4.1. Therapeutic indications

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

4.2. Posology and method of administration

Treatment with roxadustat should be initiated by a physician experienced in the management of anaemia. All other causes of anaemia should be evaluated prior to initiating therapy with Evrenzo, and when deciding to increase the dose.

Anaemia symptoms and sequelae may vary with age, gender, and overall burden of disease; a physician's evaluation of the individual patient's clinical course and condition is necessary. In addition to the presence of symptoms of anaemia, criteria such as rate of fall of haemoglobin (Hb) concentration, prior response to iron therapy, and the risk of need of red blood cell (RBC) transfusion could be of relevance in the evaluation of the individual patient's clinical course and condition.

Posology

The appropriate dose of roxadustat must be taken orally three times per week and not on consecutive days.

The dose should be individualised to achieve and maintain target Hb levels of 10 to 12 g/dL as described below.

Roxadustat treatment should not be continued beyond 24 weeks of therapy if a clinically meaningful increase in Hb levels is not achieved. Alternative explanations for an inadequate response should be sought and treated before re-starting Evrenzo.

Starting dose at treatment initiation

Adequate iron stores should be ensured prior to initiating treatment.

Patients not currently treated with an erythropoiesis-stimulating agent (ESA)

For patients initiating anaemia treatment not previously treated with ESA the recommended starting dose of roxadustat is 70 mg three times per week in patients weighing less than 100 kg and 100 mg three times per week in patients weighing 100 kg and over.

Patients converting from an ESA

Patients currently treated with an ESA can be converted to roxadustat, however, conversion of dialysis patients otherwise stable on ESA treatment is only to be considered when there is a valid clinical reason (see sections 4.4 and 5.1).

Conversion of non-dialysis patients otherwise stable on ESA treatment has not been investigated. A decision to treat these patients with roxadustat should be based on a benefit-risk consideration for the individual patient.

The recommended starting dose of roxadustat is based on the average prescribed ESA dose in the 4 weeks before conversion (see Table 1). The first roxadustat dose should replace the next scheduled dose of the current ESA.

Table 1. Starting doses of roxadustat to be taken three times per week in patients converting from an ESA

Darbepoetin alfa intravenous or subcutaneous dose (micrograms/week)

Epoetin intravenous or subcutaneous dose (IU/week)

Methoxy polyethylene glycol-epoetin beta intravenous or subcutaneous dose (micrograms/monthly)

Roxadustat dose (milligrams three times per week)

Less than 25

Less than 5,000

Less than 80

70

25 to less than 40

5,000 up to 8,000

80 up to and including 120

100

40 up to and including 80

More than 8,000 up to and including 16,000

More than 120 up to and including 200

150

More than 80

More than 16,000

More than 200

200

ESA: erythropoiesis-stimulating agent.

Dose adjustment and Hb monitoring

The individualised maintenance dose ranges from 20 mg to 400 mg three times per week (see section Maximum recommended dose). Hb levels should be monitored every two weeks until the desired Hb level of 10 to 12 g/dL is achieved and stabilised, and every 4 weeks thereafter, or as clinically indicated.

The dose of roxadustat can be adjusted stepwise up or down from the starting dose 4 weeks after treatment start, and every 4 weeks thereafter except if the Hb increases by more than 2 g/dL, in which case the dose should be reduced by one step immediately. When adjusting the dose of roxadustat, consider the current Hb level and the recent rate of change in Hb level over the past 4 weeks, and follow the dose adjustment steps according to the dose adjustment algorithm described in Table 2.

The stepwise dose adjustments up or down should follow the sequence of the available doses: 20 mg-40 mg-50 mg-70 mg-100 mg-150 mg-200 mg-250 mg-300 mg-400 mg (only for CKD patients on dialysis).

Table 2. Dose adjustment rules

Change in Hb over the previous 4 weeks1

Current Hb level (g/dL):

Lower than 10.5

10.5 to 11.9

12.0 to 12.9

13.0 or higher

Change in value of more than +1.0 g/dL

No change

Reduce dose by one step

Reduce dose by one step

Withhold dosing, monitor Hb level and resume dosing when Hb is less than 12.0 g/dL, at a dose that is reduced by two steps

Change in value between -1.0 and +1.0 g/dL

Increase dose by one step

No change

Reduce dose by one step

Change in value of less than -1.0 g/dL

Increase dose by one step

Increase dose by one step

No change

The dose of roxadustat should not be adjusted more frequently than once every 4 weeks, except if Hb increases by more than 2 g/dL at any time within a 4-week period, in which case the dose should be reduced by one step immediately.

1Change in haemoglobin (Hb) over the previous 4 weeks = (present Hb value) – (previous Hb value drawn 4 weeks ago).

If additional dose reduction is required for a patient already on the lowest dose (20 mg three times per week), do not reduce the 20 mg dose by breaking the tablet, but reduce the dose frequency to twice per week. If further dose reduction is needed, the dose frequency may be further reduced to once weekly.

Maintenance dose

After stabilisation to target Hb levels between 10 to 12 g/dL, the Hb levels should continue to be monitored regularly and the dose adjustment rules followed (see Table 2).

Patients starting dialysis while on roxadustat treatment

No specific dose adjustment is required for CKD patients who start dialysis while on treatment with roxadustat. Normal dose adjustment rules (see Table 2) should be followed.

Concomitant roxadustat treatment with inducers or inhibitors

When initiating or discontinuing concomitant treatment with strong inhibitors (e.g. gemfibrozil) or inducers (e.g. rifampicin) of CYP2C8, or inhibitors (e.g. probenecid) of UGT1A9: the Hb levels should be monitored routinely and the dose adjustment rules followed (see Table 2; see also sections 4.5 and 5.2).

Maximum recommended dose

Patients not on dialysis do not exceed a roxadustat dose of 3 mg/kg body weight or 300 mg three times per week, whichever is lower.

Patients on dialysis do not exceed a roxadustat dose of 3 mg/kg body weight or 400 mg three times per week, whichever is lower.

Missed dose

If a dose is missed, and there is more than 1 day until the next scheduled dose, the missed dose must be taken as soon as possible. If one day or less remains before the next scheduled dose, the missed dose must be skipped, and the next dose must be taken on the next scheduled day. In each case, the regular dosing schedule should be resumed thereafter.

Special populations

Elderly

No adjustment of the starting dose is required in elderly patients (see section 5.2).

Patients with hepatic impairment

No adjustment of the starting dose level is required in patients with mild hepatic impairment (Child-Pugh class A) (see sections 4.4 and 5.2).

Caution is recommended when prescribing roxadustat to patients with moderate hepatic impairment. The starting dose is to be reduced by half or to the dose level that is closest to half the starting dose when initiating treatment in 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) as the safety and efficacy has not been evaluated in this population (see sections 4.4 and 5.2).

Paediatric population

Safety and efficacy of roxadustat in paediatric patients under 18 years of age have not been established. No data are available.

Method of administration

Evrenzo film-coated tablets are to be taken orally with or without food. Tablets are to be swallowed whole and not chewed, broken or crushed due to the absence of clinical data under these conditions, and to protect the light-sensitive tablet core from photodegradation.

The tablets should be taken at least 1 hour after administration of phosphate binders (except lanthanum) or other medicinal products containing multivalent cations such as calcium, iron, magnesium or aluminium (see sections 4.5 and 5.2).

4.3. Contraindications

Evrenzo is contraindicated in the following conditions:

• 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).

4.4. Special warnings and precautions for use

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.

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 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 an individual benefit-risk assessment.

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.

Secondary hypothyroidism

Cases of secondary hypothyroidism have been reported with the use of roxadustat (see section 4.8). These reactions were reversible upon roxadustat withdrawal. Monitoring of thyroid function is recommended as clinically indicated.

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.

4.5. Interaction with other medicinal products and other forms of interaction

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. 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 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 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 increased the AUC and Cmax 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.

4.6. Fertility, pregnancy and lactation

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.

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

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 (SOC)

Frequency category

Adverse reaction

Infections and infestations

Common

Sepsis

Blood and lymphatic system disorders

Common

Thrombocytopenia

Endocrine disorders

Not known

Secondary hypothyroidism

Metabolism and nutrition disorders

Very common

Hyperkalaemia

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, mediastinal disorders

Uncommon

Pulmonary embolism

Gastrointestinal disorders

Very common

Nausea, diarrhoea

Common

Constipation, vomiting

Hepatobiliary disorders

Uncommon

Hyperbilirubinaemia

Skin and subcutaneous tissue disorders

Not known

Dermatitis Exfoliative Generalised (DEG)

General disorders and administration site conditions

Very common

Peripheral oedema

Investigations

Not known

Blood thyroid stimulating hormone (TSH) decreased, blood copper increased

1This 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).

In CKD patients not on dialysis, the overall incidence of Ischaemic central nervous system vascular conditions events was higher in the roxadustat group (3.9%) as compared to the placebo group (2.4%) and the follow-up adjusted incidence rate was higher in the roxadustat group (2.3) as compared to placebo group (1.8). Cerebral infarction demonstrated a 0.2% higher occurrence in the roxadustat group compared to placebo (0.6% vs 0.4%).

In CKD patients on dialysis, the overall incidence of events from Ischaemic central nervous system vascular conditions events was similar in the roxadustat treatment group (4.8%) as compared to the active control group (4.2%). The incident rate/100 patient exposure years (PEY) was 2.8 in the roxadustat treatment group as compared to 2.2 in the active control group. Ischemic stroke demonstrated a 0.2% higher occurrence in the roxadustat group compared to active comparator (0.8% vs 0.6%).

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).

Skin reactions

Dermatitis exfoliative generalised, part of severe cutaneous adverse reactions (SCARs), has been reported during post-marketing surveillance and has shown an association with roxadustat treatment (frequency not known).

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Single supratherapeutic doses of roxadustat 5 mg/kg (up to 510 mg) in healthy subjects were associated with a transient increase in heart rate, an increased frequency of mild to moderate musculoskeletal pain, headaches, sinus tachycardia, and less commonly, low blood pressure, all these findings were non-serious. Roxadustat overdose can elevate Hb levels above the desired level (10 - 12 g/dL), which should be managed with discontinuation or reduction of roxadustat dosage (see section 4.2) and careful monitoring and treatment as clinically indicated. Roxadustat and its metabolites are not significantly removed by haemodialysis (see section 5.2).