DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION Blood pressure decreases associated with any dose of ramipril capsules depend, in part, on the presence or absence of volume depletion (e.g., past and current diuretic use) or the presence or absence of renal artery stenosis. If such circumstances are suspected to be present, the initial starting dose should be 1.25 mg once daily. Reduction in Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes Ramipril capsules should be given at an initial dose of 2.5 mg, once day for week, mg, once day for the next weeks, and then increased as tolerated, to maintenance dose of 10 mg, once day. If the patient is hypertensive or recently post myocardial infarction, it can also be given as divided dose. Hypertension The recommended initial dose for patients not receiving diuretic is 2.5 mg once day. Dosage should be adjusted according to the blood pressure response. The usual maintenance dosage range is 2.5 to 20 mg per day administered as single dose or in two equally divided doses. In some patients treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval. In such patients, an increase in dosage or twice daily administration should be considered. If blood pressure is not controlled with ramipril capsules alone, diuretic can be added. After the initial dose of ramipril capsules, the patient should be observed under medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour. (See WARNINGS and PRECAUTIONS, Drug Interactions.) If possible, the dose of any concomitant diuretic should be reduced which may diminish the likelihood of hypotension. The appearance of hypotension after the initial dose of ramipril capsules does not preclude subsequent careful dose titration with the drug, following effective management of the hypotension. The ramipril capsule is usually swallowed whole. The ramipril capsule can also be opened and the contents sprinkled on small amount (about oz.) of apple sauce or mixed in oz. (120 ml) of water or apple juice. To be sure that ramipril is not lost when such mixture is used, the mixture should be consumed in its entirety. The described mixtures can be pre-prepared and stored for up to 24 hours at room temperature or up to 48 hours under refrigeration. Concomitant administration of ramipril capsules with potassium supplements, potassium salt substitutes, or potassium-sparing diuretics can lead to increases of serum potassium. (See PRECAUTIONS.) In patients who are currently being treated with diuretic, symptomatic hypotension occasionally can occur following the initial dose of ramipril capsules. To reduce the likelihood of hypotension, the diuretic should, if possible, be discontinued two to three days prior to beginning therapy with ramipril capsules. (See WARNINGS.) Then, if blood pressure is not controlled with ramipril capsules alone, diuretic therapy should be resumed. If the diuretic cannot be discontinued, an initial dose of 1.25 mg ramipril capsules should be used to avoid excess hypotension. Dosage Adjustment in Renal Impairment In patients with creatinine clearance <40 ml/min/1.73m2 (serum creatinine approximately >2.5 mg/dl) doses only 25% of those normally used should be expected to induce full therapeutic levels of ramiprilat. (See CLINICAL PHARMACOLOGY.) Hypertension: For patients with hypertension and renal impairment, the recommended initial dose is 1.25 mg ramipril capsules once daily. Dosage may be titrated upward until blood pressure is controlled or to maximum total daily dose of mg.

ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS Hypertension Ramipril has been evaluated for safety in over 4,000 patients with hypertension; of these, 1,230 patients were studied in US controlled trials, and 1,107 were studied in foreign controlled trials. Almost 700 of these patients were treated for at least one year. The overall incidence of reported adverse events was similar in ramipril and placebo patients. The most frequent clinical side effects (possibly or probably related to study drug) reported by patients receiving ramipril in US placebo-controlled trials were: headache (5.4%), dizziness (2.2%) and fatigue or asthenia (2.0%), but only the last was more common in ramipril patients than in patients given placebo. Generally, the side effects were mild and transient, and there was no relation to total dosage within the range of 1.25 to 20 mg. Discontinuation of therapy because of side effect was required in approximately 3% of US patients treated with ramipril. The most common reasons for discontinuation were: cough (1.0%), dizziness (0.5%), and impotence (0.4%). Of observed side effects considered possibly or probably related to study drug that occurred in US placebo-controlled trials in more than 1% of patients treated with ramipril, only asthenia (fatigue) was more common on ramipril than placebo (2% vs. 1%). PATIENTS IN US PLACEBO CONTROLLED STUDIES RamiprilPlacebo(n=651)(n=286)n n Asthenia (Fatigue) 13 2 In placebo-controlled trials, there was also an excess of upper respiratory infection and flu syndrome in the ramipril group, not attributed at that time to ramipril. As these studies were carried out before the relationship of cough to ACE inhibitors was recognized, some of these events may represent ramipril-induced cough. In later 1-year study, increased cough was seen in almost 12% of ramipril patients, with about 4% of patients requiring discontinuation of treatment. Percentage of Patients with Adverse Events Possibly/ Probably Related to Study Drug HOPE Study:Safety data in the HOPE trial were collected as reasons for discontinuation or temporary interruption of treatment. The rate of angioedema was the same as in previous clinical trials (see WARNINGS). RamiprilPlacebo(n=4645)(n=4652)%%Discontinuation at any time 3432Permanent discontinuation2928Reasons for stopping Cough 72Hypotension or Dizziness1.9 1.5 Angioedema0.30.1Other adverse experiences reported in controlled clinical trials (in less than 1% of ramipril patients), or rarer events seen in postmarketing experience, include the following (in some, causal relationship to drug use is uncertain): Body As Whole: Anaphylactoid reactions. (See WARNINGS.) Cardiovascular: Symptomatic hypotension (reported in 0.5% of patients in US trials) (See WARNINGS and PRECAUTIONS), syncope and palpitations. Hematologic: Pancytopenia, hemolytic anemia and thrombocytopenia. Renal: Some hypertensive patients with no apparent pre-existing renal disease have developed minor, usually transient, increases in blood urea nitrogen and serum creatinine when taking ramipril, particularly when ramipril was given concomitantly with diuretic. (See WARNINGS.) Acute renal failure. Angioneurotic Edema: Angioneurotic edema has been reported in 0.3% of patients in US clinical trials. (See WARNINGS.) Gastrointestinal: Hepatic failure, hepatitis, jaundice, pancreatitis, abdominal pain (sometimes with enzyme changes suggesting pancreatitis), anorexia, constipation, diarrhea, dry mouth, dyspepsia, dysphagia, gastroenteritis, increased salivation and taste disturbance. Dermatologic: Apparent hypersensitivity reactions (manifested by urticaria, pruritus, or rash, with or without fever), photosensitivity, purpura, onycholysis, pemphigus, pemphigoid, erythema multiforme, toxic epidermal necrolysis, and Stevens-Johnson syndrome. Neurologic and Psychiatric: Anxiety, amnesia, convulsions, depression, hearing loss, insomnia, nervousness, neuralgia, neuropathy, paresthesia, somnolence, tinnitus, tremor, vertigo, and vision disturbances. Miscellaneous: As with other ACE inhibitors, symptom complex has been reported which may include positive ANA, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia, fever, vasculitis, eosinophilia, photosensitivity, rash and other dermatologic manifestations. Additionally, as with other ACE inhibitors, eosinophilic pneumonitis has been reported. Fetal/Neonatal Morbidity and Mortality. See WARNINGS: Fetal/Neonatal Morbidity and Mortality. Other: Arthralgia, arthritis, dyspnea, edema, epistaxis, impotence, increased sweating, malaise, myalgia, and weight gain. Post-Marketing Experience: In addition to adverse events reported from clinical trials, there have been rare reports of hypoglycemia reported during ramipril therapy when given to patients concomitantly taking oral hypoglycemic agents or insulin. The causal relationship is unknown. Clinical Laboratory Test Findings: Creatinine and Blood Urea Nitrogen: Increases in creatinine levels occurred in 1.2% of patients receiving ramipril alone, and in 1.5% of patients receiving ramipril and diuretic. Increases in blood urea nitrogen levels occurred in 0.5% of patients receiving ramipril alone and in 3% of patients receiving ramipril with diuretic. None of these increases required discontinuation of treatment. Increases in these laboratory values are more likely to occur in patients with renal insufficiency or those pretreated with diuretic and, based on experience with other ACE inhibitors, would be expected to be especially likely in patients with renal artery stenosis. (See WARNINGS and PRECAUTIONS.) Since ramipril decreases aldosterone secretion, elevation of serum potassium can occur. Potassium supplements and potassium-sparing diuretics should be given with caution, and the patients serum potassium should be monitored frequently. (See WARNINGS and PRECAUTIONS.) Hemoglobin and Hematocrit: Decreases in hemoglobin or hematocrit (a low value and decrease of g/dl or 5% respectively) were rare, occurring in 0.4% of patients receiving ramipril alone and in 1.5% of patients receiving ramipril plus diuretic. No US patients discontinued treatment because of decreases in hemoglobin or hematocrit. Other (causal relationships unknown): Clinically important changes in standard laboratory tests were rarely associated with ramipril administration. Elevations of liver enzymes, serum bilirubin, uric acid, and blood glucose have been reported, as have cases of hyponatremia and scattered incidents of leukopenia, eosinophilia, and proteinuria. In US trials, less than 0.2% of patients discontinued treatment for laboratory abnormalities; all of these were cases of proteinuria or abnormal liver-function tests.

BOXED WARNING SECTION.

When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, Ramipril should be discontinued as soon as possible. See WARNINGS: Fetal/neonatal Morbidity and Mortality.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

Carcinogenesis, Mutagenesis, Impairment of Fertility No evidence of 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 human cell line, or forward gene-mutation assay in Chinese hamster ovary cell line. Several metabolites and degradation products of ramipril were also negative in the Ames test. study in rats with dosages as great as 500 mg/kg/day did not produce adverse effects on fertility.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY Mechanism of Action Ramipril and ramiprilat inhibit angiotensin-converting enzyme (ACE) in human subjects and animals. ACE is peptidyl dipeptidase that catalyzes the conversion of angiotensin to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in small increase of serum potassium. In hypertensive patients with normal renal function treated with ramipril alone for up to 56 weeks, approximately 4% of patients during the trial had an abnormally high serum potassium and an increase from baseline greater than 0.75 mEq/L, and none of the patients had an abnormally low potassium and decrease from baseline greater than 0.75 mEq/L. In the same study, approximately 2% of patients treated with ramipril and hydrochlorothiazide for up to 56 weeks had abnormally high potassium values and an increase from baseline of 0.75 mEq/L or greater, and approximately 2% had abnormally low values and decreases from baseline of 0.75 mEq/L or greater. (See PRECAUTIONS.) Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. The effect of ramipril on hypertension appears to result at least in part from inhibition of both tissue and circulating ACE activity, thereby reducing angiotensin II formation in tissue and plasma. ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, potent vasodepressor peptide, play role in the therapeutic effects of ramipril remains to be elucidated. While the mechanism through which ramipril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, ramipril has an antihypertensive effect even in patients with low-renin hypertension. Although ramipril was antihypertensive in all races studied, black hypertensive patients (usually low-renin hypertensive population) had smaller average response to monotherapy than non-black patients. Pharmacokinetics and Metabolism Following oral administration of ramipril, peak plasma concentrations of ramipril are reached within one hour. The extent of absorption is at least 50-60% and is not significantly influenced by the presence of food in the GI tract, although the rate of absorption is reduced. In trial in which subjects received ramipril capsules or the contents of identical capsules dissolved in water, dissolved in apple juice, or suspended in apple sauce, serum ramiprilat levels were essentially unrelated to the use or nonuse of the concomitant liquid or food. Cleavage of the ester group (primarily in the liver) converts ramipril to its active diacid metabolite, ramiprilat. Peak plasma concentrations of ramiprilat are reached 2-4 hours after drug intake. The serum protein binding of ramipril is about 73% and that of ramiprilat about 56%; in vitro, these percentages are independent of concentration over the range of 0.01 to 10ug/ml. Ramipril is almost completely metabolized to ramiprilat, which has about times the ACE inhibitory activity of ramipril, and to the diketopiperazine ester, the diketopiperazine acid, and the glucuronides of ramipril and ramiprilat, all of which are inactive. After oral administration of ramipril, about 60% of the parent drug and its metabolites is eliminated in the urine, and about 40% is found in the feces. Drug recovered in the feces may represent both biliary excretion of metabolites and/or unabsorbed drug, however the proportion of dose eliminated by the bile has not been determined. Less than 2% of the administered dose is recovered in urine as unchanged ramipril. Blood concentrations of ramipril and ramiprilat increase with increased dose, but are not strictly dose-proportional. The 24-hour AUC for ramiprilat, however, is dose-proportional over the 2.5-20 mg dose range. The absolute bioavailabilities of ramipril and ramiprilat were 28% and 44%, respectively, when mg of oral ramipril was compared with the same dose of ramipril given intravenously. Plasma concentrations of ramiprilat decline in triphasic manner (initial rapid decline, apparent elimination phase, terminal elimination phase). The initial rapid decline, which represents distribution of the drug into large peripheral compartment and subsequent binding to both plasma and tissue ACE, has half-life of 2-4 hours. Because of its potent binding to ACE and slow dissociation from the enzyme, ramiprilat shows two elimination phases. The apparent elimination phase corresponds to the clearance of free ramiprilat and has half-life of 9-18 hours. The terminal elimination phase has prolonged half-life (>50 hours) and probably represents the binding/dissociation kinetics of the ramiprilat/ACE complex. It does not contribute to the accumulation of the drug. After multiple daily doses of ramipril 5-10 mg, the half-life of ramiprilat concentrations within the therapeutic range was 13-17 hours. After once-daily dosing, steady-state plasma concentrations of ramiprilat are reached by the fourth dose. Steady-state concentrations of ramiprilat are somewhat higher than those seen after the first dose of ramipril, especially at low doses (2.5 mg), but the difference is clinically insignificant. In patients with creatinine clearance less than 40 ml/min/1.73m2, peak levels of ramiprilat are approximately doubled, and trough levels may be as much as quintupled. In multiple-dose regimens, the total exposure to ramiprilat (AUC) in these patients is 3-4 times as large as it is in patients with normal renal function who receive similar doses. The urinary excretion of ramipril, ramiprilat, and their metabolites is reduced in patients with impaired renal function. Compared to normal subjects, patients with creatinine clearance less than 40 ml/min/1.73m2 had higher peak and trough ramiprilat levels and slightly longer times to peak concentrations. (See DOSAGE AND ADMINISTRATION.) In patients with impaired liver function, the metabolism of ramipril to ramiprilat appears to be slowed, possibly because of diminished activity of hepatic esterases, and plasma ramipril levels in these patients are increased about 3-fold. Peak concentrations of ramiprilat in these patients, however, are not different from those seen in subjects with normal hepatic function, and the effect of given dose on plasma ACE activity does not vary with hepatic function. Pharmacodynamics Single doses of ramipril of 2.5-20 mg produce approximately 60-80% inhibition of ACE activity hours after dosing with approximately 40-60% inhibition after 24 hours. Multiple oral doses of ramipril of 2.0 mg or more cause plasma ACE activity to fall by more than 90% hours after dosing, with over 80% inhibition of ACE activity remaining 24 hours after dosing. The more prolonged effect of even small multiple doses presumably reflects saturation of ACE binding sites by ramiprilat and relatively slow release from those sites. Pharmacodynamics and Clinical Effects Reduction in Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes The Heart Outcomes Prevention Evaluation study (HOPE study) was large, multi-center, randomized, placebo controlled,2x2 factorial design, double-blind study conducted in 9,541 patients (4,645 on ramipril) who were 55 years or older and considered at high risk of developing major cardiovascular event because of history of coronary artery disease, stroke, peripheral vascular disease, or diabetes that was accompanied by at least one other cardiovascular risk factor (hypertension, elevated total cholesterol levels, low HDL levels, cigarette smoking, or documented microalbuminuria). Patients were either normotensive or under treatment with other antihypertensive agents. Patients were excluded if they had clinical heart failure or were known to have low ejection fraction (<0.40). This study was designed to examine the long-term (mean of five years) effects of ramipril (10 mg orally once day) on the combined endpoint of myocardial infarction, stroke or death from cardiovascular causes. The HOPE study results showed that ramipril (10 mg/day) significantly reduced the rate of myocardial infarction, stroke or death from cardiovascular causes (651/4645 vs. 826/4652, relative risk 0.78), as well as the rates of the components of the combined endpoint. Ramipril PlaceboRelative RiskOutcome(N=4645)(N=4652)(95% CI)no. (%)P valueCombined End-point(MI, stroke, or death from CV cause) 651 (14.0%) 826 (17.8%) 0.78 (0.70-0.86), P=0.0001 Component End-pointDeath from Cardiovascular Causes 282 (6.1%) 377 (8.1%) 0.74 (0.64-0.87), P=0.0002 Myocardial infarction 459 (9.9%) 570 (12.3%) 0.80 (0.70-0.90), P=0.0003 Stroke 156 (3.4%) 226 (4.9%) 0.68 (0.56-0.84), P=0.0002 Overall Mortality(Death from any Cause) 482 (10.4%) 569 (12.2%) 0.84 (0.75-0.95), P=0.005 This effect was evident after about one year of treatment. Figure 1: Kaplan-Meier Estimates of the composite outcome of MI, Stroke, or Death from CV causes in the Ramipril Group and the Placebo Group. The relative risk of the composite outcomes in the Ramipril Group as compared with the Placebo Group was 0.78% (95% confidence interval, 0.70-0.86). Ramipril was effective in different demographic subgroups, (i.e., gender, age), subgroups defined by underlying disease (e.g., cardiovascular disease, hypertension), and subgroups defined by concomitant medication. There were insufficient data to determine whether or not ramipril was equally effective in ethnic subgroups. This study was designed with prespecified substudy in diabetics with at least one other cardiovascular risk factor. Effects of ramipril on the combined endpoint and its components were similar in diabetics (n=3,577) to those in the overall study population. RamiprilPlaceboRelativeOutcome(N=1808)(N=1769)Risk Reductionno. (%)(95% CI)Combined End-point(MI, stroke, or death from CV cause) 277 (15.3%) 351 (19.8%) 0.25 (0.12-0.36), P=0.0004 Component End-pointDeath from Cardiovascular Causes 112 (6.2%) 172 (9.7%) 0.37 (0.21-0.51), P=0.0001 Myocardial infarction 185 (10.2%) 229 (12.9%) 0.22 (0.06-0.36), P=0.01 Stroke 76 (4.2%) 108 (6.1%) 0.33 (0.10-0.50), P=0.007 Figure 2: The Beneficial Effect of Treatment with Ramipril on the Composite Outcome of Myocardial Infarction, Stroke, or Death from Cardiovascular Causes Overall and in Various Subgroups. Cerebrovascular disease was defined as stroke or transient ischemic attacks. The size of each symbol is proportional to the number of patients in each group. The dashed line indicates overall relative risk. The benefits of ramipril were observed among patients who were taking aspirin or other anti-platelet agents, beta-blockers, and lipid-lowering agents as well as diuretics and calcium channel blockers. Hypertension Administration of ramipril to patients with mild to moderate hypertension results in 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.) Use of ramipril in combination with thiazide diuretics gives blood pressure lowering effect greater than that seen with either agent alone. In single-dose studies, doses of 5-20 mg of ramipril lowered blood pressure within 1-2 hours, with peak reductions achieved 3-6 hours after dosing. The antihypertensive effect of single dose persisted for 24 hours. In longer term (4-12 weeks) controlled studies, once-daily doses of 2.5-10 mg were similar in their effect, lowering supine or standing systolic and diastolic blood pressures 24 hours after dosing by about 6/4 mm Hg more than placebo. In comparisons of peak vs. trough effect, the trough effect represented about 50-60% of the peak response. In 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. (See DOSAGE AND ADMINISTRATION.) 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 years. Abrupt withdrawal of ramipril has not resulted in rapid increase in blood pressure. Ramipril has been compared with other ACE inhibitors, beta-blockers, and thiazide diuretics. It 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. Except for thiazides, no formal interaction studies of ramipril with other antihypertensive agents have been carried out. Limited experience in controlled and uncontrolled trials combining ramipril with calcium channel blocker, loop diuretic, or triple therapy (beta-blocker, vasodilator, and diuretic) indicate no unusual drug-drug interactions. Other ACE inhibitors have had less than additive effects with beta adrenergic blockers, presumably because both drugs lower blood pressure by inhibiting parts of the renin-angiotensin system. Ramipril was less effective in blacks than in caucasians. The effectiveness of ramipril was not influenced by age, sex, or weight. In baseline controlled study of 10 patients with mild essential hypertension, blood pressure reduction was accompanied by 15% increase in renal blood flow. In healthy volunteers, glomerular filtration rate was unchanged. figure. figure.

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS Ramipril is contraindicated in patients who are hypersensitive to this product or any other angiotensin converting enzyme inhibitor (e.g., patient who has experienced angioedema during therapy with any other ACE inhibitor).

DESCRIPTION SECTION.

DESCRIPTION Ramipril is 2-aza-bicyclo [3.3.0]-octane-3-carboxylic acid derivative. It is white, crystalline substance soluble in polar organic solvents and buffered aqueous solutions. Ramipril melts between 105C and 112C. The CAS Registry Number is 87333-19-5. Ramiprils chemical name is (2S,3aS,6aS)-1[(S)-N-[(S)-1-Carboxy-3-phenylpropyl] alanyl] octahydrocyclopenta [b]pyrrole-2-carboxylic acid, 1-ethyl ester; its structural formula is:Its molecular formula is C23H32N2O5, and its molecular weight is 416.5. Ramiprilat, the diacid metabolite of ramipril, is non-sulfhydryl angiotensin converting enzyme inhibitor. Ramipril is converted to ramiprilat by hepatic cleavage of the ester group. Ramipril is supplied as hard shell capsules for oral administration containing 1.25 mg, 2.5 mg, mg, and 10 mg of ramipril. The inactive ingredients present are pregelatinized starch NF, gelatin, and titanium dioxide. The 1.25 mg capsule shell contains yellow iron oxide, the 2.5 mg capsule shell contains D&C yellow 10, D&C red 28, FD&C red 40 and yellow iron oxide, the mg capsule shell contains D&C red 28, D&C yellow 10, FD&C blue and FD&C red 40, and the 10 mg capsule shell contains D&C red 28, FD&C blue 1, FD&C red 40 and black iron oxide. structure.

DRUG INTERACTIONS SECTION.

Drug Interactions Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including ramipril.. With nonsteroidal anti-inflammatory agents: Rarely, concomitant treatment with ACE inhibitors and nonsteroidal anti-inflammatory agents have been associated with worsening of renal failure and an increase in serum potassium. With diuretics: Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with ramipril. The possibility of hypotensive effects with ramipril can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with ramipril. If this is not possible, the starting dose should be reduced. (See DOSAGE AND ADMINISTRATION.) With potassium supplements and potassium-sparing diuretics: Ramipril can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution, and the patients serum potassium should be monitored frequently. With lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If diuretic is also used, the risk of lithium toxicity may be increased. Other: Neither ramipril nor its metabolites have been found to interact with food, digoxin, antacid, furosemide, cimetidine, indomethacin, and simvastatin. The combination of ramipril and propranolol showed no adverse effects on dynamic parameters (blood pressure and heart rate). The co-administration of ramipril and warfarin did not adversely affect the anticoagulant effects of the latter drug. Additionally, co-administration of ramipril with phenprocoumon did not affect minimum phenprocoumon levels or interfere with the subjects state of anti-coagulation.

GERIATRIC USE SECTION.

Geriatric Use Of the total number of patients who received ramipril in US clinical studies of ramipril 11.0% were 65 and over while 0.2% were 75 and over. No overall differences in effectiveness or safety 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, but greater sensitivity of some older individuals cannot be ruled out. One pharmacokinetic study conducted in hospitalized elderly patients indicated that peak ramiprilat levels and area under the plasma concentration time curve (AUC) for ramiprilat are higher in older patients.

HOW SUPPLIED SECTION.

HOW SUPPLIED Ramipril is available in potencies of 1.25 mg, 2.5 mg, mg, and 10 mg in hard gelatin capsules. Ramipril 2.5 mg capsules are supplied as hard gelatin capsules with white opaque body and orange opaque cap. The body has RP 2.5 and the cap has > both printed in black: bottles of 30 (NDC 21695-821-30). Ramipril mg capsules are supplied as hard gelatin capsules with white opaque body and red opaque cap. The body has RP 5 and the cap has > both printed in black: bottles of 30 (NDC 21695-822-30). Ramipril 10 mg capsules are supplied hard gelatin capsules with white opaque body and blue opaque cap. The body has RP 10 and the cap has > both printed in black: bottles of 30 (NDC 21695-823-30).Dispense in well-closed container with safety closure. Store at controlled room temperature, 20 to 25oC (68 to 77oF) with excursions permitted between 15 to 30oC (59 to 86oF). (See USP). Manufactured for: Cobalt Laboratories, Bonita Springs, Florida, U.S.A., 34134 Item Number: LFT0129AB Date: May 2009Repackaged by: Rebel Distributors Corp, Thousand Oaks, CA 91320.

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE Reduction in Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes Ramipril capsules are indicated in patients 55 years or older at high risk of developing major cardiovascular event because of history of coronary artery disease, stroke, peripheral vascular disease, or diabetes that is accompanied by at least one other cardiovascular risk factor (hypertension, elevated total cholesterol levels, low HDL levels, cigarette smoking, or documented microalbuminuria), to reduce the risk of myocardial infarction, stroke, or death from cardiovascular causes. Ramipril capsules can be used in addition to other needed treatment (such as antihypertensive, antiplatelet or lipid-lowering therapy). Hypertension Ramipril capsules are indicated for the treatment of hypertension. It may be used alone or in combination with thiazide diuretics. In using ramipril capsules, consideration should be given to the fact that another angiotensin converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen-vascular disease. Available data are insufficient to show that ramipril capsules do not have similar risk. (See WARNINGS.) In considering use of ramipril capsules, it should be noted that in controlled trials ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks. In addition, ACE inhibitors (for which adequate data are available) cause higher rate of angioedema in black than in non-black patients. (See WARNINGS, Angioedema.).

INFORMATION FOR PATIENTS SECTION.

Information for Patients Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to ACE inhibitors during pregnancy. These patients should be asked to report pregnancies to their physicians as soon as possible.. Angioedema: Angioedema, including laryngeal edema, can occur with treatment with ACE inhibitors, especially following the first dose. Patients should be so advised and told 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. Symptomatic Hypotension: Patients should be cautioned that lightheadedness can occur, especially during the first days of therapy, and it should be reported. Patients should be told that if syncope occurs, ramipril should be discontinued until the physician has been consulted. All patients should be cautioned that inadequate fluid intake or excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope. Hyperkalemia: Patients should be told not to use salt substitutes containing potassium without consulting their physician. Neutropenia: Patients should be told to promptly report any indication of infection (e.g., sore throat, fever), which could be sign of neutropenia.

LABORATORY TESTS SECTION.

Clinical Laboratory Test Findings: Creatinine and Blood Urea Nitrogen: Increases in creatinine levels occurred in 1.2% of patients receiving ramipril alone, and in 1.5% of patients receiving ramipril and diuretic. Increases in blood urea nitrogen levels occurred in 0.5% of patients receiving ramipril alone and in 3% of patients receiving ramipril with diuretic. None of these increases required discontinuation of treatment. Increases in these laboratory values are more likely to occur in patients with renal insufficiency or those pretreated with diuretic and, based on experience with other ACE inhibitors, would be expected to be especially likely in patients with renal artery stenosis. (See WARNINGS and PRECAUTIONS.) Since ramipril decreases aldosterone secretion, elevation of serum potassium can occur. Potassium supplements and potassium-sparing diuretics should be given with caution, and the patients serum potassium should be monitored frequently. (See WARNINGS and PRECAUTIONS.) Hemoglobin and Hematocrit: Decreases in hemoglobin or hematocrit (a low value and decrease of g/dl or 5% respectively) were rare, occurring in 0.4% of patients receiving ramipril alone and in 1.5% of patients receiving ramipril plus diuretic. No US patients discontinued treatment because of decreases in hemoglobin or hematocrit. Other (causal relationships unknown): Clinically important changes in standard laboratory tests were rarely associated with ramipril administration. Elevations of liver enzymes, serum bilirubin, uric acid, and blood glucose have been reported, as have cases of hyponatremia and scattered incidents of leukopenia, eosinophilia, and proteinuria. In US trials, less than 0.2% of patients discontinued treatment for laboratory abnormalities; all of these were cases of proteinuria or abnormal liver-function tests.

NURSING MOTHERS SECTION.

Nursing Mothers Ingestion of single 10 mg oral dose of ramipril resulted in undetectable amounts of ramipril and its metabolites in breast milk. However, because multiple doses may produce low milk concentrations that are not predictable from single doses, women receiving ramipril should not breast feed.

OVERDOSAGE SECTION.

OVERDOSAGE Single oral doses in rats and mice of 10-11 g/kg resulted in significant lethality. In dogs, oral doses as high as g/kg induced only mild gastrointestinal distress. Limited data on human overdosage are available. The most likely clinical manifestations would be symptoms attributable to hypotension. Laboratory determinations of serum levels of ramipril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of ramipril overdose. No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of ramipril and its metabolites. Similarly, it is not known which, if any, of these substances can be usefully removed from the body by hemodialysis. Angiotensin II could presumably serve as specific antagonist-antidote in the setting of ramipril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of ramipril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat ramipril overdose by infusion of normal saline solution.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SECTION. Representative Sample of Label 2.5 mgRx onlyNDC 21695-821-30RAMIPRIL CAPSULES2.5 mg30 capsulesRebel Distributors. Ramipril 2.5mg.

PEDIATRIC USE SECTION.

Pediatric Use Safety and effectiveness in pediatric patients have not been established. Irreversible kidney damage has been observed in very young rats given single dose of ramipril.

PRECAUTIONS SECTION.

PRECAUTIONS Impaired Renal Function: As consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin converting enzyme inhibitors, including ramipril, may be associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine may occur. Experience with another angiotensin converting enzyme inhibitor suggests that these increases are usually reversible upon discontinuation of ramipril and/or diuretic therapy. In such patients renal function should be monitored during the first few weeks of therapy. Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when ramipril has been given concomitantly with diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of ramipril and/or discontinuation of the diuretic may be required. Evaluation of the hypertensive patient should always include assessment of renal function. (See DOSAGE AND ADMINISTRATION.) Hyperkalemia: In clinical trials, hyperkalemia (serum potassium greater than 5.7 mEq/L) occurred in approximately 1% of hypertensive patients receiving ramipril. In most cases, these were isolated values, which resolved despite continued therapy. None of these patients was discontinued from the trials because of hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes, which should be used cautiously, if at all, with ramipril. (See Drug Interactions.) Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough. Impaired Liver Function: Since ramipril is primarily metabolized by hepatic esterases to its active moiety, ramiprilat, patients with impaired liver function could develop markedly elevated plasma levels of ramipril. No formal pharmacokinetic studies have been carried out in hypertensive patients with impaired liver function. However, since the renin-angiotensin system may be activated in patients with severe liver cirrhosis and/or ascites, particular caution should be exercised in treating these patients. Surgery/Anesthesia: In patients undergoing surgery or during anesthesia with agents that produce hypotension, ramipril may block angiotensin II formation that would otherwise occur secondary to compensatory renin release. Hypotension that occurs as result of this mechanism can be corrected by volume expansion. Information for Patients Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to ACE inhibitors during pregnancy. These patients should be asked to report pregnancies to their physicians as soon as possible.. Angioedema: Angioedema, including laryngeal edema, can occur with treatment with ACE inhibitors, especially following the first dose. Patients should be so advised and told 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. Symptomatic Hypotension: Patients should be cautioned that lightheadedness can occur, especially during the first days of therapy, and it should be reported. Patients should be told that if syncope occurs, ramipril should be discontinued until the physician has been consulted. All patients should be cautioned that inadequate fluid intake or excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope. Hyperkalemia: Patients should be told not to use salt substitutes containing potassium without consulting their physician. Neutropenia: Patients should be told to promptly report any indication of infection (e.g., sore throat, fever), which could be sign of neutropenia. Drug Interactions Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including ramipril.. With nonsteroidal anti-inflammatory agents: Rarely, concomitant treatment with ACE inhibitors and nonsteroidal anti-inflammatory agents have been associated with worsening of renal failure and an increase in serum potassium. With diuretics: Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with ramipril. The possibility of hypotensive effects with ramipril can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with ramipril. If this is not possible, the starting dose should be reduced. (See DOSAGE AND ADMINISTRATION.) With potassium supplements and potassium-sparing diuretics: Ramipril can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution, and the patients serum potassium should be monitored frequently. With lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If diuretic is also used, the risk of lithium toxicity may be increased. Other: Neither ramipril nor its metabolites have been found to interact with food, digoxin, antacid, furosemide, cimetidine, indomethacin, and simvastatin. The combination of ramipril and propranolol showed no adverse effects on dynamic parameters (blood pressure and heart rate). The co-administration of ramipril and warfarin did not adversely affect the anticoagulant effects of the latter drug. Additionally, co-administration of ramipril with phenprocoumon did not affect minimum phenprocoumon levels or interfere with the subjects state of anti-coagulation. Carcinogenesis, Mutagenesis, Impairment of Fertility No evidence of 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 human cell line, or forward gene-mutation assay in Chinese hamster ovary cell line. Several metabolites and degradation products of ramipril were also negative in the Ames test. study in rats with dosages as great as 500 mg/kg/day did not produce adverse effects on fertility. Pregnancy Pregnancy Categories (first trimester) and (second and third trimesters). See WARNINGS: Fetal/Neonatal Morbidity and Mortality. Nursing Mothers Ingestion of single 10 mg oral dose of ramipril resulted in undetectable amounts of ramipril and its metabolites in breast milk. However, because multiple doses may produce low milk concentrations that are not predictable from single doses, women receiving ramipril should not breast feed. Geriatric Use Of the total number of patients who received ramipril in US clinical studies of ramipril 11.0% were 65 and over while 0.2% were 75 and over. No overall differences in effectiveness or safety 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, but greater sensitivity of some older individuals cannot be ruled out. One pharmacokinetic study conducted in hospitalized elderly patients indicated that peak ramiprilat levels and area under the plasma concentration time curve (AUC) for ramiprilat are higher in older patients. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Irreversible kidney damage has been observed in very young rats given single dose of ramipril.

PREGNANCY SECTION.

Pregnancy Pregnancy Categories (first trimester) and (second and third trimesters). See WARNINGS: Fetal/Neonatal Morbidity and Mortality.

WARNINGS SECTION.

WARNINGS Anaphylactoid and Possibly Related Reactions Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including ramipril) may be subject to variety of adverse reactions, some of them serious. Head and Neck Angioedema Patients with history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor. (See alsoCONTRAINDICATIONS). Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with angiotensin converting enzyme inhibitors. Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, treatment with ramipril should be discontinued and appropriate therapy instituted immediately. Where there is involvement of the tongue, glottis, or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine solution 1:1,000 (0.3 ml to 0.5 ml) should be promptly administered. (See ADVERSE REACTIONS.) Intestinal Angioedema Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain. In large U.S. postmarketing study, angioedema (defined as reports of angio, face, larynx, tongue, or throat edema) was reported in 3/1523 (0.20%) of black patients and in 8/8680 (0.09%) of white patients. These rates were not different statistically. Anaphylactoid reactions during desensitization: Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge. Anaphylactoid reactions during membrane exposure: Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. Hypotension Ramipril can cause symptomatic hypotension, after either the initial dose or later dose when the dosage has been increased. Like other ACE inhibitors, ramipril has been only rarely associated with hypotension in uncomplicated hypertensive patients. Symptomatic hypotension is most likely to occur in patients who have been volume- and/or salt-depleted as result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Volume and/or salt depletion should be corrected before initiating therapy with ramipril. In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or azotemia and, rarely, with acute renal failure and death. In such patients, ramipril therapy should be started under close medical supervision; they should be followed closely for the first weeks of treatment and whenever the dose of ramipril or diuretic is increased. If hypotension occurs, the patient should be placed in supine position and, if necessary, treated with intravenous infusion of physiological saline. Ramipril treatment usually can be continued following restoration of blood pressure and volume. Hepatic Failure Rarely, ACE inhibitors, including ramipril, have been associated with syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up. Neutropenia/Agranulocytosis As with other ACE inhibitors, rarely, mild in isolated cases severe reduction in the red blood cell count and hemoglobin content, white blood cell or platelet count may develop. In isolated cases, agranulocytosis, pancytopenia, and bone marrow depression may occur. Hematological reactions to ACE inhibitors are more likely to occur in patients with collagen vascular disease (e.g. systemic lupus erythematosus, scleroderma) and renal impairment. Monitoring of white blood cell counts should be considered in patients with collagen-vascular disease, especially if the disease is associated with impaired renal function. Fetal/Neonatal Morbidity and Mortality ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, ACE inhibitors should be discontinued as soon as possible. The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to the ACE inhibitor exposure. In published retrospective epidemiological study, infants whose mothers had taken an ACE inhibitor during their first trimester of pregnancy appeared to have an increased risk of major congenital malformations compared with infants whose mothers had not undergone first trimester exposure to ACE inhibitor drugs. The number of cases of birth defects is small and the findings of this study have not yet been confirmed.Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE inhibitors will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intraamniotic environment. If oligohydramnios is observed, ramipril should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Infants with histories of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function. Ramipril which crosses the placenta can be removed from the neonatal circulation by these means, but limited experience has not shown that such removal is central to the treatment of these infants. No teratogenic effects of ramipril were seen in studies of pregnant rats, rabbits, and cynomolgus monkeys. On body surface area basis, the doses used were up to approximately 400 times (in rats and monkeys) and times (in rabbits) the recommended human dose.