TRIATEC

Ramipril is a prodrug belonging to the angiotensin-converting enzyme (ACE) inhibitor class of medications.

It is metabolized to ramiprilat in the liver and, to a lesser extent, kidneys.

Ramiprilat is a potent, competitive inhibitor of ACE, the enzyme responsible for the conversion of angiotensin I (ATI) to angiotensin II (ATII).

ATII regulates blood pressure and is a key component of the renin-angiotensin-aldosterone system (RAAS).

Ramipril may be used in the treatment of hypertension, congestive heart failure, nephropathy, and to reduce the rate of death, myocardial infarction and stroke in individuals at high risk of cardiovascular events.

For the management of mild to severe hypertension.

May be used to reduce cardiovascular mortality following myocardial infarction in hemodynamically stable individuals who develop clinical signs of congestive heart failure within a few days following myocardial infarction.

To reduce the rate of death, myocardial infarction and stroke in individuals at high risk of cardiovascular events.

May be used to slow the progression of renal disease in individuals with hypertension, diabetes mellitus and microalubinuria or overt nephropathy.

Ramipril is an

ACE inhibitor similar to benazepril, fosinopril and quinapril.

It is an inactive prodrug that is converted to ramiprilat in the liver, the main site of activation, and kidneys.

Ramiprilat confers blood pressure lowing effects by antagonizing the effect of the RAAS.

RAAS is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance.

During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from the granular cells of the juxtaglomerular apparatus in the kidneys.

In the blood stream, renin cleaves circulating angiotensinogen to ATI, which is subsequently cleaved to ATII by ACE.

ATII increases blood pressure using a number of mechanisms.

First, it stimulates the secretion of aldosterone from the adrenal cortex.

Aldosterone travels to the distal convoluted tubule (DCT) and collecting tubule of nephrons where it increases sodium and water reabsorption by increasing the number of sodium channels and sodium-potassium ATPases on cell membranes.

Second, ATII stimulates the secretion of vasopressin (also known as antidiuretic hormone or ADH) from the posterior pituitary gland.

ADH stimulates further water reabsorption from the kidneys via insertion of aquaporin-2 channels on the apical surface of cells of the DCT and collecting tubules.

Third, ATII increases blood pressure through direct arterial vasoconstriction.

Stimulation of the

Type 1 ATII receptor on vascular smooth muscle cells leads to a cascade of events resulting in myocyte contraction and vasoconstriction.

In addition to these major effects, ATII induces the thirst response via stimulation of hypothalamic neurons.

ACE inhibitors inhibit the rapid conversion of ATI to ATII and antagonize RAAS-induced increases in blood pressure.

ACE (also known as kininase II) is also involved in the enzymatic deactivation of bradykinin, a vasodilator.

Inhibiting the deactivation of bradykinin increases bradykinin levels and may sustain the effects of ramiprilat by causing increased vasodilation and decreased blood pressure.

The extent of absorption is at least 50-60%.

Food decreases the rate of absorption from the GI tract without affecting the extent of absorption.

The absolute bioavailabilities of ramipril and ramiprilat were 28% and 44%, respectively, when oral administration was compared to intravenous administration.

The serum concentration of ramiprilat was unchanged when capsules were opened and the contents dissolved in water, dissolved in apple juice, or suspended in apple sauce.

Hepatic metabolism accounts for 75% of total ramipril metabolism.

Label 25% of hepatic metabolism produces the active metabolite ramiprilat via liver esterase enzymes. 100% of renal metabolism converts ramipril to ramiprilat.

Other metabolites, diketopiperazine ester, the diketopiperazine acid, and the glucuronides of ramipril and ramiprilat, are inactive.

Hover over products below to view reaction partners Ramipril Diketopiperazine acid Diketopiperazine ester Ramiprilat.

Following oral administration, about 60% of the dose is eliminated in the urine as unchanged ramipril (<2%) and its metabolites.

About 40% of the dose is found in the feces, representing both unabsorbed drug and drugs and metabolites eliminated via biliary excretion.

The urinary excretion of ramipril may be reduced in patients with impaired renal function.

Plasma concentrations of ramiprilat decline in a triphasic manner.

Initial rapid decline represents distribution into tissues and has a half life of 2-4 hours.

The half life of the apparent elimination phase is 9-18 hours, which is thought to represent clearance of free drug.

The half-life of the terminal elimination phase is > 50 hours and thought to represent clearance of drug bound to ACE due to its slow dissociation.

The half life of ramiprilat after multiple daily doses (MDDs) is dose-dependent, ranging from 13-17 hours with 5-10 mg MDDs to 27-36 hours for 2.5 mg MDDs.

The renal clearance of ramipril and ramiprilat was reported to be 7.2 and 77.4 mL/min/1.73m 2.

The mean renal clearance of ramipril and ramiprilat is reported to be 10.7 and 126.8 mL/min in healthy elderly patients with normal renal function, additionally the Cmax of ramiprilat is approximately 20% higher in this population.

While the pharmacokinetics of ramipril appear unaffected by reduced renal function, the plasma concentration and half-life of ramiprilat are increased.

In patient's with hepatic failure the concentration of ramipril is initially increased while the tmax of ramiprilat is prolonged due to a reduced ability to metabolize the drug.

However, steady state concentrations of ramiprilat are the same in hepatic failure as in healthy patients.

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Symptoms of overdose may include excessive peripheral vasodilation (with marked hypotension and shock), bradycardia, electrolyte disturbances, and renal failure.

Cases of

ACE inhibitor induced hepatotoxicity have been reported in humans and presented as acute jaundice and elevated liver enzymes.

Removal of the

ACE inhbitor resulted in a decline in liver enzymes and re-challenge produced a subsequent increase.

There were no observed tumerogenic effects at chronic doses up to 500 mg/kg/day to rats for 24 months or at doses up to 1000 mg/kg/day to mice for 18 months.

For both species doses were administered by gavage and equivalent to 200 time the maximum recommended human exposure based on 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 of ramipril also produced negative results in the Ames test.

No effects on fertility were seen in rats at doses up to 500 mg/kg/day. No teratogenicity was observed in rats and cynomolgus monkeys at doses 400 times the maximum recommended human exposure nor in rabbites at 2 times the maximum recommended human exposure.

LD 50 10 g/kg (rat).

LD 50 10.5 g/kg (mouse).

LD 50 1 g/kg (dog).

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.