Bempedoic acid

Bempedoic acid and its glucuronide weakly inhibit OATP1B1 and OATP1B3 at clinically relevant concentrations. Coadministration of bempedoic acid with medicinal products that are substrates of OATP1B1 or OATP1B3 (i.e., bosentan, fimasartan, asunaprevir, glecaprevir, grazoprevir, voxilaprevir, and statins such as atorvastatin, pravastatin, fluvastatin, pitavastatin, rosuvastatin, and simvastatin) may result in increased plasma concentrations of these medicinal products.

Bempedoic acid inhibits OAT2 in vitro, which may be the mechanism responsible for minor elevations in serum creatinine and uric acid. Inhibition of OAT2 by bempedoic acid may also potentially increase plasma concentrations of medicinal products that are substrates of OAT2. Bempedoic acid may also weakly inhibit OAT3 at clinically relevant concentrations.

There are limited data available in patients with severe renal impairment (defined as estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m²), and patients with end-stage renal disease (ESRD) on dialysis have not been studied. Additional monitoring for adverse reactions may be warranted in these patients when bempedoic acid is administered.

No data are available in patients with severe hepatic impairment (Child-Pugh C). Periodic liver function tests should be considered for patients with severe hepatic impairment.

Potential risk of myopathy with concomitant use of statins

Bempedoic acid increases plasma concentrations of statins. Patients receiving bempedoic acid as adjunctive therapy to a statin should be monitored for adverse reactions that are associated with the use of high doses of statins. Statins occasionally cause myopathy. In rare cases, myopathy may take the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and can lead to fatality. All patients receiving bempedoic acid in addition to a statin should be advised of the potential increased risk of myopathy and told to report promptly any unexplained muscle pain, tenderness, or weakness. If such symptoms occur while a patient is receiving treatment with bempedoic acid and a statin, a lower maximum dose of the same statin or an alternative statin, or discontinuation of bempedoic acid and initiation of an alternative lipid-lowering therapy should be considered under close monitoring of lipid levels and adverse reactions. If myopathy is confirmed by a creatine phosphokinase (CPK) level >10 × upper limit of normal (ULN), bempedoic acid and any statin that the patient is taking concomitantly should be immediately discontinued.

Myositis with a CPK level >10 × ULN was rarely reported with bempedoic acid and background simvastatin 40 mg therapy. Doses of simvastatin >40 mg should not be used with bempedoic acid.

The pharmacokinetic interactions between bempedoic acid 180 mg and simvastatin 40 mg, atorvastatin 80 mg, pravastatin 80 mg, and rosuvastatin 40 mg were evaluated in clinical trials. Administration of a single dose of simvastatin 40 mg with steady-state bempedoic acid 180 mg resulted in a 2-fold increase in simvastatin acid exposure. Elevations of 1.4-fold to 1.5-fold in AUC of atorvastatin, pravastatin, and rosuvastatin (administered as single doses) and/or their major metabolites were observed when coadministered with bempedoic acid 180 mg. Higher elevations have been observed when these statins were coadministered with a supratherapeutic 240 mg dose of bempedoic acid.

Bempedoic acid is contraindicated during pregnancy.

There are no or limited amount of data from the use of bempedoic acid in pregnant women. Studies in animals with bempedoic acid have shown reproductive toxicity.

Because bempedoic acid decreases cholesterol synthesis and possibly the synthesis of other cholesterol derivatives needed for normal foetal development, bempedoic acid may cause foetal harm when administered to pregnant women. Bempedoic acid should be discontinued prior to conception or as soon as pregnancy is recognized.

It is unknown whether bempedoic acid/metabolites are excreted in human milk. Because of the potential for serious adverse reactions, women taking bempedoic acid should not breast-feed their infants. Bempedoic acid is contraindicated during breast-feeding.

Women of childbearing potential

Women of childbearing potential should use effective contraception during treatment.

Fertility

No data on the effect of bempedoic acid on human fertility are available. Based on animal studies, no effect on reproduction or fertility is expected with bempedoic acid.

Bempedoic acid has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The safety profile of bempedoic acid has been studied in 4 placebo-controlled phase 3 primary hyperlipidaemia studies (N=3 621) including patients with hypercholesterolemia on maximum tolerated statin dose (2 studies; n=3 008) and patients on no or low dose statins (2 studies; n=613). The most commonly reported adverse reactions with bempedoic acid during pivotal trials were hyperuricaemia (3.8%), pain in extremity (3.1%), anaemia (2.5%), and gout (1.4%). 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; 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 bempedoic acid, based on incidence rates from phase 3 primary hyperlipidaemia studies and exposure adjusted incidence rates from CLEAR Outcomes study, are displayed by system organ class and frequency in the table below.

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).

Adverse reactions:

^a Hyperuricaemia includes hyperuricaemia and blood uric acid increased
^b (CLEAR Outcomes study) Weight decrease was observed only in patients with a baseline body mass index (BMI) of ≥30 kg/m², with a mean body weight reduction of -2.28 kg at month 36. Mean reduction in body weight was ≤0.5 kg in patients with a baseline BMI of 25 to <30 kg/m². Bempedoic acid was not associated with a mean change in body weight in patients with a baseline BMI of <25 kg/m².

Description of selected adverse reactions

Hepatic enzyme elevations

Increases in serum transaminases (AST and/or ALT) have been reported with bempedoic acid. In the phase 3 primary hyperlipidaemia studies, the incidence of elevations (≥3× ULN) in hepatic transaminase levels was 0.7% for patients treated with bempedoic acid and 0.3% for placebo. 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%). These elevations in transaminases were not associated with other evidence of liver dysfunction.

Increased serum uric acid

Increases in serum uric acid were observed in clinical trials with bempedoic acid possibly related to inhibition of renal tubular OAT2. In the phase 3 primary hyperlipidemia studies, a mean increase of 47.6 micromole/L (0.8 mg/dL) in uric acid compared to baseline was observed with bempedoic acid 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. In the phase 3 primary hyperlipidemia studies, gout was reported in 1.4% of patients treated with bempedoic acid and 0.4% of patients treated with placebo. In the CLEAR Outcomes study, a mean increase of 47.6 micromole/L (0.8 mg/dL) in uric acid compared to baseline was observed in bempedoic acidtreated patients at month 3, and gout was also reported more frequently in bempedoic acid-treated patients (3.1%) than placebo-treated patients (2.1%). 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.

Effects on serum creatinine and blood urea nitrogen

Bempedoic acid has been shown to increase serum creatinine and blood urea nitrogen (BUN). In the phase 3 primary hyperlipidemia studies, a mean increase of 4.4 micromole/L (0.05 mg/dL) in serum creatinine and a mean increase of 0.61 mmol/L (1.7 mg/dL) in BUN compared to baseline was observed with bempedoic acid 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 treatment. 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, representing a drugendogenous 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 bempedoic acid therapy, particularly in patients with medical conditions or receiving medicinal products that require monitoring of estimated creatinine clearance.

Decreased haemoglobin

Decreases in haemoglobin were observed in clinical trials with bempedoic acid. In the phase 3 primary hyperlipidaemia studies, 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 hyperlipidemia 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%).

Elderly population

Of the 3 621 patients treated with bempedoic acid in the phase 3 primary hyperlipidemia studies, 2 098 (58%) were >65 years old. In the CLEAR Outcomes study, 4 141 patients (59%) treated with bempedoic acid were ≥65 years of age and 1 066 patients (15%) treated with bempedoic acid were ≥75 years of age. No overall difference in safety was observed between elderly and the younger population.