COVERAM

Perindopril erbumine tablets

USP contain the tert-butylamine salt of perindopril, the ethyl ester of a non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor.

Perindopril erbumine is chemically described as (2S,3DS,7DS)-1-[(S)-N-[(S)-1-Carboxy-butyl]alanyl]hexahydro-2-indolinecarboxylic acid, 1-ethyl ester, compound with tert-butylamine (1:1).

Its molecular formula is

C 19 H 32 N 2 O 5 C 4 H 11 N. Its structural formula is: Perindopril erbumine USP is a white or almost white, crystalline powder, slightly hygroscopic with a molecular weight of 368.47 (free acid) or 441.61 (salt form).

It is freely soluble in water (60% w/w), alcohol and chloroform.

Perindopril is the free acid form of perindopril erbumine, is a pro-drug and metabolized in vivo by hydrolysis of the ester group to form perindoprilat, the biologically active metabolite.

USP are available in 2 mg, 4 mg and 8 mg strengths for oral administration.

In addition to perindopril erbumine, each tablet contains the following inactive ingredients: anhydrous lactose, silica hydrophobic colloidal anhydrous, microcrystalline cellulose, and magnesium stearate.

Perindopril erbumine tablets are indicated for the treatment of patients with essential hypertension.

Perindopril erbumine tablets are indicated for treatment of patients with stable coronary artery disease to reduce the risk of cardiovascular mortality or nonfatal myocardial infarction. 1.1 Hypertension Perindopril erbumine tablets are indicated for the treatment of patients with essential hypertension.

Perindopril erbumine tablets may be used alone or given with other classes of antihypertensives, especially thiazide diuretics. 1.2 Stable Coronary Artery Disease Perindopril erbumine tablets are indicated for treatment of patients with stable coronary artery disease to reduce the risk of cardiovascular mortality or nonfatal myocardial infarction.

Perindopril erbumine tablets can be used with conventional treatment for management of coronary artery disease, such as antiplatelet, antihypertensive or lipid-lowering therapy.

Lactation General anesthesia Angor de Prinzmetal

Recent history of myocardial infarction Stenosing periphery arterial disease Asthma First degree atrial cell Chronic obstructive Bronchopneumopathy Cardiomyopathy restrictive Congenital Cardiology Diabetes Child under 15 years of age Female likely to be pregnant Pregnancy Hyperthyroidism Heart failure Coronary heart failure Hepatic impairment Renal impairment Surgical intervention Newborn exposed in utero to the medicine Phoechromocytoma Psoriasis Psoriasis, history Sports Subject to strict fasting Treatment of desensitization in progress Cardiac valvulopathy.

Perindopril erbumine is a pro-drug for perindoprilat, which inhibits ACE in human subjects and animals.

The mechanism through which perindoprilat lowers blood pressure is believed to be primarily inhibition of ACE activity.

ACE is a peptidyl dipeptidase that catalyzes conversion of the inactive decapeptide, angiotensin I, to the vasoconstrictor, angiotensin II.

II is a potent peripheral vasoconstrictor, which stimulates aldosterone secretion by the adrenal cortex, and provides negative feedback on renin secretion.

Inhibition of ACE results in decreased plasma angiotensin II, leading to decreased vasoconstriction, increased plasma renin activity and decreased aldosterone secretion.

The latter results in diuresis and natriuresis and may be associated with a small increase of serum potassium.

ACE is identical to kininase

II, an enzyme that degrades bradykinin.

Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of perindopril erbumine remains to be elucidated.

While the principal mechanism of perindopril in blood pressure reduction is believed to be through the renin-angiotensin-aldosterone system, ACE inhibitors have some effect even in apparent low-renin hypertension.

Perindopril has been studied in relatively few black patients, usually a low-renin population, and the average response of diastolic blood pressure to perindopril was about half the response seen in nonblack patients, a finding consistent with previous experience of other ACE inhibitors. 12.2 Pharmacodynamics After administration of perindopril, ACE is inhibited in a dose and blood concentration-related fashion, with the maximal inhibition of to 90% attained by 8 mg persisting for to 12 hours.

Twenty-four hour

ACE inhibition is about 60% after these doses.

The degree of

ACE inhibition achieved by a given dose appears to diminish over time (the ID 50 increases).

The pressor response to an angiotensin

I infusion is reduced by perindopril, but this effect is not as persistent as the effect on ACE; there is about 35% inhibition at 24 hours after a 12 mg dose. 12.3 Pharmacokinetics Absorption: Oral administration of perindopril erbumine results in peak plasma concentrations that occur at approximately 1 hour.

The absolute oral bioavailability of perindopril is about 75%.

Following absorption, approximately to 50% of systemically available perindopril is hydrolyzed to its active metabolite, perindoprilat, which has a mean bioavailability of about 25%.

Peak plasma concentrations of perindoprilat are attained to 7 hours after perindopril administration.

Oral administration of perindopril erbumine with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state.

However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant.

In clinical trials, perindopril was generally administered in a non-fasting state.

With 4 mg, 8 mg and 16 mg doses of perindopril erbumine, C max and AUC of perindopril and perindoprilat increase in a dose-proportional manner following both single oral dosing and at steady state during a once-a-day multiple dosing regimen.

Approximately 60% of circulating perindopril is bound to plasma proteins, and only to 20% of perindoprilat is bound.

Therefore, drug interactions mediated through effects on protein binding are not anticipated.

Following oral administration perindopril exhibits multicompartment pharmacokinetics including a deep tissue compartment (ACE binding sites).

The mean half-life of perindopril associated with most of its elimination is approximately 0.8 to 1 hours.

Perindopril is extensively metabolized following oral administration, with only to 12% of the dose recovered unchanged in the urine.

Six metabolites resulting from hydrolysis, glucuronidation and cyclization via dehydration have been identified.

These include the active

ACE inhibitor, perindoprilat (hydrolyzed perindopril), perindopril and perindoprilat glucuronides, dehydrated perindopril and the diastereoisomers of dehydrated perindoprilat.

In humans, hepatic esterase appears to be responsible for the hydrolysis of perindopril.

The active metabolite, perindoprilat, also exhibits multicompartment pharmacokinetics following the oral administration of perindopril erbumine.

Formation of perindoprilat is gradual with peak plasma concentrations occurring between and 7 hours.

The subsequent decline in plasma concentration shows an apparent mean half-life of to 10 hours for the majority of the elimination, with a prolonged terminal elimination half-life of to 120 hours resulting from slow dissociation of perindoprilat from plasma/tissue ACE binding sites.

During repeated oral once daily dosing with perindopril, perindoprilat accumulates about 1.5 to 2 fold and attains steady state plasma levels in to 6 days.

The clearance of perindoprilat and its metabolites is almost exclusively renal.

Plasma concentrations of both perindopril and perindoprilat in elderly patients (greater than 70 years) are approximately twice those observed in younger patients, reflecting both increased conversion of perindopril to perindoprilat and decreased renal excretion of perindoprilat.

Perindoprilat clearance is reduced in congestive heart failure patients, resulting in a 40% higher dose interval AUC.

With perindopril doses of 2 mg to 4 mg, perindoprilat AUC increases with decreasing renal function.

At creatinine clearances of to 80 mL/min, AUC is about double that at 100 mL/min. When creatinine clearance drops below 30 mL/min, AUC increases more markedly.

In a limited number of patients studied, perindopril clearance by dialysis ranged from about to 80 mL/min. Perindoprilat clearance by dialysis ranged from about to 90 mL/min.

The bioavailability of perindoprilat is increased in patients with impaired hepatic function.

Plasma concentrations of perindoprilat in patients with impaired liver function were about 50% higher than those observed in healthy subjects or hypertensive patients with normal liver function.

Mechanism of action

Bisoprolol is a beta-blocker with a high affinity for beta-1 receptors, without intrinsic sympathomimetic activity, or membrane stabilizing effect.

It has only a low affinity for beta-2 receptors in smooth bronchi and vessel muscles and beta-2 receptors involved in metabolic regulation.

As a result, bisoprolol generally does not alter airway resistance and has no metabolic effects related to action on beta-2 receptors.

The beta-1 selectivity of bisoprolol extends beyond therapeutic doses.

• Liver enzymes (increase) (Rare)
• Hypoglycaemia (Rare)
• Hypertriglyceridaemia (Rare)
• Antinuclear body (increase) (Rare)
• ASAT (increase)
• ALT (increase)
• Psoriasiform eruption (Very rare)
• Alopecia (Very rare)
• Psoriasis (Very rare)
• Psoriasis (aggravation) (Very rare)
• Rash
• Pruritus Coldness at the ends (Common)
• Numbness of the extremities (Common)
• Asthenia (Common)
• Fatigue (Common)
• Hepatitis (Rare)
• Hypersensitivity (Rare)
• Lupic syndrome (Exceptional)
• Angioedema Lacrymal hyposecretion (Rare)
• Conjunctivitis (Very rare)
• Vertigo (Common)
• Allergic Rhinitis (Rare)
• Hearing disorder (Rare)
• Depression (Uncommon)
• Sleep disorder (Uncommon)
• Nightmare (Rare)
• Hallucination (Rare)
• Bradycardia (Very common)
• Raynaud's syndrome (Common)
• Atrialculoventric block (Uncommon)
• Orthostatic hypotension (Uncommon)
• Hypotension (Common)
• Heart failure (aggravation) (Common)
• Intermittent clauding (aggravation) (Common)
• Syncope (Rare)
• Congestive puff Digestive disorder (Common)
• Vomiting Constipation
• Nausea Abdominal pain Diarrhoea Cramp (Uncommon)
• Muscle weakness (Uncommon)
• Arthropathy (Uncommon)
• Headache (Common)
• Bronchospasm (Uncommon)
• Erection disorder (Rare).

In animals, doses of perindopril up to 2,500 mg/kg in mice, 3,000 mg/kg in rats and 1,600 mg/kg in dogs were non-lethal.

Past experiences were scant but suggested that overdosage with other ACE inhibitors was also fairly well tolerated by humans.

The most likely manifestation is hypotension, and treatment should be symptomatic and supportive.

Therapy with the

ACE inhibitor should be discontinued, and the patient should be observed.

Dehydration, electrolyte imbalance and hypotension should be treated by established procedures.

Among the reported cases of perindopril overdosage, patients who were known to have ingested a dose of 80 mg to 120 mg required assisted ventilation and circulatory support.

One additional patient developed hypothermia, circulatory arrest and died following ingestion of up to 180 mg of perindopril.

The intervention for perindopril overdose may require vigorous support.

Laboratory determinations of serum levels of perindopril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of perindopril overdose.

No data are available to suggest physiological maneuvers ( e.g., maneuvers to change the pH of the urine) that might accelerate elimination of perindopril and its metabolites.

Perindopril can be removed by hemodialysis, with clearance of 52 mL/min for perindopril and 67 mL/min for perindoprilat.

II could presumably serve as a specific antagonist-antidote in the settling of perindopril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities.

Because the hypotensive effect of perindopril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat perindopril overdose by infusion of normal saline solution.

Perindopril erbumine tablets are contraindicated in patients known to be hypersensitive (including angioedema) to this product or to any other ACE inhibitor.

Perindopril erbumine tablets are also contraindicated in patients with hereditary or idiopathic angioedema.

Do not co-administer aliskiren with perindopril erbumine tablets in patients with diabetes.

Perindopril erbumine tablets are contraindicated in combination with neprilysin inhibitor (e.g., sacubitril).

Do not administer perindopril erbumine tablets within 36 hours of switching to or from sacubitril/valsartan, a neprilysin inhibitor.

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

Do not co-administer aliskiren with perindopril erbumine tablets in patients with diabetes Do not take a neprilysin inhibitor with perindopril erbumine tablets.

Do not administer perindopril erbumine tablets within 36 hours of switching to or from sacubitril/valsartan.

The recommended initial dose is 4 mg once a day. The dosage may be titrated upward until blood pressure, when measured just before the next dose, is controlled or to a maximum of 16 mg per day. Stable Coronary Artery Disease Perindopril erbumine tablets should be given at an initial dose of 4 mg once daily for 2 weeks, and then increased, as tolerated, to a maintenance dose of 8 mg once daily. 2.1 Hypertension Use in Uncomplicated Hypertensive Patients: In patients with essential hypertension, the recommended initial dose is 4 mg once a day. The dose may be titrated, as needed to a maximum of 16 mg per day. The usual maintenance dose range is 4 mg to 8 mg administered as a single daily dose or in two divided doses.

The recommended initial daily dosage of perindopril erbumine tablets for the elderly is 4 mg daily, given in one or two divided doses.

Experience with perindopril erbumine tablets is limited in the elderly at doses exceeding 8 mg. Dosages above 8 mg should be administered with careful blood pressure monitoring and dose titration.

In patients who are currently being treated with a diuretic, symptomatic hypotension can occur following the initial dose of perindopril erbumine tablets.

Consider reducing the dose of diuretic prior to starting perindopril erbumine tablets. 2.2 Stable Coronary Artery Disease In patients with stable coronary artery disease, perindopril erbumine tablets should be given at an initial dose of 4 mg once daily for 2 weeks, and then increased as tolerated, to a maintenance dose of 8 mg once daily.

In elderly patients (greater than 70 years), perindopril erbumine tablets should be given as a 2 mg dose once daily in the first week, followed by 4 mg once daily in the second week and 8 mg once daily for maintenance dose if tolerated. 2.3 Dose Adjustment in Renal Impairment and Dialysis Perindoprilat elimination is decreased in renally impaired patients.

Perindopril erbumine tablets are not recommended in patients with creatinine clearance <30 mL/min. For patients with lesser degrees of impairment, the initial dosage should be 2 mg/day and dosage should not exceed 8 mg/day. During dialysis, perindopril is removed with the same clearance as in patients with normal renal function.

Perindopril Erbumine T ablets

USP, 2 mg are white to off-white colored round biconvex, uncoated tablets, with debossing “D” on one side and “5” & “7” on either side of the breakline on another side.

Bottles of 100 NDC 65862-286-01 Perindopril Erbumine T ablets USP, 4 mg are white to off-white colored capsule shaped uncoated tablets, with debossing “D” on one side and “5” & “8” on either side of the breakline on another side.

Bottles of 100 NDC 65862-287-01 Perindopril Erbumine T ablets USP, 8 mg are white to off-white colored round biconvex uncoated tablets, with debossing “D” on one side and “5” & “9” on either side of breakline on another side.

Bottles of 100 NDC 65862-288-01 Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) .

Protect from moisture.

Keep out of the reach of children.

For further information, please call Aurobindo Pharma USA, Inc. at 1-866-850-2876.

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 perindopril erbumine 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 perindopril erbumine, unless it is considered lifesaving 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 perindopril erbumine for hypotension, oliguria, and hyperkalemia.

Radioactivity was detectable in fetuses after administration of 14 C-perindopril to pregnant rats.

Milk of lactating rats contained radioactivity following administration of 14 C-perindopril.

It is not known whether perindopril is secreted in human milk.

Because many drugs are secreted in human milk, caution should be exercised when perindopril erbumine is given to nursing mothers.

Neonates With a History of in utero Exposure to Perindopril Erbumine: 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.

Perindopril, 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 of perindopril erbumine in pediatric patients have not been established.

The mean blood pressure effect of perindopril was somewhat smaller in patients over 60 than in younger patients, although the difference was not significant.

Plasma concentrations of both perindopril and perindoprilat were increased in elderly patients compared to concentrations in younger patients.

No adverse effects were clearly increased in older patients with the exception of dizziness and possibly rash.

Start at a low dose and titrate slowly as needed.

Monitor for dizziness because of potential for falls.

Experience with perindopril erbumine in elderly patients at daily doses exceeding 8 mg is limited.