Eplerenone (Page 4 of 4)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Eplerenone was non-genotoxic in a battery of assays including in vitro bacterial mutagenesis (Ames test in Salmonella spp. and E. Coli), in vitro mammalian cell mutagenesis (mouse lymphoma cells), in vitro chromosomal aberration (Chinese hamster ovary cells), in vivo rat bone marrow micronucleus formation, and in vivo/ex vivo unscheduled DNA synthesis in rat liver.

There was no drug-related tumor response in heterozygous P53 deficient mice when tested for 6 months at dosages up to 1000 mg/kg/day (systemic AUC exposures up to 9 times the exposure in humans receiving the 100 mg/day therapeutic dose). Statistically significant increases in benign thyroid tumors were observed after 2 years in both male and female rats when administered eplerenone 250 mg/kg/day (highest dose tested) and in male rats only at 75 mg/kg/day. These dosages provided systemic AUC exposures approximately 2 to 12 times higher than the average human therapeutic exposure at 100 mg/day. Repeat dose administration of eplerenone to rats increases the hepatic conjugation and clearance of thyroxin, which results in increased levels of TSH by a compensatory mechanism. Drugs that have produced thyroid tumors by this rodent-specific mechanism have not shown a similar effect in humans.

Male rats treated with eplerenone at 1000 mg/kg/day for 10 weeks (AUC 17 times that at the 100 mg/day human therapeutic dose) had decreased weights of seminal vesicles and epididymides and slightly decreased fertility. Dogs administered eplerenone at dosages of 15 mg/kg/day and higher (AUC 5 times that at the 100 mg/day human therapeutic dose) had dose-related prostate atrophy. The prostate atrophy was reversible after daily treatment for 1 year at 100 mg/kg/day. Dogs with prostate atrophy showed no decline in libido, sexual performance, or semen quality. Testicular weight and histology were not affected by eplerenone in any test animal species at any dosage.

14 CLINICAL STUDIES

14.2 Hypertension

The safety and efficacy of eplerenone has been evaluated in clinical studies of 3091 hypertensive patients. The studies included 46% women, 14% Blacks, and 22% elderly (age ≥65). The studies excluded patients with elevated baseline serum potassium (>5.0 mEq/L) and elevated baseline serum creatinine (generally >1.5 mg/dL in males and >1.3 mg/dL in females).

Two fixed-dose, placebo-controlled, 8- to 12-week monotherapy studies in patients with baseline diastolic blood pressures of 95 to 114 mm Hg were conducted to assess the antihypertensive effect of eplerenone. In these two studies, 611 patients were randomized to eplerenone and 140 patients to placebo. Patients received eplerenone in doses of 25 mg to 400 mg daily as either a single daily dose or divided into two daily doses. The mean placebo-subtracted reductions in trough cuff blood pressure achieved by eplerenone in these studies at doses up to 200 mg are shown in Figures 3 and 4.

Figure
(click image for full-size original)
Figure
(click image for full-size original)

Patients treated with eplerenone 50 mg to 200 mg daily experienced significant decreases in sitting systolic and diastolic blood pressure at trough with differences from placebo of 6 to 13 mm Hg (systolic) and 3 to 7 mm Hg (diastolic). These effects were confirmed by assessments with 24-hour ambulatory blood pressure monitoring (ABPM). In these studies, assessments of 24-hour ABPM data demonstrated that eplerenone, administered once or twice daily, maintained antihypertensive efficacy over the entire dosing interval. However, at a total daily dose of 100 mg, eplerenone administered as 50 mg twice per day produced greater trough cuff (4/3 mm Hg) and ABPM (2/1 mm Hg) blood pressure reductions than 100 mg given once daily.

Blood pressure lowering was apparent within 2 weeks from the start of therapy with eplerenone, with maximal antihypertensive effects achieved within 4 weeks. Stopping eplerenone following treatment for 8 to 24 weeks in six studies did not lead to adverse event rates in the week following withdrawal of eplerenone greater than following placebo or active control withdrawal. Blood pressures in patients not taking other antihypertensives rose 1 week after withdrawal of eplerenone by about 6/3 mm Hg, suggesting that the antihypertensive effect of eplerenone was maintained through 8 to 24 weeks.

Blood pressure reductions with eplerenone in the two fixed-dose monotherapy studies and other studies using titrated doses, as well as concomitant treatments, were not significantly different when analyzed by age, gender, or race with one exception. In a study in patients with low renin hypertension, blood pressure reductions in Blacks were smaller than those in whites during the initial titration period with eplerenone.

Eplerenone has been studied concomitantly with treatment with ARBs, calcium channel blockers and beta -blockers. When administered concomitantly with one of these drugs eplerenone usually produced its expected antihypertensive effects.

16 HOW SUPPLIED/STORAGE AND HANDLING

Eplerenone tablets, 25 mg, are yellow diamond shape biconvex film-coated tablets, debossed with “E1” on one side and plain on the other side. They are supplied as follows:

NDC Number Size
16729-293-10 Bottle of 30 tablets
16729-293-15 Bottle of 90 tablets
16729-293-16 Bottle of 500 tablets
16729-293-17 Bottle of 1000 tablets
16729-293-82 Hospital Unit Dose Blister Packages of 100 (10 x 10 unit dose)

Eplerenone tablets, 50 mg, are yellow diamond shape biconvex film-coated tablets, debossed with “E2” on one side and plain on the other side. They are supplied as follows:

NDC Number Size
16729-294-10 Bottle of 30 tablets
16729-294-15 Bottle of 90 tablets
16729-294-16 Bottle of 500 tablets
16729-294-17 Bottle of 1000 tablets
16729-294-82 Hospital Unit Dose Blister Packages of 100 (10 x 10 unit dose)

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

Advise patients receiving eplerenone tablets:

  • Not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician. [See Warnings and Precautions (5.1).]
  • To call their physician if they experience dizziness, diarrhea, vomiting, rapid or irregular heartbeat, lower extremity edema, or difficulty breathing. [See Warnings and Precautions (5.1).]

Manufactured For:
Accord Healthcare, Inc.,
1009 Slater Road,
Suite 210-B,
Durham, NC 27703,
USA.

Manufactured By:
Intas Pharmaceuticals Limited,
Plot No. : 457, 458,
Village – Matoda,
Bavla Road, Ta.- Sanand,
Dist.- Ahmedabad – 382 210,
INDIA.

10 3268 1 696340

Issued April 2019

PRINCIPAL DISPLAY PANEL — 25 mg Tablet — Bottle of 30

NDC 16729- 293 -10

Eplerenone Tablets

25 mg

Rx only

30 Tablets

PRINCIPAL DISPLAY PANEL -- 25 mg Tablet -- Bottle of 30
(click image for full-size original)

PRINCIPAL DISPLAY PANEL — 50 mg Tablet — Bottle of 30

NDC 16729- 294 -10

Eplerenone Tablets

50 mg

Rx only

30 Tablets

PRINCIPAL DISPLAY PANEL -- 50 mg Tablet -- Bottle of 30
(click image for full-size original)
EPLERENONE
eplerenone tablet, film coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:16729-293
Route of Administration ORAL DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
EPLERENONE (EPLERENONE) EPLERENONE 25 mg
Inactive Ingredients
Ingredient Name Strength
LACTOSE MONOHYDRATE
CELLULOSE, MICROCRYSTALLINE
CROSCARMELLOSE SODIUM
HYPROMELLOSE 2910 (3 MPA.S)
HYPROMELLOSE 2910 (6 MPA.S)
TALC
MAGNESIUM STEARATE
TITANIUM DIOXIDE
POLYETHYLENE GLYCOL 400
POLYSORBATE 80
FERRIC OXIDE YELLOW
FERRIC OXIDE RED
Product Characteristics
Color yellow Score no score
Shape DIAMOND Size 7mm
Flavor Imprint Code E1
Contains
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:16729-293-10 30 TABLET, FILM COATED in 1 BOTTLE None
2 NDC:16729-293-15 90 TABLET, FILM COATED in 1 BOTTLE None
3 NDC:16729-293-16 500 TABLET, FILM COATED in 1 BOTTLE None
4 NDC:16729-293-17 1000 TABLET, FILM COATED in 1 BOTTLE None
5 NDC:16729-293-82 100 TABLET, FILM COATED in 1 BOX, UNIT-DOSE None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA206922 10/09/2018
EPLERENONE
eplerenone tablet, film coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:16729-294
Route of Administration ORAL DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
EPLERENONE (EPLERENONE) EPLERENONE 50 mg
Inactive Ingredients
Ingredient Name Strength
LACTOSE MONOHYDRATE
CELLULOSE, MICROCRYSTALLINE
CROSCARMELLOSE SODIUM
HYPROMELLOSE 2910 (3 MPA.S)
HYPROMELLOSE 2910 (6 MPA.S)
TALC
MAGNESIUM STEARATE
TITANIUM DIOXIDE
POLYETHYLENE GLYCOL 400
POLYSORBATE 80
FERRIC OXIDE YELLOW
FERRIC OXIDE RED
Product Characteristics
Color yellow Score no score
Shape DIAMOND Size 9mm
Flavor Imprint Code E2
Contains
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:16729-294-10 30 TABLET, FILM COATED in 1 BOTTLE None
2 NDC:16729-294-15 90 TABLET, FILM COATED in 1 BOTTLE None
3 NDC:16729-294-16 500 TABLET, FILM COATED in 1 BOTTLE None
4 NDC:16729-294-17 1000 TABLET, FILM COATED in 1 BOTTLE None
5 NDC:16729-294-82 100 TABLET, FILM COATED in 1 BOX, UNIT-DOSE None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA206922 10/09/2018
Labeler — Accord Healthcare, Inc. (604222237)
Registrant — Accord Healthcare, Inc. (604222237)
Establishment
Name Address ID/FEI Operations
Intas Pharmaceuticals Limited 725927649 manufacture (16729-293), analysis (16729-293), manufacture (16729-294), analysis (16729-294)

Revised: 11/2023 Accord Healthcare, Inc.

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