Ramipril (Page 6 of 6)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of a tumorigenic effect was found when ramipril was given by gavage to rats for up to 24 months at doses of up to 500 mg/kg/day or to mice for up to 18 months at doses of up to 1000 mg/kg/day. (For either species, these doses are about 200 times the maximum recommended human dose when compared on the basis of body surface area.) No mutagenic activity was detected in the Ames test in bacteria, the micronucleus test in mice, unscheduled DNA synthesis in a human cell line, or a forward gene‑mutation assay in a Chinese hamster ovary cell line. Several metabolites and degradation products of ramipril were also negative in the Ames test. A study in rats with dosages as great as 500 mg/kg/day did not produce adverse effects on fertility.

No teratogenic effects of ramipril were seen in studies of pregnant rats, rabbits, and cynomologus monkeys. On a body surface area basis, the doses used were up to approximately 400 times (in rats and monkeys) and 2 times (in rabbits) the recommended human dose.

14 CLINICAL STUDIES

14.1 Hypertension

Ramipril has been compared with other ACE inhibitors, beta-blockers, and thiazide diuretics as monotherapy for hypertension. It was approximately as effective as other ACE inhibitors and as atenolol.

Administration of ramipril to patients with mild to moderate hypertension results in a reduction of both supine and standing blood pressure to about the same extent with no compensatory tachycardia. Symptomatic postural hypotension is infrequent, although it can occur in patients who are salt- and/or volume-depleted [see Warnings and Precautions (5.5)] . Use of ramipril in combination with thiazide diuretics gives a blood pressure lowering effect greater than that seen with either agent alone.

In single-dose studies, doses of 5 mg to 20 mg of ramipril lowered blood pressure within 1 to 2 hours, with peak reductions achieved 3 to 6 hours after dosing. The antihypertensive effect of a single dose persisted for 24 hours. In longer term (4 to 12 weeks) controlled studies, once-daily doses of 2.5 mg to 10 mg were similar in their effect, lowering supine or standing systolic and diastolic blood pressures 24 hours after dosing by about 6/4 mmHg more than placebo. In comparisons of peak vs. trough effect, the trough effect represented about 50 to 60% of the peak response. In a titration study comparing divided (bid) vs. qd treatment, the divided regimen was superior, indicating that for some patients, the antihypertensive effect with once-daily dosing is not adequately maintained.

In most trials, the antihypertensive effect of ramipril increased during the first several weeks of repeated measurements. The antihypertensive effect of ramipril has been shown to continue during long-term therapy for at least 2 years. Abrupt withdrawal of ramipril has not resulted in a rapid increase in blood pressure. Ramipril has been compared with other ACE inhibitors, beta-blockers, and thiazide diuretics. Ramipril was approximately as effective as other ACE inhibitors and as atenolol. In both Caucasians and Blacks, hydrochlorothiazide (25 or 50 mg) was significantly more effective than ramipril.

Ramipril was less effective in blacks than in Caucasians. The effectiveness of ramipril was not influenced by age, sex, or weight.

In a baseline controlled study of 10 patients with mild essential hypertension, blood pressure reduction was accompanied by a 15% increase in renal blood flow. In healthy volunteers, glomerular filtration rate was unchanged.

14.3 Heart Failure Post-Myocardial Infarction

Ramipril was studied in the AIRE trial. This was a multinational (mainly European) 161-center, 2006-patient, double-blind, randomized, parallel-group study comparing ramipril to placebo in stable patients, 2 to 9 days after an acute myocardial infarction, who had shown clinical signs of congestive heart failure at any time after the myocardial infarction. Patients in severe (NYHA class IV) heart failure, patients with unstable angina, patients with heart failure of congenital or valvular etiology, and patients with contraindications to ACE inhibitors were all excluded. The majority of patients had received thrombolytic therapy at the time of the index infarction, and the average time between infarction and initiation of treatment was 5 days.

Patients randomized to ramipril treatment were given an initial dose of 2.5 mg twice daily. If the initial regimen caused undue hypotension, the dose was reduced to 1.25 mg, but in either event doses were titrated upward (as tolerated) to a target regimen (achieved in 77% of patients randomized to ramipril) of 5 mg twice daily. Patients were then followed for an average of 15 months, with the range of follow-up between 6 and 46 months.

The use of ramipril was associated with a 27% reduction (p=0.002) in the risk of death from any cause; about 90% of the deaths that occurred were cardiovascular, mainly sudden death. The risks of progression to severe heart failure and of congestive heart failure-related hospitalization were also reduced, by 23% (p=0.017) and 26% (p=0.011), respectively. The benefits of ramipril therapy were seen in both genders, and they were not affected by the exact timing of the initiation of therapy, but older patients may have had a greater benefit than those under 65. The benefits were seen in patients on (and not on) various concomitant medications. At the time of randomization these included aspirin (about 80% of patients), diuretics (about 60%), organic nitrates (about 55%), beta-blockers (about 20%), calcium channel blockers (about 15%), and digoxin (about 12%).

16 HOW SUPPLIED/STORAGE AND HANDLING

Ramipril Capsules USP are available in 1.25 mg, 2.5 mg, 5 mg, and 10 mg in hard gelatin capsules.

Ramipril Capsules USP, 1.25 mg are supplied as yellow opaque capsules with “54 328” printed in black ink.

Ramipril Capsules USP, 2.5 mg are supplied as orange opaque capsules with “54 794” printed in black ink.

Ramipril Capsules USP, 5 mg are supplied as red opaque capsules with “54 145” printed in black ink.

Ramipril Capsules USP, 10 mg are supplied as blue opaque capsules with “54 602” printed in black ink.

Storage

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Dispense in light-resistant, tight container with child-resistant closure.

17 PATIENT COUNSELING INFORMATION

17.1 Angioedema

Angioedema, including laryngeal edema, can occur rarely with treatment with ACE inhibitors, especially following the first dose. Advise patients to report immediately any signs or symptoms suggesting angioedema (swelling of face, eyes, lips, or tongue, or difficulty in breathing) and to take no more drug until they have consulted with the prescribing physician.

17.2 Neutropenia

Advise patients to report promptly any indication of infection (e.g., sore throat, fever), which could be a sign of neutropenia.

17.3 Symptomatic Hypotension

Inform patients that lightheadedness can occur, especially during the first days of therapy, and it should be reported. Advise patients to discontinue ramipril if syncope (fainting) occurs, and to follow up with their health care providers.

Inform patients that inadequate fluid intake or excessive perspiration, diarrhea, or vomiting while taking ramipril can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope.

17.4 Pregnancy

Female patients of childbearing age should be told about the consequences of exposure to ramipril during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.

17.5 Hyperkalemia

Advise patients not to use salt substitutes containing potassium without consulting their physician.

Roxane Laboratories, Inc.

Columbus, Ohio 43216

10004223/08

Revised June 2014

© RLI, 2014

PRINCIPAL DISPLAY PANEL — 10mg — 30 count

RAMIPRIL CAPSULES 10MG #30

GENERIC FOR ALTACE

NDC: 45865-0441-30

PDP
(click image for full-size original)
RAMIPRIL
ramipril capsule
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:45865-441(NDC:0054-0109)
Route of Administration ORAL DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
RAMIPRIL (RAMIPRILAT) RAMIPRIL 10 mg
Inactive Ingredients
Ingredient Name Strength
D&C RED NO. 28
FD&C BLUE NO. 1
GELATIN
STARCH, CORN
TITANIUM DIOXIDE
Product Characteristics
Color blue Score no score
Shape CAPSULE Size 12mm
Flavor Imprint Code 54;602
Contains
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:45865-441-49 100 CAPSULE in 1 BOTTLE None
2 NDC:45865-441-30 30 CAPSULE in 1 BOTTLE None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA077900 06/18/2008
Labeler — Medsource Pharmaceuticals (833685915)
Registrant — Medsource Pharmaceuticals (833685915)
Establishment
Name Address ID/FEI Operations
Medsource Pharmaceuticals 833685915 repack (45865-441)

Revised: 12/2019 Medsource Pharmaceuticals

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