Contraindications, special warnings and precautions for use

Contraindications

OROXAT is contraindicated in the following conditions:

• Hypersensitivity to the active substance, peanut, soya or to any of the excipients
• Third trimester of pregnancy
• Breastfeeding

Special warnings and precautions for use

Cardiovascular and mortality risk

Overall, the cardiovascular and mortality risk for treatment with OROXAT has been estimated to be comparable to the cardiovascular and mortality risk for ESA therapy based on data from direct comparison of both therapies (see SmPC section 5.1). Since, for patients with anaemia associated with CKD and not on dialysis, this risk could not be estimated with sufficient confidence versus placebo, a decision to treat these patients with OROXAT should be based on similar considerations that would be applied before treating with an ESA. Further, several contributing factors have been identified that may impose this risk, including treatment, non-responsiveness, and converting stable ESA treated dialysis patients (see SmPC sections 4.2 and 5.1).

In the case of non-responsiveness, treatment with OROXAT should not be continued beyond 24 weeks after the start of treatment (see SmPC section 4.2).

Conversion of dialysis patients otherwise stable on ESA treatment is only to be considered when there is a valid clinical reason (see SmPC section 4.2). Conversion of stable ESA treated patients with anaemia associated with CKD and not on dialysis was not studied. A decision to treat these patients with OROXAT should be based on a benefit risk consideration for the individual patient.

Thrombotic vascular events

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

Vascular access thrombosis (VAT) was reported as very common amongst patients with dialysis-dependent CKD (DD-CKD) in clinical studies (see SmPC section 4.8).

In patients with DD-CKD, rates of VAT in OROXAT-treated patients were highest in the first 12 weeks following initiation of treatment, at Hb values more than 12 g/dL and in the setting of a Hb rise of more than 2 g/dL over 4 weeks. It is recommended to monitor Hb levels and adjust the dose using the dose adjustment rules (see SmPC Table 2) to avoid Hb levels of more than 12 g/dL and Hb rise of more than 2 g/dL over 4 weeks.

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

Seizures

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

Serious infections

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

Sepsis

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

Secondary hypothyroidism

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

Inadequate response to therapy

Inadequate response to therapy with OROXAT should prompt a search for causative factors. Nutrient deficiencies should be corrected. lntercurrent infections, occult blood loss, haemolysis, severe aluminium toxicity, underlying haematologic diseases or bone marrow fibrosis may also compromise the erythropoietic response. A reticulocyte count shouId be considered as part of the evaluation. If typical causes of non-response are excluded, and the patient has reticulocytopenia, an examination of the bone marrow should be considered. In the absence of an addressable cause for an inadequate response to therapy, OROXAT should not be continued beyond 24 weeks of therapy.

Hepatic impairment

Caution is warranted when OROXAT is administered to patients with moderate hepatic impairment (Child-Pugh class B). OROXAT is not recommended for use in patients with severe hepatic impairment (Child-Pugh class C) (see SmPC section 5.2).

Pregnancy and contraception

OROXAT should not be initiated in women planning on becoming pregnant, during pregnancy or when anaemia associated with CKD is diagnosed during pregnancy. In such cases, alternative therapy should be started, if appropriate. If pregnancy occurs while OROXAT is being administered, treatment should be discontinued and alternative treatment started, if appropriate. Women of chiId bearing potential must use highly effective contraception during treatment and for at least one week after the last dose of OROXAT (see SmPC sections 4.3, 4.6).

Misuse

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

Excipients

OROXAT contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. OROXAT contains Allura Red AC aluminium lake (see SmPC section 6.1) which may cause allergic reactions. OROXAT contains traces of soya lecithin. Patients who are allergic to peanut or soya, should not use this medicinal product.

CKD, chronic kidney disease; CNS, central nervous system; DD, dialysis-dependent; DVT, deep vein thrombosis; ESA, erythropoiesis-stimulating agent; Hb, haemoglobin; PE, pulmonary embolism; TVE, thrombolic vascular events; VAT, vascular access thrombosis.

The cardiovascular safety of OROXAT was assessed in a meta-analysis of adjudicated major adverse cardiovascular events

ACM: all-cause mortality

MACE: a composite of ACM, non-fatal myocardial infarction (MI) and stroke

MACE+: a composite of ACM, non-fatal MI, stroke, and hospitalisation for either unstable angina or congestive heart failure

ACM, all-cause mortality; CKD, chronic kidney disease; CV, cardiovascular; ESA, erythropoiesis-stimulating agent; MI, myocardial infarction.

No increase in CV or mortality risk with OROXAT compared with ESA in patients with NDD- and IDD-CKD (OT)*

HR OROXAT vs ESA (95% CI)

ACM: all-cause mortality

MACE: a composite of ACM, non-fatal myocardial infarction (MI) and stroke

MACE+: a composite of ACM, non-fatal MI, stroke, and hospitalisation for either unstable angina or congestive heart failure

For patients with anaemia associated with CKD and not on dialysis, this risk could not be estimated with sufficient confidence versus placebo, so a decision to treat these patients with roxadustat should be based on similar considerations that would be applied before treating with an ESA.

NDD and IDD pool compared with ESA

Baseline characteristics and treatment discontinuation rates were comparable between the pooled OROXAT and pooled ESA patients. The on-treatment analyses support no evidence of increased cardiovascular safety or mortality risk with OROXAT compared with ESA in patients with symptomatic anaemia associated with NDD-CKD or IDD-CKD.

ACM, all-cause mortality; Cl, confidence interval; CKD, chronic kidney disease; ESA, erythropoiesis-stimulating agent; Hb, haemoglobin; HR, hazard ratio; IDD, incident-dialysis-dependent; IR, incidence rate (number of patients with event/100 patient years); MACE, time to first occurrence of death, myocardial infarction or stroke; MACE+, time to first occurrence of death, myocardial infarction, stroke, and hospitalisation for either unstable angina and/or congestive heart failure; NDD, non-dialysis-dependent; OT, on-treatment.

*Please see OROXAT SmPC for further information on CV and mortality risk.

Data for patients converting from ESA in stable dialysis should be interpreted with caution due to an inherent risk in switching to a new treatment (OT)*

Conversion of dialysis patients otherwise stable on ESA treatment is only to be considered when there is a valid clinical reason.

HR OROXAT vs ESA (95% CI)

ACM: all-cause mortality

MACE: a composite of ACM, non-fatal myocardial infarction (MI) and stroke

MACE+: a composite of ACM, non-fatal MI, stroke, and hospitalisation for either unstable angina or congestive heart failure

SDD pool in an ESA conversion setting (OT analysis)

Patients allocated to OROXAT were switched from an ESA at the start of the study. The inherent risk in switching to any new treatment vs. remaining on a treatment with a stabilised Hb may confound the observed results. Therefore, any comparison of treatment effect estimates cannot be reliably established.

ACM, all-cause mortality; Cl, confidence interval; ESA, erythropoiesis-stimulating agent; Hb, haemoglobin; HR, hazard ratio; IR, incidence rate (number of patients with event/100 patient years); MACE, time to first occurrence of death, myocardial infarction or stroke; MACE+, time to first occurrence of death, myocardial infarction, stroke, and hospitalisation for either unstable angina and/or congestive heart failure; OT, on-treatment; SDD, stable-dialysis-dependent.

*Please see OROXAT SmPC for further information on CV and mortality risk.

Initial Hb monitoring requirements for OROXAT are similar to other treatments for symptomatic anaemia associated with CKD

Increasing Hb levels with anaemia of CKD treatments can be associated with an increased risk of adverse events:

• Rapid rises in Hb e.g. >2 g/dL over 4 weeks, or very high Hb levels (>12 g/dL) can be associated with an increased risk of thrombotic compIications9
• For patients started on OROXAT, Hb levels should be monitored every 2 weeks until the target Hb level of 10-12 g/dL is achieved and stabilised, and every 4 weeks thereafter or as clinically indicated1

With OROXAT, the dose can be individualised to achieve and maintain target levels of 10-12 g/dL.

CKD, chronic kidney disease; Hb, haemoglobin.