Evrenzo Adverse Reactions

Adverse Reactions from Clinical Trials: This monograph summarizes the adverse reactions potentially associated with roxadustat observed in clinical trials and their approximate incidence rates. Because clinical trials are conducted under a wide variety of conditions, the incidence rates of adverse reactions observed in a drug clinical trial cannot be directly compared to those observed in another drug clinical trial and may not reflect the actual incidence rates observed in clinical practice.
Summary of Safety Data: In China, safety data were obtained from two Phase 2 clinical trials and two Phase 3 clinical trials: including one Phase 2 study FGCL-4592-047 (N=91) involving NDD CKD patients with anemia, one Phase 2 study FGCL-4592-048 (N=96) involving DD CKD patient with anemia, one Phase 3 study FGCL-4592-808 (N=154) involving NDD CKD patients with anemia, and one Phase 3 study FGCL-4592-806 (N=305) involving DD CKD patients with anemia. In these clinical trials, a total of 554 subjects were treated with roxadustat, 229 subjects received the drug for > 6 months and 102 subjects for ≥ 1 year. The dose ranged from 1.2-2.5 mg/kg (50-180 mg) TIW in the Phase 2 studies and from 1.2-2.5 mg/kg (20-200 mg) TIW in the Phase 3 studies.
In the global development program of roxadustat, including studies conducted in China, a total of 947 healthy subjects and 12,386 chronic kidney disease patients with anemia were received the study drug. Among the healthy subjects, 863 received roxadustat and 84 received placebo; among the CKD patients with anemia, there were 5,994 NDD patients with anemia and 6,392 DD patients with anemia. Of these, 7,227 patients received roxadustat, while the remaining 5,159 patients received either active comparators (i.e., epoetin alfa, darbepoetin) or placebo.
Adverse Reactions in the Clinical Trials in China: DD CKD patients with anemia: FGCL-4592-806 was a randomized, open-label, active-controlled (epoetin alfa) Phase 3 study evaluating the efficacy and safety of roxadustat for treatment of anemia in patients with dialysis dependent CKD. Patients were randomized in a 2:1 ratio to receive treatment with either oral roxadustat or epoetin alfa. The study included a 26-week initial treatment period followed by a 26-week extension treatment period (for subjects randomized to the roxadustat group only). Table 8 lists the adverse reactions reported during the 26-week initial treatment period of FGCL-4592-806 with an incidence rate of ≥ 1% and severity grade of ≥ 3 (adverse events are coded by MedDRA 19.1 and listed by System Organ Class and Preferred Term). The incidence rate of adverse events related to roxadustat was relatively low (< 5%), with most events being of Grades 1-2. These adverse events were consistent with the known complications in CKD patients. (See Table 8.)

Click on icon to see table/diagram/image

Of the 111 subjects participated in the extension treatment period (Weeks 27-52) of Study FGCL-4592-806, there were 4 cases of hypertension (3.6%) with adverse reaction incidence rates of ≥ 1%, which were similar to those observed during the 26-week initial treatment period.
NDD CKD patients with anemia: FGCL-4592-808 was a randomized, multicenter, double-blind, placebo-controlled study conducted in the NDD CKD patient with anemia. Patients were randomized in a 2:1 ratio to receive either roxadustat or placebo treatment. The study included a 26-week initial treatment period followed by a 26-week extension treatment period. The initial treatment period comprised an 8-week double-blind treatment period followed by an 18-week open-label treatment period. Table 9 lists all adverse reactions with the reported incidence rates of ≥ 1% (adverse events are coded by MedDRA 19.1 and listed by System Organ Class and Preferred Term) during the double-blind, placebo-controlled 8-week treatment period of Study FGCL-4592-808. (See Table 9.)

Click on icon to see table/diagram/image

A total of 131 patients (roxadustat group: N=87, placebo group: N=44) entered the open-label initial treatment period to receive roxadustat treatment. During the Week 9-27 initial treatment period of Study FGCL-4592-808, adverse reactions with the reported incidence rate of ≥ 1% included 4 (3.1%) cases of ALT elevation and 2 (1.6%) cases of AST elevation. Adverse reactions with a reported incidence rate of < 1% but with severity of ≥ 3 included cold sweat, hypertension, cerebellar infarction, and blood pressure increased, with each occurring in 1 (0.8%) case. The adverse reactions reported during the 52-week extension treatment period of the study were similar to those observed in the initial treatment period.
Cardiovascular Adverse Events in Completed Trials in China: Erythropoiesis stimulating agents (ESAs) have been reported to potentially increase the risk of cardiovascular events in CKD patients. This section describes cardiovascular adverse events observed in roxadustat clinical trials. The cardiovascular adverse events include myocardial infarction, cardiac failure, cerebrovascular accidents, thrombosis, and severe hypertension, as reported in the study.
Two randomized clinical trials have been conducted with subjects on dialysis. In the Phase 2 Study FGCL-4592-048, 74 subjects received roxadustat treatment; in the Phase 3 Study FGCL-4592-806, 204 subjects received 6 months of initial treatment with roxadustat, with 111 of these subjects continuing treatment for up to 1 year. Two randomized clinical trials have been conducted with subjects not on dialysis. In the Phase 2 Study FGCL-4592-047, 61 subjects received roxadustat treatment, and in the Phase 3 Study FGCL-4592-808, 128 subjects received 6 months of roxadustat treatment. The incidence rates of cardiovascular events in these clinical trials are listed in Table 10. (See Table 10.)

Click on icon to see table/diagram/image

Adverse Reactions from Global Pivotal Phase 3 Clinical Trials and Post-marketing Experience: In the roxadustat global CKD Anemia development program, a total of 6 pivotal Phase 3 studies have been completed, including 3 studies comparing roxadustat with placebo in NDD CKD patients with anemia (FGCL-4592-060/ANDES, 1517-CL-0608/ALPS, and D5740C00001/OLYMPUS) and 3 studies comparing roxadustat with epoetin alfa in DD CKD patients with anemia (FGCL 4592-063/HIMALAYAS, FGCL-4592-064/SIERRAS, D5740C00002/ROCKIES). These 6 Phase 3 clinical trials included 8150 patients with CKD, of whom 4326 received roxadustat (7185.9 patient exposure years, PEY), 1940 received epoetin alfa (3743.6 PEY), and 1884 received placebo (2323.2 PEY).
DD CKD patients with anemia: Adverse reactions were determined based on pooled data from 3 randomized open-label active-controlled studies (FGCL-4592-063, FGCL-4592-064, D5740C00002), involving 3880 patients. Of these, 1940 patients were treated with roxadustat and 1940 patients were treated with epoetin alfa. The mean duration of exposure for patients receiving roxadustat was 1.71 years, with 63% of patients exposed for > 1 year and 43% of patients exposed for > 2 years. For patients receiving epoetin alfa, the mean duration of exposure was 1.93 years, with 71% of patients exposed for > 1 year and 52% of patients exposed for > 2 years.
In a subgroup analysis of 1526 DD patients who started dialysis within 4 months before receiving their first dose of either roxadustat (N=760) or epoetin alfa (N=766) (incident dialysis [ID] patients), the mean duration of exposure to roxadustat was 1.45 years, with 51% of patients exposed for more than 1 year and 30% of patients exposed for more than 2 years. The mean duration of exposure to epoetin alfa was 1.55 years, with 54% of patients exposed for > 1 year and 34% of patients exposed for > 2 years. The incidence of adverse reactions reported in this subgroup was consistent with that observed in the overall DD patients.
NDD CKD patients with anemia: Adverse reactions were determined based on pooled data from 3 randomized double-blind placebo-controlled studies (FGCL-4592-060, 1517-CL-0608, D5740C00001), including 4270 patients.
Among these, 2386 patients were treated with roxadustat and 1884 patients were treated with placebo. The mean duration of exposure for patients receiving roxadustat was 1.62 years, with 71% of patients exposed for > 1 year and 34% of patients exposed for > 2 years. For the placebo group, the mean duration of exposure was 1.23 years, with 53% of patients exposed for > 1 year and 21% of patients exposed for > 2 years.
Adverse Reactions: Adverse Drug Reactions are listed by MedDRA System Organ Class (SOC) and frequency, as detailed in Table 11. 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), and not known (cannot be estimated from the available data). (See Table 11.)

Click on icon to see table/diagram/image

Description of Selected Adverse Reactions: Skin Reactions: Dermatitis exfoliative generalized, part of severe cutaneous adverse reactions (SCARs), has been reported during post-marketing surveillance and has shown an association with roxadustat treatment (frequency not known).