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Name:Perindopril Erbumine
Manufacturer:Roxane Laboratories, Inc.
Category:Prescription Marketed Drugs


These highlights do not include all the information needed to use Perindopril Erbumine Tablets safely and effectively. See full prescribing information for Perindopril Erbumine Tablets. Perindopril Erbumine Tablets 2 mg, 4 mg and 8 mg Initial U.S. Approval: 1993

PERINDOPRIL ERBUMINE - perindopril erbumine tablet 
Roxane Laboratories, Inc.

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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use Perindopril Erbumine Tablets safely and effectively. See full prescribing information for Perindopril Erbumine Tablets. Perindopril Erbumine Tablets 2 mg, 4 mg and 8 mg Initial U.S. Approval: 1993

RECENT MAJOR CHANGES

WARNING: AVOID USE IN PREGNANCY

When pregnancy is detected, Perindopril Erbumine Tablets should be discontinued as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury to or death of the developing fetus. (5.4)


INDICATIONS AND USAGE

  • Perindopril Erbumine Tablets are indicated for the treatment of patients with essential hypertension. (1.1)
  • 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. (1.2)

DOSAGE AND ADMINISTRATION

Hypertension

  • 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. (2.1)

Stable Coronary Artery Disease

  • Perindopril Erbumine Tablets should be given at an initial dose of 4 mg once daily for two weeks, and then increased, as tolerated, to a maintenance dose of 8 mg once daily. (2.2)

DOSAGE FORMS AND STRENGTHS

Tablets: 2, 4 and 8 mg (3)


CONTRAINDICATIONS

  • Angioedema related to previous treatment with an ACE inhibitor, or a history of hereditary or idiopathic angioedema. (4, 5.1)

WARNINGS AND PRECAUTIONS

  • Watch for anaphylactoid reactions, including angioedema. (5.1)
  • Monitor renal function during therapy. (5.8)
  • Assess for hypotension and hyperkalemia. (5.2, 5.6)

ADVERSE REACTIONS

  • Hypertension: Most common adverse events (incidence greater than or equal to 5%) are cough, dizziness and back pain. (6.1)
  • Stable Coronary Artery Disease: Most common adverse events leading to discontinuation were cough, drug intolerance, and hypotension. (6.1) 

To report SUSPECTED ADVERSE REACTIONS, contact Roxane Laboratories, Inc. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.


DRUG INTERACTIONS

  • Diuretics: Excessive drop in blood pressure. (7.1)
  • Potassium-sparing diuretics/potassium supplements: Hyperkalemia. (7.2)
  • Lithium: Increase serum lithium levels, symptoms of lithium toxicity. (7.3)
  • Injectable gold: Nitritoid reactions (facial flushing, nausea, vomiting, and hypotension). (7.4)

USE IN SPECIFIC POPULATIONS

  • Geriatrics: Start at low daily dose (4 mg or less) and titrate slowly as needed. Experience with doses exceeding 8 mg is limited. (8.5)
  • Dosage adjustment may be necessary in renally impaired patients. (8.7)


See 17 for PATIENT COUNSELING INFORMATION

Revised: 07/2010

FULL PRESCRIBING INFORMATION: CONTENTS*
* Sections or subsections omitted from the full prescribing information are not listed

1 INDICATIONS AND USAGE

1.1 Hypertension

1.2 Stable Coronary Artery Disease

2 DOSAGE AND ADMINISTRATION

2.1 Hypertension

2.2 Stable Coronary Artery Disease

2.3 Dose Adjustment in Renal Impairment and Dialysis

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Anaphylactoid and Possibly Related Reactions

5.2 Hypotension

5.3 Neutropenia/Agranulocytosis

5.4 Fetal/Neonatal Morbidity and Mortality

5.5 Impaired Renal Function

5.6 Hyperkalemia

5.7 Cough

5.8 Hepatic Failure

5.9 Surgery/Anesthesia

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.4 Postmarketing Experience  

6.5 Clinical Laboratory Test Findings  

7 DRUG INTERACTIONS

7.1 Diuretics

7.2 Potassium Supplements and Potassium-Sparing Diuretics

7.3 Lithium

7.4 Gold

7.5 Digoxin

7.6 Gentamicin

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment 

8.7 Hepatic Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Hypertension

14.2 Stable Coronary Artery Disease

16 HOW SUPPLIED/STORAGE AND HANDLING

Storage

17 PATIENT COUNSELING INFORMATION

PRINCIPAL DISPLAY PANEL

PRINCIPAL DISPLAY PANEL

PRINCIPAL DISPLAY PANEL


FULL PRESCRIBING INFORMATION

WARNING: AVOID USE IN PREGNANCY

When pregnancy is detected, discontinue Perindopril Erbumine Tablets as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury to or death of the developing fetus. (5.4)

1 INDICATIONS AND USAGE

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.

2 DOSAGE AND ADMINISTRATION

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.

Use in Elderly Patients

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 [see Use in Specific Populations (8.5)].

Use with Diuretics

In patients currently being treated with a diuretic, symptomatic hypotension can occur following the initial dose of perindopril. Consider reducing the dose of diuretic prior to starting perindopril erbumine tablets [see Drug Interactions (7.1)].

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 is 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.

3 DOSAGE FORMS AND STRENGTHS

Perindopril Erbumine Tablets, 2 mg, 4 mg and 8 mg for oral administration.

4 CONTRAINDICATIONS

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.

5 WARNINGS AND PRECAUTIONS

5.1 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 perindopril erbumine tablets) may be subject to a variety of adverse reactions, some of them serious. Black patients receiving ACE inhibitors have a higher incidence of angioedema compared to nonblacks.

Head and Neck Angioedema

Angioedema involving the face, extremities, lips, tongue, glottis or larynx has been reported in patients treated with ACE inhibitors, including perindopril erbumine tablets (0.1% of patients treated with perindopril erbumine tablets in U.S. clinical trials). Angioedema associated with involvement of the tongue, glottis or larynx may be fatal. In such cases, discontinue perindrpril erbumine tablets treatment immediately and observe until the swelling disappears. When involvement of the tongue, glottis, or larynx appears likely to cause airway obstruction, administer appropriate therapy, such as subcutaneous epinephrine solution 1:1000 (0.3 to 0.5 mL), promptly.

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.

5.2 Hypotension

Perindopril erbumine tablets can cause symptomatic hypotension. Perindopril erbumine tablets has been associated with hypotension in 0.3% of uncomplicated hypertensive patients in U.S. placebo-controlled trials. Symptoms related to orthostatic hypotension were reported in another 0.8% of patients.

Symptomatic hypotension is most likely to occur in patients who have been volume or salt-depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea or vomiting [see Dosage and Administration (2.1)].

ACE inhibitors may cause excessive hypotension, and may be associated with oliguria or azotemia, and rarely with acute renal failure and death. In patients with ischemic heart disease or cerebrovascular disease such an excessive fall in blood pressure could result in a myocardial infarction or a cerebrovascular accident.

In patients at risk of excessive hypotension, perindopril erbumine tablets therapy should be started under very close medical supervision. Patients should be followed closely for the first two weeks of treatment and whenever the dose of perindopril erbumine tablets and/or diuretic is increased.

If excessive hypotension occurs, the patient should be placed immediately in a supine position and, if necessary, treated with an intravenous infusion of physiological saline. Peridopril erbumine tablets treatment can usually be continued following restoration of volume and blood pressure.

5.3 Neutropenia/Agranulocytosis

ACE inhibitors have been associated with agranulocytosis and bone marrow depression, most frequently in patients with renal impairment, especially patients with a collagen vascular disease such as systemic lupus erythematosus or scleroderma.

5.4 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, patent ductus arteriosus, and other structural cardiac malformations, as well as neurological malformations, have been reported following exposure to ACE inhibitors during the first trimester of pregnancy.

When patients become pregnant, healthcare providers should make every effort to discontinue the use of perindorpil erbumine tablets as soon as possible. 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 intra-amniotic environment.

If oligohydramnios is observed, perindopril erbumine tablets should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST) or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and healthcare providers 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 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.

5.5 Impaired Renal Function

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. Renal function should be monitored periodically in patients receiving perindopril erbumine tablets [see Dosage and Administration (2.3)].

In patients with severe congestive heart failure, where renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including perindopril erbumine tablets, may be associated with oliguria, progressive azotemia, and, rarely, acute renal failure and death.

In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine may occur; usually reversible upon discontinuation of the ACE inhibitor . In such patients, renal function should be monitored during the first few weeks of therapy.

Some perindopril erbumine tablets-treated patients have developed minor and transient increases in blood urea nitrogen and serum creatinine especially in those concomitantly treated with a diuretic.

5.6 Hyperkalemia

Elevations of serum potassium have been observed in some patients treated with ACE inhibitors, including perindopril erbumine tablets. Most cases were isolated single values that did not appear clinically relevant and were rarely a cause for withdrawal. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus and the concomitant use of agents such as potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes [see Drug Interactions (7.2)].

Serum potassium should be monitored periodically in patients receiving perindopril erbumine tablets.

5.7 Cough

Presumably because of the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, generally resolving after discontinuation of therapy. Consider ACE inhibitor-induced cough in the differential diagnosis of cough.

5.8 Hepatic Failure

Rarely, ACE inhibitors have been associated with a 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.

5.9 Surgery/Anesthesia

In patients undergoing surgery or during anesthesia with agents that produce hypotension, perindopril erbumine tablets may block angiotensin II formation that would otherwise occur secondary to compensatory renin release. Hypotension attributable to this mechanism can be corrected by volume expansion.

6 ADVERSE REACTIONS

Because clinical trials are conducted under widely varying conditions, adverse event 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.

6.1 Clinical Trials Experience

The following adverse reactions are discussed elsewhere in labeling:

Hypertension

Perindopril erbumine tablets have been evaluated for safety in approximately 3,400 patients with hypertension in U.S. and foreign clinical trials. The data presented here are based on results from the 1,417 perindopril erbumine tablets-treated patients who participated in the U.S. clinical trials. Over 220 of these patients were treated with perindopril erbumine tablets for at least one year.

In placebo-controlled U.S. clinical trials, the incidence of premature discontinuation of therapy due to adverse events was 6.5% in patients treated with perindopril erbumine tablets and 6.7% in patients treated with placebo. The most common causes were cough, headache, asthenia and dizziness.

Among 1,012 patients in placebo-controlled U.S. trials, the overall frequency of reported adverse events was similar in patients treated with perindopril erbumine tablets and in those treated with placebo (approximately 75% in each group). The only adverse events whose incidence on perindopril erbumine tablets was at least 2% greater than on placebo were cough (12% vs 4.5%) and back pain (5.8% vs 3.1%).

Dizziness was not reported more frequently in the perindopril group (8.2%) than in the placebo group (8.5%), but its likelihood increased with dose, suggesting a causal relationship with perindopril.

Stable Coronary Artery Disease

Perindopril has been evaluated for safety in EUROPA, a double-blind, placebo-controlled study in 12,218 patients with stable coronary artery disease. The overall rate of discontinuation was about 22% on drug and placebo. The most common medical reasons for discontinuation that were more frequent on perindopril than placebo were cough, drug intolerance and hypotension.

6.4 Postmarketing Experience  

Voluntary reports of adverse events in patients taking perindopril erbumine that have been received since market introduction and are of unknown causal relationship to perindopril erbumine include: cardiac arrest, eosinophilic pneumonitis, neutropenia/agranulocytosis, pancytopenia, anemia (including hemolytic and aplastic), thrombocytopenia, acute renal failure, nephritis, hepatic failure, jaundice (hepatocellular or cholestatic), symptomatic hyponatremia, bullous pemphigoid, pemphigus, acute pancreatitis, falls, psoriasis, exfoliative dermatitis and a syndrome which may include: arthralgia/arthritis, vasculitis, serositis, myalgia, fever, rash or other dermatologic manifestations, a positive antinuclear antibody (ANA), leukocytosis, eosinophilia or an elevated erythrocyte sedimentation rate (ESR).

6.5 Clinical Laboratory Test Findings  

Hematology

Small decreases in hemoglobin and hematocrit occur frequently in hypertensive patients treated withperindopril erbumineN, but are rarely of clinical importance. In controlled clinical trials, no patient was discontinued from therapy due to the development of anemia. Leukopenia (including neutropenia) was observed in 0.1% of patients in U.S. clinical trials [see Warnings and Precautions (5.3)].

Liver Function Tests  

 Elevations in ALT (1.6% perindopril erbumine versus 0.9% placebo) and AST (0.5% perindopril erbumine versus 0.4% placebo) have been observed in placebo-controlled clinical trials. The elevations were generally mild and transient and resolved after discontinuation of therapy.

7 DRUG INTERACTIONS

7.1 Diuretics

Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of perindopril erbumine therapy. The possibility of hypotensive effects can be minimized by either decreasing the dose of or discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretic therapy cannot be altered, provide close medical supervision with the first dose of perindopril erbumine, for at least two hours and until blood pressure has stabilized for another hour [see Warnings and Precautions (5.2)].

The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition.

7.2 Potassium Supplements and Potassium-Sparing Diuretics

Perindopril erbumine may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, monitor the patient’s serum potassium frequently.

7.3 Lithium

Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. Frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity.

7.4 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 perindopril erbumine.

7.5 Digoxin

A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with perindopril erbumine, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded.

7.6 Gentamicin

Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

 Pregnancy Category D [see Boxed Warning and Warnings and Precautions (5.4)]. Radioactivity was detectable in fetuses after administration of 14C-perindopril to pregnant rats.

8.3 Nursing Mothers

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

8.4 Pediatric Use

 Safety and effectiveness of perindopril erbumine in pediatric patients have not been established.

8.5 Geriatric Use

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 with 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.

8.6 Renal Impairment 

Dosage adjustment may be necessary in renally impaired patients [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

The bioavailability of perindoprilat is increased in patients with impaired hepatic function [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE

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.

Angiotensin 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.

11 DESCRIPTION

Perindopril Erbumine Tablets 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,3∝S,7∝S)-1-[(S)-N-[(S)-1-Carboxy-butyl]alanyl]hexahydro-2-indolinecarboxylic acid, 1-ethyl ester, compound with ter-butylamine (1:1). Its molecular formula is C19H32N2O5C4H11N. Its structural formula is:

Perindopril.jpg

Perindopril erbumine is a white, crystalline powder 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.

Perindopril Erbumine Tablets 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: lactose (anhydrous), magnesium stearate, microcrystalline cellulose and silicon dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Perindopril erbumine tablets are 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. Angiotensin 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 tablets 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 80 to 90% attained by 8 mg persisting for 10 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 ID50 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 tablets results in peak plasma concentrations that occur at approximately 1 hour. The absolute oral bioavailability of perindopril is about 75%. Following absorption, approximately 30 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 3 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 tablets, Cmax 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.

Distribution

Approximately 60% of circulating perindopril is bound to plasma proteins, and only 10 to 20% of perindoprilat is bound. Therefore, drug interactions mediated through effects on protein binding are not anticipated.

Metabolism and Elimination

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 hour.

Perindopril is extensively metabolized following oral administration, with only 4 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 multiexponential pharmacokinetics following the oral administration of perindopril erbumine tablets. Formation of perindoprilat is gradual with peak plasma concentrations occurring between 3 and 7 hours. The subsequent decline in plasma concentration shows an apparent mean half-life of 3 to 10 hours for the majority of the elimination, with a prolonged terminal elimination half-life of 30 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 3 to 6 days. The clearance of perindoprilat and its metabolites is almost exclusively renal.

Elderly

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. [see Dosage and Administration (2.1) and Use in Specific Populations (8.5)].

Heart Failure

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

Renal Impairment

With perindopril doses of 2 mg to 4 mg, perindoprilat AUC increases with decreasing renal function. At creatinine clearances of 30 to 80 mL/min, AUC is about double that of 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 40 to 80 mL/min. Perindoprilat clearance by dialysis ranged from 40 to 90 mL/min [see Dosage and Administration (2.3)].

Hepatic Impairment

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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

No evidence of carcinogenic effect was observed in studies in rats and mice when perindopril was administered at dosages up to 20 times (mg/kg) or 2 to 4 times (mg/m2) the maximum proposed clinical doses (16 mg/day) for 104 weeks.

Mutagenesis

No genotoxic potential was detected for perindopril erbumine tablets, perindoprilat and other metabolites in various in vitro and in vivo investigations, including the Ames test, the Saccharomycescerevisiae D4 test, cultured human lymphocytes, TK ± mouse lymphoma assay, mouse and rat micronucleus tests and Chinese hamster bone marrow assay.

Impairment of Fertility

There was no meaningful effect on reproductive performance or fertility in the rat given up to 30 times (mg/kg) or 6 times (mg/m2) the proposed maximum clinical dosage of perindopril erbumine tablets during the period of spermatogenesis in males or oogenesis and gestation in females.

14 CLINICAL STUDIES

14.1 Hypertension

In placebo-controlled studies of perindopril monotherapy (2 mg to 16 mg once daily) in patients with a mean blood pressure of about 150/100 mm Hg, 2 mg had little effect, but doses of 4 mg to 16 mg lowered blood pressure. The 8 mg and 16 mg doses were indistinguishable, and both had a greater effect than the 4 mg dose. In these studies, doses of 8 mg and 16 mg per day gave supine, trough blood pressure reductions of 9 to 15/5 to 6 mm Hg. When once daily and twice daily dosing were compared, the twice daily dosing regimen was generally slightly superior, but by not more than about 0.5 mm Hg to 1 mm Hg. After 2 mg to 16 mg doses of perindopril, the trough mean systolic and diastolic blood pressure effects were about 75 to 100% of peak effects.

Perindopril’s effects on blood pressure were similar when given alone or on a background of 25 mg hydrochlorothiazide. In general, the effect of perindopril occurred promptly, with effects increasing slightly over several weeks.

Formal interaction studies of perindopril erbumine have not been carried out with antihypertensive agents other than thiazides. Limited experience in controlled and uncontrolled trials coadministering perindopril erbumine with a calcium channel blocker, a loop diuretic or triple therapy (beta-blocker, vasodilator and a diuretic), does not suggest any unexpected interactions. In general, ACE inhibitors have less than additive effects when given with beta-adrenergic blockers, presumably because both work in part through the renin-angiotensin system.

In uncontrolled studies in patients with insulin-dependent diabetes, perindopril did not appear to affect glycemic control. In long-term use, no effect on urinary protein excretion was seen in these patients.

The effectiveness of perindopril erbumine was not influenced by sex and it was less effective in black patients than in nonblack patients. In elderly patients (greater than or equal to 60 years), the mean blood pressure effect was somewhat smaller than in younger patients, although the difference was not significant.

14.2 Stable Coronary Artery Disease

The EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) was a multicenter, randomized, double-blind and placebo-controlled study conducted in 12,218 patients who had evidence of stable coronary artery disease without clinical heart failure. Patients had evidence of coronary artery disease documented by previous myocardial infarction more than 3 months before screening, coronary revascularization more than 6 months before screening, angiographic evidence of stenosis (at least 70% narrowing of one or more major coronary arteries), or positive stress test in men with a history of chest pain. After a run-in period of 4 weeks during which all patients received perindopril 2 mg to 8 mg, the patients were randomly assigned to perindopril 8 mg once daily (N=6,110) or matching placebo (N=6,108). The mean follow-up was 4.2 years. The study examined the long-term effects of perindopril on time to first event of cardiovascular mortality, nonfatal myocardial infarction, or cardiac arrest in patients with stable coronary artery disease.

The mean age of patients was 60 years; 85% were male, 92% were taking platelet inhibitors, 63% were taking β blockers, and 56% were taking lipid-lowering therapy. The EUROPA study showed that perindopril significantly reduced the relative risk for the primary endpoint events (Table 1). This beneficial effect is largely attributable to a reduction in the risk of nonfatal myocardial infarction. This beneficial effect of perindopril on the primary outcome was evident after about one year of treatment (Figure 1). The outcome was similar across all predefined subgroups by age, underlying disease or concomitant medication (Figure 2).

Table 1: Primary Endpoint and Relative Risk Reduction
Perindopril (N=6,110) Placebo (N=6,108) RRR (95% CI) P
Combined Endpoint
Cardiovascular Mortality, Non-fatal MI, or Cardiac Arrest 488 (8%) 603 (9.9%) 20% (9 to 29) 0.0003
Component Endpoint
Cardiovascular Mortality 215 (3.5%) 249(4.1%) 14% (-3 to 28) 0.107
Nonfatal MI 295 (4.8%) 378 (6.2%) 22% (10 to 33) 0.001
Cardiac Arrest 6 (0.1%) 11 (0.2%) 46% (-47 to 80) 0.22

CI: confidence interval; RRR: relative risk reduction; MI: myocardial infarction

Figure 1: Time to First Occurrence of Primary Endpoint

Peridopril Figure 1.jpg

Figure 2: Beneficial Effect of Perindopril Treatment of Primary Endpoint in Predefined Subgroups

Peridopril Figure 2.jpg

Size of squares proportional to the number of patients in that group. Dashed line indicates overall relative risk.

16 HOW SUPPLIED/STORAGE AND HANDLING

Perindopril Erbumine Tablets are supplied as white to off-white, round, biconvex tablets. The 2 mg tablets are debossed with product identification "54 551" on one side and scored on the other side. The 4 mg tablets are debossed with product identification "54 327" on one side and scored on the other side. The 8 mg tablets are debossed with product identification "54 715" on one side and scored on the other side.

0054-0110-13 2 mg, white to off-white tablet, bottle of 30
0054-0110-25 2 mg, white to off-white tablet, bottle of 100
0054-0111-13 4 mg, white to off-white tablet, bottle of 30
0054-0111-25 4 mg, white to off-white tablet, bottle of 100
0054-0111-29 4 mg, white to off-white tablet, bottle of 500
0054-0112-13 8 mg, white to off-white tablet, bottle of 30
0054-0112-25 8 mg, white to off-white tablet, bottle of 100
0054-0112-29 8 mg, white to off-white tablet, bottle of 500

Storage

Store at controlled room temperature 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Protect from moisture. Keep out of the reach of children. 

17 PATIENT COUNSELING INFORMATION

Inform female patients of childbearing age that use of drugs, such as perindopril erbumine, that act on the renin-angiotensin system during pregnancy may cause serious problems in the fetus and infant. Patients taking perindopril erbumine who are or plan to become pregnant should immediately notify their healthcare provider.

Tell patients to report immediately signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, hoarseness or difficulty in swallowing or breathing) and to take no more drug before consulting a healthcare provider.

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

10005475/02 Revised February 2011

©RLI, 2011

PRINCIPAL DISPLAY PANEL

0054-0110-25 2 mg tablet, bottle of 100

Roxane Laboratories, Inc.

0054-0110-25.jpg

PRINCIPAL DISPLAY PANEL

0054-0111-25 4 mg tablet, bottle of 100

Roxane Laboratories, Inc.

0054-0111-25.jpg

PRINCIPAL DISPLAY PANEL

0054-0112-25 8 mg tablet, bottle of 100

Roxane Laboratories, Inc.

0054-0112-25.jpg


PERINDOPRIL ERBUMINE 
perindopril erbumine tablet
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0054-0110
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
PERINDOPRIL ERBUMINE (PERINDOPRIL) PERINDOPRIL ERBUMINE 2 mg
Inactive Ingredients
Ingredient Name Strength
LACTOSE  
MAGNESIUM STEARATE  
CELLULOSE, MICROCRYSTALLINE  
SILICON DIOXIDE  
Product Characteristics
Color WHITE Score 2 pieces
Shape ROUND Size 6mm
Flavor Imprint Code 54;551
Contains     
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:0054-0110-25 100 TABLET ( TABLET) in 1 BOTTLE None

Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA090072 11/10/2009

PERINDOPRIL ERBUMINE 
perindopril erbumine tablet
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0054-0111
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
PERINDOPRIL ERBUMINE (PERINDOPRIL) PERINDOPRIL ERBUMINE 4 mg
Inactive Ingredients
Ingredient Name Strength
LACTOSE  
MAGNESIUM STEARATE  
CELLULOSE, MICROCRYSTALLINE  
SILICON DIOXIDE  
Product Characteristics
Color WHITE Score 2 pieces
Shape ROUND Size 7mm
Flavor Imprint Code 54;327
Contains     
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:0054-0111-25 100 TABLET ( TABLET) in 1 BOTTLE None

Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA090072 11/10/2009

PERINDOPRIL ERBUMINE 
perindopril erbumine tablet
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0054-0112
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
PERINDOPRIL ERBUMINE (PERINDOPRIL) PERINDOPRIL ERBUMINE 8 mg
Inactive Ingredients
Ingredient Name Strength
LACTOSE  
MAGNESIUM STEARATE  
CELLULOSE, MICROCRYSTALLINE  
SILICON DIOXIDE  
Product Characteristics
Color WHITE Score 2 pieces
Shape ROUND Size 9mm
Flavor Imprint Code 54;715
Contains     
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:0054-0112-25 100 TABLET ( TABLET) in 1 BOTTLE None

Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA090072 11/10/2009

Labeler - Roxane Laboratories, Inc. (833490464)
Registrant - Roxane Laboratories, Inc. (833490464)
Establishment
Name Address ID/FEI Operations
Boehringer Ingelheim Roxane Inc 058839929 MANUFACTURE
Establishment
Name Address ID/FEI Operations
Cipla Ltd. 916940208 API MANUFACTURE

Revised: 07/2010 Roxane Laboratories, Inc.



Source: http://dailymed.nlm.nih.gov
Reproduced with permission of U.S. National Library of Medicine


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