Nexlizet Adverse Reactions

Summary of the safety profile: The most commonly reported adverse reactions in Nexlizet were hyperuricaemia (4.7%) and constipation (4.7%).
In placebo-controlled phase 3 primary hyperlipidaemia studies (N=3,621) with bempedoic acid, more patients on bempedoic acid compared to placebo discontinued treatment due to muscle spasms (0.7% versus 0.3%), diarrhoea (0.5% versus < 0.1%), pain in extremity (0.4% versus 0), and nausea (0.3% versus 0.2%) although differences between bempedoic acid and placebo were not significant. The safety profile in the cardiovascular outcomes study (CLEAR Outcomes) with bempedoic acid; (N=13,965) was consistent with the overall safety profile described in the phase 3 primary hyperlipidaemia studies.
Tabulated list of adverse reactions: Adverse reactions reported with Nexlizet are displayed by system organ class and frequency in Table 4. Any additional adverse reactions that have been reported with bempedoic acid (based on incidence rates from phase 3 primary hyperlipidaemia studies and exposure adjusted incidence rates from CLEAR Outcomes study), or ezetimibe have also been presented to provide a more comprehensive adverse reaction profile for Nexlizet.
Frequencies are defined as: 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 4.)

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Description of selected adverse reactions: Increased serum uric acid: Nexlizet increases serum uric acid possibly due to inhibition of renal tubular OAT2 by bempedoic acid (see Interactions). A mean increase of 35.7 micromole/L (0.6 mg/dL) in uric acid compared to baseline was observed with Nexlizet at week 12. The elevations in serum uric acid usually occurred within the first 4 weeks of treatment and returned to baseline following discontinuation of treatment. There were no reports of gout with Nexlizet. In the phase 3 primary hyperlipidaemia studies of bempedoic acid, gout was reported in 1.4% of patients treated with bempedoic acid and 0.4% of patients treated with placebo. In both treatment groups, patients who reported gout were more likely to have a medical history of gout and/or baseline levels of uric acid above the ULN (see Precautions).
Effects on serum creatinine and blood urea nitrogen: Nexlizet increases serum creatinine and blood urea nitrogen (BUN). A mean increase of 1.8 micromole/L (0.02 mg/dL) in serum creatinine and a mean increase of 1.0 mmol/L (2.7 mg/dL) in BUN compared to baseline was observed with Nexlizet at week 12. The elevations in serum creatinine and BUN usually occurred within the first 4 weeks of treatment, remained stable, and returned to baseline following discontinuation of therapy. Similar mean increases in serum creatinine (5.8 micromole/L (0.066 mg/dL)) and BUN (0.82 mmol/L (2.3 mg/dL)) were observed with bempedoic acid in the CLEAR Outcomes study.
The observed elevations in serum creatinine may be associated with bempedoic acid inhibition of OAT2-dependent renal tubular secretion of creatinine (see Interactions), representing a drug-endogenous substrate interaction, and does not appear to indicate worsening renal function. This effect should be considered when interpreting changes in estimated creatinine clearance in patients on Nexlizet therapy, particularly in patients with medical conditions or receiving medicinal products that require monitoring of estimated creatinine clearance.
Hepatic enzyme elevations: Hepatic transaminase (AST and/or ALT) elevations of ≥3x ULN were reported in 2.4% of patients treated with Nexlizet compared with no patients on placebo. In four phase 3 primary hyperlipidaemia studies of bempedoic acid, the incidence of elevations (≥3× ULN) in hepatic transaminase levels (AST and/or ALT) was 0.7% for patients treated with bempedoic acid and 0.3% for placebo. In controlled clinical combination trials of ezetimibe initiated concurrently with a statin, the incidence of consecutive elevations (≥3× ULN) in hepatic transaminase levels was 1.3% for patients treated with ezetimibe administered with statins and 0.4% for patients treated with statins alone. In the CLEAR Outcomes study, the incidence of elevations >3× ULN in hepatic transaminase levels also occurred more frequently in bempedoic acid-treated patients (1.6%) than in placebo-treated patients (1.0%). The elevations in transaminases with bempedoic acid or ezetimibe were not associated with other evidence of liver dysfunction (see Precautions).
Decreased haemoglobin: In the phase 3 primary hyperlipidaemia studies of bempedoic acid, a decrease in haemoglobin from baseline of ≥20 g/L and <lower limit of normal (LLN) was observed in 4.6% of patients in the bempedoic acid group compared with 1.9% of patients on placebo. Greater than 50 g/L and <LLN decreases in haemoglobin were reported at similar rates in bempedoic acid and placebo groups (0.2% versus 0.2%, respectively). The decreases in haemoglobin usually occurred within the first 4 weeks of treatment and returned to baseline following discontinuation of treatment. Among patients who had normal haemoglobin values at baseline, 1.4% in the bempedoic acid group and 0.4% in the placebo group experienced haemoglobin values below LLN while on treatment. In the phase 3 primary hyperlipidaemia studies, anaemia was reported in 2.5% of patients treated with bempedoic acid and 1.6% of patients treated with placebo. In the CLEAR Outcomes study, similar decreases in haemoglobin were observed, and anaemia was also reported more frequently in bempedoic acid-treated patients (4.7%) compared to placebo-treated patients (3.9%).