Ivrenzo

I N S T R U C T I O N for medical use of the medicinal product IVRENZO (IVRENZO)

Composition:

Active substance: roxadustat;

One film-coated tablet contains roxadustat 20 mg, 50 mg, 70 mg, 100 mg, or 150 mg;

Excipients: lactose monohydrate; microcrystalline cellulose (E460 (i)); sodium croscarmellose (E468); povidone (E1201); magnesium stearate (E470b);

film coating: Opadry II 85G150004 Red: poly(vinyl alcohol) (E1203); talc (E553b); macrogol (E1521); Allura Red AC aluminium lake (E129); titanium dioxide (E171); lecithin (soy) (E322).

Excipients with known effect

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

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

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

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

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

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

20 mg tablets: oval-shaped, red film-coated tablets, with embossed marking «20»;

50 mg tablets: oval-shaped, red film-coated tablets, with embossed marking «50»;

70 mg tablets: round, red film-coated tablets, with embossed marking «70»;

100 mg tablets: oval-shaped, red film-coated tablets, with embossed marking «100»;

150 mg tablets: almond-shaped, red film-coated tablets, with embossed marking «150».

Pharmacotherapeutic group. Antianaemic agents. Other antianaemic agents. Roxadustat.

ATC code B03XA05.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Roxadustat is a prolyl hydroxylase inhibitor (HIF-PHI). The activity of HIF-PH enzymes regulates intracellular levels of hypoxia-inducible factor (HIF), a transcription factor that controls the expression of genes involved in erythropoiesis. Activation of the HIF pathway is a key adaptive response to hypoxia, promoting increased red blood cell production. By reversibly inhibiting HIF-PH, roxadustat stimulates a coordinated erythropoietic response, including increased endogenous erythropoietin levels in plasma, regulation of iron transporter proteins, and reduction of hepcidin levels (an iron-regulatory protein that increases during inflammation in chronic kidney disease (CKD)). As a result, iron bioavailability improves, hemoglobin production increases, and red blood cell mass rises.

Pharmacodynamic Effects

Effect on QTc and Heart Rate

A thorough QT (TQT) study of roxadustat administered at a single therapeutic dose of 2.75 mg/kg and a single supratherapeutic dose of 5 mg/kg (up to 510 mg) in healthy volunteers showed no prolongation of the QTc interval. The same TQT study demonstrated placebo-corrected increases in heart rate of 9–10 beats per minute at 8–12 hours after the 2.75 mg/kg dose and 15–18 beats per minute at 6–12 hours after the 5 mg/kg dose.

Pharmacokinetics

Roxadustat exposure in plasma (area under the plasma concentration-time curve [AUC] and maximum plasma concentration [Cmax]) is dose-proportional within the recommended therapeutic dose range. At a dosing regimen of three times per week, steady-state plasma concentrations of roxadustat are achieved within one week (three doses), with minimal accumulation. The pharmacokinetics of roxadustat do not change over time.

Absorption

Peak plasma concentrations (Cmax) are typically reached within 2 hours after dosing on an empty stomach.

Administration of roxadustat with food reduced Cmax by 25%, but did not alter AUC compared to fasting conditions. Therefore, roxadustat may be administered with or without food (see section "Method of Administration and Dosage").

Distribution

Roxadustat is highly bound to human plasma proteins (approximately 99%), primarily to albumin. The blood-to-plasma concentration ratio of roxadustat is 0.6. The apparent volume of distribution at steady state is 24 L.

Metabolism

Based on in vitro data, roxadustat is a substrate for CYP2C8, UGT1A9, BCRP, OATP1B1, OAT1, and OAT3. Roxadustat is not a substrate for OATP1B3 or P-gp. Roxadustat is primarily metabolized to hydroxy-roxadustat and roxadustat-O-glucuronide. Unchanged roxadustat is the main circulating component in human plasma; no individual metabolite in human plasma accounted for more than 10% of total drug-related exposure, and no unique human metabolites were observed.

Elimination

The mean effective half-life (t_1/2) of roxadustat is approximately 15 hours in patients with CKD.

The apparent total clearance (CL/F) of roxadustat is 1.1 L/h in non-dialysis-dependent patients with CKD and 1.4 L/h in dialysis-dependent patients with CKD. Roxadustat and its metabolites are not significantly removed by hemodialysis.

After oral administration of radiolabeled roxadustat to healthy volunteers, the mean extent of radioactivity recovery was 96% (50% in feces, 46% in urine).

Twenty-eight percent of the roxadustat dose was excreted unchanged in feces. Less than 2% of the dose was excreted unchanged in urine.

Pharmacokinetics in Specific Patient Populations

Special Populations

Age, Sex, Body Weight, and Race

No clinically significant differences in roxadustat pharmacokinetics were observed based on age (≥18 years), sex, race, body weight, renal function (eGFR), or dialysis status in adult patients with anemia due to CKD.

Hemodialysis
In dialysis-dependent patients with CKD, no notable differences in pharmacokinetic parameters were observed when roxadustat was administered 2 hours before or 1 hour after hemodialysis. A negligible fraction of roxadustat is cleared by dialysis (relative to total clearance).

Hepatic Impairment

Following a single 100 mg dose of roxadustat, the mean AUC of roxadustat was 23% higher and the mean Cmax was 16% lower in patients with moderate hepatic impairment (Child-Pugh class B) and normal renal function compared to subjects with normal hepatic and renal function. In patients with moderate hepatic impairment (Child-Pugh class B) and normal renal function, an increase in AUC_inf of unbound roxadustat (+70%) was observed compared to healthy volunteers.

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

Specific Drug Interactions

Based on in vitro data, roxadustat is an inhibitor of CYP2C8, BCRP, OATP1B1, and OAT3 (see section "Interaction with Other Medicinal Products and Other Forms of Interaction"). Concomitant administration of roxadustat did not affect the pharmacokinetics of rosiglitazone (a moderately sensitive CYP2C8 substrate). Roxadustat may inhibit intestinal, but not hepatic, UGT1A1 and showed no inhibition of other CYP-metabolizing enzymes or transporters, nor induction of CYP enzymes at clinically relevant concentrations. There is no clinically significant effect of oral adsorbent charcoal or omeprazole on the pharmacokinetics of roxadustat. Clopidogrel has no significant effect on roxadustat exposure in patients with CKD.

Clinical characteristics.

Indications.

The medicinal product Ivrenzo is indicated for the treatment of anaemia associated with chronic kidney disease (CKD) in adult patients.

Contraindications.

The medicinal product Ivrenzo is contraindicated in the following conditions:

• Hypersensitivity to the active substance, peanut, soya or to any of the excipients listed in the section "Composition".
• Third trimester of pregnancy (see sections "Special precautions" and "Use in pregnancy or breast-feeding").
• Breast-feeding (see section "Use in pregnancy or breast-feeding").

Interaction with other medicinal products and other forms of interaction

Effect of other medicinal products on roxadustat

Phosphate binders and other products containing polyvalent cations

Concomitant administration of roxadustat with the phosphate binders sevelamer carbonate or calcium acetate in healthy volunteers reduced roxadustat AUC by 67% and 46%, and Cmax by 66% and 52%, respectively. Roxadustat may form chelate complexes with polyvalent cations, for example, when administered with phosphate binders or other agents containing calcium, iron, magnesium or aluminium. Staggered administration of phosphate binders (with an interval of at least 1 hour) did not have a 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 polyvalent cations (see section "Dosage and administration**"**). This restriction does not apply to lanthanum carbonate, as concomitant administration of roxadustat with lanthanum carbonate did not result in a clinically significant change in plasma exposure of roxadustat.

Modulators of CYP2C8 or UGT1A9 activity

Roxadustat is a substrate of CYP2C8 and UGT1A9. Concomitant administration of roxadustat with gemfibrozil (a CYP2C8 and OATP1B1 inhibitor) or probenecid (a UGT and OAT1/OAT3 inhibitor) in healthy volunteers increased roxadustat AUC by 2.3-fold and Cmax by 1.4-fold. Haemoglobin levels should be monitored at the start and upon discontinuation of concomitant treatment with gemfibrozil, probenecid, other strong inhibitors or inducers of CYP2C8, or other strong inhibitors of UGT1A9. The roxadustat dose should be adjusted according to the dose adjustment guidelines (see Table 2) based on haemoglobin monitoring.

Effect 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 uptake and elimination of statins by liver and intestinal cells. Concomitant administration of 200 mg roxadustat with simvastatin in healthy volunteers increased AUC and Cmax of simvastatin by 1.8- and 1.9-fold, respectively, and AUC and Cmax of simvastatin acid (the active metabolite of simvastatin) by 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. Concomitant administration of 200 mg roxadustat and rosuvastatin increased AUC and Cmax of rosuvastatin by 2.9- and 4.5-fold, respectively. Concomitant administration of 200 mg roxadustat with atorvastatin increased AUC and Cmax of atorvastatin by 2.0- and 1.3-fold, respectively.

Interaction with other statins is also expected. This interaction should be considered when co-administering statins with roxadustat; monitor for statin-related adverse reactions and the need to reduce statin doses. Refer to the prescribing information for statins when determining the appropriate statin dose for individual patients.

Roxadustat may increase plasma exposure of other medicinal products that are substrates of BCRP or OATP1B1. Monitor for possible adverse reactions with concomitantly administered medicinal products and adjust doses accordingly.

Roxadustat and erythropoiesis-stimulating agents (ESAs)

Concomitant administration of roxadustat and erythropoiesis-stimulating agents is not recommended, as this combination has not been studied.

Special precautions for use

Cardiovascular risk and risk of death

Overall, the cardiovascular disease risk and mortality risk with roxadustat treatment is considered comparable to that with treatment with erythropoiesis-stimulating agents, based on data from direct comparison of both treatment methods (see section "Pharmacodynamics"). Since this risk cannot be reliably assessed compared to placebo in patients with anemia associated with CKD who are not on dialysis, the decision to treat such patients with roxadustat should be based on similar considerations as would apply to initiating treatment with erythropoiesis-stimulating agents.

Additionally, several contributing factors have been identified that may increase this risk, including lack of response to treatment and switching stable patients receiving erythropoiesis-stimulating agents to other therapies (see section "Dosage and administration"). If there is no response to treatment, roxadustat should not be continued beyond 24 weeks (see section "Dosage and administration"). Conversion of dialysis patients who are otherwise stable on erythropoiesis-stimulating agents should only be considered if there are compelling clinical reasons (see section "Dosage and administration"). For stable non-dialysis CKD patients with anemia previously treated with erythropoiesis-stimulating agents, this risk cannot be assessed, as such patients were not studied. The decision to treat these patients with roxadustat should be based on an individual assessment of benefit-risk balance.

Vascular access thrombosis

The risk of vascular access thrombosis (VAT) should be carefully weighed against the benefit of roxadustat use, especially in patients with prior risk factors for VAT, including obesity and history of VAT (e.g., deep vein thrombosis [DVT] and pulmonary embolism [PE]). In clinical trial participants, DVT was reported as common and PE as uncommon. Most cases of DVT and PE were serious.

In clinical studies, VAT occurred commonly in dialysis-dependent CKD patients (see section "Adverse reactions").

Among dialysis patients with CKD receiving roxadustat, VAT rates were highest during the first 12 weeks after treatment initiation when hemoglobin levels exceeded 12 g/dL (120 g/L) and when hemoglobin increased by more than 2 g/dL (20 g/L) within 4 weeks. Hemoglobin levels should be monitored and doses adjusted according to dose modification rules (see Table 2) to avoid hemoglobin levels above 12 g/dL (120 g/L) and increases in hemoglobin exceeding 2 g/dL (20 g/L) within 4 weeks.

Patients presenting with signs and symptoms of VAT should be promptly evaluated and treated according to standard medical practice. The decision to interrupt or discontinue treatment should be based on individual patient risk assessment.

Seizures

In clinical studies, seizures were reported commonly in patients receiving roxadustat (see section "Adverse reactions"). Roxadustat should be used with caution in patients with a history of seizures (seizures or convulsive episodes), epilepsy, or conditions associated with seizure predisposition, such as central nervous system (CNS) infections. The decision to interrupt or discontinue treatment should be based on individual patient risk assessment.

Serious infections

The most common serious infections were pneumonia and urinary tract infections. Patients with signs and symptoms of infection should be promptly evaluated and treated according to standard medical practice.

Sepsis

Sepsis was one of the most common serious infections and included fatal cases. Patients with signs and symptoms of sepsis (e.g., systemic infection with hypotension and potential for organ failure) should be immediately evaluated and treated according to standard medical practice.

Secondary hypothyroidism

Cases of secondary hypothyroidism have been reported with roxadustat use (see section "Adverse reactions"). These reactions were reversible upon discontinuation of roxadustat. Monitoring of thyroid function is recommended based on clinical indications.

Inadequate response to therapy

In case of inadequate response to roxadustat therapy, causative factors should be identified. Nutritional deficiencies should be corrected. Concurrent infectious diseases, occult blood loss, hemolysis, severe toxicity due to aluminum-containing compounds, underlying hematological disorders, or bone marrow fibrosis may impair erythropoietic response. Reticulocyte count should be considered as part of the evaluation. If typical causes of non-response are excluded and the patient has reticulocytopenia, bone marrow examination should be considered. If the cause of inadequate response is not addressed, Irevanzo should not be continued beyond 24 weeks of therapy.

Hepatic impairment

Caution is required when prescribing roxadustat to patients with moderate hepatic impairment (Child-Pugh class B). Irevanzo is not recommended for patients with severe hepatic impairment (Child-Pugh class C) (see section "Pharmacokinetic properties").

Pregnancy and contraception

Roxadustat should not be prescribed to women planning pregnancy, pregnant women, or women diagnosed with CKD-related anemia during pregnancy. In such cases, alternative therapy should be initiated if needed. If pregnancy occurs during roxadustat treatment, therapy should be discontinued and, if necessary, alternative treatment initiated. Women of reproductive potential should use highly effective contraception during treatment and for at least one week after the last dose of Irevanzo (see sections "Contraindications" and "Use during pregnancy and breastfeeding").

Improper use

Improper use may lead to excessive increase in hematocrit levels, which may be associated with life-threatening cardiovascular complications.

Excipients

Irevanzo contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Irevanzo contains the colouring agent aluminium lake Allura Red AC (see section "Composition"), which may cause allergic reactions.

Irevanzo contains traces of soy lecithin. Patients with allergy to peanuts or soy should not take this medicinal product.

Use during pregnancy and breastfeeding

Pregnancy, women of reproductive potential and contraception

There are no data on roxadustat use in pregnant women. Animal studies have shown reproductive toxicity.

Roxadustat is contraindicated during the third trimester of pregnancy (see sections "Contraindications" and "Special precautions for use").

Roxadustat is not recommended during the first and second trimesters of pregnancy (see section "Special precautions for use").

If pregnancy occurs during Irevanzo treatment, therapy should be discontinued and alternative treatment initiated if necessary (see section "Contraindications").

Breastfeeding

It is unknown whether roxadustat/metabolites are excreted in human breast milk. Available animal studies have shown excretion of roxadustat into milk. Irevanzo is contraindicated during breastfeeding (see section "Contraindications").

Fertility

Animal studies did not reveal any effect of roxadustat on fertility in males or females. However, changes in male rat reproductive organs were observed. The potential effect of roxadustat on male fertility is currently unknown. Increased embryonic death was observed in female animals at toxic doses. Women of reproductive potential should use highly effective contraception during treatment and for at least one week after the last dose of Irevanzo.

Effect on ability to drive and use machines

Roxadustat has negligible influence on the ability to drive or operate machinery. However, seizures have been reported during Irevanzo treatment (see section "Special precautions for use"). Therefore, caution should be exercised when driving or operating machinery.

Method of Administration and Dosage

Treatment with roxadustat should be initiated by a physician experienced in the management of anemia. All other potential causes of anemia should be evaluated prior to starting therapy with the medicinal product Ivenzo and when making decisions regarding dose escalation.

The symptoms and consequences of anemia may vary depending on the patient's age, sex, and overall severity of the disease; therefore, clinical assessment by a physician of the disease course and individual patient status is required. In evaluating the patient's condition, in addition to the presence of symptoms of anemia, the following criteria should be considered: rate of decline in hemoglobin (Hb) concentration, prior response to iron therapy, and risk of requiring red blood cell transfusions; individual clinical presentation and the patient’s general condition may also be relevant.

Method of Administration

Film-coated tablets should be taken orally with or without food. Tablets must be swallowed whole and should not be chewed, broken, or crushed due to the lack of clinical data on administration under these conditions, as well as to protect the light-sensitive tablet core from photodegradation.

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 aluminum (see sections "Pharmacokinetic Properties" and "Interaction with Other Medicinal Products and Other Forms of Interaction").

Dosage

The appropriate dose of roxadustat should be administered orally three times a week, but not on consecutive days.

The dose should be individually adjusted to achieve and maintain target hemoglobin levels between 10 and 12 g/dL, as described below.

Treatment with roxadustat should not be continued beyond 24 weeks if a clinically significant increase in hemoglobin levels has not been achieved. Before reinitiating treatment with Ivenzo, alternative causes of inadequate response should be investigated.

Initial Treatment Dose

Prior to initiating treatment, adequate iron stores should be ensured in the patient.

Patients not receiving erythropoiesis-stimulating agents (ESAs) at treatment initiation

For patients initiating anemia treatment who have not previously received ESAs, the recommended initial dose of roxadustat is 70 mg three times a week if body weight is less than 100 kg, and 100 mg three times a week if body weight is 100 kg or more.

Patients transitioning from ESA therapy

Patients currently receiving ESA therapy may be switched to roxadustat; however, switching patients who are on dialysis and otherwise stable on ESA treatment should only be considered in the presence of compelling clinical reasons (see section "Special Warnings").

Conversion of non-dialysis patients who are otherwise stable on ESA therapy has not been studied. The decision to treat such patients with roxadustat should be based on an individual benefit-risk assessment for each patient.

The recommended initial dose of roxadustat is based on the average prescribed ESA dose during the 4 weeks prior to conversion (see Table 1). The first dose of roxadustat should replace the next scheduled dose of the current ESA.

Table 1. Initial doses of roxadustat (three times weekly) for patients transitioning from ESA therapy

Darbepoetin alfa for intravenous or subcutaneous dose (mcg/week)	Intravenous or subcutaneous epoetin dose (IU/week)	Methoxy polyethylene glycol-epoetin beta intravenous or subcutaneous dose (mcg/month)	Roxadustat dose (mg, three times a week)
Less than 25	Less than 5,000	Less than 80	70
From 25 to less than 40	From 5,000 to 8,000	From 80 to 120 inclusive	100
From 40 to 80 inclusive	More than 8,000 to 16,000 inclusive	More than 120 to 200 inclusive	150
More than 80	More than 16,000	More than 200	200

Dosage Adjustment and Hemoglobin Level Monitoring

The individual maintenance dose ranges from 20 mg to 400 mg administered three times a week (see below "Maximum Recommended Dose"). Hemoglobin levels should be monitored every two weeks until the desired hemoglobin level of 10 g/dL (100 g/L) to 12 g/dL (120 g/L) is achieved and stabilized, and thereafter every four weeks or as clinically indicated.

The dose of roxadustat may be gradually increased or decreased four weeks after initiation of treatment, and then every four weeks, unless hemoglobin levels increase by more than 2 g/dL (12 g/L); in this case, the dose should be decreased by one step immediately. During dose adjustment of roxadustat, the current hemoglobin level and the rate of change in hemoglobin level over the preceding four weeks should be considered, and dose adjustment steps should follow the algorithm described in Table 2.

Gradual dose adjustment (increase or decrease) should follow the sequence of available doses: 20 mg – 40 mg – 50 mg – 70 mg – 100 mg – 150 mg – 200 mg – 250 mg – 300 mg – 400 mg (only for dialysis-dependent CKD patients).

	Table 2. Dose adjustment guidelines
	Change in hemoglobin over the last 4 weeks1	Current hemoglobin level (g/dL)
		Below 10.5 (105 g/L)	10.5 to 11.9 (105–119 g/L)	12.0 to 12.9 (120–129 g/L)	13.0 (130 g/L) or higher
	Change in hemoglobin greater than +1.0 g/dL (10 g/L)	No change	Reduce dose by one step	Reduce dose by one step	Temporarily discontinue treatment, monitor hemoglobin levels, and resume therapy when hemoglobin is below 12.0 g/dL (120 g/L), at a dose reduced by two steps
	Change in hemoglobin between -1.0 and +1.0 g/dL (-10 and +10 g/L)	Increase dose by one step	No change	Reduce dose by one step
	Change in hemoglobin less than -1.0 g/dL (10 g/L)	Increase dose by one step	Increase dose by one step	No change
Roxadustat dose should not be adjusted more frequently than once every 4 weeks, except in cases where hemoglobin increases by more than 2 g/dL (20 g/L) at any time during a 4-week period; in such cases, the dose should be immediately reduced by one step. 1 Change in hemoglobin (Hb) over the previous 4 weeks = (current Hb value) – (previous Hb value obtained 4 weeks ago).

If further dose reduction is required for a patient already receiving the lowest dose (20 mg three times weekly), the 20 mg dose should not be reduced by splitting the tablet; instead, the frequency of administration should be reduced to twice weekly. If further dose reduction is necessary, the frequency of administration may be reduced further to once weekly.

Maintenance dose

After stabilization to the target Hb level of 10 g/dL (100 g/L) to 12 g/dL (120 g/L), hemoglobin levels should continue to be monitored regularly, and dose adjustment rules should be followed (see Table 2).

Patients initiating dialysis during roxadustat treatment

For patients with CKD who initiate dialysis during roxadustat treatment, no special dose adjustment is required. Standard dose adjustment rules should be followed (see Table 2).

Concomitant treatment with roxadustat and inducers or inhibitors

At initiation or discontinuation of concomitant treatment with strong inhibitors (e.g., gemfibrozil) or inducers (e.g., rifampicin) of CYP2C8, or inhibitors (e.g., probenecid) of UGT1A9, hemoglobin levels should be monitored regularly and dose adjustment rules followed (see Table 2; see also sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacokinetic properties").

Maximum recommended dose

For patients not on dialysis, the roxadustat dose should not exceed 3 mg/kg body weight or 300 mg three times weekly, whichever is lower.

For dialysis patients, the roxadustat dose should not exceed 3 mg/kg body weight or 400 mg three times weekly, whichever is lower.

Missed dose

If a dose is missed and more than 1 day remains until the next scheduled dose, the missed dose should be taken as soon as possible. If only one day or less remains until the next scheduled dose, the missed dose should not be taken, and the next dose should be taken on the scheduled day. In each individual case, the regular dosing schedule should then be resumed.

Special populations

Elderly patients

Dose adjustment is not required for elderly patients (see section "Pharmacokinetic properties").

Patients with hepatic impairment

No initial dose adjustment is required for patients with mild hepatic impairment (Child-Pugh class A) (see sections "Special precautions for use" and "Pharmacokinetic properties").

Caution is recommended when prescribing roxadustat to patients with moderate hepatic impairment. The initial dose should be reduced by half or to the dose level closest to half the initial dose at the start of treatment in patients with moderate hepatic impairment (Child-Pugh class B). Ivrenzo is not recommended for patients with severe hepatic impairment (Child-Pugh class C), as the safety and efficacy of the drug have not been evaluated in this population (see sections "Special precautions for use" and "Pharmacokinetic properties").

Children

The safety and efficacy of roxadustat in children (under 18 years of age) have not been established. No data are available.

Overdose

Single doses of roxadustat exceeding the therapeutic dose of 5 mg/kg (up to 510 mg) in healthy volunteers were associated with transient increases in heart rate, increased frequency of mild and moderate musculoskeletal pain, headache, sinus tachycardia, and less frequently, low blood pressure; adverse effects were generally not serious. Roxadustat overdose may increase hemoglobin levels above the desired range (10–12 g/dL (100–120 g/L)), which should be managed by discontinuing or reducing the roxadustat dose (see section "Posology and method of administration") and careful monitoring and treatment as clinically indicated. Roxadustat and its metabolites are not significantly removed by hemodialysis (see section "Pharmacological properties").

Adverse reactions

Short description of the safety profile

The safety of Ivenzo was evaluated in 3542 non-dialysis (NDD) patients and 3353 dialysis-dependent (DD) patients with anemia and CKD who received at least one dose of roxadustat.

The most common (≥ 10%) adverse reactions associated with roxadustat are hypertension (13.9%), vascular access thrombosis (12.8%), diarrhea (11.8%), peripheral edema (11.7%), hyperkalemia (10.9%), and nausea (10.2%).

The most frequent (≥ 1%) serious adverse reactions associated with roxadustat were sepsis (3.4%), hyperkalemia (2.5%), hypertension (1.4%), and deep vein thrombosis (1.2%).

List of adverse reactions in a table

Adverse reactions observed during clinical studies and/or in the post-marketing period are listed in this section by frequency categories defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); not known (cannot be estimated from the available data).

Table 3. Adverse reactions
MedDRA system organ class	Frequency category	Adverse reaction
Infections and infestations	Common	Sepsis
Endocrine disorders	Unknown	Secondary hypothyroidism
Metabolism and nutrition disorders	Very common	Hyperkalaemia
Psychiatric disorders	Common	Insomnia
Nervous system disorders	Common	Convulsions, headache
Vascular disorders	Very common	Hypertension, vascular access thrombosis (VAT) 1
	Common	Deep vein thrombosis (DVT)
Gastrointestinal disorders	Very common	Nausea, diarrhoea
	Common	Constipation, vomiting
Skin and subcutaneous tissue disorders	Unknown	Generalized exfoliative dermatitis (GED)
Hepatobiliary disorders	Uncommon	Hyperbilirubinaemia
Respiratory, thoracic and mediastinal disorders	Uncommon	Pulmonary embolism
General disorders and administration site conditions	Very common	Peripheral oedema
Investigations	Unknown	Decreased blood thyroid-stimulating hormone (TSH) level
1 This adverse reaction is associated with patients with CKD who were on dialysis during roxadustat treatment.

Description of individual adverse reactions

Thrombovascular events

In non-dialysis-dependent patients with CKD, cases of VTE 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 dialysis-dependent patients with CKD, VTE 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 patient with events per 100 patient-years of exposure) in the ESA group (see section "Special warnings and precautions for use").

In non-dialysis-dependent patients with CKD, 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 patient with events per 100 patient-years of exposure) in the placebo group. In dialysis-dependent patients with CKD, 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 "Special warnings and precautions for use").

In dialysis-dependent patients with CKD, 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 "Special warnings and precautions for use").

Seizures

In non-dialysis-dependent patients with CKD, 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 "Special warnings and precautions for use").

In dialysis-dependent patients with CKD, 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 "Special warnings and precautions for use").

Sepsis

In non-dialysis-dependent patients with CKD, 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 dialysis-dependent patients, 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 "Special warnings and precautions for use").

Skin reactions

During post-marketing surveillance, generalized exfoliative dermatitis, which is part of severe cutaneous adverse reactions (SCARs), has been reported in association with roxadustat treatment (frequency unknown).

Reporting of suspected adverse reactions

Reporting of adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 4 years.

Storage conditions. Store at a temperature not exceeding 30 °C.

Packaging. 12 film-coated tablets in a blister; 1 blister and package leaflet in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Delpharm Meppel B.V., the Netherlands / Delpharm Meppel B.V., the Netherlands.

Manufacturer's address and place of business.

Hogemaat 2, 7942 JG Meppel, the Netherlands / Hogemaat 2, 7942 JG Meppel, the Netherlands.

Marketing authorization holder.

Astellas Pharma Europe B.V., the Netherlands / Astellas Pharma Europe B.V., the Netherlands.

Address of the marketing authorization holder.

Sylviusweg, 62, 2333 BE Leiden, the Netherlands / Sylviusweg, 62, 2333 BE Leiden, the Netherlands.