Perindopril Erbumine

Pronunciation

Class: Angiotensin-Converting Enzyme Inhibitors
VA Class: CV800
Chemical Name: (2S - (1(R*(R*)),2α,3aβ,7aβ)) - 1 - (2 - ((1 - (Ethoxycarbonyl)butyl)amino) - 1 - oxopropyl)octahydro - 1H - indole - 2 - carboxylic acid
Molecular Formula: C19H32N2O5
CAS Number: 82834-16-0
Brands: Aceon

Warning(s)

  • May cause fetal and neonatal morbidity and mortality if used during pregnancy.1 42 43 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

  • If pregnancy is detected, discontinue perindopril as soon as possible.1 43

Introduction

Nonsulfhydryl ACE inhibitor.1

Uses for Perindopril Erbumine

Hypertension

Management of hypertension (alone or in combination with other classes of antihypertensive agents).1 2

One of several preferred initial therapies in hypertensive patients with heart failure, postmyocardial infarction, high coronary disease risk, diabetes mellitus, chronic renal failure, and/or cerebrovascular disease.21

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Can be used as monotherapy for initial management of uncomplicated hypertension; however, thiazide diuretics are preferred by JNC 7.21

CHF

Management of symptomatic CHF, usually in conjunction with cardiac glycosides, diuretics, and β-adrenergic blocking agents.20 23 24 25 26 27

Diabetic Nephropathy

A first-line agent in the treatment of diabetic nephropathy in hypertensive patients with type 2 diabetes mellitus.6 31 32 33 34 35 36 37 38

Perindopril Erbumine Dosage and Administration

Administration

Oral Administration

Administer orally once or twice daily1 without regard to meals.2 In clinical studies, administration in 2 divided doses was only slightly more effective than once-daily dosing.1

Dosage

Available as perindopril erbumine; dosage expressed in terms of perindopril erbumine.1

Adults

Hypertension
Oral

Initially, 4 mg once daily as monotherapy.1 Adjust dosage at approximately monthly intervals (more aggressively in high-risk patients) to achieve BP control.6 21

In patients currently receiving diuretic therapy, discontinue diuretic, if possible, 2–3 days before initiating perindopril.1 May cautiously resume diuretic therapy if BP not controlled adequately with perindopril alone.1 If diuretic cannot be discontinued, initiate therapy at 2–4 mg daily (given in 1 dose or 2 divided doses) under close medical supervision for several hours until BP has stabilized.1

Usual dosage: 4–8 mg once daily.1 2 21

Prescribing Limits

Adults

Hypertension
Oral

Maximum 16 mg daily.1

Special Populations

Renal Impairment

Hypertension

Initially, 2 mg daily in patients with renal impairment (Clcr >30 mL/minute); titrate until BP is controlled or to maximum of 8 mg daily. (See Renal Impairment under Cautions.)1

Geriatric Patients

Hypertension

Initially, 4 mg daily, given in 1 dose or 2 divided doses.1 Adjust dosage to achieve BP control.1 Administer dosages >8 mg daily with caution and under close medical supervision.1

Cautions for Perindopril Erbumine

Contraindications

  • Known hypersensitivity (e.g., history of angioedema) to perindopril or another ACE inhibitor.1

Warnings/Precautions

Warnings

Hypotension

Possible symptomatic hypotension, particularly in volume- and/or salt-depleted patients (e.g., those treated with diuretics).1 13 Risk of marked hypotension, sometimes associated with oliguria, azotemia, and, rarely, acute renal failure and death in patients with CHF with or without associated renal insufficiency.1 Severe hypotension may result in MI or stroke in patients with ischemic cardiovascular or cerebrovascular disease.1

Hypotension may occur in patients undergoing surgery or during anesthesia with agents that produce hypotension; recommended treatment is fluid volume expansion.1

To minimize potential for hypotension, correct volume and/or salt depletion (e.g., by withholding diuretic therapy, increasing sodium intake) prior to initiation of perindopril.1 (See Dosage under Dosage and Administration.)

In patients at risk of excessive hypotension, initiate therapy under close medical supervision; monitor closely for first 2 weeks following initiation of perindopril or any increase in perindopril or diuretic dosage.1

If excessive hypotension occurs, immediately place patient in supine position and, if necessary, administer IV infusion of 0.9% sodium chloride injection.1 Perindopril therapy usually can be continued following restoration of volume and BP.1

Hematologic Effects

Neutropenia and agranulocytosis reported with captopril; risk appears to depend principally on presence of renal impairment and/or presence of collagen vascular disease (e.g., systemic lupus erythematosus, scleroderma); risk with perindopril is unknown.1

Fetal/Neonatal Morbidity and Mortality

Possible fetal and neonatal morbidity and mortality when used during pregnancy.1 (See Boxed Warning.)

Possible fetal and neonatal morbidity and mortality when used during pregnancy.1 43 (See Boxed Warning.) Such potential risks occur throughout pregnancy, especially during the second and third trimesters.43

Also may increase the risk of major congenital malformations when administered during the first trimester of pregnancy.42 43

Discontinue as soon as possible when pregnancy is detected, unless continued use is considered lifesaving.1 42 43 Nearly all women can be transferred successfully to alternative therapy for the remainder of their pregnancy.13

Hepatic Effects

Clinical syndrome that usually is manifested initially by cholestatic jaundice and may progress to fulminant hepatic necrosis (occasionally fatal) reported rarely with ACE inhibitors.1

If jaundice or marked elevation of liver enzymes occurs, discontinue drug and monitor patient.1

Sensitivity Reactions

Anaphylactoid reactions and/or head and neck angioedema possible; angioedema associated with tongue, glottis, or larynx may be fatal.1 If angioedema occurs, promptly discontinue perindopril and observe patient until swelling disappears.1 Immediate medical intervention (e.g., epinephrine) for involvement of tongue, glottis, or larynx.1

Intestinal angioedema possible; consider in differential diagnosis of patients who develop abdominal pain.1

Anaphylactoid reactions reported in patients receiving ACE inhibitors while undergoing LDL apheresis with dextran sulfate absorption or following initiation of hemodialysis that utilized high-flux membrane.1

Life-threatening anaphylactoid reactions reported in at least 2 patients receiving ACE inhibitors while undergoing desensitization treatment with hymenoptera venom.1

Contraindicated in patients with a history of angioedema associated with ACE inhibitors.1

General Precautions

Renal Effects

Transient increases in BUN and Scr possible, especially in patients with preexisting renal impairment or those receiving concomitant diuretic therapy.1 Possible increases in BUN and Scr in patients with unilateral or bilateral renal artery stenosis; generally reversible following discontinuance of therapy.1

Possible oliguria, progressive azotemia, and, rarely, acute renal failure and/or death in patients with severe CHF.1

Closely monitor renal function for the first few weeks of therapy in hypertensive patients with unilateral or bilateral renal-artery stenosis.1 Some patients may require dosage reduction or discontinuance of ACE inhibitor or diuretic.1

Hyperkalemia

Possible hyperkalemia, especially in patients with renal impairment or diabetes mellitus and those receiving drugs that can increase serum potassium concentration (e.g., potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes).1 (See Specific Drugs under Interactions.)

Monitor serum potassium concentration carefully in these patients.1

Cough

Persistent and nonproductive cough; resolves after drug discontinuance.1

Specific Populations

Pregnancy

Category C (1st trimester); Category D (2nd and 3rd trimesters).1 (See Boxed Warning.)

Lactation

Distributed into milk in rats; not known whether perindopril is distributed into milk in humans.1 Caution if used in nursing women.1

Pediatric Use

Safety and efficacy not established in pediatric patients.1

Geriatric Use

Possible lesser effect on BP in those >60 years of age than in younger patients.1 Increased plasma concentrations of perindopril and perindoprilat.1 Dizziness and possibly rash may occur more frequently in geriatric patients.1

Renal Impairment

Deterioration of renal function may occur (see Renal Effects under Cautions).1 Systemic exposure to perindoprilat may be increased with decreasing renal function.1

Initial dosage adjustment recommended in patients with renal impairment.1 (See Renal Impairment under Dosage and Administration.) Safety and efficacy not established in patients with Clcr <30 mL/minute.1

Hepatic Impairment

Increased bioavailability of perindoprilat.1

Blacks

BP reduction may be smaller in black patients compared with nonblack patients;1 5 6 however, no apparent population difference during combined therapy with ACE inhibitor and thiazide diuretic.5 6 Use in combination with a diuretic.5 6

Higher incidence of angioedema reported with ACE inhibitors (as monotherapy) in blacks compared with other races.1 19 21

Common Adverse Effects

Cough, proteinuria, palpitation, sinusitis, viral infection, dyspepsia, fever, upper extremity pain, hypertonia.1

Dizziness reported at a rate similar to that with placebo, but incidence increases with increased dosage, suggesting causal relation to the drug.1

Interactions for Perindopril Erbumine

Specific Drugs

Drug

Interaction

Comments

Digoxin

No effect on digoxin concentrations; effect on perindopril/perindoprilat concentrations has not been excluded1

Diuretics

Increased hypotensive effect1

If possible, discontinue diuretic before initiating perindopril1 (see Dosage under Dosage and Administration)

Diuretics, potassium-sparing (amiloride, spironolactone, triamterene)

Enhanced hyperkalemic effect1

Use with caution; monitor serum potassium concentrations frequently1

Gentamicin

Possible interaction based on animal data; no studies in humans1

Use with caution1

Lithium

Increased serum lithium concentrations; possible toxicity1

Use with caution; monitor serum lithium concentrations frequently1

Potassium supplements or potassium-containing salt substitutes

Enhanced hyperkalemic effect1

Use with caution; monitor serum potassium concentrations frequently1

Perindopril Erbumine Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability of perindopril is 75%; mean bioavailability of perindoprilat is 25%.1

Peak plasma concentrations of perindopril and perindoprilat are achieved within 1 and 3–7 hours, respectively.1

Onset

Antihypertensive effects occur promptly, with effects increasing slightly over several weeks.1

Duration

Maximal antihypertensive effect (inhibition of 80–90% of ACE activity) persists for about 10–12 hours; at 24 hours, only 60% of ACE activity is blocked.1

Food

Food does not affect rate or extent of absorption of perindopril but reduces bioavailability of perindoprilat by about 35%.1

Special Populations

In patients with hepatic impairment, increased perindoprilat bioavailability.1

In patients with renal impairment, increased perindoprilat concentrations with decreasing renal function.1

In patients >70 years of age, increased plasma perindopril and perindoprilat concentrations (resulting from increased conversion of perindopril to perindoprilat and decreased renal excretion of perindoprilat).1

Distribution

Extent

Appears to cross the blood-brain barrier only slightly in rats.1

Crosses the placenta and is distributed into milk in rats.1

Plasma Protein Binding

Perindopril: 60%.1

Perindoprilat: 10–20%.1

Elimination

Metabolism

Extensively metabolized in the liver to 6 metabolites, including an active metabolite, perindoprilat.1

Elimination Route

Eliminated principally in urine (as metabolites).1

Removed by renal dialysis.1

Half-life

Perindopril: 0.8–1 hour.1

Perindoprilat: 3–10 hours.1

Special Populations

In patients with CHF, decreased clearance and increased AUC of perindoprilat.1

Stability

Storage

Oral

Tablets

20–25°C.1 Protect from moisture.1

Actions

  • Prodrug; not pharmacologically active until hydrolyzed in the liver to perindoprilat.1 2

  • Suppresses the renin-angiotensin-aldosterone system.1

Advice to Patients

  • Risk of angioedema, anaphylactoid reactions, or other sensitivity reactions.1 Importance of reporting sensitivity reactions (e.g., edema of face, eyes, lips, tongue, or extremities; hoarseness; swallowing or breathing with difficulty) immediately to clinician and of discontinuing the drug.1

  • Importance of reporting signs of infection (e.g., sore throat, fever).1

  • Risk of hypotension.1 Importance of informing clinicians promptly if lightheadedness or fainting occurs.1

    Importance of adequate fluid intake; risk of volume depletion with excessive perspiration, dehydration, vomiting, or diarrhea.1

  • Risks of use during pregnancy.1 (See Boxed Warning.)

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (including salt substitutes containing potassium).1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of advising patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Perindopril Erbumine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

2 mg

Aceon (scored)

Xoma

4 mg

Aceon (scored)

Xoma

8 mg

Aceon (scored)

Xoma

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Aceon 2MG Tablets (SOLVAY): 100/$199.00 or 200/$383.98

Aceon 4MG Tablets (SOLVAY): 30/$77.99 or 90/$207.97

Aceon 8MG Tablets (SOLVAY): 100/$278.49 or 200/$556.97

Perindopril Erbumine 2MG Tablets (AUROBINDO PHARMA): 100/$75.99 or 300/$199.98

Perindopril Erbumine 4MG Tablets (ROXANE): 100/$80.99 or 300/$211.98

Perindopril Erbumine 8MG Tablets (ROXANE): 100/$88.99 or 300/$227.97

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions November 2, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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4. Reviewers’ comments in enalapril/enalaprilat (personal observations).

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6. National Heart, Lung, and Blood Institute National High Blood Pressure Education Program. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). Bethesda, MD: National Institutes of Health; 1997 Nov. (NIH publication No. 98-4080.)

7. Saunders E. Tailoring treatment to minority patients. Am J Med. 1990; 88(Suppl 3B):21-23S.

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33. American Diabetes Association. Clinical Practice Recommendations 2002. Position Statement. Diabetic nephropathy. Diabetes Care. 2002; 25(Suppl 1):S85-9.

34. Lewis EJ, Hunsicker LG, Bain RP et al. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med. 1993; 329:1456-62. [IDIS 321612] [PubMed 8413456]

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