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 healthy subjects increased roxadustat AUC by 2.3-fold and C_max by 1.4-fold. Monitor Hb levels when initiating or discontinuing concomitant treatment with gemfibrozil, probenecid, other strong inhibitors or inducers of CYP2C8 or other strong inhibitors of UGT1A9. Adjust the dose of roxadustat following dose adjustment rules based on Hb monitoring.

Roxadustat is an inhibitor of BCRP and OATP1B1. These transporters play an important role in the intestinal and hepatic uptake and efflux of statins. Co-administration of 200 mg of roxadustat with simvastatin in healthy subjects increased the AUC and C_max of simvastatin 1.8- and 1.9-fold, respectively, and the AUC and C_max of simvastatin acid (the active metabolite of simvastatin) 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. Co-administration of 200 mg of roxadustat with rosuvastatin increased the AUC and C_max of rosuvastatin 2.9- and 4.5-fold, respectively. Co-administration of 200 mg of roxadustat with atorvastatin increased the AUC and C_max of atorvastatin 2.0- and 1.3-fold, respectively.

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

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

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).

Roxadustat 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.

It is not recommended to combine administration of roxadustat and erythropoiesis stimulating agents (ESAs) as the combination has not been studied.

Co-administration of roxadustat with phosphate binders sevelamer carbonate or calcium acetate in healthy subjects decreased roxadustat AUC by 67% and 46% and C_max by 66% and 52%, respectively. Roxadustat may form a chelate with multivalent cations such as in phosphate binders or other products containing calcium, iron, magnesium or aluminium. Staggered administration of phosphate binders (at least 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 medicinal products or supplements containing multivalent cations. This restriction does not apply to lanthanum carbonate, as the co-administration of roxadustat with lanthanum carbonate did not result in a clinically meaningful change in the plasma exposure of roxadustat.

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.

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.

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 breast-feeding.

Fertility

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.

Roxadustat has minor influence on the ability to drive and use machines. Seizures have been reported during treatment with roxadustat. Therefore, caution should be exercised when driving or using machines.

Summary of the safety profile

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

Tabulated list of adverse reactions

Adverse reactions observed during clinical studies are listed in this 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).

¹ This adverse reaction is associated with CKD patients who were on dialysis while receiving roxadustat.

Description of selected adverse reactions

Thrombotic vascular events

In CKD patients not on dialysis, DVT events 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 CKD patients on dialysis, DVT 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 patients with events per 100 patient years of exposure) in the ESA group.

In CKD patients not on dialysis, 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 patients with events per 100 patient years of exposure) in the placebo group. In CKD patients on dialysis, 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.

In CKD patients on dialysis, 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.

Seizures

In CKD patients not on dialysis, 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.

In CKD patients on dialysis, 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.

Sepsis

In CKD patients not on dialysis, 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 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.