of adult patients with symptomatic anaemia associated with chronic kidney disease (CKD).

HOS-098859 · has-interaction-information · PDF-Seite 8

Effect of other medicinal products on roxadustat Phosphate binders and other products containing multivalent cations Co-administration of roxadustat with phosphate binders sevelamer carbonate or calcium acetate in healthy subjects decreased roxadustat AUC by 67% and 46% and Cmax by 66% and 52%, respectively. Roxadustat may form a chelate with multivalent cations such as in phosphate binders or other products containing calcium, iron, magnesium or aluminium. Staggered administration of phosphate binders (at least 1 hour apart) had no clinically significant effect on roxadustat exposure in patients with CKD. Roxadustat should be taken at least 1 hour after administration of phosphate binders or other medicinal products or supplements containing multivalent cations (see section 4.2). This restriction does not apply to lanthanum carbonate, as the co-administration of roxadustat with lanthanum carbonate did not result in a clinically meaningful change in the plasma exposure of roxadustat. Modifiers of CYP2C8 or UGT1A9 activity Roxadustat is a substrate of CYP2C8 and UGT1A9. Co-administration of roxadustat with gemfibrozil (CYP2C8 and OATP1B1inhibitor) or probenecid (UGT and OAT1/OAT3 inhibitor) in healthy subjects increased roxadustat AUC by 2.3-fold and Cmax by 1.4-fold. Hb levels are to be monitored when initiating or discontinuing concomitant treatment with gemfibrozil, probenecid, other strong inhibitors or inducers of CYP2C8 or other strong inhibitors of UGT1A9. The dose of roxadustat is to be adjusted following dose adjustment rules (see Table 2) based on Hb monitoring. Effects of roxadustat on other medicinal products OATP1B1 or BCRP substrates Roxadustat is an inhibitor of BCRP and OATP1B1. These transporters play an important role in the intestinal and hepatic uptake and efflux of statins. Co-administration of 200 mg of roxadustat with simvastatin in healthy subjects increased the AUC and Cmax of simvastatin 1.8- and 1.9-fold, respectively, and the AUC and Cmax of simvastatin acid (the active metabolite of simvastatin) 1.9- and 8 2.8-fold, respectively. The concentrations of simvastatin and simvastatin acid also increased when simvastatin was administered 2 hours before or 4 or 10 hours after roxadustat. Co-administration of 200 mg of roxadustat with rosuvastatin increased the AUC and Cmax of rosuvastatin 2.9- and 4.5-fold, respectively. Co-administration of 200 mg of roxadustat with atorvastatin

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HOS-098860 · has-pregnancy-information · PDF-Seite 9

Pregnancy, women of childbearing potential and contraception There are no data on the use of roxadustat in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Roxadustat is contraindicated during the third trimester of pregnancy (see sections 4.3 and 4.4). Roxadustat is not recommended during the first and second trimester of pregnancy (see section 4.4). If pregnancy occurs while Evrenzo is being administered, treatment should be discontinued and switched to alternative treatments, if appropriate (see section 4.3). Breast-feeding It is unknown whether roxadustat/metabolites are excreted in human milk. Available animal data have shown excretion of roxadustat in milk (for details see section 5.3). Evrenzo is contraindicated during breast-feeding (see sections 4.3 and 5.3). Fertility In animal studies, there were no effects of roxadustat on male and female fertility. However, changes in rat male reproductive organs were observed. The potential effects of roxadustat on male fertility in humans is currently unknown. At a maternally toxic dose, increased embryonic loss was observed (see section 5.3). Women of childbearing potential must use highly effective contraception during treatment and for at least one week after the last dose of Evrenzo.

HOS-098858 · has-warning-information · PDF-Seite 6

Cardiovascular and mortality risk Overall, the cardiovascular and mortality risk for treatment with roxadustat has been estimated to be comparable to the cardiovascular and mortality risk for ESA therapy based on data from direct comparison of both therapies (see section 5.1). Since, for patients with anaemia associated with CKD and not on dialysis, this risk could not be estimated with sufficient confidence versus placebo, a decision to treat these patients with roxadustat should be based on similar considerations that would be applied before treating with an ESA. Further, several contributing factors have been identified that may impose this risk, including treatment non-responsiveness, and converting stable ESA treated dialysis patients (see sections 4.2 and 5.1). In the case of non-responsiveness, treatment with roxadustat should not be continued beyond 24 weeks after the start of treatment (see section 4.2). Conversion of dialysis patients otherwise stable on ESA treatment is only to be considered when there is a valid clinical reason (see section 4.2). For stable ESA treated patients with anaemia associated with CKD and not on dialysis, this risk could not be estimated as these patients have not been studied. A decision to treat these patients with roxadustat should be based on a benefit risk consideration for the individual patient. Thrombotic vascular events The reported risk of thrombotic vascular events (TVEs) including deep vein thrombosis (DVT), pulmonary embolism (PE) and cerebral infarction should be carefully weighed against the benefits of roxadustat treatment particularly in patients with pre-existing risk factors for TVE, including obesity and prior history of TVEs. The majority of DVT, PE and cerebral infarction events were serious. Fatal cases of cerebral infarction have been reported. 6 A rapid increase in Hb values has been observed in some cases of cerebrovascular accidents. Vascular access thrombosis (VAT) was reported as very common amongst the CKD patients on dialysis in clinical studies (see section 4.8). In these patients, rates of VAT in roxadustat-treated patients were highest in the first 12 weeks following initiation of treatment, particularly at Hb values more than 12 g/dL and with Hb rise of more than 2 g/dL over 4 weeks. It is recommended to closely monitor Hb levels and adjust the dose using the dose adjustment rules (see Table 2) to avoid these levels. Patients wi

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