EVRENZO Film-coated tablet Ref.[27944] Active ingredients: Roxadustat

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) should be carefully weighed against the benefits to be derived from treatment with roxadustat particularly in patients with pre-existing risk factors for TVE, including obesity and prior history of TVEs (e.g., deep vein thrombosis [DVT] and pulmonary embolism [PE]). Deep vein thrombosis was reported as common and pulmonary embolism as uncommon amongst the patients in clinical studies. The majority of DVT and PE events were serious.

Vascular access thrombosis (VAT) was reported as very common amongst the CKD patients on dialysis in clinical studies (see section 4.8).

In CKD patients on dialysis, rates of VAT in roxadustat-treated patients were highest in the first 12 weeks following initiation of treatment, at Hb values more than 12 g/dL and in the setting of Hb rise of more than 2 g/dL over 4 weeks. It is recommended to monitor Hb levels and adjust the dose using the dose adjustment rules (see Table 2) to avoid Hb levels of more than 12 g/dL and Hb rise of more than 2 g/dL over 4 weeks.

Patients with signs and symptoms of TVEs should be promptly evaluated and treated according to standard of care. The decision to interrupt or discontinue treatment should be based on a benefit-risk consideration for the individual patient.

Seizures

Seizures were reported as common amongst the patients in clinical studies receiving roxadustat (see section 4.8). Roxadustat should be used with caution in patients with a history of seizures (convulsions or fits), epilepsy or medical conditions associated with a predisposition to seizure activity such as central nervous system (CNS) infections. The decision to interrupt or discontinue treatment should be based on a benefit-risk consideration of the individual patient.

Serious infections

The most commonly reported serious infections were pneumonia and urinary tract infections. Patients with signs and symptoms of an infection should be promptly evaluated and treated according to standard of care.

Sepsis

Sepsis was one of the most commonly reported serious infections and included fatal events. Patients with signs and symptoms of sepsis (e.g., an infection that spreads throughout the body with low blood pressure and the potential for organ failure) should be promptly evaluated and treated according to standard of care.

Inadequate response to therapy

Inadequate response to therapy with roxadustat should prompt a search for causative factors. Nutrient deficiencies should be corrected. Intercurrent infections, occult blood loss, haemolysis, severe aluminium toxicity, underlying haematologic diseases or bone marrow fibrosis may also compromise the erythropoietic response. A reticulocyte count should be considered as part of the evaluation. If typical causes of non-response are excluded, and the patient has reticulocytopenia, an examination of the bone marrow should be considered. In the absence of an addressable cause for an inadequate response to therapy, Evrenzo should not be continued beyond 24 weeks of therapy.

Hepatic impairment

Caution is warranted when roxadustat is administered to patients with moderate hepatic impairment (Child-Pugh class B). Evrenzo is not recommended for use in patients with severe hepatic impairment (Child-Pugh class C) (see section 5.2).

Pregnancy and contraception

Roxadustat should not be initiated in women planning on becoming pregnant, during pregnancy or when anaemia associated with CKD is diagnosed during pregnancy. In such cases, alternative therapy should be started, if appropriate. If pregnancy occurs while roxadustat is being administered, treatment should be discontinued and alternative treatment started, if appropriate. Women of childbearing potential must use highly effective contraception during treatment and for at least one week after the last dose of Evrenzo (see sections 4.3 and 4.6).

Misuse

Misuse may lead to an excessive increase in packed cell volume. This may be associated with life-threatening complications of the cardiovascular system.

Excipients

Evrenzo contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. Evrenzo contains Allura Red AC aluminium lake (see section 6.1) which may cause allergic reactions. Evrenzo contains traces of soya lecithin. Patients who are allergic to peanut or soya, should not use this medicinal product.

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 C_max 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 C_max by 1.4-fold. Monitor Hb levels when initiating or discontinuing concomitant treatment with gemfibrozil, probenecid, other strong inhibitors or inducers of CYP2C8 or other strong inhibitors of UGT1A9. Adjust the dose of roxadustat 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 C_max of simvastatin 1.8- and 1.9-fold, respectively, and the AUC and C_max of simvastatin acid (the active metabolite of simvastatin) 1.9- and 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 C_max of rosuvastatin 2.9- and 4.5-fold, respectively. Co-administration of 200 mg of roxadustat with atorvastatin increased the AUC and C_max of atorvastatin 2.0- and 1.3-fold, respectively.

Interactions are also expected with other statins. When co-administered with roxadustat, consider this interaction, monitor for adverse reactions associated with statins and for the need of statin dose reduction. Refer to statin prescribing information when deciding on the appropriate statin dose for individual patients.

Roxadustat may increase the plasma exposure of other medicinal products that are substrates of BCRP or OATP1B1. Monitor for possible adverse reactions of co-administered medicinal products and adjust dose accordingly.

Roxadustat and ESAs

It is not recommended to combine administration of roxadustat and ESAs as the combination has not been studied.

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.

Roxadustat has minor influence on the ability to drive and use machines. Seizures have been reported during treatment with Evrenzo (see section 4.4). Therefore, caution should be exercised when driving or using machines.

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 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:

¹ This adverse reaction is associated with CKD patients who were on dialysis while receiving roxadustat.

Description of selected adverse reactions

Thrombotic vascular events

In CKD patients not on dialysis, DVT events were uncommon, occurring in 1.0% (0.6 patients with events per 100 patient years of exposure) in the roxadustat group, and 0.2% (0.2 patients with events per 100 patient years of exposure) in the placebo group. In CKD patients on dialysis, DVT events occurred in 1.3% (0.8 patients with events per 100 patient years of exposure) in the roxadustat group and 0.3% (0.1 patients with events per 100 patient years of exposure) in the ESA group (see section 4.4).

In CKD patients not on dialysis, pulmonary embolism was observed in 0.4% (0.2 patients with events per 100 patient years of exposure) in the roxadustat group, compared to 0.2% (0.1 patients with events per 100 patient years of exposure) in the placebo group. In CKD patients on dialysis, pulmonary embolism was observed in 0.6% (0.3 patients with events per 100 patient years of exposure) in the roxadustat group, compared to 0.5% (0.3 patients with events per 100 patient years of exposure) in the ESA group (see section 4.4).

In CKD patients on dialysis, vascular access thrombosis was observed in 12.8% (7.6 patients with events per 100 patient years of exposure) in the roxadustat group, compared to 10.2% (5.4 patients with events per 100 patient years of exposure) in the ESA group (see section 4.4).

Seizures

In CKD patients not on dialysis, seizures occurred in 1.1% (0.6 patients with events per 100 patient years of exposure) in the roxadustat group, and 0.2% (0.2 patients with events per 100 patient years of exposure) in the placebo group (see section 4.4).

In CKD patients on dialysis, seizures occurred in 2.0% (1.2 patients with events per 100 patient years of exposure) in the roxadustat group, and 1.6% (0.8 patients with events per 100 patient years of exposure) in the ESA group (see section 4.4).

Sepsis

In CKD patients not on dialysis, sepsis was observed in 2.1% (1.3 patients with events per 100 patient years of exposure) in the roxadustat group, compared to 0.4% (0.3 patients with events per 100 patient years of exposure) in the placebo group. In patients on dialysis, sepsis was observed in 3.4% (2.0 patients with events per 100 patient years of exposure) in the roxadustat group, compared to 3.4% (1.8 patients with events per 100 patient years of exposure) in the ESA group (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.