Epaned (enalapril maleate)

Dosage of enalapril maleate (oral tablets or solution) is expressed in terms of the salt. Dosage of enalaprilat (IV injection) is expressed in terms of enalaprilat.

Dosage of enalapril maleate and enalaprilat must be adjusted according to the patient's tolerance and response.

Since enalapril maleate is a prodrug of enalaprilat and is well absorbed following oral administration, dosage of the two drugs is not identical and clinicians must give careful attention to the dosage when converting from oral to IV therapy or vice versa.

Because of the risk of inducing hypotension, initiation of enalapril maleate or enalaprilat therapy requires consideration of recent antihypertensive therapy, the extent of blood pressure elevation, sodium intake, fluid status, and other clinical circumstances. If therapy is initiated in patients already receiving a diuretic, symptomatic hypotension may occur following the initial dose of the angiotensin-converting enzyme (ACE) inhibitor. The possibility of hypotension may be minimized by discontinuing the diuretic, reducing the diuretic dosage, or cautiously increasing salt intake prior to initiation of oral enalapril maleate or IV enalaprilat therapy.

No dosing information is available for this tab.

When enalapril is used in fixed combination with hydrochlorothiazide, consider the drug interactions associated with hydrochlorothiazide in addition to those associated with enalapril. Consult the full prescribing information for the fixed-combination preparation for specific information.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Ace Inhibitors/Sacubitril

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Sacubitril is a neprilysin inhibitor. Overlapping inhibition of Angiotensin Converting Enzyme (ACE) and neprilysin may increase the risk of angioedema.(1,2)

CLINICAL EFFECTS: Concurrent use may result in angioedema.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of sacubitril and an ACE inhibitor is contraindicated. Allow a 36 hour washout period when switching between an ACE inhibitor and sacubitril.(1-3) Monitor patients for signs of angioedema (swelling of the face, lips, tongue, and/or throat).(2)

DISCUSSION: Higher incidence of angioedema was seen in clinical trials with omapatrilat, a combined ACE and neprilysin inhibitor. In the OCTAVE trial, the incidence and severity of angioedema was worse with omapatrilat (2.2%) than with enalapril (0.7%).(2) For this reason, overlap of sacubitril, a neprilysin inhibitor, with an ACE inhibitor is contraindicated and a 36 hour washout period is recommended when switching agents. The 36 hour window is designed to cover at least three half-lives of all ACE inhibitors.(1)

Ace Inhibitors; Arbs; Eras; Aliskiren/Sparsentan

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Sparsentan is an antagonist of the endothelin type A receptor and the angiotensin II type 1 receptor which are thought to contribute to the pathogenesis of IgA nephropathy.(1) Coadministration with renin-angiotensin-aldosterone system (RAAS) inhibitors and endothelin receptor antagonists (ERAs) may result in additive inhibition of angiotensin. RAAS inhibitors include ACE inhibitors, angiotensin II receptor blockers (ARBs), and aliskiren.

CLINICAL EFFECTS: Concurrent use of sparsentan with renin-angiotensin-aldosterone system (RAAS) inhibitors and endothelin receptor antagonists (ERAs) may result in hypotension, syncope, hyperkalemia, and changes in renal function (including renal failure).(1)

PREDISPOSING FACTORS: Patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion may be at risk of developing acute kidney injury on sparsentan.(1) Patients with advanced kidney disease or taking concomitant potassium-increasing drugs (e.g., potassium supplements, potassium-sparing diuretics), or using potassium-containing salt substitutes are at increased risk for developing hyperkalemia.(1)

PATIENT MANAGEMENT: Do not coadminister sparsentan with renin-angiotensin-aldosterone system (RAAS) inhibitors and endothelin receptor antagonists (ERAs). Prior to initiating treatment with sparsentan, discontinue use of renin-angiotensin-aldosterone system (RAAS) inhibitors and endothelin receptor antagonists (ERAs).(1) RAAS inhibitors include ACE inhibitors, angiotensin II receptor blockers (ARBs), and aliskiren.

DISCUSSION: The US manufacturer of sparsentan states that concomitant use of sparsentan with renin-angiotensin-aldosterone system (RAAS) inhibitors and endothelin receptor antagonists (ERAs) is contraindicated.(1) RAAS inhibitors include ACE inhibitors, angiotensin II receptor blockers (ARBs), and aliskiren.

Selected Nephrotoxic Agents/Bacitracin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Bacitracin may cause renal failure due to glomerular and tubular necrosis. Concurrent administration of other nephrotoxic agents may result in additive renal toxicity.(1-3)

CLINICAL EFFECTS: Concurrent use of bacitracin with other potentially nephrotoxic agents may result in renal toxicity.(1-3)

PREDISPOSING FACTORS: Dehydration and high-dose bacitracin may predispose to adverse renal effects.(1)

PATIENT MANAGEMENT: Health Canada states that bacitracin is contraindicated in patients with renal impairment, including those taking other nephrotoxic drugs.(1) The Canadian and US manufacturers of bacitracin state that concomitant use of bacitracin with other potentially nephrotoxic agents should be avoided.(2,3)

DISCUSSION: Renal impairment is a major toxicity of bacitracin. Cases of nephrotoxicity have been reported when bacitracin was used off-label.(1-3)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Ace Inhibitors/Mtor Inhibitors

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: ACE inhibitors cause reduced bradykinin metabolism, leading to an increase in bradykinin which can cause vasodilation. mTOR inhibitors may also cause a reduction in bradykinin metabolism.

CLINICAL EFFECTS: Concomitant therapy can increase the risk of vasodilation leading to an increase in angioedema risk.

PREDISPOSING FACTORS: History of previous angioedema.

PATIENT MANAGEMENT: Patients may be more susceptible to developing angioedema if concomitantly taking an ACE inhibitor and mTOR inhibitor. Consider switching the patient to an angiotensin receptor blocker. Monitor patients receiving concurrent therapy with ACE inhibitors and mTOR inhibitors closely for signs and symptoms of angioedema (swollen skin, hoarseness, a tight or swollen throat, or trouble breathing). Instruct patients to report angioedema symptoms immediately.

DISCUSSION: A retrospective, single center analysis looked at renal allograft recipients treated with mTOR inhibitors and ACE inhibitors over an 8 year-period. Out of 137 patients on concomitant ACE inhibitor and mTOR inhibitor therapy, 9 patients (6.6%) developed angioedema. Concomitant ACE inhibitor and mTOR inhibitor therapy increased the risk of developing angioedema 3.7-fold. Eight of these patients tolerated therapy with an angiotensin receptor blocker (ARB). 2 patients (1.2%) on concomitant mTOR inhibitor and ARB therapy developed angioedema. Treatment with an ACE inhibitor or mTOR inhibitor alone resulted in a significantly lower incidence of angioedema.(1) In a pooled analysis of randomized double-blind oncology clinical trials, the incidence of angioedema in patients taking everolimus with an ACE inhibitor was 6.8% compared to 1.3% in the control arm with an ACE inhibitor.(2) There are case reports of patients on concomitant ACE inhibitor and sirolimus/everolimus that developed angioedema. In the majority of cases, patients had tolerated chronic therapy with an ACE inhibitor before the addition of sirolimus/everolimus.(3-7) The interaction may be dose-dependent.(7)

Ace Inhibitors; Arbs/Aliskiren

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown.

CLINICAL EFFECTS: In the ALTITUDE study, concurrent use of aliskiren for 18-24 months in patients maintained on either an ACE inhibitor or an ARB resulted in an increase in non-fatal stroke, renal complications, hyperkalemia, and hypotension.(1,2)

PREDISPOSING FACTORS: Patients with Type II diabetes and/or renal impairment may be at a higher risk from this combination.(1)

PATIENT MANAGEMENT: Novartis no longer recommends the concurrent use of aliskiren with either an ACE inhibitor or an ARB.(1,3) Hypertension regimens of patients receiving concurrent therapy should be re-evaluated.(1) Concurrent use of aliskiren in diabetic patients receiving either an ACE inhibitor or an ARB is contraindicated.(2,4) Avoid the combination in patients with CrCl less than 60 ml/min.(5)

DISCUSSION: ALTITUDE was a multinational study designed to evaluate the use of aliskiren for more than 1 year in patients with Type II diabetes and renal impairment, who are known to have a high risk for cardiovascular and renal events. Aliskiren was given with optimal cardiovascular treatment, including an ACE inhibitor or ARB. After 18-24 months of concurrent therapy with aliskiren and either an ACE inhibitor or an ARB, there was an increase in non-fatal stroke, renal complications, hyperkalemia, and hypotension.(1,2)

Ace Inhibitors; Arbs/Lithium

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Angiotensin converting enzyme inhibitors (ACEI) or angiotensin II receptor blocker (ARB)-induced sodium loss or volume depletion may result in decreased renal clearance of lithium.(1)

CLINICAL EFFECTS: Concurrent use of ACEI or ARBs may result in elevated lithium levels and lithium toxicity. Lithium has a narrow therapeutic range. Unintended increases in lithium concentrations may lead to lithium toxicity. Early symptoms of lithium toxicity may include: lethargy, muscle weakness or stiffness, new onset or coarsening of hand tremor, vomiting, diarrhea, confusion, ataxia, blurred vision, bradycardia, tinnitus, or nystagmus. Severe toxicity may produce multiple organ dysfunction (e.g. seizures, coma, renal failure, cardiac arrhythmias, cardiovascular collapse) and may be fatal.(1)

PREDISPOSING FACTORS: Risk factors for lithium toxicity include: acute renal impairment, chronic renal disease, dehydration, low sodium diet, and concomitant use of multiple medications which may impair renal elimination of lithium (e.g. ACEI, ARBs, NSAIDs, diuretics).(1) Patients who require higher therapeutic lithium levels to maintain symptom control are particularly susceptible to these factors.

PATIENT MANAGEMENT: If concurrent therapy cannot be avoided, monitor closely. Evaluate renal function and most recent lithium levels. If renal function is not stable, whenever possible delay initiation of concurrent therapy until renal function is stable. The onset of lithium toxicity due to concomitant therapy with an ACEI or ARB may be delayed for 3-5 weeks.(2) Patients receiving this combination should be observed for signs of lithium toxicity when the ACEI or ARB dose is increased or if additional risk factors for lithium toxicity emerge. If an ACEI or ARB is required in a patient stabilized on lithium therapy, check baseline lithium concentration, consider empirically lowering the lithium dose, then recheck lithium levels 5 to 7 days after ACEI or ARB initiation. Adjust lithium, ACEI or ARB dose as required and continue frequent (e.g. weekly) monitoring of lithium until levels have stabilized. If lithium is to be started in a patient stabilized on an ACEI or ARB, consider starting with a lower lithium dose and titrate slowly as half-life may be prolonged.(1) Monitor lithium concentrations frequently until stabilized on the combination. If an interacting drug is discontinued, the lithium level may fall. Monitor lithium concentration and adjust dose if needed.(1) Counsel patient to assure they know signs and symptoms of lithium toxicity and understand the importance of follow-up laboratory testing.

DISCUSSION: Elevated lithium levels and lithium toxicity have been reported during concomitant administration of lithium and an ACEI(3-17) or an ARB(18-20). Other factors, such as dehydration, acute or worsening of chronic renal impairment, or acute changes in sodium intake may increase the occurrence of a clinically important interaction.

Ace Inhibitors; Arbs/Sodium Phosphate Bowel Cleanser

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Bowel cleansing with sodium phosphate causes dehydration, decreased intravascular volume and hyperphosphatemia, which increases phosphate levels in the renal tubules. Abnormally high levels of calcium and phosphate in the renal tubules may precipitate out, resulting in renal injury.(1)

CLINICAL EFFECTS: Use of sodium phosphate for bowel cleansing in patients maintained on angiotensin converting enzyme (ACE) inhibitors, angiotension receptor blockers (ARBs) may increase the risk of acute phosphate nephropathy, which is an acute kidney injury associated with deposits of calcium phosphate crystal in the renal tubules that may result in permanent renal function impairment. Acute phosphate nephropathy presents as acute kidney injury with minimal proteinuria and a bland urine sediment.(2) Use of sodium phosphate products at laxative doses has not been associated with acute kidney injury.(3)

PREDISPOSING FACTORS: Patients who may be at an increased risk of acute phosphate nephropathy include those who are over age 55; are hypovolemic or have decreased intravascular volume; have baseline kidney disease, bowel obstruction, or active colitis; and who are using medications that affect renal perfusion or function (such as diuretics, ACE inhibitors, ARBs, and possibly nonsteroidal anti-inflammatory drugs (NSAIDs).(2)

PATIENT MANAGEMENT: If possible, use an alternative agent for bowel cleansing.(1) Use sodium phosphate products with caution in patients taking medications that affect kidney function or perfusion, such as ACE inhibitors or ARBs. Obtain baseline and post-procedure labs (electrolytes, calcium, phosphate, BUN, creatinine, and [in smaller, frail individuals] glomerular filtration rate). Instruct patients to drink sufficient quantities of clear fluids before, during, and after bowel cleansing and to avoid other laxatives that contain sodium phosphate. Consider hospitalization and intravenous hydration during bowel cleansing to support frail patients who may be unable to drink an appropriate volume of fluid or who may be without assistance at home.(2) Use of an electrolyte solution for rehydration may decrease the risk of acute phosphate nephropathy.(4,5)

DISCUSSION: Since May 2006, the FDA has received 20 reports of acute phosphate nephropathy associated with the use of Osmo Prep. Concomitant medications included ACE inhibitors or ARBs (11), diuretics (6), and NSAIDs (4).(2) In a retrospective review of colonoscopy patients, simultaneous use of ACE inhibitors or ARBs significantly increased the risk of acute kidney injury from oral sodium phosphate. Diuretic use was also a risk factor.(6) In a case series study of 21 cases of acute phosphate nephropathy in patients who had used oral sodium phosphate, 14 patients received an ACE inhibitor or ARB, 4 used a diuretic, and 3 used an NSAID.(7) Cases have also been reported with rectal products.(8)

Ace Inhibitors; Arbs/Trimethoprim

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: ACE Inhibitors, Angiotensin Receptor Blockers (ARBs), and trimethoprim have all been proven to increase serum potassium levels. The increase is achieved by reduction in potassium elimination by trimethoprim(1,2) and a decrease in angiotensin activity by ACE Inhibitors and ARBs. The use of these medications in combination can have an additive effect on serum potassium resulting in potentially dangerous levels.(1-5)

CLINICAL EFFECTS: Concurrent use of trimethoprim and ACE Inhibitors or Angiotensin Receptor Blockers may result in increased serum potassium levels,(1-5) which may be fatal.(2)

PREDISPOSING FACTORS: The interaction may be more significant in elderly patients and patients with renal insufficiency.(1)

PATIENT MANAGEMENT: Use trimethoprim with caution in patients maintained on ACE Inhibitors or ARBs. Patients using these medications concurrently should have their serum potassium monitored. In the elderly or renally impaired, alternative antibiotic therapy should be considered.

DISCUSSION: In a retrospective review of patients in Ontario maintained on an ACE inhibitor or ARB who were admitted to a hospital for hyperkalemia within 14 days of receiving a prescription for SMX-TMP, amoxicillin, ciprofloxacin, norfloxacin, or nitrofurantion, 371 patients were identified. More than half of the patients with hyperkalemia had received SMX-TMP. Patients receiving SMX-TMP had a 7-fold increased risk of hyperkalemia compared to patients receiving other antibiotics. No risk was found with the other antibiotics.(1) A retrospective review of patients in Ontario maintained on an ACE inhibitor or ARB examined those who died within 7 days of filling an outpatient prescription for amoxicillin, ciprofloxacin, norfloxacin, nitrofurantoin, or SMX-TMP. Patients receiving SMX-TMP had an increased risk of death (adjusted odds ratio 1.38) compared to amoxicillin. Risk was slightly higher at 14 days (adjusted odds ration 1.54). This corresponded to 3 sudden deaths within 14 days per 1000 SMX-TMP prescriptions.(2) A review of nine case reports of hyperkalemia with SMX-TMP found that 2 patients were receiving concurrent ACE inhibitors (enalapril and benazepril). One of these patients had severe hyperkalemia with a peak potassium level of 7.4 mEq/l.(3) Hyperkalemia has also been reported with concurrent SMX-TMP and enalapril(4) and with quinapril.(5)

Selected Nephrotoxic Agents/Colistimethate

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Colistimethate can cause nephrotoxicity.(1,2) Concurrent administration of other nephrotoxic agents may result in an increased risk of nephrotoxicity.(1) It is suspected that cephalothin interferes with the excretion of colistimethate resulting in enhanced nephrotoxicity.(2,3)

CLINICAL EFFECTS: Concurrent use of colistimethate with other nephrotoxic agents may result in additive nephrotoxic effects.

PREDISPOSING FACTORS: Factors predisposing to nephrotoxicity include higher cumulative doses of colistimethate, longer treatment duration, hypovolemia, and critical illness.

PATIENT MANAGEMENT: Concurrent use of potentially nephrotoxic agents with colistimethate should be avoided.(1,2) If concurrent use is necessary, it should be undertaken with great caution.(1)

DISCUSSION: In a case control study of 42 patients on intravenous colistimethate sodium, NSAIDs were identified as an independent risk factor for nephrotoxicity (OR 40.105, p=0.044).(4) In 4 case reports, patients developed elevated serum creatinine and blood urea nitrogen following concurrent colistimethate and cephalothin (3 patients) or when colistimethate followed cephalothin therapy (1 patient).(3) A literature review found that individual nephrotoxic agents, including aminoglycosides, vancomycin, amphotericin, IV contrast, diuretics, ACE inhibitors, ARBs, NSAIDs, and calcineurin inhibitors, were not consistently associated with additive nephrotoxicity when used with colistimethate. However, when multiple agents (at least 2 additional potential nephrotoxins) were used concurrently, there was a significant correlation to colistimethate nephrotoxicity.(5)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Ace Inhibitors/Acemetacin; Proglumetacin; Salsalate

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: NSAIDs inhibit prostaglandin synthesis which can lead to afferent arteriolar vasoconstriction and decreased renal blood flow. ACE inhibitors can cause vasodilation of the efferent renal arteriole which may result in decreased glomerular filtration rate.

CLINICAL EFFECTS: Concurrent use of ACE inhibitors with NSAIDs may result in decreased antihypertensive effects. In patients with existing renal impairment, the use of these agents together may also result in further deterioration of renal clearance caused by renal hypoperfusion.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients maintained on ACE inhibitors should be monitored for a loss of blood pressure control and a change in renal function if an NSAID is added to their regimen. Patients receiving concurrent therapy may require higher doses of ACE inhibitors. If blood pressure control cannot be achieved or if the patient's renal function deteriorates, the NSAID may need to be discontinued. Patients should be monitored for hypotension if NSAIDs are withdrawn from concurrent ACE inhibitor therapy.

DISCUSSION: Indomethacin has been shown to inhibit the antihypertensive effect of captopril, cilazapril, enalapril, losartan, perindopril, and valsartan. Ibuprofen has been shown to decrease the antihypertensive effects of captopril. Two separate case reports describe individuals suspected of ACEI-associated angioedema precipitated by NSAIDs. Both cases reported symptom resolution after cessation of the NSAID. Studies have shown that sulindac does not affect the antihypertensive effects of captopril and enalapril. One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Ace Inhibitors/Azathioprine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown. Azathioprine-induced impairment of hematopoiesis and ACE inhibitor-induced decreases in erythropoietin may result in additive effects on bone marrow.(1,2)

CLINICAL EFFECTS: The concurrent use of azathioprine and an ACE inhibitor may result in anemia or leucopenia.(1-6) ACE inhibitors have been used to correct post-transplantation erythrocytosis in patients who also received azathioprine.(7)

PREDISPOSING FACTORS: Patients with reduced or absent thiopurine S-methyltransferase (TPMT) or nucleotide diphosphatase (NUDT15) activity are at higher risk of accumulating thiopurine metabolites and severe myelosuppression. Approximately 0.3 % of patients of European, Latino, or African descent have mutations of the TPMT gene resulting in little to no TPMT activity (homozygous deficiency), and approximately 10 % have intermediate TPMT activity (heterozygous deficiency). NUDT15 deficiency is not seen in patients of African descent and is seen in less than 1 % of patients of European descent. Approximately 1 % of patients of East Asian descent, 0.5 % of patients of central/south Asian descent, and 2 % of patients of Latino descent have homozygous NUDT15 deficiency. About 17 % of patients of East Asian descent, 13 % of patients of central/south Asian descent, and 8 % of patients of Latino descent have heterozygous NUDT15 deficiency.(8)

PATIENT MANAGEMENT: Patients receiving concurrent therapy with azathioprine and an ACE inhibitor should be closely monitored for hematological changes. One of the agents may need to be discontinued.

DISCUSSION: In a study in 15 kidney-transplant patients receiving azathioprine, enalapril and captopril were replaced by nifedipine or clonidine. Hematocrit and hemoglobin levels increased from 37.5% to 39.7% and from 12.8 g/dl to 13.5 g/dl, respectively,10 to 12 weeks after ACE inhibitor withdrawal. Reticulocytes and erythropoietin concentrations rose from 14.1/1000 to 20.6/1000 and from 14.3 mU/ml to 29.3m U/ml, respectively. There were no changes in azathioprine levels.(1) A retrospective review compared azathioprine-treated patients to patients receiving azathioprine and ACE inhibitors. Hematocrit, hemoglobin, and haptoglobin levels were significantly lower in the group receiving ACE inhibitors, 19.7%, 17.2%, and 45%, respectively.(2) Three case reports document the development of leucopenia during the concurrent administration of captopril and azathioprine.(3-5) Another case report documented the development of anemia with concurrent enalapril and azathioprine.(6) Enalapril has been used to treat post-renal transplant erythrocytosis in patients receiving azathioprine.(7)

Ace Inhibitors/Dipeptidyl Peptidase-Iv Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Bradykinin can cause vasodilation and increase vascular permeability both directly and by stimulating release of substance P, which also increases vascular permeability.(1) Bradykinin is primarily metabolized by angiotensin-1 converting enzyme (ACE). If ACE is inhibited by ACE inhibitors, other metabolic enzymes become more significant in bradykinin metabolism, including dipeptidyl peptidase-IV (DPP-IV). DPP-IV inhibitors can inhibit both bradykinin and substance P metabolism.(2)

CLINICAL EFFECTS: Concomitant therapy can increase the risk of vasodilation leading to an increase in angioedema risk.(1-3)

PREDISPOSING FACTORS: History of previous angioedema.

PATIENT MANAGEMENT: Patients may be more susceptible to developing angioedema if concomitantly taking an ACE inhibitor and DPP-IV inhibitor. Consider switching the patient to an angiotensin receptor blocker or a different anti-diabetic medication. Use caution in patients receiving concurrent therapy.(3) Monitor closely for signs and symptoms of angioedema (swollen skin, hoarseness, a tight or swollen throat, or trouble breathing). Instruct patients to report angioedema symptoms immediately.

DISCUSSION: A pre-marketing surveillance compared incidence of angioedema in patients on vildagliptin versus a comparator. In all patients combined regardless of ACE inhibitor therapy, there was no association between vildagliptin and angioedema. However among patients taking an ACE inhibitor, vildagliptin was associated with an increased risk of angioedema (odds ratio 9.29 (95% CI 1.22-70.70) from pooled data; odds ratio of 4.57 (95% CI 1.57-13.28) in the meta-analysis). This interaction may be dose-related.(4) In a pooled analysis of data from 19 clinical trials of patients on sitagliptin versus a comparator, there was no difference in the incidence of angioedema between patients on ACE inhibitors and sitagliptin compared to patients on ACE inhibitors alone or patients not on ACE inhibitors.(5) However, events were not adjudicated and encompassed urticaria, anaphylaxis, and hypersensitivity reactions, which may have confounded the results.(6) A disproportionality analysis of the WHO pharmacovigilance database found 340,686 reports of bradykinin-mediated angioedema. Of those, 345 reports involved patients on concomitant ACE inhibitor and DPP-IV inhibitor, with a reporting odds ratio of 42.77 (95% CI 36.93-49.53). There was no association between use of a DPP-IV inhibitor without an ACE inhibitor and angioedema.(7)

Ace Inhibitors/High-Dose Aspirin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: NSAIDs inhibit prostaglandin synthesis which can lead to afferent arteriolar vasoconstriction and decreased renal blood flow. ACE inhibitors can cause vasodilation of the efferent renal arteriole which may result in decreased glomerular filtration rate.

CLINICAL EFFECTS: Concurrent use of aspirin may result in decreased antihypertensive effects of the ACE inhibitor. Concurrent use of ACE inhibitors with aspirin and diuretics may result in increased risk of acute kidney injury (AKI).

PREDISPOSING FACTORS: Low water intake/dehydration, drug sensitivity, greater than 75 years of age, and use of diuretics can lead to hypovolemia and increased risk of AKI.

PATIENT MANAGEMENT: Monitor patients receiving doses of aspirin higher than 150 mg daily for decreased antihypertensive effects of their ACE inhibitor. The use of alternative agents may need to be considered. Concurrent use of ACE inhibitors with aspirin and diuretics should be used with caution and monitored for signs of AKI.

DISCUSSION: Several studies have documented decreased effectiveness of various ACE inhibitors, including captopril, enalapril, and lisinopril following the addition of aspirin therapy. Conflicting evidence exists on the use of small (less than 150 mg) daily doses of aspirin with ACE inhibitors, although some guidelines still suggest they may be beneficial. In a population based cohort study, the concurrent use of NSAIDs with renin-angiotensin system (RAS) inhibitors in 5,710 hypertensive patients stabilized on antihypertensive therapy required hypertension treatment intensification. Adjusted hazard ratios (HR) for hypertension treatment intensification were 1.34 [95% CI 1.05-1.71] for NSAIDs in general, 1.79 (95% CI 1.15-2.78) for diclofenac and 2.02 (95% CI 1.09-3.77) for piroxicam. There were significant interactions between NSAIDs and angiotensin converting enzyme inhibitors (ACE inhibitors; HR 4.09, 95% CI 2.02-8.27) or angiotensin receptor blockers (ARBs; HR 3.62, 95% CI 1.80-7.31), but not with other antihypertensive drugs. In a computational study, the risk of AKI using triple therapy (combination of a diuretic, renin-angiotensin system (RAS) inhibitor, and NSAID) was assessed. The study found the following factors may increase an individual's susceptibility to AKI: low water intake, drug sensitivity, greater than 75 years of age, and renal impairment.(20,21) In an observational study, current use of a triple therapy combination was associated with an increased rate of acute kidney injury (rate ratio (RR) 1.31, 95% confidence interval (CI) 1.12-1.53). The highest risk of AKI associated with triple therapy were observed in the first 30 days of use (RR 1.82, CI 1.35-2.46).(22) One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Ace Inhibitors/Hymenoptera Venom Immunotherapy

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Angiotensin converting enzyme (ACE) inhibitors block the conversion of angiotensin I to angiotensin II, resulting in vasodilation and disrupting the compensatory response during anaphylaxis. Concurrent use of ACE inhibitors may increase the risk and severity of an anaphylactoid reaction to Hymenoptera venom immunotherapy.(1-15)

CLINICAL EFFECTS: Angiotensin converting enzyme (ACE) inhibitors may increase the risk and severity of an anaphylactoid reaction to Hymenoptera venom immunotherapy.(1-15)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Administration of Hymenoptera venom immunotherapy in patients on angiotensin converting enzyme (ACE) inhibitors should be approached with caution. In patients taking ACE inhibitors, consider temporarily withholding ACE inhibitor therapy prior to each immunotherapy procedure. If patients cannot safely discontinue ACE inhibitors, monitor patients closely for signs of an anaphylactoid reaction.(1-15)

DISCUSSION: Patients on angiotensin converting enzyme (ACE) inhibitors may be at increased risk of an anaphylactoid reaction to Hymenoptera venom immunotherapy. Clinical studies and guideline recommendations for concurrent use of ACE inhibitors and Hymenoptera venom immunotherapy range from use with caution to a relative contraindication. Patients should be informed of the potential risk of the possible interaction.(1-22)

Ace Inhibitors/Racecadotril

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Bradykinin can cause vasodilation and increase vascular permeability both directly and by stimulating release of substance P, which also increases vascular permeability.(1) Bradykinin is primarily metabolized by angiotensin-1 converting enzyme (ACE). If ACE is inhibited by ACE inhibitors, other metabolic enzymes become more significant in bradykinin metabolism, including neutral endopeptidase (NEP). Racecadotril inhibits NEP which is involved in the degradation of bradykinin.(2)

CLINICAL EFFECTS: Concomitant therapy can increase the risk of vasodilation leading to an increase in angioedema risk.(1)

PREDISPOSING FACTORS: History of previous angioedema.

PATIENT MANAGEMENT: Patients may be more susceptible to developing angioedema if concomitantly taking an ACE inhibitor and racecadotril.(1) Consider switching the patient to an angiotensin receptor blocker. Use caution in patients receiving concurrent therapy.(3) Monitor closely for signs and symptoms of angioedema (swollen skin, hoarseness, a tight or swollen throat, or trouble breathing). Instruct patients to report angioedema symptoms immediately.

DISCUSSION: Angioedema has been reported with racecadotril. Concurrent use of racecadotril and an ACE inhibitor may increase the risk of angioedema. A review of the French national pharmacovigilance database found 11 reports of angioedema in patients concomitantly taking an ACE inhibitor and racecadotril. In 9 cases, the temporal relationship between onset of drug combination and onset of angioedema was highly suggestive of a causal link.(3)

Ace Inhibitors/Selected Nsaids; Salicylates

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: NSAIDs inhibit prostaglandin synthesis which can lead to afferent arteriolar vasoconstriction and decreased renal blood flow. ACE inhibitors can cause vasodilation of the efferent renal arteriole which may result in decreased glomerular filtration rate.

CLINICAL EFFECTS: Concurrent use of ACE inhibitors with NSAIDs may result in decreased antihypertensive effects. In patients with existing renal impairment, the use of these agents together may also result in further deterioration of renal clearance caused by renal hypoperfusion. Concurrent use of ACE inhibitors with NSAIDs and diuretics may result in increased risk of acute kidney injury (AKI).

PREDISPOSING FACTORS: Low water intake/dehydration, drug sensitivity, greater than 75 years of age, and renal impairment may increase an individuals susceptibility to AKI.

PATIENT MANAGEMENT: Patients maintained on ACE inhibitors should be monitored for a loss of blood pressure control and a change in renal function if an NSAID is added to their regimen. Patients receiving concurrent therapy may require higher doses of ACE inhibitors. If blood pressure control cannot be achieved or if the patient's renal function deteriorates, the NSAID may need to be discontinued. Patients should be monitored for hypotension if NSAIDs are withdrawn from concurrent ACE inhibitor therapy. Concurrent use of ACE inhibitors with NSAIDs and diuretics should be used with caution and monitored closely for signs of AKI.

DISCUSSION: In a computational study, the risk of AKI using triple therapy (combination of a diuretic, renin-angiotensin system (RAS) inhibitor, and NSAID) was assessed. The study found the following factors may increase an individual's susceptibility to AKI: low water intake, drug sensitivity, greater than 75 years of age, and renal impairment.(30,31) In an observational study, current use of a triple therapy combination was associated with an increased rate of acute kidney injury (rate ratio (RR) 1.31, 95% confidence interval (CI) 1.12-1.53). The highest risk of AKI associated with triple therapy were observed in the first 30 days of use (RR 1.82, CI 1.35-2.46).(32) Indomethacin has been shown to inhibit the antihypertensive effect of captopril, cilazapril, enalapril, losartan, perindopril, and valsartan. Ibuprofen has been shown to decrease the antihypertensive effects of captopril. Two separate case reports describe individuals suspected of ACEI-associated angioedema precipitated by NSAIDs. Both cases reported symptom resolution after cessation of the NSAID. Studies have shown that sulindac does not affect the antihypertensive effects of captopril and enalapril. One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Ace Inhibitors; Arbs/Drospirenone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Drospirenone has antimineralocorticoid activity and may cause hyperkalemia. ACE inhibitors and angiotensin II receptor antagonists may also increase potassium levels.(1)

CLINICAL EFFECTS: Concurrent use of drospirenone and ACE inhibitors or angiotensin II receptor antagonists may result in hyperkalemia.(1)

PREDISPOSING FACTORS: Renal insufficiency, hepatic dysfunction, adrenal insufficiency, and use of potassium supplements, potassium-sparing diuretics, heparin, and NSAIDs may increase potassium levels.(1)

PATIENT MANAGEMENT: Patients receiving drospirenone with either an ACE inhibitor or an angiotensin II receptor antagonist should have their serum potassium level checked during the first treatment cycle.(1)

DISCUSSION: Drospirenone has antimineralocorticoid activity comparable to 25 mg of spironolactone and may result in hyperkalemia. Concurrent use of ACE inhibitors or angiotensin II receptor antagonists may also increase potassium levels.(1) In a study in 24 mildly hypertensive postmenopausal women who received concurrent drospirenone/estradiol (3 mg/1 mg) with enalapril (10 mg), mean serum potassium levels were 0.22 mEq/L higher than in the placebo group. On day 14 of concurrent therapy, the ratios for serum potassium maximum concentration (Cmax) and area-under-curve (AUC) were 0.955 and 1.010, respectively. No patient developed hyperkalemia.(1)

Ace Inhibitors; Arbs/Loop Diuretics

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown. The initial hypotensive effect of the ACE inhibitors is mainly the result of suppression of the renin-angiotensin-aldosterone system. The ACE inhibitors inhibit the formation of angiotensin II and angiotensin II receptor antagonists block the action of angiotensin II, thereby lowering aldosterone levels with subsequent sodium and water depletion. Agents such as the loop diuretics that cause sodium and water loss may exaggerate the hypotensive state.

CLINICAL EFFECTS: The addition of an ACE inhibitor to a patient receiving a loop diuretic may result in severe postural hypotension. This effect is transient and is not expected to occur during long-term dosing. Symptomatic hypotension may result in patients treated with loop diuretics who are started on an angiotensin II receptor antagonist. Concurrent use of a renin-angiotensin system (RAS) inhibitor with diuretics and NSAIDs may result in increased risk of acute kidney injury (AKI).

PREDISPOSING FACTORS: Addition of an ACE inhibitor or an angiotensin II receptor antagonist to a patient already receiving a diuretic or who is sodium depleted. Low water intake/dehydration, drug sensitivity, greater than 75 years of age, and renal impairment may increase an individual's susceptibility to AKI.

PATIENT MANAGEMENT: In patients without heart failure, it may be advisable to discontinue the diuretic, reduce the dose of the diuretic, or increase salt intake prior to the initiation of the ACE inhibitor. If hypotension occurs, place the patient in a supine position. Hypotension is most likely when the ACE inhibitor is initiated. However, if subsequent hypotension occurs, a dosage adjustment or discontinuation of one agent may be required. Intravascular volume depletion should be corrected in patients prior to the initiation of an angiotensin II receptor antagonist. Concurrent use of a RAS inhibitor with loop diuretics and NSAIDs should be used with caution and monitored closely for signs of AKI.

DISCUSSION: In a computational study, the risk of AKI using triple therapy with a diuretic, renin-angiotensin system (RAS) inhibitor, and NSAID was assessed. The study found the following factors may increase an individual's susceptibility to AKI: low water intake, drug sensitivity, greater than 75 years of age, and renal impairment.(4,5) In an observational study, current use of a triple therapy with a diuretic, RAS inhibitor, and NSAID, was associated with an increased rate of acute kidney injury (rate ratio (RR) 1.31, 95% confidence interval (CI) 1.12-1.53). The highest risk of AKI associated with triple therapy were observed in the first 30 days of use (RR 1.82, CI 1.35-2.46). (6) Severe postural hypotension(1,2) and transient postural hypotension(3) has been reported in patients receiving concurrent captopril and furosemide. The effect is transient and may be more prevalent in patients who are sodium depleted.(8) Reversible renal failure(9) and decreased renal function(10) have been reported in patients receiving concurrent administration with enalapril and furosemide. In a study in which electrolytes were replaced with saline or Ringer's solution, no postural hypotension was noted; however, significant decreases in diastolic blood pressure occurred at three, four, and six hours after concurrent administration.(11)

Selected Ace Inhibitors/Indomethacin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: NSAIDs inhibit prostaglandin synthesis which can lead to afferent arteriolar vasoconstriction and decreased renal blood flow. ACE inhibitors can cause vasodilation of the efferent renal arteriole which may result in decreased glomerular filtration rate.

CLINICAL EFFECTS: Concurrent use of ACE inhibitors with NSAIDs may result in decreased antihypertensive effects. In patients with existing renal impairment, the use of these agents together may also result in further deterioration of renal clearance caused by renal hypoperfusion. Concurrent use of ACE inhibitors with NSAIDs and diuretics may result in increased risk of acute kidney injury (AKI).

PREDISPOSING FACTORS: Low water intake/dehydration, drug sensitivity, greater than 75 years of age, and renal impairment may increase an individuals susceptibility to AKI.

PATIENT MANAGEMENT: Patients maintained on ACE inhibitors should be monitored for a loss of blood pressure control and a change in renal function if an NSAID is added to their regimen. Patients receiving concurrent therapy may require higher doses of ACE inhibitors. If blood pressure control cannot be achieved or if the patient's renal function deteriorates, the NSAID may need to be discontinued. Patients should be monitored for hypotension if NSAIDs are withdrawn from concurrent ACE inhibitor therapy.

DISCUSSION: Indomethacin has been shown to inhibit the antihypertensive effect of captopril, cilazapril, enalapril, losartan, perindopril, and valsartan. Ibuprofen has been shown to decrease the antihypertensive effects of captopril. Two separate case reports describe individuals suspected of ACEI-associated angioedema precipitated by NSAIDs. Both cases reported symptom resolution after cessation of the NSAID. In a computational study, the risk of AKI using triple therapy (combination of a diuretic, renin-angiotensin system (RAS) inhibitor, and NSAID) was assessed. The study found the following factors may increase an individual's susceptibility to AKI: low water intake, drug sensitivity, greater than 75 years of age, and renal impairment.(30,31) In an observational study, current use of a triple therapy combination was associated with an increased rate of acute kidney injury (rate ratio (RR) 1.31, 95% confidence interval (CI) 1.12-1.53). The highest risk of AKI associated with triple therapy were observed in the first 30 days of use (RR 1.82, CI 1.35-2.46).(32) One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Selected Ace Inhibitors/Potassium Sparing Diuretics

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: ACE inhibitors may decrease the renal excretion of potassium.

CLINICAL EFFECTS: Concurrent use of potassium sparing diuretics with an ACE inhibitor may result in hyperkalemia.

PREDISPOSING FACTORS: Impaired renal function; diabetes mellitus.

PATIENT MANAGEMENT: Monitor serum potassium and adjust the dosage accordingly in patients receiving concurrent therapy with a potassium sparing diuretic and an ACE inhibitors. In all patients taking eplerenone who start taking an ACE inhibitor, check serum potassium and creatinine levels after 3-7 days of concurrent therapy.

DISCUSSION: In a nested case-control study of heart failure patients receiving continuous ACE inhibitor/ARB therapy (n = 1,491,894), the risk of hyperkalemia was significantly associated with concomitant spironolactone use (odds ratio (OR) = 13.59; confidence interval (CI) = 11.63-15.88).(20) In a systemic literature review and meta-analysis of 20 randomized controlled studies, it was found that treatment with spironolactone and ACEI/ARB combination therapy compared to ACEI/ARB therapy alone increased the mean serum potassium concentration by 0.19 mEq/L (95% CI, 0.12-0.26 mEq/L).(21) A retrospective cohort study in patients with hypertension, diabetes, and albuminuria between 2008 and 2018 examined the efficacy and safety of mineralocorticoid receptor antagonists eplerenone and spironolactone in combination with ACEI/ARB compared to ACEI/ARB alone. Hyperkalemia was more frequent in combination therapy patients (n=1,282) versus monotherapy (n=5,484) (22.3 vs 10.9 per 100 person-years for combination and monotherapy, respectively; HR = 1.78, 95% CI: 1.42, 2.24).(22) Several studies have indicated that serum potassium levels increase when ACE inhibitors and ARB therapy is initiated and decrease when the drug is lowered. There are case reports of hyperkalemia during concurrent therapy with ARBs and spironolactone and with aliskiren and spironolactone. Based on this data, serum potassium levels should be monitored in patients receiving concomitant ACE inhibitors with potassium sparing diuretics. Selected ACE inhibitors linked to this monograph include: benazepril, captopril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril, and trandolapril.

Selected Ace Inhibitors/Potassium Supplements

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: ACE inhibitors may decrease the renal excretion of potassium.

CLINICAL EFFECTS: Concurrent use of potassium supplements with ACE inhibitors may result in hyperkalemia.

PREDISPOSING FACTORS: Impaired renal function; diabetes mellitus.

PATIENT MANAGEMENT: Monitor serum potassium and adjust the dosage accordingly in patients receiving concurrent therapy with potassium supplements and ACE inhibitors.

DISCUSSION: Several studies have indicated that serum potassium levels increase when ACE inhibitors is initiated and decrease when the drug is lowered. Based on this data, serum potassium levels should be monitored in patients receiving potassium supplements with ACE inhibitors. Selected ACE inhibitors linked to this monograph include: benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, quinapril, ramipril, and trandolapril.

Selected Ace Inhibitors/Tizanidine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Tizanidine is an alpha-2 agonist. Concurrent use with ACE inhibitors may result in additive effects on blood pressure.(1)

CLINICAL EFFECTS: Concurrent use of antihypertensives and tizanidine may result in hypotension.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for hypotension. The risk of hypotension may be decreased by careful titration of tizanidine dosages and monitoring for hypotension prior to dose advancement. Counsel patients about the risk of orthostatic hypotension.(1)

DISCUSSION: Severe hypotension has been reported following the addition of tizanidine to existing lisinopril therapy.(2-4)

Selected Antihypertensive Agents/Selected Maois

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Both MAOIs and antihypertensive agents may increase the risk of postural hypotension.(1,2)

CLINICAL EFFECTS: Postural hypotension may occur with concurrent therapy of MAOIs and antihypertensive agents.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of phenelzine states all patients should be followed closely for symptoms of postural hypotension. Hypotensive side effects have occurred in patients who have been hypertensive and normotensive, as well as hypotensive at initiation of phenelzine.(1) The manufacturer of tranylcypromine states hypotension has been observed most commonly but not exclusively in patients with pre-existing hypertension. Tranylcypromine doses greater than 30 mg daily have a major side effect of postural hypotension and can lead to syncope. Gradual dose titration is recommended to decrease risk of postural hypotension. Combined use with other agents known to cause hypotension have shown to have additive side effects and should be monitored closely.(2) Monitor the patient for signs and symptoms of postural hypotension including dizziness, lightheadedness, or weakness, especially upon standing. Monitor blood pressure as well as orthostatic vitals and adjust antihypertensive therapy, including decreasing the dose, dividing doses, or scheduling doses at bedtime, as needed to maintain goal blood pressure. If blood pressure remains hypotensive, consider decreasing the dose of phenelzine or tranylcypromine. In some cases, discontinuation of one or both agents may be necessary.(3) Normotensive patients on stable antihypertensive therapy who are started on either phenelzine or tranylcypromine may be at increased risk for hypotension. Hypertensive patients on stable phenelzine or tranylcypromine who require antihypertensive therapy would be at decreased risk for hypotension.

DISCUSSION: A review article describes the pharmacology of phenelzine and tranylcypromine as non-selective MAOIs which inhibit both type A and type B substrates. Orthostatic hypotension is described as the most common MAOI side effect and usually occurs between initiation and the first 3-4 weeks of therapy.(3) In a double-blind study, 71 patients were randomized to receive a 4-week trial of either tranylcypromine, amitriptyline, or the combination. The number of patients reporting dizziness at 4 weeks was not different between the three treatment groups (tranylcypromine 52.4%; amitriptyline 65%; combination 66.7%). Blood pressure (BP) assessment noted a significant drop in standing BP in the tranylcypromine group compared to baseline (systolic BP change = -10 mmHg; p<0.02 and diastolic BP change = -9 mmHg; p<0.02). Combination therapy also had a significant drop in standing BP compared to baseline (systolic BP change = -9 mmHg; p<0.02). Patients receiving amitriptyline had no significant change in BP from baseline at 4 weeks. All three groups had a trend toward increasing orthostatic hypotension in BP changes from lying to standing. The change in orthostatic hypotension was significant in the amitriptyline group with an average systolic BP orthostatic drop of -9 mmHg (p<0.05).(4) A randomized, double-blind study of 16 inpatients with major depressive disorder were treated with either phenelzine or tranylcypromine. Cardiovascular assessments were completed at baseline and after 6 weeks of treatment. After 6 weeks, 5/7 patients (71%) who received phenelzine had a decrease in standing systolic BP greater than 20 mmHg from baseline. Head-up tilt systolic and diastolic BP decreased from baseline in patients on phenelzine (98/61 mmHg v. 127/65 mmHg, respectively; systolic change p=0.02 and diastolic change p=0.02). After 6 weeks, 6/9 patients (67%) who received tranylcypromine had a decrease in standing systolic BP greater than 20 mmHg from baseline. Head-up tilt systolic and diastolic BP decreased from baseline in patients on tranylcypromine (113/71 mmHg v. 133/69 mmHg, respectively; systolic change p=0.09 and diastolic change p=0.07).(5) Selected MAOIs linked to this monograph include: phenelzine and tranylcypromine. Selected antihypertensive agents include: ACE inhibitors, alpha blockers, ARBs, beta blockers, calcium channel blockers, aprocitentan, clonidine, hydralazine, moxonidine, and sparsentan.

Selected Antihypertensives And Vasodilators/Apomorphine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Apomorphine causes dose-dependent decreases in blood pressure. Concurrent use with antihypertensive agents may result in additive effects on blood pressure.(1)

CLINICAL EFFECTS: Concurrent use of antihypertensives and apomorphine may result in orthostatic hypotension with or without dizziness, nausea, or syncope.(1)

PREDISPOSING FACTORS: The risk of orthostatic hypotension may be increased during dose escalation of apomorphine and in patients with renal or hepatic impairment.(1)

PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for hypotension. Counsel patients about the risk of orthostatic hypotension.(1)

DISCUSSION: Healthy volunteers who took sublingual nitroglycerin (0.4 mg) concomitantly with apomorphine experienced a mean largest decrease in supine systolic blood pressure (SBP) of 9.7 mm Hg and in supine diastolic blood pressure (DBP) of 9.3 mm Hg, and a mean largest decrease in standing SBP and DBP of 14.3 mm Hg and 13.5 mm Hg, respectively. The maximum decrease in SBP and DBP was 65 mm Hg and 43 mm Hg, respectively. When apomorphine was taken alone, the mean largest decrease in supine SBP and DBP was 6.1 mm Hg and 7.3 mm Hg, respectively, and in standing SBP and DBP was 6.7 mm Hg and 8.4 mm Hg, respectively.(1)

*History of angioedema related to angiotensin-converting enzyme (ACE) inhibitor therapy and those with hereditary or idiopathic angioedema.

*Known hypersensitivity to enalapril, enalaprilat, or any ingredient in the formulation.

*Concomitant aliskiren therapy in patients with diabetes mellitus.

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

• Angioedema
• Hereditary angioedema
• Pregnancy

• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Hymenoptera venom desensitization therapy
• Hyperkalemia
• Hyponatremia
• Hypotension
• Renal artery stenosis

• Aortic valve stenosis
• Bone marrow depression
• Disease of liver
• Hypertrophic cardiomyopathy
• Immunosuppression
• Neutropenic disorder

The most common adverse effect reported in >=3% of patients receiving enalapril for hypertension was fatigue. In patients receiving enalapril for heart failure, the most common adverse effects reported in >6% of patients were hypotension and dizziness. The most common adverse effect reported in 3.4% of patients receiving enalaprilat was hypotension.

More Frequent

• Hypotension

Less Frequent

• Fever
• Hyperkalemia

Rare or Very Rare

• Acute myocardial infarction
• Acute pancreatitis
• Acute renal failure
• Agranulocytosis
• Anaphylaxis
• Angioedema
• Atrial fibrillation
• Bradycardia
• Bronchospastic pulmonary disease
• Chest pain
• Drug-induced hepatitis
• Eosinophilia
• Eosinophilic pneumonia
• Erythema multiforme
• Exfoliative dermatitis
• Head and neck angioedema
• Ileus
• Intestinal angioedema
• Laryngeal edema
• Leukocytosis
• Myositis
• Neutropenic disorder
• Obstructive hyperbilirubinemia
• Pemphigus
• Pharyngeal edema
• Pulmonary edema
• Pulmonary thromboembolism
• Stevens-johnson syndrome
• Tachycardia
• Thrombocytopenic disorder
• Tongue swelling
• Toxic epidermal necrolysis
• Vasculitis

More Frequent

• Cough
• Dizziness

Less Frequent

• Arthralgia
• Bronchitis
• Diarrhea
• Dysgeusia
• Dyspnea
• Fatigue
• General weakness
• Headache disorder
• Orthostatic hypotension
• Skin rash
• Syncope
• Vertigo

Rare or Very Rare

• Acute cognitive impairment
• Anorexia
• Ataxia
• Black tarry stools
• Blurred vision
• Conjunctivitis
• Constipation
• Cramps
• Depression
• Drowsy
• Dyspepsia
• Erectile dysfunction
• Flushing
• Glossitis
• Gynecomastia
• Hyperhidrosis
• Loss of sense of smell
• Myalgia
• Pruritus of skin
• Raynaud's phenomenon
• Skin photosensitivity
• Stomatitis
• Tinnitus
• Urticaria

No enhanced messaging available.

Antihypertensive effects of enalapril maleate have been established in hypertensive pediatric patients 1 month to 16 years of age. Enalapril maleate is not recommended for neonates or for pediatric patients with a glomerular filtration rate of <30 mL/minute per 1.73 m2; no data are available. The adverse effect profile of enalapril maleate in pediatric patients is similar to that in adults. Safety and efficacy of enalaprilat injection in pediatric patients have not been established.

Infants exposed in utero to ACE inhibitors should be observed closely for hypotension, oliguria, and hyperkalemia. If oliguria occurs, supportive measures (e.g., administration of fluids and pressor agents) to correct hypotension and renal perfusion should be considered. Exchange transfusion or dialysis may be required to reverse hypotension and/or substitute for impaired renal function. Enalapril, which crosses the placenta, has been removed from neonatal circulation by peritoneal dialysis with some clinical benefit. The manufacturer states that the drug theoretically may be removed by exchange transfusion; however, this latter procedure has not been used to date.

Drugs that act on the renin-angiotensin system (e.g., ACE inhibitors, angiotensin II receptor antagonists) reduce fetal renal function and increase fetal and neonatal morbidity and mortality when used in pregnancy during the second and third trimesters. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal effects include skull hypoplasia, anuria, hypotension, renal failure, and death. Most epidemiologic data evaluating antihypertensive use in the first trimester and the development of fetal abnormalities have not differentiated a risk between medications affecting the renin-angiotensin system and other antihypertensive agents.

Appropriate management of maternal hypertension during pregnancy is necessary to optimize outcomes for the mother and fetus. Discontinue enalapril as soon as possible when pregnancy is detected. In the rare situation that use of enalapril is deemed necessary, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intraamniotic environment. Fetal testing may be appropriate, based on the week of pregnancy; however, oligohydramnios may not appear until after the fetus has sustained irreversible injury. If oligohydramnios is observed, discontinue enalapril unless it is considered lifesaving for the mother. Closely observe infants with histories of in utero exposure to enalapril for hypotension, oliguria, and hyperkalemia.

Enalapril and enalaprilat are excreted into human milk.

Because exposure may cause serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or enalapril, taking into account the importance of the drug to the woman.

The manufacturer provides no specific dosage recommendations in geriatric patients.

Enalapril is substantially eliminated by the kidneys; because geriatric patients have a greater likelihood of decreased renal function and therefore an increased risk of toxicity, renal function should be monitored and dosage should be selected carefully.