Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: Astellas Pharma Europe B.V., Sylviusweg 62, 2333 BE Leiden, The Netherlands
Evrenzo is indicated for treatment of adult patients with symptomatic anaemia associated with chronic kidney disease (CKD).
Treatment with roxadustat should be initiated by a physician experienced in the management of anaemia. All other causes of anaemia should be evaluated prior to initiating therapy with Evrenzo, and when deciding to increase the dose.
Anaemia symptoms and sequelae may vary with age, gender, and overall burden of disease; a physician’s evaluation of the individual patient’s clinical course and condition is necessary. In addition to the presence of symptoms of anaemia, criteria such as rate of fall of haemoglobin (Hb) concentration, prior response to iron therapy, and the risk of need of red blood cell (RBC) transfusion could be of relevance in the evaluation of the individual patient’s clinical course and condition.
The appropriate dose of roxadustat must be taken orally three times per week and not on consecutive days.
The dose should be individualised to achieve and maintain target Hb levels of 10 to 12 g/dL as described below.
Roxadustat treatment should not be continued beyond 24 weeks of therapy if a clinically meaningful increase in Hb levels is not achieved. Alternative explanations for an inadequate response should be sought and treated before re-starting Evrenzo.
Adequate iron stores should be ensured prior to initiating treatment.
For patients initiating anaemia treatment not previously treated with ESA the recommended starting dose of roxadustat is 70 mg three times per week in patients weighing less than 100 kg and 100 mg three times per week in patients weighing 100 kg and over.
Patients currently treated with an ESA can be converted to roxadustat, however, conversion of dialysis patients otherwise stable on ESA treatment is only to be considered when there is a valid clinical reason (see sections 4.4 and 5.1).
Conversion of non-dialysis patients otherwise stable on ESA treatment has not been investigated. A decision to treat these patients with roxadustat should be based on a benefit-risk consideration for the individual patient.
The recommended starting dose of roxadustat is based on the average prescribed ESA dose in the 4 weeks before conversion (see Table 1). The first roxadustat dose should replace the next scheduled dose of the current ESA.
Table 1. Starting doses of roxadustat to be taken three times per week in patients converting from an ESA:
| Darbepoetin alfa intravenous or subcutaneous dose (micrograms/week) | Epoetin intravenous or subcutaneous dose (IU/week) | Methoxy polyethylene glycol-epoetin beta intravenous or subcutaneous dose (micrograms/monthly) | Roxadustat dose (milligrams three times per week) |
|---|---|---|---|
| Less than 25 | Less than 5000 | Less than 80 | 70 |
| 25 to less than 40 | 5000 up to 8000 | 80 up to and including 120 | 100 |
| 40 up to and including 80 | More than 8000 up to and including 16000 | More than 120 up to and including 200 | 150 |
| More than 80 | More than 16000 | More than 200 | 200 |
ESA: erythropoiesis-stimulating agent
The individualised maintenance dose ranges from 20 mg to 400 mg three times per week (see section maximum recommended dose). Hb levels should be monitored every two weeks until the desired Hb level of 10 to 12 g/dL is achieved and stabilised, and every 4 weeks thereafter, or as clinically indicated.
The dose of roxadustat can be adjusted stepwise up or down from the starting dose 4 weeks after treatment start, and every 4 weeks thereafter except if the Hb increases by more than 2 g/dL, in which case the dose should be reduced by one step immediately. When adjusting the dose of roxadustat, consider the current Hb level and the recent rate of change in Hb level over the past 4 weeks, and follow the dose adjustment steps according to the dose adjustment algorithm described in Table 2.
The stepwise dose adjustments up or down should follow the sequence of the available doses: 20 mg-40 mg-50 mg-70 mg-100 mg-150 mg-200 mg-250 mg-300 mg-400 mg (only for CKD patients on dialysis).
Table 2. Dose adjustment rules:
| Change in Hb over the previous 4 weeks1 | Current Hb level (g/dL) | |||
|---|---|---|---|---|
| Lower than 10.5 | 10.5 to 11.9 | 12.0 to 12.9 | 13.0 or higher | |
| Change in value of more than +1.0 g/dL | No change | Reduce dose by one step | Reduce dose by one step | Withhold dosing, monitor Hb level and resume dosing when Hb is less than 12.0 g/dL, at a dose that is reduced by two steps |
| Change in value between -1.0 and +1.0 g/dL | Increase dose by one step | No change | Reduce dose by one step | |
| Change in value of less than -1.0 g/dL | Increase dose by one step | Increase dose by one step | No change | |
The dose of roxadustat should not be adjusted more frequently than once every 4 weeks, except if Hb increases by more than 2 g/dL at any time within a 4-week period, in which case the dose should be reduced by one step immediately.
1 Change in haemoglobin (Hb) over the previous 4 weeks = (present Hb value) - (previous Hb value drawn 4 weeks ago).
If additional dose reduction is required for a patient already on the lowest dose (20 mg three times per week), do not reduce the 20 mg dose by breaking the tablet, but reduce the dose frequency to twice per week. If further dose reduction is needed, the dose frequency may be further reduced to once weekly.
After stabilisation to target Hb levels between 10 to 12 g/dL, the Hb levels should continue to be monitored regularly and the dose adjustment rules followed (see Table 2).
No specific dose adjustment is required for CKD patients who start dialysis while on treatment with roxadustat. Normal dose adjustment rules (see Table 2) should be followed.
When initiating or discontinuing concomitant treatment with strong inhibitors (e.g. gemfibrozil) or inducers (e.g. rifampicin) of CYP2C8, or inhibitors (e.g. probenecid) of UGT1A9: the Hb levels should be monitored routinely and the dose adjustment rules followed (see Table 2; see also sections 4.5 and 5.2).
Patients not on dialysis do not exceed a roxadustat dose of 3 mg/kg body weight or 300 mg three times per week, whichever is lower.
Patients on dialysis do not exceed a roxadustat dose of 3 mg/kg body weight or 400 mg three times per week, whichever is lower.
If a dose is missed, and there is more than 1 day until the next scheduled dose, the missed dose must be taken as soon as possible. If one day or less remains before the next scheduled dose, the missed dose must be skipped, and the next dose must be taken on the next scheduled day. In each case, the regular dosing schedule should be resumed thereafter.
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 dose when initiating treatment in patients with moderate hepatic impairment (Child-Pugh class B). Evrenzo is not recommended for use in patients with severe hepatic impairment (Child-Pugh class C) as the safety and efficacy has not been evaluated in this population (see sections 4.4 and 5.2).
Safety and efficacy of roxadustat in paediatric patients under 18 years of age have not been established. No data are available.
Evrenzo film-coated tablets are to be taken orally with or without food. Tablets are to be swallowed whole and not chewed, broken or crushed due to the absence of clinical data under these conditions, and to protect the light-sensitive tablet core from photodegradation.
The tablets should be taken at least 1 hour after administration of phosphate binders (except lanthanum) or other medicinal products containing multivalent cations such as calcium, iron, magnesium or aluminium (see sections 4.5 and 5.2).
Single supratherapeutic doses of roxadustat 5 mg/kg (up to 510 mg) in healthy subjects were associated with a transient increase in heart rate, an increased frequency of mild to moderate musculoskeletal pain, headaches, sinus tachycardia, and less commonly, low blood pressure, all these findings were non-serious. Roxadustat overdose can elevate Hb levels above the desired level (10-12 g/dL), which should be managed with discontinuation or reduction of roxadustat dosage (see section 4.2) and careful monitoring and treatment as clinically indicated. Roxadustat and its metabolites are not significantly removed by haemodialysis (see section 5.2).
4 years.
This medicinal product does not require any special storage conditions.
PVC/aluminium perforated unit dose blisters in a carton containing 12 × 1 film-coated tablets.
No special requirements for disposal.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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