When pregnancy is detected, discontinue perindopril as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.
Heart failure with reduced ejection fraction (off-label use):
Note: If tolerated, an angiotensin II receptor-neprilysin inhibitor is generally preferred over an angiotensin-converting enzyme inhibitor (ACC [Maddox 2021]).
Oral: Initial: 2 mg once daily; as tolerated, may increase dose (eg, double) every ≥2 weeks to a target dose of 8 to 16 mg once daily (ACC/AHA [Yancy 2017]; ACCF/AHA [Yancy 2013]). In closely monitored hospitalized patients, may titrate more rapidly as tolerated (Meyer 2021).
Hypertension, chronic:
Note: For patients who warrant combination therapy (BP >20/10 mm Hg above goal or suboptimal response to initial monotherapy), may use with another appropriate agent (eg, long-acting dihydropyridine calcium channel blocker or thiazide diuretic) (ACC/AHA [Whelton 2018]).
Oral: Initial: 4 mg once daily; evaluate response after ~2 to 4 weeks and titrate dose (eg, increase the daily dose by doubling) as needed up to 16 mg once daily; if additional blood pressure control is needed, consider combination therapy. Patients with severe asymptomatic hypertension and no signs of acute end organ damage should be evaluated for medication titration within 1 week (ACC/AHA [Whelton 2018]; Mann 2021).
Stable coronary artery disease: Oral: Initial: 4 mg once daily for 2 weeks; then increase as tolerated to 8 mg once daily.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
CrCl >80 mL/minute: No dosage adjustment necessary.
CrCl ≥30 to ≤80 mL/minute: Initial: 2 mg/day; maximum maintenance dose: 8 mg/day.
CrCl <30 mL/minute: Use is not recommended. 2 mg once every 48 hours has been recommended for patients with CrCl 15 to 30 mL/minute (Coversyl Canadian product labeling).
Hemodialysis: Perindopril and its metabolites are dialyzable. 2 mg on dialysis days (given after dialysis) has been recommended (Coversyl Canadian product labeling).
There are no dosage adjustments provided in the manufacturer's labeling; use with caution (perindoprilat bioavailability is increased with hepatic impairment).
Hypertension, chronic: >65 years of age: Oral: Initial: 4 mg/day in 1 or 2 divided doses; ACC/AHA recommends consideration of lower initial doses with titration per response (Aronow 2011). Experience with doses >8 mg/day is limited.
Stable coronary artery disease: >70 years of age: Oral: Initial: 2 mg once daily for 1 week; then increase as tolerated to 4 mg once daily for 1 week; then increase as tolerated to 8 mg once daily.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral, as erbumine:
Generic: 2 mg, 4 mg, 8 mg
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral, as erbumine:
Coversyl: 2 mg, 4 mg, 8 mg
Generic: 2 mg, 4 mg, 8 mg
Hypertension, chronic: Management of hypertension.
Stable coronary artery disease: To reduce the risk of cardiovascular mortality or nonfatal myocardial infarction in patients with stable coronary artery disease.
Heart failure with reduced ejection fraction
The brand name Coversyl represents different salt forms of perindopril (ie, erbumine/tert-butylamine or arginine) in multiple international markets
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
Some reactions occurred at an incidence of >1% but ≤ placebo.
>10%:
Central nervous system: Headache (24%)
Respiratory: Cough (12%; incidence higher in women, 3:1)
1% to 10%:
Cardiovascular: Edema (4%), chest pain (2%), ECG abnormality (2%), palpitations (1%)
Central nervous system: Hypertonia (3%), sleep disorder (3%), depression (2%), paresthesia (2%), drowsiness (1%), nervousness (1%)
Dermatologic: Skin rash (2%)
Endocrine & metabolic: Increased serum triglycerides (1%), menstrual disease (1%)
Gastrointestinal: Diarrhea (4%), abdominal pain (3%), dyspepsia (2%), nausea (2%), vomiting (2%), flatulence (1%)
Genitourinary: Urinary tract infection (3%), proteinuria (2%), sexual disorder (male: 1%)
Hepatic: Increased serum ALT (2%)
Hypersensitivity: Seasonal allergy (2%)
Infection: Viral infection (3%)
Neuromuscular & skeletal: Weakness (8%), back pain (6%), leg pain (5%), arm pain (3%), arthralgia (1%), arthritis (1%), myalgia (1%), neck pain (1%)
Otic: Tinnitus (2%), otic infection (1%)
Respiratory: Upper respiratory tract infection (9%), sinusitis (5%), rhinitis (5%), pharyngitis (3%)
Miscellaneous: Fever (2%)
<1%, postmarketing, and/or case reports: Amnesia, anaphylaxis, angioedema, anxiety, arthralgia, bronchitis, bruise, cardiac conduction disturbance, cerebrovascular accident, chills, conjunctivitis, constipation, diaphoresis, dyspnea, epistaxis, erythema, facial edema, flank pain, fluid retention, gastroenteritis, gout, heart murmur, hematoma, hematuria, hyperglycemia, hypokalemia, hypotension, increased appetite, increased serum alkaline phosphatase, increased serum AST, increased serum cholesterol, increased serum creatinine, increased uric acid, leukopenia, malaise, migraine, myocardial infarction, nephrolithiasis, neutropenia, orthostatic hypotension, otalgia, pain, pruritus, psoriasis (Song 2021), psychological disorder (psychosexual disorder), pulmonary fibrosis, purpura, rhinorrhea, sneezing, syncope, tinea, urinary frequency, urinary retention, vaginitis, vasodilation, ventricular premature contractions, vertigo, visual hallucination (Doane 2013), xeroderma, xerostomia
Hypersensitivity (eg, angioedema) to perindopril, other ACE inhibitors, or any component of the formulation; hereditary/idiopathic angioedema; concomitant use with aliskiren in patients with diabetes mellitus; concomitant use or within 36 hours of switching to or from a neprilysin inhibitor (eg, sacubitril)
Canadian labeling: Additional contraindications (not in US labeling): Concomitant use with aliskiren in patients with moderate to severe renal impairment (GFR <60 mL/minute/1.73 m2); women who are pregnant, planning to become pregnant, or women of childbearing potential not using adequate contraception; breastfeeding; hereditary problems of galactose intolerance, glucose-galactose malabsorption, or the congenital lactase deficiency; concomitant use with sacubitril/valsartan; extracorporeal treatments leading to contact of blood with negatively charged surfaces; unilateral or bilateral renal artery stenosis
Concerns related to adverse effects:
• Angioedema: At any time during treatment (especially following first dose), angioedema may occur rarely with ACE inhibitors; it may involve the head and neck (potentially compromising airway) or the intestine (presenting with abdominal pain). Black patients and patients with idiopathic or hereditary angioedema or previous angioedema associated with ACE inhibitor therapy may be at an increased risk. Risk may also be increased with concomitant use of mTOR inhibitor (eg, everolimus) or neprilysin inhibitor (eg, sacubitril) therapy. Prolonged frequent monitoring may be required especially if tongue, glottis, or larynx are involved as they are associated with airway obstruction. Patients with a history of airway surgery may have a higher risk of airway obstruction. Aggressive early and appropriate management is critical. Use in patients with previous angioedema associated with ACE inhibitor therapy is contraindicated.
• Cholestatic jaundice: A rare toxicity associated with ACE inhibitors includes cholestatic jaundice, which may progress to fulminant hepatic necrosis (some fatal); discontinue if marked elevation of hepatic transaminases or jaundice occurs.
• Cough: An ACE inhibitor cough is a dry, hacking, nonproductive one that usually occurs within the first few months of treatment and should generally resolve within 1 to 4 weeks after discontinuation of the ACE inhibitor. Other causes of cough should be considered (eg, pulmonary congestion in patients with heart failure) and excluded prior to discontinuation.
• Hematologic effects: Another ACE inhibitor, captopril, has been associated with neutropenia with myeloid hypoplasia and agranulocytosis; anemia and thrombocytopenia have also occurred. Patients with renal impairment are at high risk of developing neutropenia. Patients with both renal impairment and collagen vascular disease (eg, systemic lupus erythematosus) are at an even higher risk of developing neutropenia. Periodically monitor CBC with differential in these patients.
• Hyperkalemia: May occur with ACE inhibitors; risk factors include renal impairment, diabetes mellitus, concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium containing salts. Use cautiously, if at all, with these agents and monitor potassium closely.
• Hypersensitivity reactions: Anaphylactic/anaphylactoid reactions can occur with ACE inhibitors. Severe anaphylactoid reactions may be seen during hemodialysis (eg, CVVHD) with high-flux dialysis membranes (eg, AN69), and rarely, during low density lipoprotein apheresis with dextran sulfate cellulose. Rare cases of anaphylactoid reactions have been reported in patients undergoing sensitization treatment with hymenoptera (bee, wasp) venom while receiving ACE inhibitors.
• Hypotension/syncope: Symptomatic hypotension with or without syncope can occur (usually with the first several doses); effects are most often observed in volume-depleted patients; correct volume depletion prior to initiation; close monitoring of patient is required especially with initial dosing and dosing increases; blood pressure must be lowered at a rate appropriate for the patient's clinical condition. Although dose reduction may be necessary, hypotension is not a reason for discontinuation of future ACE inhibitor use especially in patients with heart failure where a reduction in systolic blood pressure is a desirable observation.
• Renal function deterioration: May be associated with deterioration of renal function and/or increases in BUN and serum creatinine, particularly in patients with low renal blood flow (eg, renal artery stenosis, heart failure) whose GFR is dependent on efferent arteriolar vasoconstriction by angiotensin II; deterioration may result in oliguria, acute renal failure, and progressive azotemia. Small increases in serum creatinine may occur following initiation; consider discontinuation only in patients with progressive and/or significant deterioration in renal function (Bakris 2000).
Disease-related concerns:
• Aortic stenosis: Use with caution in patients with severe aortic stenosis; may reduce coronary perfusion resulting in ischemia.
• Ascites: Avoid use in patients with ascites due to cirrhosis or refractory ascites; if use cannot be avoided in patients with ascites due to cirrhosis, monitor blood pressure and renal function carefully to avoid rapid development of renal failure (AASLD [Runyon 2012]).
• Cardiovascular disease: Initiation of therapy in patients with ischemic heart disease or cerebrovascular disease warrants close observation due to the potential consequences posed by falling blood pressure (eg, MI, stroke). Fluid replacement, if needed, may restore blood pressure; therapy may then be resumed. Discontinue therapy in patients whose hypotension recurs.
• Collagen vascular disease: Use with caution in patients with collagen vascular disease especially with concomitant renal impairment; may be at increased risk for hematologic toxicity.
• Hepatic impairment: Use with caution in patients with hepatic impairment.
• Hypertrophic cardiomyopathy with left ventricular outflow tract obstruction: Use with caution in patients with hypertrophic cardiomyopathy and left ventricular outflow tract obstruction since reduction in afterload may worsen symptoms associated with this condition (AHA/ACC [Ommen 2020]).
• Renal artery stenosis: Use with caution in patients with unstented unilateral/bilateral renal artery stenosis. When unstented unilateral or bilateral renal artery stenosis is present, use is generally avoided due to the elevated risk of deterioration in renal function unless possible benefits outweigh risks.
• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment may be needed. Avoid rapid dosage escalation which may lead to further renal impairment.
Special populations:
• Pregnancy: [US Boxed Warning]: Drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as possible once pregnancy is detected.
• Race/Ethnicity: In Black patients, the BP-lowering effects of ACE inhibitors may be less pronounced. The exact mechanism is not known; differences in the renin-angiotensin-aldosterone system, low renin levels, and salt sensitivity more commonly found in Black patients may contribute (Brewster 2013; Helmer 2017). In addition, Black patients may be at an increased risk of angioedema associated with ACE inhibitors (Brown 1996; Maroteau 2020; Miller 2008; Montinaro 2020; Woodard-Grice 2010).
• Surgical patients: In patients on chronic ACE inhibitor therapy, intraoperative hypotension may occur with induction and maintenance of general anesthesia; use with caution before, during, or immediately after major surgery. Cardiopulmonary bypass, intraoperative blood loss, or vasodilating anesthesia increases endogenous renin release. Use of ACE inhibitors perioperatively will blunt angiotensin II formation and may result in hypotension. However, discontinuation of therapy prior to surgery is controversial. If continued preoperatively, avoidance of hypotensive agents during surgery is prudent (Hillis 2011). Based on current research and clinical guidelines in patients undergoing noncardiac surgery, continuing ACE inhibitors is reasonable in the perioperative period. If ACE inhibitors are held before surgery, it is reasonable to restart postoperatively as soon as clinically feasible (ACC/AHA [Fleisher 2014]).
Dosage form specific issues:
• Lactose: Some formulations may contain lactose.
None known.
Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Aliskiren: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Aliskiren may enhance the hypotensive effect of Angiotensin-Converting Enzyme Inhibitors. Aliskiren may enhance the nephrotoxic effect of Angiotensin-Converting Enzyme Inhibitors. Management: Aliskiren use with ACEIs or ARBs in patients with diabetes is contraindicated. Combined use in other patients should be avoided, particularly when CrCl is less than 60 mL/min. If combined, monitor potassium, creatinine, and blood pressure closely. Risk D: Consider therapy modification
Allopurinol: Angiotensin-Converting Enzyme Inhibitors may enhance the potential for allergic or hypersensitivity reactions to Allopurinol. Risk C: Monitor therapy
Alteplase: Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Alteplase. Specifically, the risk for angioedema may be increased. Risk C: Monitor therapy
Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When used at chemotherapy doses, hold blood pressure lowering medications for 24 hours before amifostine administration. If blood pressure lowering therapy cannot be held, do not administer amifostine. Use caution with radiotherapy doses of amifostine. Risk D: Consider therapy modification
Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Angiotensin II: Angiotensin-Converting Enzyme Inhibitors may enhance the therapeutic effect of Angiotensin II. Risk C: Monitor therapy
Angiotensin II Receptor Blockers: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Angiotensin II Receptor Blockers may increase the serum concentration of Angiotensin-Converting Enzyme Inhibitors. Management: Use of telmisartan and ramipril is not recommended. It is not clear if any other combination of an ACE inhibitor and an ARB would be any safer. Consider alternatives when possible. Monitor blood pressure, renal function, and potassium if combined. Risk D: Consider therapy modification
Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Risk C: Monitor therapy
Aprotinin: May diminish the antihypertensive effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
AzaTHIOprine: Angiotensin-Converting Enzyme Inhibitors may enhance the myelosuppressive effect of AzaTHIOprine. Risk C: Monitor therapy
Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Brigatinib: May diminish the antihypertensive effect of Antihypertensive Agents. Brigatinib may enhance the bradycardic effect of Antihypertensive Agents. Risk C: Monitor therapy
Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Bromperidol: May diminish the hypotensive effect of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Risk X: Avoid combination
Dapoxetine: May enhance the orthostatic hypotensive effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Dexmethylphenidate: May diminish the therapeutic effect of Antihypertensive Agents. Risk C: Monitor therapy
Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Dipeptidyl Peptidase-IV Inhibitors: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Specifically, the risk of angioedema may be increased. Risk C: Monitor therapy
Drospirenone-Containing Products: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Risk C: Monitor therapy
Eplerenone: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Everolimus: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Specifically, the risk of angioedema may be increased. Risk C: Monitor therapy
Ferric Gluconate: Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Ferric Gluconate. Risk C: Monitor therapy
Ferric Hydroxide Polymaltose Complex: Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Ferric Hydroxide Polymaltose Complex. Specifically, the risk for angioedema or allergic reactions may be increased. Risk C: Monitor therapy
Finerenone: Angiotensin-Converting Enzyme Inhibitors may enhance the hyperkalemic effect of Finerenone. Risk C: Monitor therapy
Gelatin (Succinylated): Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Gelatin (Succinylated). Specifically, the risk of a paradoxical hypotensive reaction may be increased. Risk C: Monitor therapy
Gold Sodium Thiomalate: Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Gold Sodium Thiomalate. This combination may increase the risk of developing a nitritoid reaction. Risk C: Monitor therapy
Grass Pollen Allergen Extract (5 Grass Extract): Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Grass Pollen Allergen Extract (5 Grass Extract). Specifically, ACE inhibitors may increase the risk of severe allergic reaction to Grass Pollen Allergen Extract (5 Grass Extract). Risk X: Avoid combination
Heparin: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Heparins (Low Molecular Weight): May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Herbal Products with Blood Pressure Increasing Effects: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Herbal Products with Blood Pressure Lowering Effects: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy
Icatibant: May diminish the antihypertensive effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Iron Dextran Complex: Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Iron Dextran Complex. Specifically, patients receiving an ACE inhibitor may be at an increased risk for anaphylactic-type reactions. Management: Follow iron dextran recommendations closely regarding both having resuscitation equipment and trained personnel on-hand prior to iron dextran administration and the use of a test dose prior to the first therapeutic dose. Risk D: Consider therapy modification
Lanthanum: May decrease the serum concentration of Angiotensin-Converting Enzyme Inhibitors. Management: Administer angiotensin-converting enzyme inhibitors at least two hours before or after lanthanum. Risk D: Consider therapy modification
Levodopa-Containing Products: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products. Risk C: Monitor therapy
Lithium: Angiotensin-Converting Enzyme Inhibitors may increase the serum concentration of Lithium. Management: Lithium dosage reductions will likely be needed following the addition of an ACE inhibitor. Monitor for increased concentrations/toxic effects of lithium if an ACE inhibitor is initiated/dose increased, or if switching between ACE inhibitors. Risk D: Consider therapy modification
Loop Diuretics: May enhance the hypotensive effect of Angiotensin-Converting Enzyme Inhibitors. Loop Diuretics may enhance the nephrotoxic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nicorandil: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the combination may result in a significant decrease in renal function. Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents (Topical): May diminish the therapeutic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Risk D: Consider therapy modification
Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Potassium Salts: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Potassium-Sparing Diuretics: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Pregabalin: Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Pregabalin. Specifically, the risk of angioedema may be increased. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Racecadotril: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Specifically, the risk for angioedema may be increased with this combination. Risk C: Monitor therapy
Ranolazine: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Sacubitril: Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Sacubitril. Specifically, the risk of angioedema may be increased with this combination. Risk X: Avoid combination
Salicylates: May enhance the nephrotoxic effect of Angiotensin-Converting Enzyme Inhibitors. Salicylates may diminish the therapeutic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Sirolimus Products: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Specifically, the risk for angioedema may be increased. Risk C: Monitor therapy
Sodium Phosphates: Angiotensin-Converting Enzyme Inhibitors may enhance the nephrotoxic effect of Sodium Phosphates. Specifically, the risk of acute phosphate nephropathy may be enhanced. Management: Consider avoiding this combination by temporarily suspending treatment with ACEIs, or seeking alternatives to oral sodium phosphate bowel preparation. If the combination cannot be avoided, maintain adequate hydration and monitor renal function closely. Risk D: Consider therapy modification
Tacrolimus (Systemic): Angiotensin-Converting Enzyme Inhibitors may enhance the hyperkalemic effect of Tacrolimus (Systemic). Risk C: Monitor therapy
Temsirolimus: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Thiazide and Thiazide-Like Diuretics: May enhance the hypotensive effect of Angiotensin-Converting Enzyme Inhibitors. Thiazide and Thiazide-Like Diuretics may enhance the nephrotoxic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
TiZANidine: May enhance the hypotensive effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Tolvaptan: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Trimethoprim: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Urapidil: May interact via an unknown mechanism with Angiotensin-Converting Enzyme Inhibitors. Management: Avoid concomitant use of urapidil and angiotensin-converting enzyme (ACE) inhibitors. Risk D: Consider therapy modification
Urokinase: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Specifically, the risk of angioedema may be increased. Risk C: Monitor therapy
Perindopril active metabolite concentrations may be lowered if taken with food. Management: Administer prior to a meal.
Avoid use of angiotensin-converting enzyme (ACE) inhibitor therapy in patients who may become pregnant and who are not using effective contraception (ADA 2021).
ACE inhibitors should generally be avoided for the treatment of hypertension in patients planning to become pregnant; use should only be considered for cases of hypertension refractory to other medications (ACOG 203 2019).
Exposure to an angiotensin-converting enzyme (ACE) inhibitor during the first trimester of pregnancy may be associated with an increased risk of fetal malformations (ACOG 203 2019; ESC [Regitz-Zagrosek 2018]); however, outcomes observed may also be influenced by maternal disease (ACC/AHA [Whelton 2018]).
[US Boxed Warning]: Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as possible once pregnancy is detected. Drugs that act on the renin-angiotensin system are associated with oligohydramnios. Oligohydramnios, due to decreased fetal renal function, may lead to fetal lung hypoplasia and skeletal malformations. Their use in pregnancy is also associated with anuria, hypotension, renal failure, skull hypoplasia, and death in the fetus/neonate. Infants exposed to an ACE inhibitor in utero should be monitored for hyperkalemia, hypotension, and oliguria. Oligohydramnios may not appear until after irreversible fetal injury has occurred. Exchange transfusions or dialysis may be required to reverse hypotension or improve renal function, although data related to the effectiveness in neonates is limited.
Chronic maternal hypertension is also associated with adverse events in the fetus/infant. Chronic maternal hypertension may increase the risk of birth defects, low birth weight, premature delivery, stillbirth, and neonatal death. Actual fetal/neonatal risks may be related to duration and severity of maternal hypertension. Untreated chronic hypertension may also increase the risks of adverse maternal outcomes, including gestational diabetes, preeclampsia, delivery complications, stroke, and myocardial infarction (ACOG 203 2019).
When treatment of hypertension in pregnancy is indicated, ACE inhibitors should generally be avoided due to their adverse fetal events; use in pregnant women should only be considered for cases of hypertension refractory to other medications (ACOG 203 2019). ACE inhibitors are not recommended for the treatment of heart failure in pregnancy (Regitz-Zagrosek [ESC 2018]).
Perindopril and perindoprilat are present in breast milk (Lwin 2017).
The relative infant dose (RID) is <2% when calculated using a single breast milk concentration and compared to a weight-adjusted maternal dose of 20 mg/day. In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000).
The RID of perindopril was calculated using a milk concentration of 0.9 ng/mL, providing an estimated daily infant dose via breast milk of 135 ng/kg/day. This milk concentration was obtained following maternal administration of oral perindopril 10 mg twice daily for 2 weeks; a single milk sample was obtained 9 hours after the dose. Perindoprilat was also detected in the sample (Lwin 2017).
The manufacturer recommends that caution be exercised when administering perindopril to breastfeeding women.
BP; BUN, serum creatinine, and potassium; if patient has collagen vascular disease and/or renal impairment, periodically monitor CBC with differential.
Heart failure: Within 1 to 2 weeks after initiation and periodically thereafter, reassess renal function and serum potassium especially in patients with preexisting hypotension, hyponatremia, diabetes mellitus, azotemia, or those taking potassium supplements (ACCF/AHA [Yancy 2013]).
BP goals: May vary depending on clinical condition, different clinical practice guidelines, and expert opinion. Refer to clinical practice guidelines for specific treatment goals.
Perindopril is a prodrug for perindoprilat, which acts as a competitive inhibitor of ACE; prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor; results in lower levels of angiotensin II which, in turn, causes an increase in plasma renin activity and a reduction in aldosterone secretion.
Onset of action: Peak effect: 1 to 2 hours
Protein binding: Perindopril: ~60%; Perindoprilat: 10% to 20%
Metabolism: Hepatically hydrolyzed to active metabolite, perindoprilat (~17% to 20% of a dose) and other inactive metabolites
Bioavailability: Perindopril: ~75%; Perindoprilat ~25% (~16% with food)
Half-life elimination: Parent drug: 1.5 to 3 hours; Metabolite: Effective: 3 to 10 hours, Terminal: 30 to 120 hours
Time to peak: Chronic therapy: Perindopril: ~1 hour; Perindoprilat: 3 to 7 hours (maximum perindoprilat serum levels are 2 to 3 times higher and Tmax is shorter following chronic therapy); CHF: Perindoprilat: 6 hours
Excretion: Urine (75%, 4% to 12% as unchanged drug)
Renal function impairment: At CrCl of 30 to 80 mL/minute, perindoprilat AUC is approximately doubled.
Hepatic function impairment: Bioavailability of perindoprilat is increased, and plasma concentrations are ~50% higher.
Geriatric: Plasma concentrations of perindopril and perindoprilat in patients >70 years of age are approximately twice those observed in younger patients; renal excretion of perindoprilat decreases.
Heart failure: Clearance is reduced, resulting in a 40% higher dose-interval AUC.
Tablets (Perindopril Erbumine Oral)
2 mg (per each): $1.90 - $1.97
4 mg (per each): $0.88 - $2.30
8 mg (per each): $1.15 - $2.80
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