Roxadustat

Registered South African indications:

• Anaemia in patients with chronic kidney disease (CKD)

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Breastfeeding
• Pregnancy
• Children under 18 years

Contraindications registered in other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to peanuts or soya
• Third trimester of pregnancy
• Breastfeeding

South African recommendations

Caution in the following patient group:

• Women of children bearing potential

Moderate to severe hepatic impairment

• Roxadustat's safety and effectiveness have not been verified in CKD patients with moderate or severe liver impairment (Child-Pugh class B and C)

Vascular access thrombosis (VAT) in dialysis patients

• VAT is very common in dialysis patients during clinical trials
• The highest incidence of VAT occurs within the first 12 weeks of starting roxadustat, especially when haemoglobin levels exceed 12g/dL or when there's a rise of more than 2g/dL in haemoglobin over 4 weeks
• It is crucial to closely monitor haemoglobin levels and adjust roxadustat dosage to prevent haemoglobin levels from exceeding 12g/dL or rising more than 2g/dL over 4 weeks. Follow the specific dose adjustment guidelines provided
• Patients experiencing VAT should receive standard care treatment. The outcomes of interrupting or stopping roxadustat for VAT are not established

Seizures

• Seizures have been commonly reported in clinical trial participants receiving roxadustat
• Use roxadustat cautiously in individuals with a history of seizures, epilepsy, or medical conditions that predispose them to seizure activity, including CNS infections
• The impact of pausing or stopping roxadustat in patients experiencing seizures is not known

Serious infections

• Patients showing infection symptoms need quick evaluation and treatment
• In non-dialysis patients, serious infections were reported more frequently with roxadustat (18.9%) compared to placebo (12.9%). Fatal infections in the roxadustat group were 3.0% versus 1.0% in the placebo group
• Pneumonia, sepsis, and urinary tract infections were the most commonly reported serious infections
• No numerical imbalance in serious and fatal infections between roxadustat and ESA-treated patients on dialysis
• A direct link between roxadustat and serious infections hasn't been confirmed

Deep vein thrombosis (DVT)

• DVT has been commonly reported in clinical trials, with most events being serious
• Patients displaying DVT symptoms require quick evaluation and standard care treatment
• The consequences of stopping or pausing roxadustat for patients with DVT are unclear

Excipients

• Roxadustat includes lactose monohydrate. It's unsuitable for individuals with rare hereditary issues like galactose intolerance, lactase deficiency, or glucose-galactose malabsorption
• Contains Allura Red AC aluminium lake, which may trigger allergic reactions

Effects on ability to drive and use machines

• Roxadustat has a minimal impact on driving and operating machinery abilities
• However, due to the potential for causing seizures and dizziness, patients are advised against driving or using machinery while on roxadustat treatment

Recommendations in other jurisdictions

Pregnancy (first and second trimester) and contraception

• Do not start roxadustat in women planning to become pregnant, during pregnancy, or when CKD-associated anaemia is diagnosed during pregnancy.
• Switch to an alternative treatment if pregnancy occurs during roxadustat treatment
• Women of childbearing age must use effective contraception during and for one week after the last dose of roxadustat

Moderate to severe hepatic impairment

• Use caution when administering roxadustat to patients with moderate hepatic impairment (Child-Pugh class B)
• Roxadustat is not advised for patients with severe hepatic impairment (Child-Pugh class C)

Cardiovascular and mortality risk

• The cardiovascular and mortality risk associated with roxadustat treatment is considered comparable to that of ESA therapy based on direct comparisons
• The decision to treat patients not on dialysis with roxadustat should reflect the same considerations as for ESA treatment due to uncertain risk assessment versus placebo
• Factors like treatment non-responsiveness and unnecessary conversion from stable ESA therapy may contribute to risk. Roxadustat treatment should not extend beyond 24 weeks without response
• Conversion from ESA should only occur for clinically valid reasons

Thrombotic vascular events (TVEs)

• The risk of TVEs, including obesity and history of TVEs like DVT and PE, must be balanced against roxadustat treatment benefits. DVT is common, while PE is less common but both are often serious
• Vascular access thrombosis (VAT) is very common in dialysis patients treated with roxadustat, especially within the first 12 weeks, when Hb is above 12g/dL or rises more than 2g/dL over 4 weeks
• Monitoring Hb levels and adjusting roxadustat dosage to prevent high Hb levels or rapid increases is advised
• Prompt evaluation and standard care treatment are recommended for signs and symptoms of TVEs, with treatment continuation based on individual patient risk-benefit assessment

Seizures

• Seizures commonly occurred in patients taking roxadustat during clinical studies
• Use roxadustat cautiously in individuals with a history of seizures, epilepsy, or conditions predisposing them to seizure activity, including CNS infections
• The decision to pause or stop roxadustat should be based on evaluating the benefits versus risks for the patient

Serious infections

• Pneumonia and urinary tract infections were frequently reported as serious infections
• Prompt evaluation and standard care are advised for patients showing signs and symptoms of an infection

Sepsis

• Sepsis, including fatal cases, was among the commonly reported serious infections
• Immediate evaluation and standard treatment are crucial for patients exhibiting signs of sepsis

Secondary hypothyroidism

• Reports indicate secondary hypothyroidism occurrences with roxadustat, reversible upon discontinuation
• Monitoring thyroid function is suggested as needed

Inadequate response to therapy

• If roxadustat therapy response is inadequate, investigate for possible causes.
• Correct any nutrient deficiencies and consider other factors like infections, blood loss, haemolysis, aluminium toxicity, hematologic diseases, or bone marrow fibrosis.
• Evaluate with a reticulocyte count and, if necessary, a bone marrow examination if reticulocytopenia is present without other non-response causes.
• Discontinue roxadustat if no specific cause for the inadequate response is found within 24 weeks of treatment

Misuse

• Misusing roxadustat can cause a significant increase in packed cell volume, potentially leading to life-threatening cardiovascular complications

Excipients

• Roxadustat contains lactose, making it unsuitable for patients with rare hereditary issues like galactose intolerance, lactase deficiency, or glucose-galactose malabsorption
• It includes Allura Red AC aluminium lake, which might trigger allergic reactions
• The presence of soya lecithin in roxadustat advises against its use in individuals allergic to peanuts or soya

Effects on ability to drive and use machines

• Roxadustat marginally affects the ability to drive and operate machinery
• Given the reports of seizures during treatment, caution is advised when engaging in activities such as driving or operating machinery

Forms avail. in SA and covered in this monograph: fct

South African registered indications and dosages

Treatment with roxadustat should be initiated by a medical practitioner experienced in the management of anaemia

Anaemia in patients with chronic kidney disease (CKD)

Patients not currently treated with an Erythropoiesis Stimulating Agent (ESA) (for patients initiating anaemia treatment not previously treated with ESA)

• Oral (fct): <100kg: Initial: 70mg, 3 times per week
• Oral (fct): ≥100kg: Initial: 100mg, 3 times per week

Patients converting from an Erythropoiesis Stimulating Agent (ESA)

• Oral (fct): For patients converting anaemia therapy from ESA to roxadustat, the recommended starting dose of roxadustat is based on the average prescribed ESA dose in the 4 weeks before conversion (see table 1 below). The first roxadustat dose should replace the next scheduled dose of the current ESA

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

Darbepoetin alfa dose (micrograms/week)	Epoetin dose (IU/week)	Methoxy polyethylene glycol-epoetin beta dose (micrograms/monthly)	Roxadustat dose (milligrams three times per week)
Less than 25	Less than 5 000	Less than 80	70
25 to less than 40	5 000 up to 8 000	80 up to and including 120	100
40 up to and including 80	> 8 000 up to and including 16 000	More than 120 up to and including 200	150
More than 80	More than 16 000	More than 200	200

Dose adjustment and haemoglobin monitoring

• Oral (fct): Maintenance range: 20-400mg, 3 times a week; Monitor Hb levels every 2 weeks until the desired Hb level of 10-12g/dL is achieved and stabilised, and every 4 weeks thereafter, or as clinically indicated; Titrate dose stepwise from the starting dose 4 weeks after treatment initiation, and 4 weeks thereafter; When adjusting the dose, consider the current Hb level and the recent rate of change in Hb level over the past 4 weeks, and follow the dose adjustment steps according to the dose adjustment algorithm described in table 2 below; Max dose: Patients not on dialysis: Do not exceed a roxadustat dose of 3mg/kg bodyweight OR 300mg, three times per week, whichever is lower; Patients on dialysis: Do not exceed a roxadustat dose of 3mg/kg body weight OR 400mg, three times per week, whichever is lower

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

Table 2: Dose adjustment rules

Change in Hb over the previous 4 weeks*	Current haemoglobin (Hb) level (g/dL):
	Lower than 10.5	10.5 to 11.9	12.0 to 12.9	13.0 or higher
Change is more than +1.0g/dL	No change	Reduce dose by one step	Reduce dose by one step	Withhold dosing, monitor Hb level and resume dosing when Hb is less than 12.0g/dL, at a dose that is reduced by two steps
Change is value between -1.0 and +1.0g/dL	Increase dose by one step	No change	Reduce dose by one step
Change is value of less than -1.0g/dL	Increase dose by one step	Increase dose by one step	No change
The dose of roxadustat should not be adjusted more frequently than once every 4 weeks, except if haemoglobin (Hb) increases by more than 2g/dL at any time within a 4-week period, in which case the dose should be reduced by one step immediately

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

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Leave the blisters in the carton until required for use

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Adequate iron stores should be ensured prior to initiating treatment with roxadustat

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The dose of roxadustat should be individualised to achieve and maintain target haemoglobin levels of 10-12g/dL

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

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

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

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Concomitant roxadustat treatment with inducers or inhibitors: When initiating or discontinuing concomitant treatment with strong inhibitors (e.g. gemfibrozil) or inducers (e.g. rifampicin) of CYP2C8, or inhibitors (e.g. probenecid) of UGT1A9: the haemoglobin levels should be monitored and the dose adjustment rules must be followed (see Table 2 above)

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Roxadustat tablets are taken orally with or without food. The tablets must be swallowed whole and not chewed, broken or crushed.  The tablets should be taken at least 1 hour before or 1 hour after admin.of phosphate binders (except lanthanum) or other (medicinal) products containing multivalent cations such as calcium, iron, magnesium or aluminium)

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

Contraindicated

Pregnancy

South African recommendations

• Contraindicated
• Roxadustat is contraindicated for use in pregnant women and females of reproductive potential not using effective contraception because of the potential for foetal harm based on animal data
• There are currently no human data to establish the presence or absence of drug-associated risk with the use of roxadustat during pregnancy

Recommendations in other jurisdictions

• Third trimester: Contraindicated
• First and second trimester: Caution; not recommended
• There are no data on the use of roxadustat in pregnant women. Studies in animals have shown reproductive toxicity
• Roxadustat is contraindicated during the third trimester of pregnancy
• Roxadustat is not recommended during the first and second trimester of pregnancy
• If pregnancy occurs while roxadustat is being administered, treatment should be discontinued and switched to alternative treatments, if appropriate

Breastfeeding

South African recommendations

• Contraindicated
• Women must not breastfeed during treatment with roxadustat, because of the potential for adverse reactions from roxadustat in a breastfed infant

Recommendations in other jurisdictions

• Contraindicated
• It is unknown whether roxadustat/metabolites are excreted in human milk
• Available animal data have shown excretion of roxadustat in milk
• Roxadustat is contraindicated during breastfeeding

Fertility

South African recommendations

• Women of reproductive potential should use effective contraception for at least one week prior to starting roxadustat and until after the last dose of roxadustat is taken. At a maternally toxic dose, increased embryonic loss was observed 

Recommendations in other jurisdictions

• In animal studies, there were no effects of roxadustat on male and female fertility. However, changes in rat male reproductive organs were observed
• The potential effects of roxadustat on male fertility in humans is currently unknown. At a maternally toxic dose, increased embryonic loss was observed
• Women of childbearing potential must use highly effective contraception during treatment and for at least one week after the last dose of roxadustat

Recommendations below are applicable to South Africa and other jurisdictions

• No dose adjustment recommended
• Patients starting dialysis while on roxadustat treatment: No dose adjustment recommended
  No specific dose adjustment is required for CKD patients who start dialysis while on treatment with roxadustat. Normal dose adjustment rules (see Table 2 Adult Dosages) should be followed
  Patients on dialysis: Do not exceed a roxadustat dose of 3mg/kg body weight or 400mg, three times per week, whichever is lower
  Patients not on dialysis: Do not exceed a roxadustat dose of 3mg/kg body weight or 300mg, three times per week, whichever is lower
  The tablets can be taken before or after dialysis

South African recommendations

• Mild (Child-Pugh class A): No dose adjustment recommended
• Moderate to severe (Child-Pugh class B and C): Caution; no information available
  Consider using a lower starting dose in these patients

Recommendations in other jurisdictions

• Mild (Child-Pugh class A): No dose adjustment recommended
• Moderate (Child-Pugh Class B) : Caution; dose adjustment recommended
  The starting dose is to be reduced by half or to the dose level that is closest to half the starting dose when initiating treatment in patients with moderate hepatic impairment (Child-Pugh class B)
• Severe (Child-Pugh Class C): Caution; not recommended

Recommendations below are applicable to South Africa and other jurisdictions

• No dose adjustment recommended

Infections and Infestations

Common

• Sepsis

Endocrine Disorders

Not known

• Secondary hypothyroidism

Metabolism and Nutrition Disorders

Very common

• Hyperkalaemia

Psychiatric Disorders

Common

• Insomnia

Nervous System Disorders

Common

• Seizures
• Headache

Vascular Disorders

Very common

• Hypertension
• Vascular access thrombosis (VAT) (associated with CKD patients who were on dialysis while receiving roxadustat)

Common

• Deep vein thrombosis (DVT)

Gastrointestinal Disorders

Very common

• Nausea
• Diarrhoea

Common

• Constipation
• Vomiting

Skin and Subcutaneous Tissue Disorders

Not known

• Dermatitis Exfoliative Generalised (DEG)

Hepatobiliary Disorders

Uncommon

• Hyperbilirubinaemia

Respiratory, Thoracic, and Mediastinal Disorders

Uncommon

• Pulmonary embolism

General Disorders and Administration Site Conditions

Very common

• Peripheral oedema

Investigations

Not known

• Decreased blood thyroid stimulating hormone (TSH)

• Phosphate binders
• Sevelamer carbonate
• Products containing multivalent cations
• Calcium acetate
• Other products containing calcium, iron, magnesium, or aluminium
• Modifiers of CYP2C8 or UGT1A9 activity
• Gemfibrozil (CYP2C8 and OATP1B1 inhibitor)
• Strong inhibitors or inducers of CYP2C8
• Probenecid (UGT and OAT1/OAT3 inhibitor)
• Strong inhibitors of UGT1A9
• OATP1B1 or BCRP Substrates
• Simvastatin (including its active metabolite, simvastatin acid)
• Rosuvastatin
• Atorvastatin
• Other statins
• Erythropoiesis-Stimulating Agents (ESAs)

• Haemoglobin (Hb) levels

Specific cases may require

• Thyroid function

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 the expression of genes involved in erythropoiesis. Activation of the HIF pathway is important in the adaptative response to hypoxia to increase red blood cell production. Through the reversible inhibition of HIF-PH, roxadustat stimulates a coordinated erythropoietic response that includes the increase of plasma endogenous erythropoietin (EPO) levels, regulation of iron transporter proteins and reduction of hepcidin (an iron regulator protein that is increased during inflammation in CKD). This results in improved iron bioavailability, increased Hb production and increased red cell mass.

Film coated tablet

• Evrenzo 20 mg (Astellas Pharma) originator
• Evrenzo 50 mg (Astellas Pharma) originator
• Evrenzo 70 mg (Astellas Pharma) originator
• Evrenzo 100 mg (Astellas Pharma) originator
• Evrenzo 150 mg (Astellas Pharma) originator