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Perindopril

Class: Angiotensin-Converting Enzyme Inhibitors
- ACE Inhibitors
VA Class: CV800
Chemical Name: l-arginine (2S,3αS,7αS)-1- [(2S)-2-[[(1S)-1-(ethoxycarbonyl)butyl]amino]propanoyl]octahydro-1H-indole-2-carboxylate
Molecular Formula: C19H32N2O5•C6H14N4O5C19H32N2O5
CAS Number: 612548-45-5
Brands: Aceon, Prestalia (combination)

Medically reviewed by Drugs.com on Feb 22, 2022. Written by ASHP.

Warning

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

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

Introduction

Nonsulfhydryl ACE inhibitor.

Uses for Perindopril

Hypertension

Management of hypertension (alone or in combination with other classes of antihypertensive agents); may be used in fixed combination with amlodipine when such combined therapy is indicated.

ACE inhibitors are recommended as one of several preferred drugs for the initial management of hypertension according to current evidence-based hypertension guidelines; other preferred options include angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics. While there may be individual differences with respect to recommendations for initial drug selection and use in specific patient populations, current evidence indicates that these antihypertensive drug classes all generally produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes.

Individualize choice of therapy; consider patient characteristics (e.g., age, ethnicity/race, comorbidities, cardiovascular risk) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, cost).

A 2017 ACC/AHA multidisciplinary hypertension guideline classifies BP in adults into 4 categories: normal, elevated, stage 1 hypertension, and stage 2 hypertension. (See Table 1.)

Source: Whelton PK, Carey RM, Aronow WS et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71:e13-115.

Individuals with SBP and DBP in 2 different categories (e.g., elevated SBP and normal DBP) should be designated as being in the higher BP category (i.e., elevated BP).

Table 1. ACC/AHA BP Classification in Adults1200

Category

SBP (mm Hg)

DBP (mm Hg)

Normal

<120

and

<80

Elevated

120–129

and

<80

Hypertension, Stage 1

130–139

or

80–89

Hypertension, Stage 2

≥140

or

≥90

The goal of hypertension management and prevention is to achieve and maintain optimal control of BP. However, the BP thresholds used to define hypertension, the optimum BP threshold at which to initiate antihypertensive drug therapy, and the ideal target BP values remain controversial.

The 2017 ACC/AHA hypertension guideline generally recommends a target BP goal (i.e., BP to achieve with drug therapy and/or nonpharmacologic intervention) of <130/80 mm Hg in all adults regardless of comorbidities or level of atherosclerotic cardiovascular disease (ASCVD) risk. In addition, an SBP goal of <130 mm Hg is recommended for noninstitutionalized ambulatory patients ≥65 years of age with an average SBP of ≥130 mm Hg. These BP goals are based upon clinical studies demonstrating continuing reduction of cardiovascular risk at progressively lower levels of SBP.

Other hypertension guidelines generally have based target BP goals on age and comorbidities. Guidelines such as those issued by the JNC 8 expert panel generally have targeted a BP goal of <140/90 mm Hg regardless of cardiovascular risk and have used higher BP thresholds and target BPs in elderly patients compared with those recommended by the 2017 ACC/AHA hypertension guideline.

Some clinicians continue to support previous target BPs recommended by JNC 8 due to concerns about the lack of generalizability of data from some clinical trials (e.g., SPRINT study) used to support the 2017 ACC/AHA hypertension guideline and potential harms (e.g., adverse drug effects, costs of therapy) versus benefits of BP lowering in patients at lower risk of cardiovascular disease.

Consider potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs when deciding a patient's BP treatment goal.

For decisions regarding when to initiate drug therapy (BP threshold), the 2017 ACC/AHA hypertension guideline incorporates underlying cardiovascular risk factors. ASCVD risk assessment is recommended by ACC/AHA for all adults with hypertension.

ACC/AHA currently recommend initiation of antihypertensive drug therapy in addition to lifestyle/behavioral modifications at an SBP ≥140 mm Hg or DBP ≥90 mm Hg in adults who have no history of cardiovascular disease (i.e., primary prevention) and a low ASCVD risk (10-year risk <10%).

For secondary prevention in adults with known cardiovascular disease or for primary prevention in those at higher risk for ASCVD (10-year risk ≥10%), ACC/AHA recommend initiation of antihypertensive drug therapy at an average SBP ≥130 mm Hg or an average DBP ≥80 mm Hg.

Adults with hypertension and diabetes mellitus, chronic kidney disease (CKD), or age ≥65 years are assumed to be at high risk for cardiovascular disease; ACC/AHA state that such patients should have antihypertensive drug therapy initiated at a BP ≥130/80 mm Hg. Individualize drug therapy in patients with hypertension and underlying cardiovascular or other risk factors.

In stage 1 hypertension, experts state that it is reasonable to initiate drug therapy using the stepped-care approach in which one drug is initiated and titrated and other drugs are added sequentially to achieve the target BP. Initiation of antihypertensive therapy with 2 first-line agents from different pharmacologic classes recommended in adults with stage 2 hypertension and average BP >20/10 mm Hg above BP goal.

Black hypertensive patients generally tend to respond better to monotherapy with calcium-channel blockers or thiazide diuretics than to ACE inhibitors. However, the combination of an ACE inhibitor or an angiotensin II receptor antagonist with a calcium-channel blocker or thiazide diuretic produces similar BP lowering in black patients as in other racial groups.

ACE inhibitors may be preferred in hypertensive patients with heart failure, ischemic heart disease, diabetes mellitus, CKD, or cerebrovascular disease or post-MI.

Heart Failure

Management of heart failure, usually in conjunction with other agents such as cardiac glycosides, diuretics, and β-adrenergic blocking agents (β-blockers).

Some evidence indicates that therapy with an ACE inhibitor (enalapril) may be less effective than angiotensin receptor-neprilysin inhibitor (ARNI) therapy (e.g., sacubitril/valsartan) in reducing cardiovascular death and heart failure-related hospitalization.

ACCF, AHA, and the Heart Failure Society of America (HFSA) recommend that patients with chronic symptomatic heart failure and reduced left ventricular ejection fraction (LVEF) (NYHA class II or III) who are able to tolerate an ACE inhibitor or angiotensin II receptor antagonist be switched to therapy containing an ARNI to further reduce morbidity and mortality.

Diabetic Nephropathy

A recommended agent in the management of patients with diabetes mellitus and persistent albuminuria who have modestly elevated (30–300 mg/24 hours) or higher (>300 mg/24 hours) levels of urinary albumin excretion; slows rate of progression of renal disease in such patients.

Perindopril Dosage and Administration

General

BP Monitoring and Treatment Goals

  • Monitor BP regularly (i.e., monthly) during therapy and adjust dosage of the antihypertensive drug until BP controlled.

  • If unacceptable adverse effects occur, discontinue drug and initiate another antihypertensive agent from a different pharmacologic class.

  • If adequate BP response not achieved with a single antihypertensive agent, either increase dosage of single drug or add a second drug with demonstrated benefit and preferably with a complementary mechanism of action (e.g., calcium-channel blocker, thiazide diuretic). Many patients will require ≥2 drugs from different pharmacologic classes to achieve BP goal; if goal BP still not achieved, add a third drug.

Administration

Oral Administration

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

Dosage

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

Also available as perindopril arginine (in fixed-combination preparation with amlodipine); dosage expressed in terms of perindopril arginine.

Adults

Hypertension
Perindopril Erbumine Therapy
Oral

Initially, 4 mg once daily in patients not receiving a diuretic.

In patients currently receiving diuretic therapy, discontinue diuretic, reduce diuretic dosage, or increase salt intake, if possible, before initiating perindopril. If diuretic therapy cannot be altered, initiate therapy under close medical supervision for at least 2 hours and until BP has stabilized for an additional hour.

Usual dosage: Manufacturer states 4–8 mg once daily. Some experts state 4–16 mg once daily.

Perindopril Arginine/Amlodipine Fixed-combination Therapy
Oral

Fixed-combination perindopril/amlodipine tablets may be used for initial treatment of hypertension in patients likely to require combination therapy with multiple antihypertensive agents to control BP. Consider potential benefits and risks of initiating therapy with the fixed combination, including whether the patient is likely to tolerate the lowest available dosage of the combined drugs.

If patient's baseline BP is 170/105 mm Hg, the estimated probability of achieving SBP control (SBP <140 mm Hg) is 26, 40, or 50% and of achieving DBP control (DBP <90 mm Hg) is 31, 46, or 65% with perindopril erbumine (16 mg daily) alone, amlodipine (10 mg daily) alone, or amlodipine (10 mg daily) combined with perindopril arginine (14 mg daily), respectively.

If BP is not adequately controlled by monotherapy, can switch to perindopril/amlodipine fixed combination.

In black patients and patients with diabetes mellitus, addition of perindopril arginine (14 mg daily) to amlodipine (10 mg daily) did not provide additional antihypertensive effects beyond those achieved with amlodipine monotherapy.

If BP is adequately controlled by monotherapy with amlodipine but edema has developed, can switch to perindopril/amlodipine fixed combination to achieve BP control without edema.

When used for initial therapy of hypertension in patients likely to require combination therapy with multiple antihypertensive agents, recommended initial dosage is perindopril arginine 3.5 mg and amlodipine 2.5 mg once daily.

May adjust dosage at intervals of 7–14 days, up to maximum of perindopril arginine 14 mg and amlodipine 10 mg once daily.

Prescribing Limits

Adults

Hypertension
Oral

Perindopril erbumine: Maximum 16 mg daily.

Perindopril arginine: Maximum 14 mg daily (in fixed combination with amlodipine).

Special Populations

Renal Impairment

Hypertension

Perindopril erbumine: 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.)

Perindopril/amlodipine fixed combination: Not recommended in patients with Clcr<60 mL/minute; insufficient data to support dosage recommendations.

Hepatic Impairment

Hypertension

Perindopril/amlodipine fixed combination: Not recommended in patients with hepatic impairment; insufficient data to support dosage recommendations.

Geriatric Patients

Hypertension

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

Perindopril/amlodipine fixed combination: Not recommended in geriatric patients; insufficient data to support dosage recommendations.

Heart Failure

Perindopril/amlodipine fixed combination: Not recommended in patients with heart failure; insufficient data to support dosage recommendations.

Cautions for Perindopril

Contraindications

  • History of hereditary or idiopathic angioedema.

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

  • Concomitant therapy with aliskiren in patients with diabetes mellitus.

  • Concomitant use (within 36 hours) of a neprilysin inhibitor (e.g., sacubitril).

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

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

Also may increase the risk of major congenital malformations when administered during the first trimester of pregnancy. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal effects include skull hypoplasia, anuria, hypotension, renal failure, and death.

Discontinue ACE inhibitors (e.g., perindopril) as soon as possible when pregnancy is detected, unless continued use is considered lifesaving. Nearly all women can be transferred successfully to alternative therapy for the remainder of their pregnancy.

Sensitivity Reactions

Anaphylactoid reactions and/or head and neck angioedema possible; angioedema associated with tongue, glottis, or larynx may be fatal. Concomitant use of an ACE inhibitor and a mammalian target of rapamycin (mTOR) inhibitor or neprilysin inhibitor (e.g., sacubitril) may increase the risk of angioedema. If angioedema occurs, promptly discontinue perindopril and observe patient until swelling disappears. Immediate medical intervention (e.g., epinephrine) required for involvement of tongue, glottis, or larynx.

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

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.

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

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

Other Warnings/Precautions

Hypotension

Possible symptomatic hypotension, particularly in volume- and/or salt-depleted patients (e.g., those treated with diuretics, undergoing dialysis, with diarrhea or vomiting).

Risk of marked hypotension, sometimes associated with oliguria, azotemia, and, rarely, acute renal failure and death in patients with heart failure with or without associated renal insufficiency. Severe hypotension may result in MI or stroke in patients with ischemic cardiovascular or cerebrovascular disease.

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

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

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

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.

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.

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

Renal Effects

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

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

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

Effects on Potassium

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). (See Specific Drugs under Interactions.)

Monitor serum potassium concentration carefully in these patients.

Cough

Persistent and nonproductive cough; resolves after drug discontinuance.

Use of Fixed Combinations

When perindopril is used in fixed combination with amlodipine, consider the cautions, precautions, contraindications, and interactions associated with amlodipine.

Specific Populations

Pregnancy

Category D.

Can cause fetal and neonatal morbidity and mortality when administered to a pregnant woman. (See Boxed Warning.)

Lactation

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

Pediatric Use

If oliguria or hypotension occurs in neonates with a history of in utero exposure to perindopril, support BP and renal function; exchange transfusions or dialysis may be required. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Safety and efficacy not established in pediatric patients.

Geriatric Use

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

Renal Impairment

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

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

Hepatic Impairment

Increased bioavailability of perindoprilat.

Black Patients

BP reduction may be smaller in black patients compared with patients of other races. (See Hypertension under Uses and see Perindopril Arginine/Amlodipine Fixed-combination Therapy under Dosage and Administration.)

Higher incidence of angioedema reported with ACE inhibitors (as monotherapy) in black patients compared with other races.

Common Adverse Effects

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

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

Interactions for Perindopril

Specific Drugs

Drug

Interaction

Comments

Aliskiren

Increased risk of renal impairment (including acute renal failure), hyperkalemia, and hypotension

Dual blockade of renin-angiotensin system provides no additional benefit over monotherapy in most patients

Generally, avoid concomitant use; monitor BP, renal function, and electrolytes if used concomitantly

Angiotensin II receptor antagonists

Increased risk of renal impairment (including acute renal failure), hyperkalemia, and hypotension

Dual blockade of renin-angiotensin system provides no additional benefit over monotherapy in most patients

Generally, avoid concomitant use; monitor BP, renal function, and electrolytes if used concomitantly

Digoxin

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

Diuretics

Additive hypotensive effect

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

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

Additive hyperkalemic effect

Use with caution; monitor serum potassium concentrations frequently

Gentamicin

Possible interaction based on animal data; no studies in humans

Use with caution

Gold

Nitroid reactions reported rarely in patients receiving concomitant therapy with sodium aurothiomalate and an ACE inhibitor

Lithium

Increased serum lithium concentrations; possible toxicity

Use with caution; monitor serum lithium concentrations frequently

mTor inhibitors

Increased risk of angioedema

Monitor for signs of angioedema

Neprilysin inhibitors (e.g., sacubitril)

Increased risk of angioedema

Concomitant use contraindicated; do not administer perindopril within 36 hours of switching to or from a neprilysin inhibitor

NSAIAs (including COX-2 inhibitors)

May result in deterioration of renal function, including possible renal failure, in geriatric patients, volume-depleted patients, or patients with compromised renal function; effects usually reversible

Monitor renal function periodically

Potassium supplements or potassium-containing salt substitutes

Enhanced hyperkalemic effect

Use with caution; monitor serum potassium concentrations frequently

Perindopril Pharmacokinetics

Absorption

Bioavailability

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

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

Onset

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

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.

Food

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

Special Populations

In patients with hepatic impairment, increased perindoprilat bioavailability.

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

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).

Distribution

Extent

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

Crosses the placenta and is distributed into milk in rats.

Plasma Protein Binding

Perindopril: 60%.

Perindoprilat: 10–20%.

Elimination

Metabolism

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

Elimination Route

Eliminated principally in urine (as metabolites).

Removed by renal dialysis.

Half-life

Perindopril: 0.8–1 hour.

Perindoprilat: 3–10 hours.

Special Populations

In patients with heart failure, decreased clearance and increased AUC of perindoprilat.

Stability

Storage

Oral

Tablets

Perindopril erbumine: 20–25°C. Protect from moisture.

Perindopril arginine/amlodipine fixed combination: 25ºC (may be exposed to 15–30ºC); protect from moisture.

Actions

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

  • Suppresses the renin-angiotensin-aldosterone system.

Advice to Patients

  • Risk of angioedema, anaphylactoid reactions, or other sensitivity reactions. 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.

  • Risk of hypotension. Importance of informing clinicians promptly if lightheadedness or fainting occurs. Importance of adequate fluid intake; risk of volume depletion with excessive perspiration, dehydration, vomiting, or diarrhea.

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

  • Risk of hyperkalemia. Importance of avoiding use of potassium supplements or salt substitutes containing potassium without consulting a clinician.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Risks of use during pregnancy; importance of discussing other options for hypertension treatment if pregnancy occurs.

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

Preparations

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

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Perindopril Arginine Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

3.5 mg with Amlodipine Besylate 2.5 mg (of amlodipine)

Prestalia

Symplmed

7 mg with Amlodipine Besylate 5 mg (of amlodipine)

Prestalia

Symplmed

14 mg with Amlodipine Besylate 10 mg (of amlodipine)

Prestalia

Symplmed

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Perindopril Erbumine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

2 mg*

Aceon (scored)

Symplmed

Perindopril Erbumine Tablets

4 mg*

Aceon (scored)

Symplmed

Perindopril Erbumine Tablets

8 mg*

Aceon (scored)

Symplmed

Perindopril Erbumine Tablets

AHFS DI Essentials™. © Copyright 2022, Selected Revisions March 4, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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

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