Perindopril and Indapamide

(per IN doe pril & in DAP a mide)

• Indapamide and Perindopril
• Indapamide and Perindopril Arginine
• Indapamide and Perindopril Erbumine
• Perindopril Arginine and Indapamide
• Perindopril Erbumine and Indapamide

Refer to adult dosing; use with caution.

Oral: Administer prior to a meal in the morning.

Also see individual agents.

1% to 10%:

Central nervous system: Headache (8%), dizziness (1% to 2%)

Endocrine & metabolic: Hypokalemia (2% to 7%), hyperkalemia (1%)

Gastrointestinal: Nausea and vomiting (2%), dyspepsia (1% to 2%)

Neuromuscular & skeletal: Arthralgia (1%)

Renal: Increased blood urea nitrogen (4%)

Respiratory: Cough (3% to 6%), upper respiratory tract infection (2%), bronchitis (1%)

<1%, postmarketing, and/or case reports: Abscess (periapical), abdominal pain, acute renal failure, acute rhinitis, agranulocytosis, allergic rhinitis, altered salivation, angina pectoris, angioedema, anorexia, anxiety, aplastic anemia, arthritis (periarthritis of shoulder), asthma, atrial fibrillation, back pain, benign prostatic hyperplasia, bloating, blurred vision, brachial plexopathy, bradycardia, bronchospasm, bullous rash, cardiac arrhythmia, cataract, cerebrovascular accident, chest pain, colitis, confusion, conjunctivitis, constipation, cystitis, decreased hemoglobin, dehydration, depression, dermatitis, diaphoresis, diarrhea, disturbed sleep, drowsiness, dysgeusia, dyspnea, dysuria, ECG abnormality, eczema, edema, eosinophilia, eosinophilic pneumonitis, epigastric pain, epistaxis, erythema multiforme, erythroderma, esophagitis, exfoliative dermatitis (purpura), falling, fever, flushing, fungal skin infection, gastritis, gastroenteritis (infective and non-infective), gout, hemolytic anemia, hepatitis, herpes zoster, hyperbilirubinemia, hypercalcemia, hyperosmolar coma, hypersensitivity reaction, hypertension, hyponatremia, hypotension, impacted cerumen, impotence, increased serum creatinine, increased serum glucose, increased serum transaminases, increased uric acid, interstitial nephritis, intestinal infection, laryngitis, leukopenia, ligament disorder, limb pain, localized infection (skin and subcutaneous tissues), loss of libido, lower back pain, maculopapular rash, malaise, male genital disease (penis disorders), metabolic alkalosis, migraine, mood disorder, muscle cramps, myalgia, myocardial infarction, myopathy, myopia (acute), neck pain, neoplasm (female genital organs), nervousness, neutropenia, optic neuritis, orthostatic hypotension, osteoarthrosis (local), otitis media, pallor, palpitations, pancreatitis, paresthesia, pemphigoid, pemphigus, peripheral edema, pharyngeal disease, pharyngitis, polyuria, prolonged QT interval on ECG, pruritus, Raynaud phenomenon, reflux esophagitis, renal insufficiency, respiratory insufficiency, rhabdomyolysis, rhinitis, sciatica, sensory disturbance (skin), sinusitis, skin photosensitivity, skin rash, sprain (ankle, knee, leg), Stevens-Johnson syndrome, syncope, systemic lupus erythematosus (aggravation), tachycardia, tendon disease (enthesopathy of elbow region), tetany, thrombocytopenia, tinnitus, tonsillitis, torsades de pointes, toxic epidermal necrolysis, tracheitis, uremia, urinary frequency, urinary incontinence, urinary tract infection, venous insufficiency, ventricular tachycardia, vertigo, visual disturbance, xerostomia, weight loss

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 neutral endopeptidase inhibitors (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 renal impairment, diabetes mellitus, and 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. Indapamide may cause hypokalemia, hypochloremia, hyponatremia, hypophosphatemia, and/or hypercalcemia. Use is contraindicated in patients with hypokalemia.

• 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.

• 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 discontinuation of future ACE inhibitor use especially in patients with heart failure where a reduction in systolic blood pressure is a desirable observation.

• 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).

• Renal function deterioration: May be associated with deterioration of renal function and/or increases in serum creatinine, particularly in patients with low renal blood flow (eg, renal artery stenosis, heart failure) whose glomerular filtration rate (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).

• 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/TEN), some clinicians choose to avoid exposure to these classes.

Disease-related concerns:

• Aortic stenosis: Use perindopril with caution in patients with severe aortic stenosis; may reduce coronary perfusion resulting in ischemia.

• 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.

• Collagen vascular disease: Use perindopril with caution in patients with collagen vascular disease especially with concomitant renal 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 renal 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 (HCM) with outflow tract obstruction: Use with caution in patients with HCM and outflow tract obstruction since reduction in afterload may worsen symptoms associated with this condition (ACCF/AHA [Gersh 2011]).

• Renal artery stenosis: Use perindopril with caution in patients with unstented unilateral/bilateral renal artery stenosis. When unstented unilateral or bilateral renal artery stenosis is present or suspected, 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 preexisting renal impairment; dosage adjustment may be needed. Avoid rapid dosage escalation which may lead to further renal impairment. Patients with renal impairment may be at increased risk for hematologic toxicity. Use may be contraindicated in moderate and/or severe renal impairment. Refer to contraindications.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Black patients: ACE inhibitors' effectiveness is less in black patients than in non-blacks. In addition, ACE inhibitors cause a higher rate of angioedema in black than in non-black patients.

• Pregnancy: [Canadian 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.

Dosage form specific issues:

• Lactose: Some formulations may contain lactose; use in patients with Lapp lactose 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).