EVRENZO 50mg tablets medication leaflet

Each tablet contains 20 mg of roxadustat.

Each tablet contains 50 mg of roxadustat.

Each tablet contains 70 mg of roxadustat.

Each tablet contains 100 mg of roxadustat.

Each tablet contains 150 mg of roxadustat.

Each 20 mg film-coated tablet contains 40.5 mg of lactose, 0.9 mg of Allura Red AC aluminium lakeand 0.21 mg soya lecithin.

Each 50 mg film-coated tablet contains 101.2 mg of lactose, 1.7 mg of Allura Red AC aluminium lakeand 0.39 mg soya lecithin.

Each 70 mg film-coated tablet contains 141.6 mg of lactose, 2.1 mg of Allura Red AC aluminium lakeand 0.47 mg soya lecithin.

Each 100 mg film-coated tablet contains 202.4 mg of lactose, 2.8 mg of Allura Red AC aluminiumlake and 0.63 mg soya lecithin.

Each 150 mg film-coated tablet contains 303.5 mg of lactose, 3.7 mg of Allura Red AC aluminiumlake and 0.84 mg soya lecithin.

For the full list of excipients, see section 6.1.

Film-coated tablets (tablets).

Red, oval tablets (approximately 8 mm × 4 mm) with ‘20’ debossed on one side.

Red, oval tablets (approximately 11 mm × 6 mm) with ‘50’ debossed on one side.

Red, round tablets (approximately 9 mm) with ‘70’ debossed on one side.

Red, oval tablets (approximately 14 mm × 7 mm) with ‘100’ debossed on one side.

Red, almond-shaped tablets (approximately 14 mm × 9 mm) with ‘150’ debossed on one side.

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

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

Anaemia symptoms and sequelae may vary with age, gender, and overall burden of disease; aphysician’s evaluation of the individual patient’s clinical course and condition is necessary. In additionto 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) transfusioncould be of relevance in the evaluation of the individual patient’s clinical course and condition.

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

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

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

Adequate iron stores should be ensured prior to initiating treatment.

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

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

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

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

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

Methoxy polyethylene

Darbepoetin alfa Epoetin glycol-epoetin betaintravenous or intravenous or intravenous or Roxadustat dosesubcutaneous dose subcutaneous subcutaneous dose (milligrams three(micrograms/week) dose (IU/week) (micrograms/monthly) times per week)

Less than 25 Less than 5 000 Less than 80 7025 to less than 40 5 000 up to8 000 80 up to and including 120 100

More than 8 00040 up to and including up to and More than 120 up to and80 including including 200 15016 000

More than 80 More than16 000 More than 200 200

ESA: erythropoiesis-stimulating agent

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

The dose of roxadustat can be adjusted stepwise up or down from the starting dose 4 weeks aftertreatment start, and every 4 weeks thereafter except if the Hb increases by more than 2 g/dL, in whichcase 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, andfollow 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 patientson dialysis).

Table 2. Dose adjustment rules

Change in Hb over Current Hb level (g/dL):the previous 4 Lower thanweeks1 10.5 10.5 to 11.9 12.0 to 12.9 13.0 or higher

Change in value of No change Reduce dose Reduce dose Withhold dosing,more than by one step by one step monitor Hb level+1.0 g/dL and resume dosing

Change in value Increase dose by No change Reduce dose when Hb is lessbetween one step by one step than 12.0 g/dL, at a

- 1.0 and +1.0 g/dL dose that is reduced

Change in value of Increase dose by Increase dose No change by two stepsless than one step by one step

- 1.0 g/dL

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

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

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

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

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

When initiating or discontinuing concomitant treatment with strong inhibitors (e.g. gemfibrozil) orinducers (e.g. rifampicin) of CYP2C8, or inhibitors (e.g. probenecid) of UGT1A9: the Hb levelsshould be monitored routinely and the dose adjustment rules followed (see Table 2; see also sections4.5 and 5.2).

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

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

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

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

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 dosewhen initiating treatment in patients with moderate hepatic impairment (Child-Pugh class B). Evrenzois not recommended for use in patients with severe hepatic impairment (Child-Pugh class C) as thesafety and efficacy has not been evaluated in this population (see sections 4.4 and 5.2).

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

Evrenzo film-coated tablets are to be taken orally with or without food. Tablets are to be swallowedwhole 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 (exceptlanthanum) or other medicinal products containing multivalent cations such as calcium, iron,magnesium or aluminium (see sections 4.5 and 5.2).

Evrenzo is contraindicated in the following conditions:

* Hypersensitivity to the active substance, peanut, soya or to any of the excipients listed insection 6.1.

* Third trimester of pregnancy (see sections 4.4 and 4.6).

* Breast-feeding (see section 4.6).

Overall, the cardiovascular and mortality risk for treatment with roxadustat has been estimated to becomparable to the cardiovascular and mortality risk for ESA therapy based on data from directcomparison of both therapies (see section 5.1). Since, for patients with anaemia associated with CKDand not on dialysis, this risk could not be estimated with sufficient confidence versus placebo, adecision to treat these patients with roxadustat should be based on similar considerations that would beapplied before treating with an ESA. Further, several contributing factors have been identified thatmay impose this risk, including treatment non-responsiveness, and converting stable ESA treateddialysis patients (see sections 4.2 and 5.1). In the case of non-responsiveness, treatment withroxadustat 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 thereis a valid clinical reason (see section 4.2). For stable ESA treated patients with anaemia associatedwith 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 forthe individual patient.

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

Cases of cerebrovascular accidents, including fatal cases of cerebral infarction, have been reported inpatients treated with roxadustat.

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

In CKD patients on dialysis, rates of VAT in roxadustat-treated patients were highest in the first12 weeks following initiation of treatment, at Hb values more than 12 g/dL and in the setting of Hbrise of more than 2 g/dL over 4 weeks. It is recommended to monitor Hb levels and adjust the doseusing the dose adjustment rules (see Table 2) to avoid Hb levels of more than 12 g/dL and Hb rise ofmore than 2 g/dL over 4 weeks.

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

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

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

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

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 isrecommended as clinically indicated.

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

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).

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

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

Evrenzo contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactasedeficiency 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 usethis medicinal product.

Co-administration of roxadustat with phosphate binders sevelamer carbonate or calcium acetate inhealthy 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 productscontaining calcium, iron, magnesium or aluminium. Staggered administration of phosphate binders (atleast 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 medicinalproducts or supplements containing multivalent cations (see section 4.2). This restriction does notapply to lanthanum carbonate, as the co-administration of roxadustat with lanthanum carbonate did notresult in a clinically meaningful change in the plasma exposure of roxadustat.

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 healthysubjects increased roxadustat AUC by 2.3-fold and Cmax by 1.4-fold. Monitor Hb levels when initiatingor discontinuing concomitant treatment with gemfibrozil, probenecid, other strong inhibitors orinducers of CYP2C8 or other strong inhibitors of UGT1A9. Adjust the dose of roxadustat followingdose adjustment rules (see Table 2) based on Hb monitoring.

Roxadustat is an inhibitor of BCRP and OATP1B1. These transporters play an important role in theintestinal and hepatic uptake and efflux of statins. Co-administration of 200 mg of roxadustat withsimvastatin 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- and2.8-fold, respectively. The concentrations of simvastatin and simvastatin acid also increased whensimvastatin was administered 2 hours before or 4 or 10 hours after roxadustat. Co-administration of200 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 Cmaxof atorvastatin 2.0- and 1.3-fold, respectively.

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

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

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

There are no data on the use of roxadustat in pregnant women. Studies in animals have shownreproductive 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 andswitched to alternative treatments, if appropriate (see section 4.3).

It is unknown whether roxadustat/metabolites are excreted in human milk. Available animal data haveshown excretion of roxadustat in milk (for details see section 5.3). Evrenzo is contraindicated duringbreast-feeding (see sections 4.3 and 5.3).

In animal studies, there were no effects of roxadustat on male and female fertility. However, changesin rat male reproductive organs were observed. The potential effects of roxadustat on male fertility inhumans is currently unknown. At a maternally toxic dose, increased embryonic loss was observed (seesection 5.3). Women of childbearing potential must use highly effective contraception duringtreatment 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 reportedduring treatment with Evrenzo (see section 4.4). Therefore, caution should be exercised when drivingor using machines.

The safety of Evrenzo was evaluated in 3542 non-dialysis dependent (NDD) and 3353 dialysisdependent (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%).

Adverse reactions observed during clinical studies and/or in post-marketing experience are listed inthis 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 Frequency category Adverse reactionclass (SOC)

Infections and infestations Common Sepsis

Blood and lymphatic system Common Thrombocytopeniadisorders

Endocrine disorders Not known Secondary hypothyroidism

Metabolism and nutrition Very common Hyperkalaemiadisorders

Psychiatric disorders Common Insomnia

Nervous system disorders Common Seizures, headache

Vascular disorders Very common Hypertension, vascular accessthrombosis (VAT)1

Common Deep vein thrombosis (DVT)

Respiratory, thoracic, Uncommon Pulmonary embolismmediastinal disorders

Gastrointestinal disorders Very common Nausea, diarrhoea

Common Constipation, vomiting

MedDRA System organ Frequency category Adverse reactionclass (SOC)

Hepatobiliary disorders Uncommon Hyperbilirubinaemia

Skin and subcutaneous tissue Not known Dermatitis Exfoliativedisorders Generalised (DEG)

General disorders and Very common Peripheral oedemaadministration site conditions

Investigations Not known Blood thyroid stimulatinghormone (TSH) decreased,blood copper increased1This adverse reaction is associated with CKD patients who were on dialysis while receivingroxadustat.

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

In CKD patients not on dialysis, pulmonary embolism was observed in 0.4% (0.2 patients with eventsper 100 patient years of exposure) in the roxadustat group, compared to 0.2% (0.1 patients with eventsper 100 patient years of exposure) in the placebo group. In CKD patients on dialysis, pulmonaryembolism was observed in 0.6% (0.3 patients with events per 100 patient years of exposure) in theroxadustat 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 withevents per 100 patient years of exposure) in the roxadustat group, compared to 10.2% (5.4 patientswith events per 100 patient years of exposure) in the ESA group (see section 4.4).

In CKD patients not on dialysis, seizures occurred in 1.1% (0.6 patients with events per 100 patientyears of exposure) in the roxadustat group, and 0.2% (0.2 patients with events per 100 patient years ofexposure) 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 yearsof exposure) in the roxadustat group, and 1.6% (0.8 patients with events per 100 patient years ofexposure) in the ESA group (see section 4.4).

In CKD patients not on dialysis, sepsis was observed in 2.1% (1.3 patients with events per 100 patientyears of exposure) in the roxadustat group, compared to 0.4% (0.3 patients with events per 100 patientyears 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).

Dermatitis exfoliative generalised, part of severe cutaneous adverse reactions (SCARs), has beenreported during postmarketing surveillance and has shown an association with roxadustat treatment(frequency not known).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Single supratherapeutic doses of roxadustat 5 mg/kg (up to 510 mg) in healthy subjects wereassociated with a transient increase in heart rate, an increased frequency of mild to moderatemusculoskeletal pain, headaches, sinus tachycardia, and less commonly, low blood pressure, all thesefindings 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 (seesection 4.2) and careful monitoring and treatment as clinically indicated. Roxadustat and itsmetabolites are not significantly removed by haemodialysis (see section 5.2).

Pharmacotherapeutic group: anti-anaemic preparations, other anti-anaemic preparations, ATC code:

B03XA05.

Roxadustat is a hypoxia-inducible factor, prolyl hydroxylase inhibitor (HIF-PHI). The activity of

HIF-PH enzymes controls intracellular levels of HIF, a transcription factor that regulates theexpression of genes involved in erythropoiesis. Activation of the HIF pathway is important in theadaptative response to hypoxia to increase red blood cell production. Through the reversible inhibitionof HIF-PH, roxadustat stimulates a coordinated erythropoietic response that includes the increase ofplasma endogenous erythropoietin (EPO) levels, regulation of iron transporter proteins and reductionof hepcidin (an iron regulator protein that is increased during inflammation in CKD). This results inimproved iron bioavailability, increased Hb production and increased red cell mass.

A thorough QT (TQT) study in healthy subjects with roxadustat at a single therapeutic dose of2.75 mg/kg and a single supratherapeutic dose of 5 mg/kg (up to 510 mg) did not show a prolongationof the QTc interval. The same thorough QT study demonstrated a placebo-corrected heart rate increaseof up to 9 to 10 bpm at 8 to 12 h post-dose for the 2.75 mg/kg dose and 15 to 18 bpm at 6 to 12 hpost-dose for the dose of 5 mg/kg.

Efficacy and safety of roxadustat were evaluated for at least 52 weeks in a globally conducted phase 3program comprising of 8 multicentre and randomized studies in non-dialysis dependent (NDD) anddialysis-dependent (DD) CKD patients with anaemia (see Table 4).

Three studies in stage 3-5 CKD NDD patients were double-blind and placebo-controlled studies(ALPS, 1517-CL-0608; ANDES, FGCL-4592-060; OLYMPUS, D5740C00001) and one study wasopen-label ESA-controlled (DOLOMITES, 1517-CL-0610) using darbepoetin alfa as comparator. All

NDD studies assessed efficacy and safety in ESA-untreated patients by correcting and thereaftermaintaining Hb in the target range of 10 to 12 g/dL (Hb correction setting).

Four open-label ESA-controlled DD studies (control: epoetin alfa and/or darbepoetin alfa) in patientson haemodialysis or peritoneal dialysis assessed the efficacy and safety in different settings:

* in a Hb correction setting (HIMALAYAS, FGCL-4592-063).

* in an ESA conversion setting converting patients from treatment with an ESA to maintain Hb inthe target range (PYRENEES, 1517-CL-0613; SIERRAS, FGCL-4592-064).

* or combining the Hb correction and ESA conversion approaches (ROCKIES, D5740C00002).

Patients in the NDD studies had CKD stage 3 to 5 and were not receiving dialysis. All patients had anaverage Hb ≤10.0 g/dL except patients in the DOLOMITES study (1517-CL-0610), which allowed anaverage Hb ≤10.5 g/dL. Ferritin levels were required to be ≥30 ng/mL (ALPS, 1517-CL-0608;

ANDES, FGCL-4592-060), ≥50 ng/mL (OLYMPUS, D5740C00001) or ≥100 ng/mL (DOLOMITES,1517-CL-0610). Except for those in the (OLYMPUS, D5740C00001) study, which allowed ESAtreatment until 6 weeks prior to randomization, patients could not have received any ESA treatmentwithin 12 weeks of randomization.

Patients in the DD studies had to be on dialysis: stable DD for patients in the PYRENEES study(1517-CL-0613), which was defined as dialysis for longer than 4 months; or incident (ID), DD forpatients in the HIMALAYAS study (FGCL-4592-063), which was defined as dialysis ≥2 weeks but≤4 months. Patients in the SIERRAS (FGCL-4592-064) and ROCKIES studies (D5740C00002)included both stable (approximately 80% to 90%) and ID (approximately 10% to 20%) DD patients.

Ferritin was required to be ≥100 ng/mL in all patients. All patients required intravenous orsubcutaneous ESA for at least 8 weeks prior to randomization, except those patients in the

HIMALAYAS study (FGCL-4592-063) which excluded patients who had received any ESA treatmentwithin 12 weeks prior to randomization.

Treatment with roxadustat followed the principles of dosing instructions as described in section 4.2.

Demographics and all baseline characteristics across individual studies were comparable between theroxadustat and control groups. The median age at randomization was 55 to 69 years, with between16.6% and 31.1% in the 65-74 age range, and between 6.8% and 35% who were ≥75 years of age. Thepercentage of female patients ranged from 40.5% to 60.7%. The most commonly represented racesacross the studies were White, Black or African American and Asian. The most common CKDaetiologies were diabetic and hypertensive nephropathy. Median Hb levels ranged from 8.60 to10.78 g/dL. Approximately 50-60% of NDD patients and 80-90% of DD patients were iron replete atbaseline.

Data from seven phase 3 studies were pooled in two separate populations (three NDD and four DD)(see Table 4).

Three placebo-controlled NDD Studies (2,386 patients on roxadustat; 1,884 patients on placebo) wereincluded in the NDD pool. Data from the phase 3 ESA-controlled NDD DOLOMITES study(1517-CL-0610; 323 patients on roxadustat and 293 patients on darbepoetin alfa) are not included inthe NDD pooled analyses as this study is the only open-label, active-controlled study in the NDDpopulation.

Four ESA-controlled DD Studies (2,354 patients on roxadustat; 2,360 patients on ESA [epoetin alfaand/or darbepoetin alfa]) were included in the DD pool. Within the DD pool, two sub pools wereestablished to reflect the two different treatment settings:

* Patients in the DD population who were on dialysis for greater than 2 weeks and less than 4months were termed incident (ID) DD patients (ID DD pool) reflective of the Hb correctionsetting.

* The DD patients who were on dialysis after this threshold of four months were termed stable DDpatients (Stable DD pool) reflective of the ESA conversion setting.

Table 4. Overview on Roxadustat phase 3 development program in anaemia with CKD

Studies in NDD patients

Placebo-controlled studies (NDD pool) ESA-control(Darbepoetinalfa)

Setting Hb correction

Study ALPS ANDES OLYMPUS DOLOMITES(1517-CL-0608) (FGCL-4592-060) (D5740C00001) (1517-CL-0610)

Randomize 594 916 2760 616d (391/203) (611/305) (1384/1376) (323/293)(roxadustat/comparator)

Studies in DD patients

ESA-controlled studies (DD pool)(Epoetin alfa or Darbepoetin alfa)

Setting ESA conversion Hb correction ESA conversionand Hb correction

Study PYRENEES SIERRAS HIMALAYAS ROCKIES(1517-CL-0613) (FGCL-4592-064) (FGCL-4592-063) (D5740C00002)

Randomize 834 740 1039 2101d (414/420) (370/370) (522/517) (1048/1053)(roxadustat/comparator)

DD: dialysis dependent; ESA: erythropoiesis-stimulating agent; Hb: haemoglobin;

NDD: non-dialysis dependent.

In clinical studies, roxadustat was effective in achieving and maintaining target Hb levels (10-12 g/dL)in patients with CKD anaemia not on dialysis (see Figure 1).

Figure 1. Mean (SE) Hb (g/dL) over time up to week 52 (FAS); NDD pool (Hb correction)

FAS: full analysis set; Hb: haemoglobin; NDD: non-dialysis dependent; SE: standard error.

In NDD patients in need of anaemia treatment for Hb correction, the proportion of patients whoachieved Hb response during the first 24 weeks was higher in the roxadustat group (80.2%) comparedwith placebo (8.7%). There was a statistically significant increase in Hb from baseline to weeks 28 to36 in the roxadustat group (1.91 g/dL) compared with placebo (0.14 g/dL) and the lower limit of the95% confidence interval is above 1. In the NDD studies, an increase in Hb of at least 1 g/dL wasachieved with a median time of 4.1 weeks (see Table 5).

In the open-label ESA-controlled NDD DOLOMITES (1517-CL-0610) study, the proportion ofpatients who achieved Hb response during the first 24 weeks was non-inferior in the roxadustat group(89.5%) compared with darbepoetin alfa (78%) (see Table 5).

Table 5. Key Hb efficacy endpoints (NDD)

Population NDD CKD patients

Setting Hb correction Hb correction

NDD pool (FAS) DOLOMITES (PPS)1517-CL-0610

Roxadustat Placebo Roxadustat Darbepoetinn = 2368 n = 1865 n = 286 alfa

Endpoint/Parameter n = 273

Proportion of patients who achieved Hb response1

Responders, n (%) 1,899 (80.2) 163 (8.7) 256 (89.5) 213 (78.0)[95% CI] [78.5, 81.8] [7.5, 10.1] [85.4, 92.8] [72.6, 82.8]

Difference of proportions [95% CI] 71.5 [69.40, 73.51] 11.51 [5.66, 17.36]

Odds ratio [95% CI] 40.49 [33.01, 49.67] 2.48 [1.53, 4.04]

P value < 0.0001 ND

Change from baseline in Hb (g/dL)2

Mean (SD) baseline 9.10 (0.74) 9.10 (0.73) 9.55 (0.76) 9.54 (0.69)

Mean (SD) CFB 1.85 (1.07) 0.17 (1.08) 1.85 (1.08) 1.84 (0.97)

LS mean 1.91 0.14 1.85 1.84

LS mean difference [95% CI] 1.77 [1.69, 1.84] 0.02 [-0.13, 0.16]

P value < 0.0001 0.844

CFB: change from baseline; CI: confidence interval; CKD: chronic kidney disease; FAS: fullanalysis set; Hb: haemoglobin; LS: Least squares; ND: not done; NDD: non-dialysis dependent;

PPS: per protocol set; SD: standard deviation.1Hb response within the first 24 weeks.2Change from baseline in Hb to Weeks 28 to 36.

In clinical studies, roxadustat was effective in achieving and maintaining target Hb levels (10-12 g/dL)in CKD patients on dialysis, irrespective of prior ESA treatment (see Figures 2 and 3).

Figure 2. Mean (SE) Hb up to week 52 (FAS); ID DD subpool (Hb correction)13 Treatment

Roxadustat

Active Control0 2 4 6 8 10 12 14 16 18 20 24 28 32 36 40 44 48 52

Visit (Week)

Roxadustat 756 729 715 703 701 679 678 656 639 630 621 594 577 552 518 495 452 423 392

Active Control 759 718 695 704 703 695 679 671 655 655 628 610 596 564 534 512 483 450 412

DD: dialysis-dependent; FAS: full analysis set; Hb: haemoglobin; ID: incident; SE: standard error.

Figure 3. Mean (SE) Hb (g/dL) over time up to week 52 (FAS); stable DD subpool (ESAconversion)

DD: dialysis dependent; ESA: erythropoiesis-stimulating agent; FAS: full analysis set; Hb:haemoglobin; SE: standard error.

In DD patients in need of anaemia treatment for Hb correction and those converted from ESAtreatment, there was an increase in Hb from baseline to weeks 28 to 36 in the roxadustat group; thisincrease was comparable to that observed in the ESA group and was above the prespecifiednoninferiority margin of -0.75 g/dL. The proportion of patients who achieved Hb response during thefirst 24 weeks was similar in the roxadustat and ESA groups (see Table 6).

Mean Hemoglobin (g/dL) +/- SE

Table 6. Key Hb efficacy endpoints (DD)

Population DD Patients

Setting Hb Correction ESA Conversion

ID DD pool (FAS/PPS) Stable DD Pool (PPS)

Roxadustat ESA Roxadustat ESA

Endpoint/Parameter n = 756 n = 759 n = 1379 n = 1417

Change from baseline in Hb (g/dL)

Mean (SD) baseline 8.77 (1.20) 8.82 (1.20) 10.32 (0.99) 10.37 (0.99)

Mean (SD) CFB 2.37 (1.57) 2.12 (1.46) 0.65 (1.15) 0.36 (1.23)

LS mean 2.17 1.89 0.58 0.28

LS mean difference [95% CI] 0.28 [0.110, 0.451] 0.30 [0.228, 0.373]

P value 0.0013 < 0.0001

Proportion of patients who achieved Hb response1,2

Responders, n (%) 453 (59.9) 452 (59.6) 978 (70.9) 959 (67.7)[95% CI] [56.3, 63.4] [56.0, 63.1] [68.4, 73.3] [65.2, 70.1]

Difference of proportions [95% CI] 0.3 [-4.5, 5.1] 2.7 [-0.7, 6.0]

Odds ratio [95% CI] ND ND

P value ND ND

CFB: change from baseline; CI: confidence interval; CKD: chronic kidney disease; DD: dialysisdependent; ESA: erythropoiesis-stimulating agent; FAS: full analysis set; Hb: haemoglobin; ID:incident; LS: Least squares; ND: not done; PPS: per protocol set; SD: standard deviation.1Hb within the target range of 10.0 to 12.0 g/dL during weeks 28 to 36 without having receivedrescue therapy within 6 weeks prior to and during this 8-week evaluation period.2Data in the ID DD pool were only analysed for weeks 28 to 52.

The effects of treatment with roxadustat on use of rescue therapy, RBC transfusion and intravenousiron are presented in Table 7 (NDD) and Table 8 (DD). In clinical studies, roxadustat reduced hepcidin(regulator of iron metabolism), reduced ferritin, increased serum iron while transferrin saturation wasstable, all which were assessed over time as indicators of iron status.

The effects of treatment with roxadustat on LDL cholesterol are presented in Tables 7 and 8. Therewas a reduction in mean LDL and high density lipoprotein (HDL) cholesterol levels in roxadustat-treated patients compared with placebo or ESA-treated patients. The effect on LDL cholesterol wasmore pronounced, leading to a reduction of the LDL/HDL ratio and was observed regardless of the useof statins.

Table 7. Other efficacy endpoints: use of rescue therapy, monthly intravenous iron use andchange from baseline in LDL cholesterol (NDD)

Population NDD CKD patients

Intervention Correction Correction

NDD pool (FAS) DOLOMITES (1517-CL-0610)

Roxadustat Placebo Roxadustat Darbepoetin alfa

Endpoint/Parameter n = 2368 n = 1865 n = 322 n = 292

Number of patients withrescue therapy, n (%)1 211 (8.9) 580 (31.1)

RBC 118 (5.0) 240 (12.9)

IV iron 50 (2.1) 90 (4.8) ND

ESA 48 (2.0) 257 (13.8)

IR 10.4 41.0

Hazard ratio 0.1995% CI 0.16, 0.23 ND

P value < 0.0001

Number of Patients with

IV Iron, n (%)2 20 (6.2) 37 (12.7)

IR ND 9.9 21.2

Hazard ratio 0.4595% CI 0.26, 0.78

P value 0.004

Change from baseline in LDL cholesterol (mmol/L) to weeks 12 to 283

Analysis using ANCOVA

LS mean -0.446 0.066 -0.356 0.04795% CI -0.484, -0.409 0.017, 0.116 -0.432, -0.280 -0.033, 0.127

LS mean difference (R-comparator) -0.513 -0.40395% CI -0.573, -0.453 -0.510, -0.296

P value < 0.0001 < 0.001

P values presented for the NDD pool are nominal p values.

ANCOVA: analysis of covariance; CI: confidence interval; ESA: erythropoiesis-stimulating agent;

FAS: full analysis set; IR: incidence rate (per 100 patient-years at risk); IV: intravenous; LDL: lowdensity lipoprotein; LS: least squares; ND: not done; NDD: non-dialysis-dependent; R: roxadustat;

RBC: red blood cell;1For use of rescue therapy the NDD pool was analysed up to week 52.2During weeks 1-36.3Change from baseline in LDL cholesterol was assessed only through week 24 for study OLYMPUS(D5740C00001).

Table 8. Other efficacy endpoints: use of rescue therapy, monthly intravenous iron use andchange from baseline in LDL cholesterol (DD)

Population DD CKD patients

Intervention Correction Conversion

ID DD pool (FAS) Stable DD pool (FAS)

Endpoint/ Roxadustat ESA Roxadustat ESA

Parameter n = 756 n = 759 n = 1586 n = 1589

Mean monthly IV iron over weeks 28 - 52 (mg)1n 606 621 1414 1486

Mean (SD) 53.57 70.22 42.45 61.99(143.097) (173.33) (229.80) (148.02)

Change from baseline in LDL cholesterol (mmol/L) to weeks 12 to 28

Analysis using ANCOVA

LS mean -0.610 -0.157 -0.408 -0.03595% CI -0.700, -0.520 -0.245, -0.069 -0.449, -0.368 -0.074, 0.003

LS mean difference -0.453 -0.373(R-comparator)95% CI -0.575, -0.331 -0.418, -0.328

P value < 0.0001 < 0.0001

P values presented for the ID DD and stable DD pools are nominal p values.

ANCOVA: analysis of covariance; CI: confidence interval; CKD: chronic kidney disease; DD:dialysis-dependent; ESA: erythropoiesis-stimulating agent; FAS: full analysis set; ID: incidentdialysis; IV: intravenous; LDL: low density lipoprotein; LS: least squares; R: roxadustat.1Time period for PYRENEES (1517-CL-0613) study was up to week 36, and the time period for

ROCKIES (D5740C0002) study was from week 36 through end of study.

In the dialysis study SIERRAS (FGCL-4592-064) a significantly lower proportion of patients receiveda red blood cell transfusion during treatment in the roxadustat group compared with the EPO-alfagroup (12.5% versus 21.1%); the numerical reduction was not statistically significant in the ROCKIES(D5740C00002) study (9.8% versus 13.2%).

In the DOLOMITES study (1517-CL-0610) noninferiority of roxadustat to darbepoetin wasestablished with regards to SF-36 PF and SF-36 VT.

In the PYRENEES study (1517-CL-0613), non-inferiority of roxadustat to ESAs was establishedregarding SF-36 PF and SF-36 VT changes from baseline to weeks 12 to 28.

A meta-analysis, of adjudicated major adverse cardiovascular events (MACE; a composite of all-causemortality [ACM], myocardial infarction, stroke) and MACE+ (a composite of ACM, myocardialinfarction, stroke, and hospitalisation for either unstable angina or congestive heart failure), from thephase 3 study program was conducted in 8984 patients.

MACE, MACE+ and ACM outcomes are presented for three datasets using the pooled hazard ratio(HR) and its 95% confidence interval (CI). The three datasets include:

* A pooled placebo-controlled Hb correction dataset in NDD patients [includes patients fromstudies OLYMPUS (D5740C00001), ANDES (FGCL-4592-060) and ALPS (1517-CL-0608);see Table 4]

* A pooled ESA-controlled Hb correction dataset in NDD and ID-DD patients [includes patientsfrom studies DOLOMITES (1517-CL-0610), HIMALAYAS (FGCL-4592-063), and the

ID-DD patients of studies SIERRAS (FGCL-4592-064) and ROCKIES (D5740C00002); see

Table 4]

* A pooled ESA-controlled ESA conversion dataset in Stable DD patients [includes patientsfrom study PYRENEES (1517-CL-0613) and Stable DD patients from studies ROCKIES(D5740C00002) and SIERRAS (FGCL-4592-064); see Table 4]

MACE, MACE+ and ACM in the placebo-controlled Hb correction set of non-dialysis-dependent CKDpatients

In NDD patients the analysis for MACE, MACE+ and ACM of the on-treatment analyses included alldata from the start of study treatment until 28 days of the end of treatment follow-up. The on-treatmentanalyses used a Cox model weighted inversely for the probability of censoring (IPCW method) whichaims to correct for follow-up time differences between roxadustat and placebo including identifiedcontributors to increased risk and early discontinuation, in particular estimated glomerular filtrationrate (eGFR) determinants and Hb at baseline and over time. Whether any residual confounding ispresent with this model remains uncertain. The HRs for the on-treatment analyses were 1.26, 1.17 and1.16 (see Table 9). The ITT analyses included all data from the start of study treatment until the end ofposttreatment safety follow-up. The ITT analysis has been included to illustrate an imbalance in riskdistribution favouring placebo in the on-treatment analysis, however, ITT analyses generallydemonstrate a dilution of study drug treatment effect and in these ITT analyses bias cannot becompletely excluded, especially as ESA rescue therapy was introduced after study treatmentdiscontinuation. The HRs were 1.10, 1.07 and 1.08, with upper limits of the 95% CIs of 1.27, 1.21 and1.26, respectively.

Table 9. CV safety and mortality in placebo-controlled Hb correction NDD pool

MACE MACE+ ACM

Roxadustat Placebo Roxadustat Placebo Roxadustat Placebon = 2386 n = 1884 n = 2386 n = 1884 n = 2386 n = 1884

On-treatment

Number of patientswith events (%)344 (14.4) 166 (8.8) 448 (18.8) 242 ( 12.8) 260 (10.9) 122 (6.5)

FAIR 8.7 6.8 11.6 10 .1 6.4 5.0

HR (95% CI) 1.26 (1.02, 1.55) 1.17 (0.99, 1.40 ) 1.16 (0.90, 1.50)

ITT

Number of patientswith events (%) 480 (20.1) 350 (18.6) 578 (24.2) 432 ( 22.9) 400 (16.8) 301 (16)

FAIR 10.6 10.3 13.2 13 .2 8.3 8.1

HR (95% CI) 1.10 (0.96, 1.27) 1.07 (0.94, 1.21) 1.08 (0.93, 1.26)

ACM: all-cause mortality; ACM is a component of MACE/MACE+; CI: confidence interval;

FAIR: follow-up adjusted incidence rate (number of patients with event/100 patient years); HR: hazardratio; ITT: intent-to-treat; MACE: major adverse cardiovascular event (death, non-fatal myocardialinfarction and/or stroke); MACE+: major adverse cardiovascular event including hospitalisations foreither unstable angina and/or congestive heart failure.

MACE, MACE+ and ACM in the ESA-controlled Hb correction set of non-dialysis-dependent andincident dialysis-dependent CKD patients

In the Hb correction setting of NDD and ID-DD patients baseline characteristics and treatmentdiscontinuation rates were comparable between the pooled roxadustat and pooled ESA patients. Theanalysis for MACE, MACE+ and ACM observed on treatment showed HRs of 0.79, 0.78 and 0.78,with upper limits of the 95% CIs of 1.02, 0.98 and 1.05, respectively (see Table 10). The on-treatmentanalyses support no evidence of increased cardiovascular safety or mortality risk with roxadustatcompared with ESA in CKD patients requiring Hb correction.

Table 10. CV safety and mortality in ESA-controlled Hb correction pool

MACE MACE+ ACM

Roxadustat ESA Roxadustat ESA Roxadustat ESAn = 1083 n = 1059 n = 1083 n = 1059 n = 1083 n = 1059

On-treatment

Number ofpatients with 105 (9.7) 136 (12.8) 134 (12.4) 171 (16.1) 74 (6.8) 99 (9.3)events (%)

IR 6.5 8.2 8.3 10.3 4.6 6.0

HR (95% CI) 0.79 (0.61, 1.02) 0.78 (0.62, 0.98) 0.78 (0.57, 1.05)

ACM: all-cause mortality; ACM is a component of MACE/MACE+, CI: confidence interval;

ESA: erythropoiesis-stimulating agent; HR: hazard ratio; IR: incidence rate (number of patients withevent/100 patient years); MACE: major adverse cardiovascular event (death, non-fatal myocardialinfarction and/or stroke); MACE+: major adverse cardiovascular event including hospitalisations foreither unstable angina and/or congestive heart failure.

MACE, MACE+ and ACM in ESA-controlled ESA conversion set of stable dialysis-dependent CKDpatients

In stable DD patients converting from ESA analysis results for MACE, MACE+ and ACM observedon treatment showed HRs of 1.18, 1.03 and 1.23, with upper limits of the 95% CIs for HRs of 1.38,1.19 and 1.49, respectively (see Table 11). The results in Table 11 should be interpreted with cautionas patients allocated to roxadustat were switched from ESA at the start of the study and the impact ofan inherent risk in switching to any new treatment versus remaining on a treatment with a stabilised

Hb may confound the observed results and thus any comparison of treatment effect estimates cannotbe reliably established.

Table 11. CV safety and mortality in ESA-controlled ESA conversion stable DD pool

MACE MACE+ ACM

Roxadustat ESA Roxadustat ESA Roxadustat ESAn = 1594 n = 1594 n = 1594 n = 1594 n = 1594 n = 1594

On-treatment

Number ofpatients with 297 (18.6) 301 (18.9) 357 (22.4) 403 (25.3) 212 (13.3) 207 (13.0)events (%)

IR 10.4 9.2 12.5 12.3 7.4 6.3

HR (95% CI) 1.18 (1.00, 1.38) 1.03 (0.90, 1.19) 1.23 (1.02, 1.49)

ACM: all-cause mortality; ACM is a component of MACE/MACE+; CI: confidence interval;

ESA: erythropoiesis-stimulating agent; HR: hazard ratio; IR: incidence rate (number of patients withevent/100 patient years); MACE: major adverse cardiovascular event (death, non-fatal myocardialinfarction and/or stroke); MACE+: major adverse cardiovascular event including hospitalisations foreither unstable angina and/or congestive heart failure.

Roxadustat plasma exposure (area under the plasma drug concentration over time curve [AUC] andmaximum plasma concentrations [Cmax]) is dose-proportional within the recommended therapeuticdose range. In a three times per week dosing regimen, steady-state roxadustat plasma concentrationsare achieved within one week (3 doses) with minimal accumulation. The pharmacokinetics ofroxadustat do not change over time.

Maximum plasma concentrations (Cmax) are usually achieved at 2 hours post dose in the fasted state.

Administration of roxadustat with food decreased Cmax by 25% but did not alter AUC as comparedwith the fasted state. Therefore, roxadustat can be taken with or without food (see section 4.2).

Roxadustat is highly bound to human plasma proteins (approximately 99%), predominantly toalbumin. The blood-to-plasma ratio of roxadustat is 0.6. The apparent volume of distribution at steadystate is 24 L.

Based on in vitro data, roxadustat is a substrate for CYP2C8 and UGT1A9 enzymes, as well as BCRP,

OATP1B1, OAT1 and OAT3. Roxadustat is not a substrate for OATP1B3 or P-gp. Roxadustat isprimarily metabolised to hydroxy-roxadustat and roxadustat-O-glucuronide. Unchanged roxadustatwas the major circulating component in human plasma; no detectable metabolite in human plasmaconstituted more than 10% of total drug-related material exposure and no human specific metaboliteswere observed.

The mean effective half-life (t1/2) of roxadustat is approximately 15 hours in patients with CKD.

The apparent total body clearance (CL/F) of roxadustat is 1.1 L/h in patients with CKD not on dialysisand 1.4 L/h in patients with CKD on dialysis. Roxadustat and its metabolites are not significantlyremoved by haemodialysis.

When radiolabelled roxadustat was administered orally in healthy subjects, the mean recovery ofradioactivity was 96% (50% in faeces, 46% in urine). In faeces, 28% of the dose was excreted asunchanged roxadustat. Less than 2% of the dose was recovered in urine as unchanged roxadustat.

No clinically relevant differences in the pharmacokinetics of roxadustat were observed based onage (≥18), sex, race, body weight, renal function (eGFR) or dialysis status in adult patients withanaemia due to CKD.

In dialysis-dependent CKD patients, no marked differences in pharmacokinetic parameter values wereobserved when roxadustat was administered 2 hours before or 1 hour after haemodialysis. Dialysis is anegligible route of overall clearance of roxadustat.

Following a single dose of 100 mg roxadustat, mean roxadustat AUC was 23% higher and mean Cmaxwas 16% lower in subjects with moderate hepatic impairment (Child-Pugh Class B) and normal renalfunction compared to subjects with normal hepatic and renal functions. Subjects with moderate hepaticimpairment (Child-Pugh Class B) and normal renal function showed an increase in unboundroxadustat AUCinf (+70%) as compared to healthy subjects.

The pharmacokinetics of roxadustat in subjects with severe hepatic impairment (Child-Pugh Class C)have not been studied.

Based on in vitro data, roxadustat is an inhibitor of CYP2C8, BCRP, OATP1B1 and OAT3 (seesection 4.5). The pharmacokinetics of rosiglitazone (moderate sensitive CYP2C8 substrate) were notaffected by co-administration of roxadustat. Roxadustat may be an inhibitor of intestinal but nothepatic UGT1A1 and showed no inhibition of other CYP metabolising enzymes or transporters, orinduction of CYP enzymes at clinically relevant concentrations. There is no clinically significant effectof oral adsorptive charcoal or omeprazole on roxadustat pharmacokinetics. Clopidogrel has no effecton roxadustat exposure in patients with CKD.

In the 26-week intermittent repeat dose study in Sprague-Dawley or Fisher rats, roxadustat atapproximately 4 to 6-fold the total AUC at Maximum Recommended Human Dose (MRHD) resultedin histopathological findings including aortic and atrioventricular valves (A-V) valvulopathies. Thesefindings were present in surviving animals at the time of termination as well as in animals terminatedearly in a moribund state. Furthermore, the findings were not fully reversible as they were also presentin animals at the end of a 30-day recovery period.

Exaggerated pharmacology resulting in excessive erythropoiesis has been observed in repeated-dosetoxicity studies in healthy animals.

Haematological changes such as decreases in circulating platelets as well as increases in activatedpartial thromboplastin time and prothrombin time were noted in rats from approximately 2-fold thetotal AUC at MRHD. Thrombi were noted in the bone marrow (systemic exposures of approximately7-fold the total AUC at MRHD in rats), kidneys (systemic exposures of approximately 5 to 6-fold total

AUC at MRHD in rats), lungs (systemic exposures approximately 8- and 2-fold total AUC at MRHDin rats and cynomolgus monkeys, respectively), and the heart (systemic exposures of approximately4 to 6-fold the total AUC at MRHD in rats).

In the 26-week intermittent repeat dose study in Sprague-Dawley rats, one animal, at approximately6-fold the total AUC at MRHD showed a histologic finding of brain necrosis and gliosis. In Fisherrats, treated for the same duration, brain/hippocampal necrosis was noted in a total of four animals atthe approximately 3 to 5-fold the total AUC at MRHD.

Cynomolgus monkeys intermittently administered roxadustat for 22 or 52-weeks, did not show similarfindings at systemic exposures up to approximately 2-fold the total AUC at MRHD.

Roxadustat was negative in the in vitro Ames mutagenicity test, in vitro chromosome aberration test inhuman peripheral blood lymphocytes and an in vivo micronucleus test in mice at 40-fold the MRHDbased on a human equivalent dose.

In the mouse and rat carcinogenicity studies, animals were administered roxadustat with the clinicaldosing regimen of three times per week. Due to the rapid clearance of roxadustat in rodents, systemicexposures were not continuous throughout the dosing period. As such, possible off-target carcinogeniceffects may be underestimated.

In the 2-year mouse carcinogenicity study, significant increases in the incidence of lungbronchoalveolar carcinoma was noted in the low and high dose groups (systemic exposuresapproximately 1-fold and approximately 3-fold the total AUC at MRHD). A significant increase insubcutis fibrosarcoma was seen in females at the high dose group (systemic exposures approximately3-fold total AUC at MRHD).

In the 2-year rat carcinogenicity study, a significant increase in the incidence of mammary glandadenoma was noted at the middle dose level (systemic exposure less than 1-fold the total AUC at

MRHD). However, the finding was not dose related and the incidence of this tumour type was lower atthe highest dose level tested (systemic exposure approximately 2-fold the total AUC at MRHD) andwas therefore not considered test article related.

Similar findings from the mouse and rat carcinogenicity studies were not observed in the clinicalstudies.

Roxadustat had no effect on mating or fertility in treated male or female rats at approximately 4-foldthe human exposure at the MRHD. However, at the NOAEL in male rats, there were decreases inweights of the epididymis and the seminal vesicles (with fluid) without effects on male fertility. The

NOEL for any male reproductive organ related findings was 1.6-fold MRHD. In female rats there wereincreases in the number of non-viable embryos and post-implantation losses at this dose levelcompared to control animals.

Results from the reproductive and developmental toxicity studies in rats and rabbits demonstratedreduction of average foetal or pup body weight, average placental weight increase, abortion and pupmortalities.

Pregnant Sprague-Dawley rats administered roxadustat daily from implantation through the closure ofthe hard palate (Gestation Days 7 - 17) showed decreased foetal body weight and increased skeletalalterations at approximately 6-fold the total AUC at MRHD. Roxadustat had no effect on post-implantfoetal survival.

Pregnant New Zealand rabbits were administered roxadustat daily from Gestation Day 7 through

Gestation Day 19 and Caesarian sections were performed on Gestation Day 29. Roxadustatadministration at systemic exposures up to approximately 3-fold the total AUC at MRHD showed noembryo-foetal findings. However, one doe aborted at approximately 1-fold the total AUC at MRHDand 2 does aborted at approximately 3-fold the total AUC at MRHD, the aborting females showed thinbody condition.

In the perinatal/postnatal development study in Sprague-Dawley rats, pregnant dams wereadministered roxadustat daily from Gestation Day 7 to Lactation Day 20. During the lactation period,pups from dams administered roxadustat at approximately 2-fold the total Cmax at MRHD showed highmortality during the preweaning period and were sacrificed at weaning. Pups from dams administeredroxadustat at doses resulting in systemic exposures approximately 3-fold the human exposure at

MRHD showed a significant decrease in 21-day survival after birth (lactation index) compared withpups from control litters.

In a cross-fostering study, the most pronounced effects on rat pup viability were noted in the pupsexposed to roxadustat postnatally only, and the pup viability exposed to roxadustat until delivery waslower than that of unexposed pups.

The cross-fostering study in which pups from unexposed rats were cross fostered with dams treatedwith roxadustat (human equivalent dose approximately 2-fold MRHD), had roxadustat in pup plasmaindicating transfer of drug via the milk. Milk from these dams had roxadustat present. The pups whowere exposed to milk containing roxadustat showed a lower survival rate (85.1%) versus pups fromuntreated dams cross fostered with untreated dams (98.5% survival rate). The mean body weight of thesurviving pups exposed to roxadustat during the lactation period was also less than the control pups(no in utero exposure - no exposure in milk).

A cardiovascular safety pharmacology study showed heart rate increases following a singleadministration of 100 mg/kg roxadustat to monkeys. There was no effect on hERG or ECG. Additionalsafety pharmacology studies in rats have shown that roxadustat reduced total peripheral resistancefollowed by a reflex increase in heart rate from approximately six times the exposure at the MRHD.

Lactose monohydrate

Cellulose, microcrystalline (E460 (i))

Croscarmellose sodium (E468)

Povidone (E1201)

Magnesium stearate (E470b)

Poly(vinyl alcohol) (E1203)

Talc (E553b)

Macrogol (E1521)

Allura Red AC aluminium lake (E129)

Titanium dioxide (E171)

Lecithin (soya) (E322)

Not applicable.

4 years.

This medicinal product does not require any special storage conditions.

PVC/aluminium perforated unit dose blisters in cartons.

Pack sizes: 12 x 1 and 36 x 1 film-coated tablets.

Not all pack sizes may be marketed.

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Astellas Pharma Europe B.V.

Sylviusweg 622333 BE Leiden

The Netherlands

12 x 1 film-coated tablets

EU/1/21/1574/001 - 00536 x 1 film-coated tablets

EU/1/21/1574/006 - 010

Date of first authorisation: 18 August 2021

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu