DRUG INTERACTIONS

­ • Simvastatin:                                                                                                               Avoid concomitant use of NEXLETOL with simvastatin greater than 20 mg. 

• Pravastatin:                                                                                                                Avoid concomitant use of NEXLETOL with pravastatin greater than 40 mg. 

U.S. FDA APPROVED  DRUGS DURING 2020

Sr.No-  5

ADVERSE REACTIONS

­ Most common (incidence = 2% and greater than placebo) adverse reactions are upper respiratory tract infection, muscle spasms, hyperuricemia, back pain, abdominal pain or discomfort, bronchitis, pain in extremity, anemia, and elevated liver enzymes. 

• Tendon Rupture:                                                                                                 Tendon rupture has occurred. Discontinue NEXLETOL at the first sign of tendon rupture. Avoid NEXLETOL in patients who have a history of tendon disorders or tendon rupture. 

 PATIENT COUNSELING INFORMATION

Advise patients to read the FDA-approved patient labeling.

Risk of Hyperuricemia-                                                                                          Advise patients of the risk of elevated serum uric acid levels, including development of gout. Inform patients that serum uric acid levels may be monitored during treatment with NEXLETOL.

Patients with signs or symptoms of hyperuricemia should contact their healthcare provider if symptoms occur 

Risk of Tendon Rupture-                                                                                       Inform patients of the risk of tendon rupture.                                                           Advise patients to rest at the first sign of tendinitis or tendon rupture and to immediately contact their healthcare provider if tendinitis or tendon rupture symptoms occur 

Risk of Myopathy with Concomitant Use of Simvastatin or Pravastatin-                     Advise patients to notify their healthcare provider(s) if they are taking, or plan to take simvastatin or pravastatin.                                                                                          The risk of myopathy occurring with the use of simvastatin or pravastatin may be increased when taken with NEXLETOL. 

Pregnancy-                                                                                                               Advise pregnant women of the potential risk to a fetus based on NEXLETOL’s mechanism of action.                                                                                                Advise females to inform their healthcare provider of a known or suspected pregnancy 

Manufactured by: Piramal Healthcare UK Limited Northumberland NE61 3YA United Kingdom

Manufactured for: Esperion Therapeutics, Inc. 3891 Ranchero Drive, Suite 150 Ann Arbor, MI 48108

 CLINICAL PHARMACOLOGY

1. Mechanism of Action                                                                                       Bempedoic acid is an adenosine triphosphate-citrate lyase (ACL) inhibitor that lowers low-density lipoprotein cholesterol (LDL-C) by inhibition of cholesterol synthesis in the liver.

2. Pharmacodynamics-                                                                                 Administration of bempedoic acid in combination with maximally tolerated statins, with or without other lipid modifying agents, decreases LDL-C, non-high density lipoprotein cholesterol  (non-HDL-C), apolipoprotein B (apo B), and total cholesterol (TC) in patients with hyperlipidemia.

Cardiac Electrophysiology                                                                                           At a dose of 240 mg (1.3 times the approved recommended dose), bempedoic acid does not prolong the QT interval to any clinically relevant extent.

3. Pharmacokinetics-                                                                                        Bempedoic acid pharmacokinetic parameters are presented as the mean [standard deviation ± (SD)] unless otherwise specified.                                                               

The steady-state maximum plasma concentration (Cmax) and area under the curve (AUC) following multiple-dose administration of bempedoic acid at 180 mg/day were 20.6 ± 6.1 µg/mL and 289.0 ± 96.4 µg·h/mL, respectively.

Bempedoic acid steady-state pharmacokinetics were generally linear over a range of > 60 mg to 220 mg (approximately 33% to 122% of the recommended dosage of 180 mg daily). 

Absorption-                                                                                            Pharmacokinetic data indicate that bempedoic acid is absorbed with a median time to maximum concentration of 3.5 hours when administered as NEXLETOL 180 mg tablets.

Effect of Food-                                                                                             Concomitant food administration had no effect on the oral bioavailability of bempedoic acid.

Distribution-                                                                                                               The bempedoic acid apparent volume of distribution (V/F) was 18 L. Plasma protein binding of bempedoic acid, its glucuronide and its active metabolite, ESP15228, were 99.3%, 98.8% and 99.2%, respectively. Bempedoic acid does not partition into blood cells.

Elimination-                                                                                                                The steady-state clearance (CL/F) of bempedoic acid was 11.2 mL/min after once-daily dosing; renal clearance of unchanged bempedoic acid represented less than 2% of total clearance. The mean ± SD half-life for bempedoic acid in humans was 21 ± 11 hours at steady-state.

Metabolism-                                                                                                               The primary route of elimination for bempedoic acid is through metabolism of the acyl glucuronide. Bempedoic acid is also reversibly converted to an active metabolite (ESP15228) based on aldo-keto reductase activity observed in vitro from human liver. 

Elemination-                                                                                                        Following- single oral administration of 240 mg of bempedoic acid (1.3 times the approved recommended dose), approximately 70% of the total dose (bempedoic acid and its metabolites) was recovered in urine, primarily as the acyl glucuronide conjugate of bempedoic acid, and approximately 30% was recovered in feces.

Less than 5% of the administered dose was excreted as unchanged bempedoic acid in feces and urine combined.

Specific Populations-                                                                                            Patients with Renal Impairment Pharmacokinetics of bempedoic acid was evaluated in a single-dose pharmacokinetic study in subjects with varying degrees of renal function.

The mean bempedoic acid AUC in subjects with mild renal impairment (n = 8) were 1.5-fold higher compared to those with normal renal function (n = 6). Relative to those with normal renal function, mean bempedoic acid AUCs were higher in patients with moderate (n = 5) or severe (n = 5) renal impairment by 2.3-fold and 2.4-fold, respectively.

A population pharmacokinetic analysis was performed on pooled data from all clinical trials (n = 2261) to further evaluate the effects of renal function on the steady-state AUC of bempedoic acid.

Compared to patients with normal renal function, the mean bempedoic acid exposures were higher in patients with mild or moderate renal impairment by 1.4-fold (90% CI: 1.3, 1.4) and 1.9-fold (90% CI: 1.7, 2.0), respectively. These differences were not clinically significant.

Clinical studies of NEXLETOL did not include patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2 ) or patients with ESRD on dialysis [see Use in Specific Populations (8.6)].

Patients with Hepatic Impairment-                                                                            The pharmacokinetics of bempedoic acid and its metabolite (ESP15228) was studied in patients with normal hepatic function or mild or moderate hepatic impairment (Child-Pugh A or B) following a single dose (n = 8/group).

Compared to patients with normal hepatic function, the bempedoic acid mean Cmax and AUC were decreased by 11% and 22%, respectively, in patients with mild hepatic impairment and by 14% and 16%, respectively, in patients with moderate hepatic impairment.

Compared to patients with normal hepatic function, the ESP15228 mean Cmax and AUC were decreased by 13% and 23%, respectively, in patients with mild hepatic impairment and by 24% and 36%, respectively, in patients with moderate hepatic impairment.

This is not expected to result in lower efficacy. Bempedoic acid was not studied in patients with severe hepatic impairment (Child Pugh C) 

Other Specific Populations-                                                                                      The pharmacokinetics of bempedoic acid were not affected by age, gender, race, or weight. 

Drug Interaction Studies-                                                                                Cytochrome P450 Substrates In vitro metabolic interaction studies suggest that bempedoic acid, as well as its active metabolite and glucuronide forms are not metabolized by and do not interact with cytochrome P450 enzymes.

Transporter-mediated Drug Interactions-                                                                   In vitro drug interaction studies suggest bempedoic acid, as well as its active metabolite and glucuronide form, are not substrates of commonly characterized drug transporters with the exception of bempedoic acid glucuronide, which is an OAT3 substrate. 

Statins-                                                                                                                       The pharmacokinetic interactions between bempedoic acid (at systemic exposure relevant to the indicated ASCVD population) and simvastatin 20 mg, atorvastatin 10 mg, pravastatin 40 mg, and rosuvastatin10 mg were evaluated in clinical trials. 

Simvastatin:                                                                                                       Administration of simvastatin 20 mg with 240 mg of bempedoic acid or 40 mg with 180 mg of bempedoic acid in healthy subjects at steady-state resulted in approximately 2-fold (91% for 20 mg and 96% for 40 mg) and 1.5-fold (54% for 20 mg and 52% for 40 mg) increases in simvastatin acid AUC and Cmax, respectively 

Pravastatin:                                                                                                  Administration of pravastatin 40 mg with steady-state bempedoic acid 240 mg in healthy subjects resulted in 99% (2-fold) and 104% (2-fold) increases in pravastatin acid AUC and Cmax, respectively 

Atorvastatin and Rosuvastatin:                                                                      Elevations of 1.7-fold in AUC of atorvastatin, and rosuvastatin and/or their major metabolites were observed, suggesting a weak interaction. These elevations were generally within the individual statin exposures and do not impact dosing recommendations. 

Ezetimibe-                                                                                                                Increases in AUC and Cmax for ezetimibe were less than 20% when a single dose of ezetimibe was taken with steady-state bempedoic acid. Total ezetimibe (ezetimibe and its glucuronide form) and ezetimibe glucuronide AUC and Cmax increased approximately 1.6- and 1.8-fold,  respectively.

These elevations are not clinically meaningful and do not impact dosing recommendations.

Warfarin-                                                                                                                       In vitro studies indicate that bempedoic acid is not an inhibitor or inducer of CYP2C9. Because warfarin is primarily eliminated through CYP2C9, its pharmacokinetics is not expected to be altered by bempedoic acid. Other Bempedoic acid had no effect on the pharmacokinetics of metformin or the oral contraceptive Ortho-Novu m 1/35.

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary-                                                                                Discontinue NEXLETOL when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus.

There are no available data on NEXLETOL use in pregnant women to evaluate for a drugassociated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

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.

2. Lactation Risk Summary -                                                                                       There is no information regarding the presence of NEXLETOL in human or animal milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production.

NEXLETOL 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 NEXLETOL  

3. Pediatric Use -                                                                                                            The safety and effectiveness of NEXLETOL have not been established in pediatric patients.

4. Geriatric Use-                                                                                                           Of the 3009 patients in clinical trials of NEXLETOL, 1753 (58%) were 65 years and older, while 478 (16%) were 75 years and older. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients.

However, greater sensitivity of some older individuals cannot be ruled out.

5.Renal Impairment-                                                                                                     No dosage adjustment is necessary in patients with mild or moderate renal impairment. There is limited experience with NEXLETOL in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2 ), and NEXLETOL has not been studied in patients with end-stage renal disease (ESRD) receiving dialysis [see

6.Hepatic Impairment-                                                                                                No dosage adjustment is necessary in patients with mild or moderate hepatic impairment (Child-Pugh A or B)                                                                              Patients with severe hepatic impairment (Child-Pugh C) have not been studied.

 OVERDOSAGE-                                                                                                     There is no clinical experience with NEXLETOL overdose.                                              In the event of an overdosage, contact Poison Control (1-800-222-1222) for latest recommendations.