RAMITRIM PLUS

Ramipril is a 2-aza-bicyclo [3.3.0]-octane-3-carboxylic acid derivative.

It is a white, crystalline substance soluble in polar organic solvents and buffered aqueous solutions.

Ramipril melts between 105°-112°C. The CAS Registry Number is 87333-19-5.

Ramipril's chemical name is (2S,3aS,6aS)-1[(S)-N-[(S)-1-Carboxy-3-phenylpropyl] alanyl] octahydrocyclopenta [ b ]pyrrole-2-carboxylic acid, 1-ethyl ester.

Ramipril capsules

USP are supplied as hard gelatin capsules for oral administration containing 1.25 mg, 2.5 mg, 5 mg, and 10 mg of ramipril.

The inactive ingredients present are gelatin, meglumine, pregelatinized starch, and titanium dioxide.

The 1.25 mg capsule shell contains yellow iron oxide, the 2.5 mg capsule contains D&C yellow #10 and FD&C red #40, the 5 mg capsule shell contains FD&C blue #1 and FD&C red #40, and the 10 mg capsule shell contains FD&C blue #1.

The structural formula for ramipril is

Its empirical formula is C 23 H 32 N 2 O and its molecular weight is 416.5.

Ramiprilat, the diacid metabolite of ramipril, is a non-sulfhydryl ACE inhibitor.

Ramipril is converted to ramiprilat by hepatic cleavage of the ester group. structural formula for ramipril.

• Ramipril capsules USP are indicated for the treatment of hypertension.

It may be used alone or in combination with thiazide diuretics. .

• Ramipril capsules USP are indicated in stable patients who have demonstrated clinical signs of congestive heart failure post-myocardial infarction. 1.1 Hypertension Ramipril capsules USP are indicated for the treatment of hypertension.

It may be used alone or in combination with thiazide diuretics. 1.3 Heart Failure Post-Myocardial Infarction Ramipril capsules USP are indicated in stable patients who have demonstrated clinical signs of congestive heart failure within the first few days after sustaining acute myocardial infarction.

Administration of ramipril to such patients has been shown to decrease the risk of death (principally cardiovascular death) and to decrease the risks of failure-related hospitalization and progression to severe/resistant heart failure.

PHARMACOLOGY 12.1 Mechanism of Action Ramipril and ramiprilat inhibit ACE in human subjects and animals.

Angiotensin converting enzyme is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II.

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 a 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 a 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.

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.

Angiotensin converting enzyme is identical to kininase, an enzyme that degrades bradykinin.

Whether increased levels of bradykinin, a potent vasopressor peptide, play a 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 reninangiotensin-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 a low-renin hypertensive population) had a blood pressure lowering response to monotherapy, albeit a smaller average response, than non-Black patients. 12.2 Pharmacodynamics Single doses of ramipril of 2.5 mg to 20 mg produce approximately 60% to 80% inhibition of ACE activity 4 hours after dosing with approximately 40% to 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% 4 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. 12.3 Pharmacokinetics Absorption Following oral administration of ramipril, peak plasma concentrations (C max ) of ramipril are reached within 1 hour.

The extent of absorption is at least 50% to 60%, and is not significantly influenced by the presence of food in the gastrointestinal tract, although the rate of absorption is reduced.

In a trial in which subjects received ramipril capsules or the contents of identical capsules dissolved in water, dissolved in apple juice, or suspended in applesauce, serum ramiprilat levels were essentially unrelated to the use or non-use 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 to 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 μg/mL to10 μg/mL.

Ramipril is almost completely metabolized to ramiprilat, which has about 6 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.

Plasma 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 mg to 20 mg dose range.

The absolute bioavailabilities of ramipril and ramiprilat were 28% and 44%, respectively, when 5 mg of oral ramipril was compared with the same dose of ramipril given intravenously.

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.

Plasma concentrations of ramiprilat decline in a triphasic manner (initial rapid decline, apparent elimination phase, terminal elimination phase).

The initial rapid decline, which represents distribution of the drug into a large peripheral compartment and subsequent binding to both plasma and tissue ACE, has a half-life of to 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 a half-life of to 18 hours.

The terminal elimination phase has a 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 mg to 10 mg, the half-life of ramiprilat concentrations within the therapeutic range was to 17 hours.

In patients with creatinine clearance <40 mL/min/1.73 m 2, 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 to 4 times as large as it is in patients with normal renal function who receive similar doses.

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 a given dose on plasma ACE activity does not vary with hepatic function.

After oral administration of ramipril, about 60% of the parent drug and its metabolites are 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 a dose eliminated by the bile has not been determined.

Less than 2% of the administered dose is recovered in urine as unchanged ramipril.

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 <40 mL/min/1.73 m 2 had higher peak and trough ramiprilat levels and slightly longer times to peak concentrations.

The most common adverse reactions in patients with hypertension included headache, dizziness, fatigue, and cough.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the 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 practice.

Ramipril has been evaluated for safety in over 4000 patients with hypertension; of these, 1230 patients were studied in U.S. controlled trials, and were studied in foreign controlled trials.

Almost 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 placebo-controlled trials were: headache (5.4%), dizziness (2.2%), and fatigue or asthenia (2.0%), but only the last one 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 mg–20 mg. Discontinuation of therapy because of a side effect was required in approximately 3% of U.S. 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 U.S. placebo-controlled trials in more than 1% of patients treated with ramipril, only asthenia (fatigue) was more common on ramipril than placebo (2% [n=13/651] vs. 1% [n=2/286], respectively).

In placebo-controlled trials, there was also an excess of upper respiratory infection and flu syndrome i n 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 a later 1-year study, increased cough was seen in almost 12% of ramipril patients, with about 4% of patients requiring discontinuation of treatment.

Heart Failure Post-Myocardial Infarction AIRE Study

Adverse reactions (except laboratory abnormalities) considered possibly/probably related to study drug that occurred in more than 1% of patients and more frequently on ramipril are shown below.

The incidences are from the

AIRE study.

The follow-up time was between and 46 months for this study.

Table 1.

Possibly/ Probably Related to Study Drug—Placebo-Controlled (AIRE) Mortality Study Adverse Event Placebo (N=982) Ramipril (N=1004) Hypotension 5% 11% Cough increased 4% 8% Dizziness 3% 4% Angina pectoris 2% 3% Nausea 1% 2% Postural hypotension 1% 2% Syncope 1% 2% Vomiting 0.5% 2% Vertigo 0.7% 2% Abnormal kidney function 0.5% 1% Diarrhea 0.4% 1% Other Adverse Reactions Other adverse reactions reported in controlled clinical trials (in less than 1% of ramipril patients), or rarer events seen in post-marketing experience, include the following (in some, a causal relationship to drug is uncertain): Body as a whole: Anaphylactoid reactions.

Symptomatic hypotension (reported in 0.5% of patients in U.S. trials) , syncope, and palpitations.

Pancytopenia, hemolytic anemia, and thrombocytopenia.

Decreases in hemoglobin or hematocrit (a low value and a decrease of 5 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 a diuretic.

Acute renal failure.

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 a diuretic.

Angioneurotic edema

Angioneurotic edema has been reported in 0.3% of patients in U.S. clinical trials of ramipril.

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.

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.

Anxiety, amnesia, convulsions, depression, hearing loss, insomnia, nervousness, neuralgia, neuropathy, paresthesia, somnolence, tinnitus, tremor, vertigo, and vision disturbances.

As with other ACE inhibitors, a symptom complex has been reported which may include a 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.

Arthralgia, arthritis, dyspnea, edema, epistaxis, impotence, increased sweating, malaise, myalgia, and weight gain. 6.2 Post-Marketing Experience In addition to adverse reactions 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. 6.3 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 a diuretic.

Increases in blood urea nitrogen levels occurred in 0.5% of patients receiving ramipril alone and in 3% of patients receiving ramipril with a 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 a diuretic and, based on experience with other ACE inhibitors, would be expected to be especially likely in patients with renal artery stenosis.

As ramipril decreases aldosterone secretion, elevation of serum potassium can occur.

Use potassium supplements and potassium sparing diuretics with caution, and monitor the patient's serum potassium frequently.

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 leucopenia, 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.

Single oral doses of ramipril in rats and mice of 10 g/kg to 11 g/kg resulted in significant lethality.

In dogs, oral doses as high as 1 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 effectively removed from the body by hemodialysis.

II could presumably serve as a 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.

Angioedema related to previous treatment with an ACE inhibitor, or a history of hereditary or idiopathic angioedema.

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

• Hypertension: Initial dose is 2.5 mg to 20 mg once daily.

Adjust dosage according to blood pressure response after 2–4 weeks of treatment.

The usual maintenance dose following titration is 2.5 mg to 20 mg daily as a single dose or equally divided doses.

• Heart failure post-myocardial infarction: Starting dose of 2.5 mg twice daily.

If patient becomes hypotensive at this dose, decrease dosage to 1.25 mg twice daily.

Increase dose as tolerated toward a target dose of 5 mg twice daily, with dosage increases about 3 weeks apart.

• Dosage adjustment: See respective sections pertaining to dosage adjustment in special situations. 2.1 Hypertension The recommended initial dose for patients not receiving a diuretic is 2.5 mg once a day. Adjust dose according to blood pressure response.

The usual maintenance dosage range is 2.5 mg to 20 mg per day administered as a 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, consider an increase in dosage or twice daily administration.

If blood pressure is not controlled with ramipril alone, a diuretic can be added. 2.3 Heart Failure Post-Myocardial Infarction For the treatment of post-myocardial infarction patients who have shown signs of congestive heart failure, the recommended starting dose of ramipril is 2.5 mg twice daily (5 mg per day).

A patient who becomes hypotensive at this dose may be switched to 1.25 mg twice daily.

After one week at the starting dose, increase dose (if tolerated) toward a target dose of 5 mg twice daily, with dosage increases being about 3 weeks apart.

After the initial dose of ramipril, observe the patient under medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour.

If possible, reduce the dose of any concomitant diuretic as this may diminish the likelihood of hypotension.

The appearance of hypotension after the initial dose of ramipril does not preclude subsequent careful dose titration with the drug, following effective management of the hypotension. 2.4 General Dosing Information Generally, swallow ramipril capsules whole.

The ramipril capsule can also be opened and the contents sprinkled on a small amount (about 4 oz). of applesauce or mixed in 4 oz. (120 mL) of water or apple juice.

To be sure that ramipril is not lost when such a mixture is used, consume the mixture 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 with potassium supplements, potassium salt substitutes, or potassium-sparing diuretics can lead to increases of serum potassium. 2.5 Dosage Adjustment Renal Impairment Establish baseline renal function in patients initiating ramipril capsules.

Usual regimens of therapy with ramipril capsule may be followed in patients with estimated creatinine clearance >40 mL/min. However, in patients with worse impairment, 25 % of the usual dose of ramipril capsule is expected to produce full therapeutic levels of ramiprilat.

For patients with hypertension and renal impairment, the recommended initial dose is 1.25 mg ramipril once daily.

Dosage may be titrated upward until blood pressure is controlled or to a maximum total daily dose of 5 mg. Heart Failure Post-Myocardial Infarction For patients with heart failure and renal impairment, the recommended initial dose is 1.25 mg ramipril once daily.

The dose may be increased to 1.25 mg twice daily, and up to a maximum dose of 2.5 mg twice daily depending on clinical response and tolerability.

Blood pressure decreases associated with any dose of ramipril 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, initiate dosing at 1.25 mg once daily.

Adjust dosage according to blood pressure response.

SUPPLIED/STORAGE AND HANDLING Ramipril Capsules, USP are available in 5 mg and 10 mg hard gelatin capsules.

USP are summarized below.

USP, 5 mg are: Size "4" capsules with red cap, imprinted with 'LUPIN' in black ink and red body imprinted with 'RAMIPRIL 5 mg' in black ink, containing white to off-white powder.

NDC 63187-073-30 bottles of 30 NDC 63187-073-60 bottles of 60 NDC 63187-073-90 bottles of 90 Ramipril Capsules USP, 10 mg are: Size "4" capsules with light blue cap, imprinted with 'LUPIN' in black ink and light blue body imprinted with 'RAMIPRIL 10 mg' in black ink, containing white to off-white powder.

NDC 63187-277-30 bottles of 30 NDC 63187-277-60 bottles of 60 NDC 63187-277-90 bottles of 90 Dispense in light-resistant, tight container with child-resistant closure.

Store at 20° to 25°C (68° to 77°F) .

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death.

Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations.

Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death.

When pregnancy is detected, discontinue ramipril as soon as possible.

These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy.

Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents.

Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.

In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus.

Perform serial ultrasound examinations to assess the intra-amniotic environment.

If oligohydramnios is observed, discontinue ramipril unless it is considered life-saving for the mother.

Fetal testing may be appropriate, based on the week of pregnancy.

Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Closely observe infants with histories of in utero exposure to ramipril for hypotension, oliguria, and hyperkalemia.

Ingestion of a 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 a single dose, do not use ramipril in nursing mothers.

Neonates with a history of in utero exposure to ramipril If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion.

Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.

Ramipril, which crosses the placenta, can theoretically 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.

Safety and effectiveness in pediatric patients have not been established.

Irreversible kidney damage has been observed in very young rats given a single dose of ramipril.

Of the total number of patients who received ramipril in U.S. clinical studies of ramipril, 11.0% were ≥65 years of age while 0.2% were ≥75 years of age.

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 a 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.