Version May 2024
Hypertension: Coversyl products: Oral: Initial: Perindopril erbumine 2 mg/indapamide 0.625 mg once daily; titrate based on BP response to perindopril erbumine 4 to 8 mg/indapamide 1.25 mg once daily; may titrate further as needed to perindopril erbumine 8 mg/indapamide 2.5 mg once daily. Patients already taking one or more of these components may be switched to a combination product for individually titrated agents.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
GFR ≥60 mL/minute/1.73 m2: No dosage adjustment necessary.
GFR 30 to <60 mL/minute/1.73 m2: There are no specific dosage recommendations provided in the manufacturer's labeling; use lower doses and use with caution (perindoprilat exposure may be increased). Use of perindopril erbumine 8 mg/indapamide 1.25 mg and perindopril erbumine 8 mg/indapamide 2.5 mg is contraindicated.
GFR <30 mL/minute/1.73 m2: Use is contraindicated.
Hemodialysis: Dialyzable.
There are no dosage adjustments provided in the manufacturer's labeling; use with caution (perindoprilat systemic exposure is increased in hepatic impairment). Use is contraindicated in patients with severe impairment or hepatic encephalopathy.
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Also see individual agents.
1% to 10%:
Endocrine & metabolic: Hyperkalemia (1%), hypokalemia (2% to 7%)
Gastrointestinal: Dyspepsia (1%), nausea and vomiting (2%)
Nervous system: Dizziness (1% to 2%)
Neuromuscular & skeletal: Arthralgia (1%)
Renal: Increased blood urea nitrogen (4%)
Respiratory: Bronchitis (1%), cough (3% to 5%), upper respiratory tract infection (2%)
<1%:
Cardiovascular: Angina pectoris, cardiac arrhythmia, chest pain, collapse, ECG abnormality, edema, flushing, hypertension, orthostatic hypotension, palpitations, peripheral venous insufficiency, Raynaud disease, syncope, tachycardia
Dermatologic: Contact dermatitis, eczema, fungal skin infection, pallor, pruritus, skin rash
Endocrine & metabolic: Loss of libido (frigidity), weight loss
Gastrointestinal: Abdominal pain, altered salivation, bloating, colitis, constipation, diarrhea, duodenitis, dysgeusia, esophagitis, gastritis, gastroenteritis (infective and non-infective), intestinal infection, reflux esophagitis
Genitourinary: Benign prostatic hyperplasia, cystitis, dysuria, erectile dysfunction, male genital disease (penis disorders), polyuria, uremia, urinary frequency, urinary incontinence, urinary tract infection
Hematologic & oncologic: Neoplasm (female genital organs)
Infection: Abscess (periapical), herpes zoster infection
Local: Localized infection (skin and subcutaneous tissues)
Nervous system: Abnormal sensory symptoms (skin), altered sense of smell, anxiety, depression, drowsiness, falling, fibromyalgia syndrome (shoulder), malaise, migraine, nervousness, sciatica, sleep disturbance, vertigo
Neuromuscular & skeletal: Arthritis (periarthritis of shoulder), back pain, fascia disorder, gout, ligament disorder, limb pain, lower back pain, myopathy, neck pain (including cervicobrachial syndrome), osteoarthrosis (local), sprain (ankle, knee, leg), tendinopathy (enthesopathy of elbow region), tetany
Ophthalmic: Conjunctivitis, visual disturbance
Otic: Impacted cerumen, otitis media, tinnitus
Renal: Increased serum creatinine
Respiratory: Allergic rhinitis, asthma, epistaxis, laryngitis, pharyngeal disease, pharyngitis, respiratory insufficiency, rhinitis, sinusitis, tonsillitis, tracheitis
Miscellaneous: Fever
Frequency not defined:
Endocrine & metabolic: Hyperglycemia
Hematologic & oncologic: Decreased hemoglobin
Nervous system: Loss of consciousness, transient ischemic attacks
Renal: Kidney failure, renal colic
Postmarketing:
Cardiovascular: Acute myocardial infarction, atrial fibrillation, bradycardia, hypotension, peripheral edema, prolonged QT interval on ECG, torsades de pointes, vasculitis, ventricular tachycardia
Dermatologic: Bullous rash, diaphoresis, erythema multiforme, erythroderma, exacerbation of psoriasis, maculopapular rash, pemphigoid, pemphigus, skin photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis
Endocrine & metabolic: Dehydration, diabetes mellitus with hyperosmolar coma, hypercalcemia, hypochloremia, hypomagnesemia, hyponatremia, increased uric acid, metabolic alkalosis, SIADH
Gastrointestinal: Anorexia, epigastric pain, pancreatitis, xerostomia
Genitourinary: Anuria, oliguria
Hematologic & oncologic: Agranulocytosis, aplastic anemia, eosinophilia, hemolytic anemia, leukopenia, neutropenia, purpuric disease, thrombocytopenia
Hepatic: Hepatitis (cholestatic hepatitis and hepatic cytolysis), increased liver enzymes
Hypersensitivity: Hypersensitivity reaction (including angioedema)
Nervous system: Asthenia, cerebrovascular accident, confusion, headache, mood disorder, myasthenia, paresthesia
Neuromuscular & skeletal: Muscle cramps, muscle spasm, myalgia, rhabdomyolysis
Ophthalmic: Angle-closure glaucoma, blurred vision, cataract, choroidal effusion, myopia (acute), optic neuritis
Renal: Acute kidney injury, interstitial nephritis, kidney impairment
Respiratory: Bronchospasm, dyspnea, eosinophilic pneumonitis
Hypersensitivity to perindopril, indapamide, any other component of the formulation, or sulfonamide-derived drugs; hereditary/idiopathic angioedema or history of angioedema related to previous treatment with an ACE inhibitor; hypokalemia; severe hepatic impairment; hepatic encephalopathy; pregnant women, women planning a pregnancy, and women of reproductive potential not using adequate contraception; breastfeeding; moderate kidney impairment (GFR 30 to 59 mL/minute/1.73 m2) (Coversyl Plus [perindopril erbumine 8 mg/indapamide 1.25 mg strength only] and Coversyl Plus HD [perindopril erbumine 8 mg /indapamide 2.5 mg]); severe kidney impairment (GFR <30 mL/minute/1.73 m2); concomitant use with aliskiren-containing drugs in patients with diabetes or moderate to severe kidney impairment (GFR <60 mL/minute/1.73 m2); concomitant use with antiarrhythmic agents causing torsades de pointes; concomitant use with sacubitril/valsartan; hereditary problems of galactose intolerance, glucose-galactose malabsorption, or the total lactase deficiency; extracorporeal treatments leading to contact of blood with negatively charged surfaces; unilateral or bilateral renal artery stenosis.
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Note: Although the product labeling states this medication is contraindicated in patients with hypersensitivity to sulfonamide-containing drugs, the scientific basis of this cross-sensitivity has been challenged. See “Warnings/Precautions” for more detail.
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), dipeptidyl peptidase 4 inhibitors (eg, sitagliptin), 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 idiopathic or hereditary angioedema or 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. Consider discontinuing therapy when appropriate if symptoms of hepatic impairment (eg, fever, malaise, muscle pain, rash) present within the first weeks to months of therapy.
• CNS depression: Perindopril may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).
• 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.
• Dermatologic reactions: Maculopapular pruritic rashes have been reported with ACE inhibitors which may or may not recur when switched to another ACE inhibitor (cross reactivity has been reported). Severe reactions (eg, lichenoid eruptions, psoriasis, pemphigus like rash, rosacea, Stevens-Johnson syndrome) rarely have been observed. Severe dermatological effects have also been reported with indapamide; in most cases resolution occurred within 2 weeks of indapamide discontinuation.
• Dysgeusia: Suppression of taste or a metallic sensation in the mouth has been reported commonly with high doses of ACE inhibitors; usually occurs in the first weeks of treatment and may disappear within 1 to 3 months.
• Electrolyte disturbances: Hyperkalemia may occur with ACE inhibitors; risk factors include kidney impairment, diabetes mellitus, older patients, intercurrent events (in particular, dehydration), acute cardiac decompensation, metabolic acidosis, and concomitant use of potassium-sparing diuretics, potassium supplements, potassium-containing salts, and/or any drug associated with increases in serum potassium. Use cautiously, if at all, with these agents and monitor potassium closely. Indapamide may cause hypokalemia, hypochloremia, hyponatremia, hypophosphatemia, and/or hypercalcemia. Use is contraindicated in patients with hypokalemia. Patients with a long QT interval (congenital or iatrogenic) are at risk of arrythmias if hypokalemia occurs.
• Hematologic effects: Another ACE inhibitor, captopril, has been associated with neutropenia with myeloid hypoplasia and agranulocytosis; anemia and thrombocytopenia have also occurred. Patients with kidney impairment are at high risk of developing neutropenia. Patients with both kidney 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.
• Hypersensitivity reactions: Anaphylactic/anaphylactoid reactions can occur with ACE inhibitors. Severe anaphylactoid reactions may be seen during hemodialysis with high-flux dialysis membranes (eg, polyacrylonitrile [PAN]), 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 with ACE inhibitors (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 permanent discontinuation of future ACE inhibitor use.
• Kidney function deterioration: May be associated with deterioration of kidney 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 kidney 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 kidney function (Bakris 2000).
• Ocular effects: May cause acute transient myopia and acute angle-closure glaucoma, typically occurring within hours to weeks following initiation. Discontinue therapy immediately in patients with acute decreases in visual acuity or ocular pain; additional treatments may be needed if uncontrolled intraocular pressure persists. Risk factors may include a history of sulfonamide or penicillin allergy.
• Photosensitivity: Photosensitization may occur.
• Proteinuria: Total urinary proteins <1 g/day have been reported (<1%) with ACE inhibitors; nephrotic syndrome occurred in about one-fifth of proteinuric patients. In most cases, proteinuria subsided or cleared within six months (whether or not ACE inhibitor was continued).
• Sulfonamide (“sulfa”) allergy: The FDA-approved product labeling for many medications containing a sulfonamide chemical group includes a broad contraindication in patients with a prior allergic reaction to sulfonamides. There is a potential for cross-reactivity between members of a specific class (eg, two antibiotic sulfonamides). However, concerns for cross-reactivity have previously extended to all compounds containing the sulfonamide structure (SO2NH2). An expanded understanding of allergic mechanisms indicates cross-reactivity between antibiotic sulfonamides and nonantibiotic sulfonamides may not occur or at the very least this potential is extremely low (Brackett 2004; Johnson 2005; Slatore 2004; Tornero 2004). In particular, mechanisms of cross-reaction due to antibody production (anaphylaxis) are unlikely to occur with nonantibiotic sulfonamides. T-cell-mediated (type IV) reactions (eg, maculopapular rash) are less well understood and it is not possible to completely exclude this potential based on current insights. In cases where prior reactions were severe (Stevens-Johnson syndrome/toxic epidermal necrolysis), some clinicians choose to avoid exposure to these classes.
Disease-related concerns:
• Aldosteronism: Use is not recommended in patients with primary aldosteronism; these patients generally will not respond to anti-hypertensive drugs acting through inhibition of the renin-angiotensin system.
• Aortic stenosis: Use perindopril with caution in patients with aortic stenosis or mitral valve; may reduce coronary perfusion resulting in ischemia.
• Bariatric surgery: Dehydration: Avoid diuretics in the immediate postoperative period after bariatric surgery; electrolyte disturbances and dehydration may occur. Diuretics may be resumed, if indicated, once oral fluid intake goals are met (Ziegler 2009).
• Cardiovascular disease: Initiation of therapy in patients with ischemic heart disease, heart failure, 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. Initial perindopril dose reduction recommended for patients with heart failure; clearance of active metabolite (perindoprilat) is reduced in these patients. Use is not recommended in renovascular hypertension or heart failure.
• Collagen vascular disease: Use perindopril with caution in patients with collagen vascular disease especially with concomitant kidney impairment; may be at increased risk for hematologic toxicity. Indapamide may exacerbate or activate systemic lupus erythematosus (SLE).
• Diabetes: Use with caution in patients with prediabetes or diabetes mellitus; may see a change in glucose control.
• Gout: Hyperuricemia has been observed with indapamide use. In certain patients with a history of gout, a familial predisposition to gout, or chronic kidney failure, gout can be precipitated by indapamide.
• Hepatic impairment: Use with caution in patients with hepatic impairment; elevations of liver enzymes and/or serum bilirubin have been reported with perindopril. Prior to initiation of therapy obtain baseline transaminase and bilirubin levels. In cirrhosis, avoid electrolyte and acid/base imbalances that might lead to hepatic encephalopathy. Contraindicated in patients with severe hepatic impairment or hepatic encephalopathy.
• 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]).
• Kidney impairment: Use with caution in patients with kidney impairment; dosage adjustment may be needed. Avoid rapid dosage escalation which may lead to further kidney impairment. Patients with kidney impairment may be at increased risk for hematologic toxicity. Use may be contraindicated in moderate and/or severe kidney impairment. Refer to contraindications.
• Renal artery stenosis: Use is contraindicated in patients with unilateral or bilateral renal artery stenosis.
Special populations:
• Black patients: ACE inhibitors' effectiveness is less in Black patients than in non-Black patients. In addition, ACE inhibitors cause a higher rate of angioedema in Black patients than in non-Black patients.
Dosage form specific issues:
• Lactose: Some formulations may contain lactose; use in patients with total lactase deficiency, glucose-galactose malabsorption, or hereditary problems of galactose intolerance is contraindicated.
Other warnings/precautions:
• Surgery: 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. Discontinuation of therapy prior to surgery is controversial. If continued preoperatively, avoidance of hypotensive agents during surgery is prudent (Hillis 2011).
Not available in the US
May be product dependent
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Coversyl Plus: Perindopril erbumine 4 mg and indapamide 1.25 mg
Coversyl Plus HD: Perindopril erbumine 8 mg and indapamide 2.5 mg
Coversyl Plus LD: Perindopril erbumine 2 mg and indapamide 0.625 mg
Generic: Perindopril erbumine 2 mg and indapamide 0.625 mg, Perindopril erbumine 4 mg and indapamide 1.25 mg, Perindopril erbumine 8 mg and indapamide 2.5 mg
Administer prior to a meal in the morning.
Note: Not approved in the United States.
Hypertension: Management of mild to moderate hypertension.
ALERT: Canadian Boxed Warning: Health Canada-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling.
Beers Criteria: Diuretics (indapamide) are identified in the Beers Criteria as potentially inappropriate medications to be used with caution in patients 65 years and older due to the potential to cause or exacerbate syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatremia; monitor sodium concentration closely when initiating or adjusting the dose in older adults (Beers Criteria [AGS 2023]).
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Ajmaline: Sulfonamides may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased. Risk C: Monitor therapy
Alcohol (Ethyl): May enhance the orthostatic hypotensive effect of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy
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
Allopurinol: Thiazide and Thiazide-Like Diuretics 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
Aminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). Risk X: Avoid combination
Aminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). Risk C: Monitor therapy
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
Angiotensin-Converting Enzyme Inhibitors: 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
Anticholinergic Agents: May increase the serum concentration of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy
Antidiabetic Agents: Thiazide and Thiazide-Like Diuretics may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
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
Arginine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Arsenic Trioxide: Thiazide and Thiazide-Like Diuretics may enhance the hypotensive effect of Arsenic Trioxide. Thiazide and Thiazide-Like Diuretics may enhance the QTc-prolonging effect of Arsenic Trioxide. Management: When possible, avoid concurrent use of arsenic trioxide with drugs that can cause electrolyte abnormalities, such as the thiazide and thiazide-like diuretics. Risk D: Consider therapy modification
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
Beta2-Agonists: May enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy
Bile Acid Sequestrants: May decrease the absorption of Thiazide and Thiazide-Like Diuretics. The diuretic response is likewise decreased. Management: Consider separating administraton of bile acid sequestrants and thiazide diuretics by at least 4 hours. Monitor for decreased therapeutic effects of thiazide diuretics if coadministered with a bile acid sequestrant. Risk D: Consider therapy modification
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
Calcium Salts: Thiazide and Thiazide-Like Diuretics may increase the serum concentration of Calcium Salts. Risk C: Monitor therapy
Cardiac Glycosides: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of Cardiac Glycosides. Specifically, cardiac glycoside toxicity may be enhanced by the hypokalemic and hypomagnesemic effect of thiazide diuretics. Risk C: Monitor therapy
Corticosteroids (Systemic): May enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy
CycloPHOSphamide: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of CycloPHOSphamide. Specifically, granulocytopenia may be enhanced. Risk C: Monitor therapy
Dapoxetine: May enhance the orthostatic hypotensive effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Desmopressin: Hyponatremia-Associated Agents may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy
Dexketoprofen: May enhance the adverse/toxic effect of Sulfonamides. Risk C: Monitor therapy
Dexmethylphenidate: May diminish the therapeutic effect of Antihypertensive Agents. Risk C: Monitor therapy
Diacerein: May enhance the therapeutic effect of Diuretics. Specifically, the risk for dehydration or hypokalemia may be increased. Risk C: Monitor therapy
Diazoxide: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of Diazoxide. Risk C: Monitor therapy
Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Dichlorphenamide: Thiazide and Thiazide-Like Diuretics may enhance the hypokalemic effect of Dichlorphenamide. 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
Dofetilide: Thiazide and Thiazide-Like Diuretics may enhance the QTc-prolonging effect of Dofetilide. Thiazide and Thiazide-Like Diuretics may increase the serum concentration of Dofetilide. Management: Although hydrochlorothiazide is specifically cited as a contraindication, the risk likely extends to all thiazide and thiazide-like diuretics and may be even greater with chlorthalidone or bendroflumethiazide. Consider alternatives when possible. Risk D: Consider therapy modification
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
Flunarizine: May enhance the therapeutic effect of Antihypertensive Agents. 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
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
Indoramin: May enhance the hypotensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Ipragliflozin: May enhance the adverse/toxic effect of Thiazide and Thiazide-Like Diuretics. Specifically, the risk for intravascular volume depletion may be increased. 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. Risk C: Monitor therapy
Ivabradine: Thiazide and Thiazide-Like Diuretics may enhance the arrhythmogenic effect of Ivabradine. Risk C: Monitor therapy
Lanthanum: May decrease the serum concentration of Angiotensin-Converting Enzyme Inhibitors. Management: Administer angiotensin-converting enzyme (ACE) inhibitors at least two hours before or after lanthanum. Risk D: Consider therapy modification
Levodopa-Foslevodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Foslevodopa. Risk C: Monitor therapy
Levosulpiride: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of Levosulpiride. Risk X: Avoid combination
Licorice: May enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy
Lithium: Thiazide and Thiazide-Like Diuretics may decrease the excretion of Lithium. Management: Reduce the lithium dose if coadministered with thiazide or thiazide-like diuretics. Monitor serum lithium levels during coadministration with thiazide and thiazide-like diuretics. Risk D: Consider therapy modification
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
Loop Diuretics: May enhance the hypotensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Mecamylamine: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of Mecamylamine. Management: Consider avoiding the use of mecamylamine and thiazide diuretics. If combined, mecamylamine prescribing information suggests reducing the mecamylamine dose by 50% in order to avoid excessive hypotension. Risk D: Consider therapy modification
Methenamine: Thiazide and Thiazide-Like Diuretics may diminish the therapeutic effect of Methenamine. Risk C: Monitor therapy
Methoxsalen (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Methoxsalen (Systemic). 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
Multivitamins/Fluoride (with ADE): May enhance the hypercalcemic effect of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy
Multivitamins/Minerals (with ADEK, Folate, Iron): Thiazide and Thiazide-Like Diuretics may enhance the hypercalcemic effect of Multivitamins/Minerals (with ADEK, Folate, Iron). Risk C: Monitor therapy
Multivitamins/Minerals (with AE, No Iron): Thiazide and Thiazide-Like Diuretics may increase the serum concentration of Multivitamins/Minerals (with AE, No Iron). Specifically, thiazide diuretics may decrease the excretion of calcium, and continued concomitant use can also result in metabolic alkalosis. Risk C: Monitor therapy
Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Neuromuscular-Blocking Agents (Nondepolarizing): Thiazide and Thiazide-Like Diuretics may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing). 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: Thiazide and Thiazide-Like Diuretics may enhance the nephrotoxic effect of Nonsteroidal Anti-Inflammatory Agents. Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents (Topical): May diminish the therapeutic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents (Topical): May diminish the therapeutic effect of Thiazide and Thiazide-Like Diuretics. 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
Opioid Agonists: May enhance the adverse/toxic effect of Diuretics. Opioid Agonists may diminish the therapeutic effect of Diuretics. Risk C: Monitor therapy
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
Polyethylene Glycol-Electrolyte Solution: Angiotensin-Converting Enzyme Inhibitors may enhance the nephrotoxic effect of Polyethylene Glycol-Electrolyte Solution. Risk C: Monitor therapy
Polyethylene Glycol-Electrolyte Solution: Diuretics may enhance the nephrotoxic effect of Polyethylene Glycol-Electrolyte Solution. Risk C: Monitor therapy
Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. 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
Prazosin: Antihypertensive Agents may enhance the hypotensive effect of Prazosin. 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
Promazine: Thiazide and Thiazide-Like Diuretics may enhance the QTc-prolonging effect of Promazine. Risk X: Avoid combination
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
Reboxetine: May enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. 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
Selective Serotonin Reuptake Inhibitors: May enhance the hyponatremic effect of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy
Silodosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. 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. Risk C: Monitor therapy
Sodium Phosphates: Diuretics may enhance the nephrotoxic effect of Sodium Phosphates. Specifically, the risk of acute phosphate nephropathy may be enhanced. Risk C: Monitor therapy
Sparsentan: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Risk X: Avoid combination
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. Specifically, the risk of angioedema may be increased. Risk C: Monitor therapy
Terazosin: Antihypertensive Agents may enhance the hypotensive effect of Terazosin. 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
Tolvaptan: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Topiramate: Thiazide and Thiazide-Like Diuretics may enhance the hypokalemic effect of Topiramate. Thiazide and Thiazide-Like Diuretics may increase the serum concentration of Topiramate. Risk C: Monitor therapy
Toremifene: Thiazide and Thiazide-Like Diuretics may enhance the hypercalcemic effect of Toremifene. 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
Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Risk C: Monitor therapy
Vitamin D Analogs: Thiazide and Thiazide-Like Diuretics may enhance the hypercalcemic effect of Vitamin D Analogs. Risk C: Monitor therapy
See individual agents.
Use is contraindicated in patients who intend to become pregnant or who may become pregnant and not using effective contraception.
When used in pregnancy, angiotensin converting enzyme inhibitors can cause injury or death of the developing fetus. Discontinue as soon as possible once pregnancy is detected.
Refer to individual monographs for additional information.
Perindopril is present in breast milk (Lwin 2017); presence of indapamide is not known.
Use is contraindicated in patients who are breastfeeding. Refer to individual monographs for additional information.
Blood pressure; BUN, serum creatinine and electrolytes; hepatic function (baseline and as clinically indicated); uric acid and glucose (as appropriate); urea (when concomitant use of potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, drugs associated with increase in serum potassium, or other RAAS inhibitors is necessary); if patient has collagen vascular disease and/or kidney impairment, periodically monitor CBC with differential.
Perindopril: 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.
Indapamide: Enhances sodium, chloride, and water excretion by interfering with the transport of sodium ions across the renal tubular epithelium; diuretic effect is localized at the proximal segment of the distal tubule of the nephron.
See individual agents.
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