Chemical formula: C₁₉H₃₆O₅ Molecular mass: 344.492 g/mol PubChem compound: 10472693
Discontinue bempedoic acid when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus.
There are no available data on bempedoic acid use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, bempedoic acid was not teratogenic in rats and rabbits when administered at doses resulting in exposures up to 11 and 12 times, respectively, the human exposures at the maximum clinical dose, based on AUC. Bempedoic acid decreases cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol; therefore, bempedoic acid may cause fetal harm when administered to pregnant women based on the mechanism of action. In addition, treatment of hyperlipidemia is not generally necessary during pregnancy. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hyperlipidemia for most patients.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Bempedoic acid was not teratogenic when given orally at doses of 60 and 80 mg/kg/day, resulting in 11 and 12 times the systemic exposure in humans at the maximum recommended human dose (MRHD) of 180 mg to pregnant rats and rabbits, respectively. In an embryofetal development study in rats, bempedoic acid was given orally to pregnant rats at 10, 30, and 60 mg/kg/day during the period of organogenesis from gestation day 6 to 17. There were increases in the incidence of non-adverse fetal skeletal variations (bent long bones and bent scapula and incomplete ossification) at doses ≥10 mg/kg/day (less than the clinical exposure) in the absence of maternal toxicity. At maternally toxic doses, bempedoic acid caused decreases in the numbers of viable fetuses, increases in post-implantation loss, and increased total resorptions at 60 mg/kg/day (11 times MRHD) and reduced fetal body weight at ≥30 mg/kg/day (4 times the MRHD). No adverse development effects were observed when bempedoic acid was given to pregnant rabbits during the period of organogenesis (gestation day 6 to 18) at doses up to 80 mg/kg/day (12 times MRHD).
In a pre- and post-natal development study in pregnant rats given oral doses of bempedoic acid at 5, 10, 20, 30 and 60 mg/kg/day throughout pregnancy and lactation (gestation day 6 to lactation day 20), there were adverse effects on delivery in the presence of maternal toxicity, including: increases in stillborn pups, reductions in numbers of live pups, pup survival, pup growth and slight delays in learning and memory at ≥10 mg/kg/day (at exposures equivalent to the MRHD).
There is no information regarding the presence of bempedoic acid in human or animal milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Bempedoic acid decreases cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol and may cause harm to the breastfed infant. Because of the potential for serious adverse reactions in a breastfed infant, based on the mechanism of action, advise patients that breastfeeding is not recommended during treatment with bempedoic acid.
Bempedoic acid was negative for mutagenicity in an in vitro Ames assay and negative for clastogenicity in the vitro human lymphocyte chromosome aberration assay. Bempedoic acid was negative in both in vivo mouse micronucleus and in vivo rat bone marrow micronucleus/liver comet assay. In a 2-year rat carcinogenicity study, Wistar rats were given oral doses of bempedoic acid at 3, 10 and 30 mg/kg/day. An increased incidence of liver hepatocellular adenomas and hepatocellular adenomas combined with carcinomas, thyroid gland follicular cell adenoma and follicular cell adenomas combined with carcinomas, and pancreatic islet cell adenomas combined with carcinomas were observed in male rats at the dose of 30 mg/kg/day (exposure equivalent to the maximum recommended human dose (MRHD), based on AUC). In a 2-year mice carcinogenicity study, CD-1 mice were given oral doses of bempedoic acid at 25, 75 and 150 mg/kg/day. Bempedoic acid-related increases in the incidence of liver hepatocellular adenomas, hepatocellular carcinomas and hepatocellular adenomas combined with carcinomas in male mice were observed at 75 and 150 mg/kg/day (exposures equivalent to the MRHD). Observations of liver and thyroid tumors are consistent with PPAR alpha agonism in rodents. The human relevance of pancreatic islet cell tumor findings is unknown.
In fertility and early embryofetal development study in rats, bempedoic acid was given orally to male and female rats at 10, 30 and 60 mg/kg/day. Males were dosed for 28 days prior to mating and females were dosed 14 days prior to mating through gestation day 7. No adverse effects on fertility were observed in females in the absence of maternal toxicity. No effects were observed on male fertility outcomes, but decreases in sperm counts were observed at 60 mg/kg/day (9 times the MRHD).
Clinically significant adverse reactions:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The data described below reflect exposure to bempedoic acid in two placebo-controlled trials that included 2009 patients treated with bempedoic acid for 52 weeks (median treatment duration of 52 weeks). The mean age for bempedoic acid-treated patients was 65.4 years, 29% were women, 3% were Hispanic, 95% White, 3% Black, 1% Asian, and 1% other races. All patients received bempedoic acid 180 mg orally once daily plus maximally tolerated statin therapy alone or in combination with other lipid-lowering therapies. At baseline, 97% of patients had clinical atherosclerotic cardiovascular disease (ASCVD) and about 4% had a diagnosis of heterozygous familial hypercholesterolemia (HeFH). Patients on simvastatin 40 mg/day or higher were excluded from the trials.
Adverse reactions led to discontinuation of treatment in 11% of bempedoic acid-treated patients and 8% of placebo-treated patients. The most common reasons for bempedoic acid treatment discontinuation were muscle spasms (0.5% versus 0.3% placebo), diarrhea (0.4% versus 0.1% placebo), and pain in extremity (0.3% versus 0.0% placebo). Adverse reactions reported in at least 2% of bempedoic acid-treated patients and more frequently than in placebo-treated patients are shown in Table 1.
Table 1. Adverse Reactions (≥2% and Greater than placebo) in Bempedoic acid-Treated Patients with ASCVD and HeFH (Studies 1 and 2):
| Adverse Reaction | Bempedoic acid + Statin and ± Other Lipid Lowering Therapies (N=2009) % | Placebo (N=999) % |
|---|---|---|
| Upper respiratory tract infection | 4.5 | 4.0 |
| Muscle spasms | 3.6 | 2.3 |
| Hyperuricemia* | 3.5 | 1.1 |
| Back pain | 3.3 | 2.2 |
| Abdominal pain or discomfort† | 3.1 | 2.2 |
| Bronchitis | 3.0 | 2.5 |
| Pain in extremity | 3.0 | 1.7 |
| Anemia | 2.8 | 1.9 |
| Elevated liver enzymes‡ | 2.1 | 0.8 |
* Hyperuricemia includes hyperuricemia and blood uric acid increased.
† Abdominal pain or discomfort includes abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort.
‡ Elevated liver enzymes includes AST increased, ALT increased, hepatic enzyme increased, and liver function test increased.
Bempedoic acid was associated with an increased risk of tendon rupture, occurring in 0.5% of bempedoic acid-treated patients versus 0% of placebo-treated patients.
Bempedoic acid was associated with an increased risk of gout, occurring in 1.5% of bempedoic acid-treated patients versus 0.4% of placebo-treated patients.
Bempedoic acid was associated with an increased risk of benign prostatic hyperplasia (BPH) or prostatomegaly in men with no reported history of BPH, occurring in 1.3% of bempedoic acid-treated patients versus 0.1% of placebo-treated patients. The clinical significance is unknown.
Bempedoic acid was associated with an imbalance in atrial fibrillation, occurring in 1.7% of bempedoic acid-treated patients versus 1.1% of placebo-treated patients.
Bempedoic acid was associated with persistent changes in multiple laboratory tests within the first 4 weeks of treatment. Laboratory test values returned to baseline following discontinuation of treatment.
Overall, there was a mean increase in serum creatinine of 0.05 mg/dL compared to baseline with bempedoic acid at Week 12. Approximately 3.8% of patients treated with bempedoic acid had blood urea nitrogen values that doubled (versus 1.5% placebo), and about 2.2% of patients had creatinine values that increased by 0.5 mg/dL (versus 1.1% placebo).
Approximately 5.1% of patients (versus 2.3% placebo) had decreases in hemoglobin levels of 2 or more g/dL and below the lower limit of normal on one or more occasion. Anemia was reported in 2.8% of patients treated with bempedoic acid and 1.9% of patients treated with placebo. Hemoglobin decrease was generally asymptomatic and did not require medical intervention. Decreased leukocyte count was also observed. Approximately 9.0% of bempedoic acid-treated patients with normal baseline leukocyte count had a decrease to less than the lower limit of normal on one or more occasion (versus 6.7% placebo). Leukocyte decrease was generally asymptomatic and did not require medical intervention. In clinical trials, there was a small imbalance in skin or soft tissue infections, including cellulitis (0.8% versus 0.4%), but there was no imbalance in other infections.
Approximately 10.1% of patients (versus 4.7% placebo) had increases in platelet counts of 100× 10 9/L or more on one or more occasion. Platelet count increase was asymptomatic, did not result in increased risk for thromboembolic events, and did not require medical intervention.
Increases in hepatic transaminases (AST and/or ALT) were observed with bempedoic acid. In most cases, the elevations were transient and resolved or improved with continued therapy or after discontinuation of therapy. Increases to more than 3× the upper limit of normal (ULN) in AST occurred in 1.4% of patients treated with bempedoic acid versus 0.4% of placebo patients, and increases to more than 5× ULN occurred in 0.4% of bempedoic acid-treated versus 0.2% of placebo-treated patients. Increases in ALT occurred with similar incidence between bempedoic acid- and placebo-treated patients. Elevations in transaminases were generally asymptomatic and not associated with elevations ≥2 × ULN in bilirubin or with cholestasis.
Approximately 1.0% of patients (versus 0.6% placebo) had elevations of CK levels of 5 or more times the normal value on one or more occasions, and 0.4% of patients (versus 0.2% placebo) had elevations of CK levels of 10 or more times.
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