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    Angiotensin Converting Enzyme Inhibitors/ACEIs

    BOXED WARNING

    Neonates, pregnancy

    When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, enalapril should be discontinued as soon as possible. Women of child-bearing age should be made aware of the potential risk and ACE inhibitors should only be given after careful counseling and consideration of individual risks and benefits. Rarely (probably less often than once per 1,000 pregnancies), no alternative to ACE inhibitors will be found. In these rare cases, the pregnant women should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intraamniotic environment. The reported adverse fetal and neonatal effects (e.g., hypotension, neonatal skull hypoplasia and craniofacial deformation, fetal limb contractures, hypoplastic lung development, anuria, oligohydramnios, reversible or irreversible renal failure, and death) have been reported during ACE inhibitor exposure during the second and third trimesters. An observational study based on Tennessee Medicaid data reported that the risk of congenital malformations is significantly increased during first-trimester exposure to ACE inhibitors as well. However, a much larger observational study (n = 465,754) found that the risk of birth defects was similar in babies exposed to ACE inhibitors during the first trimester, in those exposed to other antihypertensives during the first trimester, and in those whose mothers were hypertensive but were not treated. Newborns born to mothers with hypertension, either treated or untreated, had a higher risk of birth defects than those born to mothers without hypertension. The authors concluded that the presence of hypertension likely contributed to the development of birth defects rather than the use of medications. Further evaluation of teratogenicity data associated with ACE inhibitor exposure during pregnancy is ongoing. Closely observe neonates with histories of in utero exposure to enalapril for hypotension, oliguria, and hyperkalemia. If oliguria or hypotension occurs, blood pressure and renal perfusion support may be required, as well as exchange transfusion or dialysis to reverse hypotension and/or support decreased renal function. Enalapril, which crosses the placenta, has been removed from neonatal circulation by peritoneal dialysis with some clinical benefit, and theoretically may be removed by exchange transfusion, although there is no experience with the latter procedure.

    DEA CLASS

    Rx

    DESCRIPTION

    IV and oral ACE inhibitor; used for hypertension and CHF; longer-acting than captopril but shorter-acting than other ACE inhibitors; usually dosed twice daily when given orally.

    COMMON BRAND NAMES

    Epaned, Vasotec

    HOW SUPPLIED

    Enalapril Maleate/Vasotec Oral Tab: 2.5mg, 5mg, 10mg, 20mg
    Enalaprilat/Vasotec Intravenous Inj Sol: 1mL, 1.25mg
    Epaned Oral Sol: 1mg, 1mL

    DOSAGE & INDICATIONS

    For the treatment of hypertension.
    Oral dosage
    Adults

    Initially, 2.5 to 5 mg PO once daily. In patients with hyponatremia, hypovolemia, moderate-severe CHF, renal dysfunction (i.e., Scr more than 1.6 mg/dL), or in those receiving diuretics, an initial dose of 2.5 mg is recommended. In patients at risk for hypotension or deterioration of renal function, dosage increases are generally recommended at intervals of 4 days or more. The usual dosage range is 10 to 40 mg/day PO, given in 1 to 2 divided doses. If blood pressure is not controlled with monotherapy, a diuretic may be added.

    Geriatric

    Initiate therapy at the lower end of the adult dosage range. Greater sensitivity to the usual adult dose is possible. Adjust dosage based on clinical response.

    Adolescents 17 years

    Initially, 5 mg PO once daily. The usual dosage range is 10 to 40 mg/day PO given in 1 to 2 divided doses. In patients with hyponatremia, hypovolemia, moderate-severe CHF, renal dysfunction (i.e., Scr more than 1.6 mg/dL), or in those receiving diuretics, an initial dose of 2.5 mg is recommended. In patients at risk for hypotension or deterioration of renal function, dosage increases are generally recommended at intervals of 4 days or more. If blood pressure is not controlled with monotherapy, a diuretic may be added.

    Infants, Children, and Adolescents 16 years and younger

    Initially, 0.08 mg/kg/dose PO once daily (Max: 5 mg); adjust dosage based on clinical response. Doses up to 0.58 mg/kg/day PO given in 1 to 2 divided doses (Max: 40 mg/day) have been studied. In patients with hyponatremia, hypovolemia, moderate-severe CHF, renal dysfunction, or in those receiving diuretics, a lower initial maximum dose of 2.5 mg is recommended. In patients at risk for hypotension or deterioration of renal function, dosage increases are generally recommended at intervals of 4 days or more.

    Intravenous dosage (enalaprilat)
    Adults

    Initially, 0.625 to 1.25 mg IV every 6 hours. Dosage may be titrated up to 5 mg IV every 6 hours. For patients with hyponatremia, hypovolemia, moderate-severe CHF, renal dysfunction (i.e., Scr more than 1.6 mg/dL), or in those receiving diuretics, the initial dose is 0.625 mg IV every 6 hours. For patients not at risk for excessive hypotension, the initial dosage is 1.25 mg IV every 6 hours.

    Geriatric

    Initiate therapy at the lower end of the adult dosage range. Greater sensitivity to the usual adult dose is possible. Adjust dosage based on clinical response.

    Neonates†, Infants†, Children†, and Adolescents†

    5 to 10 mcg/kg/dose IV every 8 to 24 hours (determined by blood pressure readings) (Max: 1.25 mg/dose). Monitor blood pressure and urine output carefully due to the risk of prolonged hypotension and acute renal failure, especially in neonates; select patients may require higher doses.

    For the treatment of heart failure.
    Oral dosage
    Adults

    Initially, 2.5 mg PO twice daily. In patients with hyponatremia (serum sodium less than 130 mEq/L), initiate therapy with 2.5 mg PO once daily. Increase dose as tolerated, over a period of a few days or weeks, adjusting to the clinical response of the patient up to 10 to 20 mg PO twice daily. Guidelines recommend an angiotensin-converting enzyme (ACE) inhibitor in combination with an evidence-based beta blocker and aldosterone antagonist, in select patients, for patients with chronic reduced ejection fraction heart failure (HFrEF) NYHA class I to IV to reduce morbidity and mortality. In patients with prior or current symptoms of chronic HFrEF, use of an ACE inhibitor is recommended. Continued use of an ACE inhibitor is recommended for all classes of HFrEF for those patients for whom subsequent angiotensin receptor-neprilysin inhibitor (ARNI) use is inappropriate. Use of an ACE inhibitor in patients with preserved ejection fraction heart failure (HFpEF) and hypertension is reasonable to control blood pressure.

    Infants†, Children†, and Adolescents†

    In 39 children, after a test dose, enalapril was titrated to a dose of 0.16 mg/kg/day PO by the end of the first week. Subsequently, the mean dose required for improvement in CHF was 0.36 mg/kg/day PO. In select cases, dosages up to 0.94 mg/kg/day PO have been used. A maximum dose for this indication has not been determined; however, the maximum for pediatric patients with hypertension is 40 mg/day PO.

    Neonates†

    FDA-approved labeling recommends against use in neonates due to the lack of data. Very limited data describe the use of 0.01 to 0.27 mg/kg/day PO in neonates and infants; however, there are concerns about the risk for adverse events. Cases of acute hypotension and acute renal failure have been reported after doses of 0.1 mg/kg/day PO in hypertensive infants ; therefore, conservative initial dosages and careful monitoring of blood pressure and renal function are recommended. As part of a small pediatric study (total n = 63 patients), 15 infants ages 9 days to 9 months with left-to-right shunts received enalapril; all but 1 patient in this group was less than 4 months old (neonatal-specific data was not reported separately). Four patients improved while receiving enalapril (mean dosage = 0.19 mg/kg/day PO), 6 patients experienced no change in clinical status (mean dosage = 0.27 mg/kg/day PO), and 5 patients discontinued enalapril due to adverse events (mean dosage = 0.11 mg/kg/day PO). Eight patients in the entire cohort developed renal failure within 14 days of initiating enalapril (7 of the 8 developed renal failure within 5 days); 3 of these patients were 4 weeks or younger and all 3 died. In another case series, doses of 0.1 to 0.16 mg/kg/day PO were used in 3 neonatal patients with CHF without adverse events.

    For the treatment of proteinuria† in pediatric patients.
    Oral dosage
    Children and Adolescents

    0.2 to 0.6 mg/kg/day PO given in 1 to 2 divided doses has been studied. Doses were started at the lower end of the range and titrated up based on clinical response and tolerance. A lower mean dose of 0.1 +/- 0.04 mg/kg/day PO (Max: 0.16 mg/kg/day) was used in combination with an angiotensin receptor blocker in a retrospective study of 17 pediatric patients (5 to 19 years of age) with proteinuric kidney disease of various etiologies. A maximum dose for this indication has not been defined; the maximum for pediatric patients with hypertension is 40 mg/day PO.

    For the treatment of hypertensive emergency† or hypertensive urgency†.
    Intravenous dosage (enalaprilat)
    Adults

    Doses ranging from 1.25 to 5 mg IV every 6 hours have been recommended.

    Geriatric

    Initiate therapy at the lower end of the adult dosage range. Greater sensitivity to the usual adult dose is possible. Adjust dosage based on clinical response.

    Neonates, Infants, Children, and Adolescents

    5 to 10 mcg/kg/dose IV every 8 to 24 hours (determined by blood pressure readings) (Max: 1.25 mg/dose). Monitor blood pressure and urine output carefully due to the risk of prolonged hypotension and acute renal failure, especially in neonates; select patients may require higher doses.

    For the treatment of asymptomatic left ventricular dysfunction including postmyocardial infarction† patients.
    Oral dosage
    Adults

    Initially, 2.5 mg PO twice daily. Increase gradually to 20 mg/day PO, given in divided doses. Patients should be observed for hypotension for at least 2 hours following first dose and for at least 1 hour following stabilization of blood pressure.

    For the treatment of persistent albuminuria† in patients with diabetic nephropathy† or in at-risk hypertensive patients†.
    Oral dosage
    Adults

    10 mg PO once daily (range, 5 mg/day up to 20 mg/day PO in 1 or 2 divided doses). Initial doses used in trials vary. Usually begin with a low dose and titrate to response and tolerance. Enalapril use is associated with a reduction of urinary protein excretion and reduction in the progression of clinical albuminuria. Clinical practice guidelines recommend the use of an angiotensin converting enzyme (ACE) inhibitor to slow the progression of renal disease in hypertensive patients and in diabetic patients regardless of the presence of hypertension.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    40 mg/day PO or 20 mg/day IV.

    Geriatric

    40 mg/day PO or 20 mg/day IV.

    Adolescents

    17 years: 40 mg/day PO for hypertension; safety and efficacy of IV enalaprilat has not been established; however, doses up to 10 mcg/kg/dose IV (Max: 1.25 mg/dose IV) have been used off-label.
    13 to 16 years: 0.58 mg/kg/day PO (Max: 40 mg/day PO) for hypertension; doses of up to 0.94 mg/kg/day PO have been used off-label for CHF; safety and efficacy of IV enalaprilat has not been established; however, doses up to 10 mcg/kg/dose IV (Max: 1.25 mg/dose IV) have been used off-label.

    Children

    0.58 mg/kg/day PO (Max: 40 mg/day PO) for hypertension; doses of up to 0.94 mg/kg/day PO have been used off-label for CHF; safety and efficacy of IV enalaprilat has not been established; however, doses up to 10 mcg/kg/dose IV (Max: 1.25 mg/dose IV) have been used off-label.

    Infants

    0.58 mg/kg/day PO for hypertension; however, doses as high as 0.94 mg/kg/day PO have been used off-label for CHF; safety and efficacy of IV enalaprilat has not been established; however, doses up to 10 mcg/kg/dose IV have been used off-label.

    Neonates

    Safety and efficacy have not been established; however, doses up to 0.27 mg/kg/day PO and 10 mcg/kg/dose IV have been used off-label.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    CrCl more than 30 mL/minute/1.73 m2: No adjustment necessary.
     
    CrCl 30 mL/minute/1.73 m2 or less: In adult patients, reduce initial dose to 2.5 mg PO once daily. The dose may be titrated upward gradually. The initial intravenous dose should be 0.625 mg IV. After 1 hour, if there is an inadequate response, an additional dose of 0.625 mg IV may be given. Thereafter, doses of 1.25 mg IV may be administered at 6 hour intervals. Use is not recommended in pediatric patients as data are unavailable.
     
    Intermittent hemodialysis
    2.5 mg PO after hemodialysis on dialysis days; dosage on non-dialysis days should be adjusted based on clinical response. The starting IV dose for patients receiving dialysis is 0.625 mg (administered IV over at least 5 minutes and preferably up to 1 hour) every 6 hours. Specific recommendations for pediatric patients receiving hemodialysis are not available.

    ADMINISTRATION

    Oral Administration

    May administer without regard to meals.

    Oral Liquid Formulations

    Use a calibrated device to measure the appropriate oral dosage of enalapril.
     
    Ready-to-use Oral Solution
    Solution contains enalapril 1 mg/mL.
    Storage: Store refrigerated (2 to 8 degrees C or 36 to 46 degrees F) in a tightly closed container. Patients may store at room temperature (20 to 25 degrees C or 68 to 77 degrees F) for up to 60 days.
    Powder for Oral Solution
    Final concentration after reconstitution is 1 mg/mL.
    Prior to reconstitution, tap the bottle of enalapril powder 5 times to loosen the powder.
    Add approximately one-half (75 mL) of the provided diluent (Ora-Sweet SF) to the bottle of enalapril powder and shake vigorously for 30 seconds.
    Add the remainder of the provided diluent and shake vigorously for an additional 30 seconds.
    Storage: The reconstituted solution is stable for 60 days at room temperature (25 degrees C or 77 degrees F).

    Extemporaneous Compounding-Oral

    Extemporaneous Oral Suspension Formulations
    NOTE: An FDA-approved oral solution is commercially available; commercially available products are preferred over compounded products when available.
     
    An oral suspension yielding 1 mg/mL may be formulated according to the following procedure:
    Take 10 mL of Bicitra and add to a PET bottle containing 2-tablets of enalapril 20-mg.
    Shake bottle manually for at least 5 minutes.
    Allow to stand at room temperature for 20 minutes.
    Add 30 mL of Ora-Sweet SF and shake manually for roughly 2 minutes.
    Storage: According to the authors, stability data on file with the authors indicate stability of this suspension for 4 weeks at 5 degrees C with ambient relative humidity.
    While other extemporaneous formulations have been reported , this formulation appears to have greater stability and achieves a concentration for ease of use and dosage titration.
    The manufacturer of Vasotec tablets recommends the following procedure to prepare a greater quantity (200 mL) of a 1 mg/mL suspension:
    Add 50 mL of Bicitra to a PET bottle containing ten (10) tablets of Vasotec 20-mg and shake for at least 2 minutes.
    Let concentrate stand for 60 minutes; after standing, shake the concentrate for an additional minute.
    Add 150 mL of Ora-Sweet SF and shake the suspension to disperse the ingredients.
    Storage: The resultant suspension is stable for 30 days when refrigerated at 2 to 8 degrees C (36 to 46 degrees F).

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    May be administered undiluted or in up to 50 mL of a compatible IV infusion solution.
    Administer by slow, direct IV infusion over a period of at least 5 minutes.
     
    Preparation and stability of enalaprilat dilutions for parenteral administration:
    Prepare in a sterile environment, using aseptic technique.
    Each dose should be diluted with no more than 50 mL of compatible solution for intravenous administration.
    Enalaprilat injection may be diluted with the following solutions for intravenous administration: 5% Dextrose Injection, 0.9% Sodium Chloride Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, 5% Dextrose and Lactated Ringer's Injection.
    Dilutions made with these solutions maintain full activity for at least 24 hours at room temperature.
    For a 25 mcg/mL dilution often used in neonatal or small pediatric patients: combine 1 mL of enalaprilat 1.25 mg/mL and 49 mL of compatible solution for intravenous administration.

    STORAGE

    Epaned:
    - After dispensing, store at room temperature up to 77 degrees F and use within 60 days
    - Avoid excessive heat (above 104 degrees F)
    - Protect from freezing
    - Refrigerate (between 36 and 46 degrees F)
    Vasotec:
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    ACE-inhibitor induced angioedema, Angiotensin-converting enzyme inhibitors (ACE inhibitors) hypersensitivity, Black patients, hereditary angioedema, history of angioedema

    Angiotensin-converting enzyme inhibitors (ACE inhibitors) hypersensitivity usually manifests as a result of alterations in kinin generation in sensitive individuals; there is no evidence of a specific immune-mediated reaction. However, such reactions can be potentially life-threatening, even if they are not true 'allergic' reactions. Enalapril is contraindicated in patients with a history of ACE-inhibitor induced angioedema, hereditary angioedema, or idiopathic angioedema. The risk of angioedema may be increased in patients with a history of angioedema unrelated to ACE inhibitors. If angioedema occurs, ACE inhibitor therapy should be halted and appropriate treatment instituted. The incidence of ACE-inhibitor induced angioedema is higher in Black patients than non-Black patients. In addition, ACE inhibitors are less effective in lowering blood pressure in Black patients, including the African American population.

    Hyperkalemia, renal artery stenosis, renal disease, renal failure, renal impairment

    Use enalapril with caution in patients with risk factors for hyperkalemia. ACE inhibitors can elevate serum potassium concentrations and could worsen pre-existing conditions. Hyperkalemia may be associated with serious cardiac arrhythmias. Elevated serum potassium (greater than 5.7 mEq/L) was observed in approximately 1% of hypertensive patients in clinical trials. In most cases these were isolated values which resolved despite continued therapy. Hyperkalemia was a cause of discontinuation of therapy in 0.28% of hypertensive patients. In clinical trials for cardiax failure, hyperkalemia was observed in 3.8% of patients but was not a cause for discontinuation. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes, which should be used cautiously, if at all, in patients taking enalapril. Patients with these risk factors should be monitored closely for hyperkalemia. Monitor renal function and serum potassium. Dosage adjustment of enalapril is recommended in patients with moderate to severe renal impairment or renal failure (i.e., CrCl 30 mL/minute or less). Treatment with ACE inhibitors has demonstrated favorable effects on the progression of renal disease in diabetic and nondiabetic patients; however, minor increases in BUN and serum creatinine may occur. These effects, more commonly reported in patients with renal artery stenosis or those receiving concomitant diuretic therapy, are usually reversible and are not considered a reason to withhold therapy unless accompanied by hyperkalemia. If enalapril is initiated in patients with renal artery stenosis, renal function should be monitored during the first few weeks of therapy.

    Autoimmune disease, bone marrow suppression, collagen-vascular disease, immunosuppression, scleroderma, systemic lupus erythematosus (SLE)

    Neutropenia and/or agranulocytosis have been reported during therapy with ACE inhibitors. This effect rarely occurs in uncomplicated patients but more frequently in patients with renal impairment especially if they also have a collagen-vascular disease (e.g., systemic lupus erythematosus (SLE) or scleroderma) or are receiving concomitant immunosuppression. Data from clinical trials of enalapril are insufficient to show that the drug does not cause agranulocytosis. Therefore, complete blood counts should be established prior to and during enalapril therapy whenever the drug is administered to patients with pre-existing renal disease or autoimmune disease. Enalapril should be used with caution in patients with pre-existing bone marrow suppression.

    Aortic stenosis, cardiomyopathy, cerebrovascular disease, coronary artery disease, heart failure, hyponatremia, hypotension, hypovolemia

    Enalapril is relatively contraindicated in patients who exhibit hypotension. Hypotension can occur if enalapril is administered to patients with hypovolemia or hyponatremia, or to patients receiving diuretics or other antihypertensives. Enalapril should be used cautiously in patients with congestive heart failure (initial doses should be lower than in the treatment of hypertension) because of a greater risk of developing hypotension. Hypotension may aggravate ischemia in patients with coronary artery disease or cerebrovascular disease precipitating a myocardial infarction or cerebrovascular accident. Enalapril should be used with caution in patients with aortic stenosis or hypertrophic cardiomyopathy. As with all vasodilators, ACE inhibitors should be given with caution to patients with obstruction in the outflow tract of the left ventricle.

    Dialysis, hymenoptera venom (insect sting) allergy desensitization, low-density lipoprotein apheresis

    Treatment with ACE inhibitors may increase the risk of anaphylactoid reactions in patients undergoing hymenoptera venom (insect sting) allergy desensitization. Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge. However, a retrospective analysis of 79 patients who underwent hymenoptera venom (insect sting) allergy desensitization did not show an association between ACE inhibitor therapy and increased frequency of systemic reactions to venom immunotherapy. Of 17 patients taking an ACE inhibitor while undergoing desensitization, none experienced a systemic reaction to venom immunotherapy; whereas, 13 of 62 patients not taking an ACE inhibitor experienced a systemic reaction during venom immunotherapy. Anaphylactoid reactions have been reported in patients taking ACE inhibitors (enalapril) who were receiving dialysis with high-flux membranes; the mechanism is unknown. When anaphylactoid symptoms such as nausea, abdominal cramps, burning, angioedema, shortness of breath or low blood pressure are recognized, the dialysis should be stopped and the patient should receive aggressive treatment for the hypersensitivity reaction. Anaphylactoid reactions have also occurred in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption (a procedure dependent upon devices not approved in the United States). Although a causal relationship to ACE inhibitor therapy has not been firmly established, treatment with enalapril may increase the risk for anaphylactoid reactions during membrane exposure. ACE inhibitors may also precipitate low blood pressure in dialysis patients who are volume-depleted.

    Hepatic disease, jaundice

    Enalapril is a prodrug and its conversion to its active metabolite, enalaprilat, may be delayed in patients with hepatic disease. The delay is not expected to be clinically significant in patients with stable, modest hepatic impairment; however, patients with severe hepatic impairment (e.g., cirrhosis) may not be able to adequately convert enalapril to enalaprilat. In these patients, it may be prudent to choose an ACE inhibitor that does not require hepatic activation (e.g., captopril, lisinopril). Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis, and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.

    Surgery

    In patients undergoing major surgery or during anesthesia with agents that lower blood pressure, enalapril may block angiotensin II formation secondary to compensatory renin release. Therefore, enalapril should be used with caution prior to surgery. If hypotension occurs during surgery and/or anesthesia and is considered to be due to blockade of angiotensin II formation, it can be corrected by volume expansion.

    Geriatric

    Greater sensitivity to the hypotensive effects of enalapril is possible in geriatric patients due to an age-related decline in renal function. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, antihypertensive regimens should be individualized to achieve the desired outcome while minimizing adverse effects. Antihypertensives may cause dizziness, postural hypotension, fatigue, and there is an increased risk for falls. ACE inhibitors may cause angioedema, chronic persistent non-productive cough, and may worsen renal failure. There are many drug interactions that can potentiate the effects of antihypertensives. Some agents require a gradual taper to avoid adverse consequences caused by abrupt discontinuation. Monitoring of serum potassium is necessary during treatment with an ACE inhibitor, especially in patients also receiving a potassium-sparing diuretic or potassium supplementation, since combination therapy has the potential for life-threatening elevations of serum potassium.

    Neonates, pregnancy

    When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, enalapril should be discontinued as soon as possible. Women of child-bearing age should be made aware of the potential risk and ACE inhibitors should only be given after careful counseling and consideration of individual risks and benefits. Rarely (probably less often than once per 1,000 pregnancies), no alternative to ACE inhibitors will be found. In these rare cases, the pregnant women should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intraamniotic environment. The reported adverse fetal and neonatal effects (e.g., hypotension, neonatal skull hypoplasia and craniofacial deformation, fetal limb contractures, hypoplastic lung development, anuria, oligohydramnios, reversible or irreversible renal failure, and death) have been reported during ACE inhibitor exposure during the second and third trimesters. An observational study based on Tennessee Medicaid data reported that the risk of congenital malformations is significantly increased during first-trimester exposure to ACE inhibitors as well. However, a much larger observational study (n = 465,754) found that the risk of birth defects was similar in babies exposed to ACE inhibitors during the first trimester, in those exposed to other antihypertensives during the first trimester, and in those whose mothers were hypertensive but were not treated. Newborns born to mothers with hypertension, either treated or untreated, had a higher risk of birth defects than those born to mothers without hypertension. The authors concluded that the presence of hypertension likely contributed to the development of birth defects rather than the use of medications. Further evaluation of teratogenicity data associated with ACE inhibitor exposure during pregnancy is ongoing. Closely observe neonates with histories of in utero exposure to enalapril for hypotension, oliguria, and hyperkalemia. If oliguria or hypotension occurs, blood pressure and renal perfusion support may be required, as well as exchange transfusion or dialysis to reverse hypotension and/or support decreased renal function. Enalapril, which crosses the placenta, has been removed from neonatal circulation by peritoneal dialysis with some clinical benefit, and theoretically may be removed by exchange transfusion, although there is no experience with the latter procedure.

    Breast-feeding

    Enalapril and enalaprilat have been detected in human breast milk. Because of the potential for serious adverse reactions, including hypotension, hyperkalemia, and renal impairment, in the breast-fed infant, breast-feeding should be discontinued during enalapril treatment. Some experts state that adverse effects in a nursing infant are unlikely since enalapril and enalaprilat are detected in human breast milk in small amounts. Previous American Academy of Pediatrics recommendations considered enalapril as usually compatible with breast-feeding.

    Infants, premature neonates

    Limited data exist on the blood pressure lowering effects of enalapril in children younger than 6 years af age. Additionally, enalapril is not recommended for use in pediatric patients with a glomerular filtration rate (GFR) less than 30 mL/minute/1.73 m2 since data are unavailable. Infants and neonates may be especially susceptible to prolonged, excessive, and unpredictable decreases in blood pressure. Oliguria and seizures have been reported. Oral enalapril is not recommended for neonates and premature neonates who have not reached a corrected post-conceptual age of 44 weeks due to the potential for immature renal function and due to a lack of safety and efficacy data.

    ADVERSE REACTIONS

    Severe

    hyperkalemia / Delayed / 1.0-3.8
    myocardial infarction / Delayed / 0.5-1.2
    hemolytic anemia / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    glomerulonephritis / Delayed / Incidence not known
    azotemia / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    renal tubular necrosis / Delayed / Incidence not known
    oliguria / Early / Incidence not known
    bradycardia / Rapid / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    stroke / Early / Incidence not known
    pulmonary edema / Early / Incidence not known
    atrial tachycardia / Early / Incidence not known
    cardiac arrest / Early / Incidence not known
    atrial fibrillation / Early / Incidence not known
    bronchospasm / Rapid / Incidence not known
    eosinophilic pneumonia / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    pemphigus / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    acute generalized exanthematous pustulosis (AGEP) / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    ileus / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    hepatic necrosis / Delayed / Incidence not known
    teratogenesis / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known

    Moderate

    hypotension / Rapid / 0.9-6.7
    chest pain (unspecified) / Early / 2.1-2.1
    orthostatic hypotension / Delayed / 1.6-1.6
    angina / Early / 1.5-1.5
    dyspnea / Early / 1.3-1.3
    constipation / Delayed / 0.5-1.0
    thrombocytopenia / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known
    anemia / Delayed / Incidence not known
    flank pain / Delayed / Incidence not known
    palpitations / Early / Incidence not known
    hyponatremia / Delayed / Incidence not known
    stomatitis / Delayed / Incidence not known
    melena / Delayed / Incidence not known
    glossitis / Early / Incidence not known
    jaundice / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    depression / Delayed / Incidence not known
    ataxia / Delayed / Incidence not known
    peripheral neuropathy / Delayed / Incidence not known
    confusion / Early / Incidence not known
    conjunctivitis / Delayed / Incidence not known
    blurred vision / Early / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known
    eosinophilia / Delayed / Incidence not known

    Mild

    dizziness / Early / 0.5-7.9
    headache / Early / 1.8-5.2
    fatigue / Early / 0.5-3.0
    syncope / Early / 0.5-2.2
    cough / Delayed / 1.3-2.2
    diarrhea / Early / 1.4-2.1
    abdominal pain / Early / 1.6-1.6
    vertigo / Early / 1.6-1.6
    asthenia / Delayed / 1.1-1.6
    rash / Early / 0.5-1.4
    nausea / Early / 1.1-1.4
    vomiting / Early / 1.3-1.3
    fever / Early / 0.5-1.0
    rhinorrhea / Early / Incidence not known
    hoarseness / Early / Incidence not known
    photosensitivity / Delayed / Incidence not known
    diaphoresis / Early / Incidence not known
    alopecia / Delayed / Incidence not known
    pruritus / Rapid / Incidence not known
    flushing / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known
    dyspepsia / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    xerostomia / Early / Incidence not known
    nightmares / Early / Incidence not known
    paresthesias / Delayed / Incidence not known
    dysesthesia / Delayed / Incidence not known
    drowsiness / Early / Incidence not known
    insomnia / Early / Incidence not known
    muscle cramps / Delayed / Incidence not known
    xerophthalmia / Early / Incidence not known
    tinnitus / Delayed / Incidence not known
    anosmia / Delayed / Incidence not known
    dysgeusia / Early / Incidence not known
    gynecomastia / Delayed / Incidence not known
    myalgia / Early / Incidence not known
    leukocytosis / Delayed / Incidence not known
    arthralgia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Monitor heart rate and blood pressure.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Monitor heart rate and blood pressure.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Major) Isometheptene has sympathomimetic properties. Patients taking antihypertensive agents may need to have their therapy modified. Careful blood pressure monitoring is recommended.
    Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Acetaminophen; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Monitor heart rate and blood pressure.
    Acrivastine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Monitor heart rate and blood pressure.
    Aldesleukin, IL-2: (Moderate) Angiotensin converting enzyme inhibitors, like other antihypertensive agents, may potentiate the hypotension seen with aldesleukin, IL 2.
    Alemtuzumab: (Moderate) Alemtuzumab may cause hypotension. Careful monitoring of blood pressure and hypotensive symptoms is recommended especially in patients with ischemic heart disease and in patients on antihypertensive agents.
    Aliskiren: (Major) Aliskiren-containing products are contraindicated in combination with angiotensin-converting enzyme inhibitors (ACE inhibitors) in patients with diabetes mellitus. In general, avoid combined use of two renin-angiotensin-aldosterone system (RAAS) inhibitors, particularly in patients with CrCl less than 60 mL/minute. Combination therapy increases the risk for hyperkalemia, renal impairment, and other side effects. Most patients receiving a comination of two RAAS inhibitors, such as ACE inhibitors and aliskiren do not obtain any additional benefit compared to monotherapy. Closely monitor blood pressure, renal function, and electrolytes if aliskiren must be combined with another RAAS inhibitor. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Aliskiren; Amlodipine: (Major) Aliskiren-containing products are contraindicated in combination with angiotensin-converting enzyme inhibitors (ACE inhibitors) in patients with diabetes mellitus. In general, avoid combined use of two renin-angiotensin-aldosterone system (RAAS) inhibitors, particularly in patients with CrCl less than 60 mL/minute. Combination therapy increases the risk for hyperkalemia, renal impairment, and other side effects. Most patients receiving a comination of two RAAS inhibitors, such as ACE inhibitors and aliskiren do not obtain any additional benefit compared to monotherapy. Closely monitor blood pressure, renal function, and electrolytes if aliskiren must be combined with another RAAS inhibitor. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Major) Aliskiren-containing products are contraindicated in combination with angiotensin-converting enzyme inhibitors (ACE inhibitors) in patients with diabetes mellitus. In general, avoid combined use of two renin-angiotensin-aldosterone system (RAAS) inhibitors, particularly in patients with CrCl less than 60 mL/minute. Combination therapy increases the risk for hyperkalemia, renal impairment, and other side effects. Most patients receiving a comination of two RAAS inhibitors, such as ACE inhibitors and aliskiren do not obtain any additional benefit compared to monotherapy. Closely monitor blood pressure, renal function, and electrolytes if aliskiren must be combined with another RAAS inhibitor. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Major) Aliskiren-containing products are contraindicated in combination with angiotensin-converting enzyme inhibitors (ACE inhibitors) in patients with diabetes mellitus. In general, avoid combined use of two renin-angiotensin-aldosterone system (RAAS) inhibitors, particularly in patients with CrCl less than 60 mL/minute. Combination therapy increases the risk for hyperkalemia, renal impairment, and other side effects. Most patients receiving a comination of two RAAS inhibitors, such as ACE inhibitors and aliskiren do not obtain any additional benefit compared to monotherapy. Closely monitor blood pressure, renal function, and electrolytes if aliskiren must be combined with another RAAS inhibitor. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Aliskiren; Valsartan: (Major) Aliskiren-containing products are contraindicated in combination with angiotensin-converting enzyme inhibitors (ACE inhibitors) in patients with diabetes mellitus. In general, avoid combined use of two renin-angiotensin-aldosterone system (RAAS) inhibitors, particularly in patients with CrCl less than 60 mL/minute. Combination therapy increases the risk for hyperkalemia, renal impairment, and other side effects. Most patients receiving a comination of two RAAS inhibitors, such as ACE inhibitors and aliskiren do not obtain any additional benefit compared to monotherapy. Closely monitor blood pressure, renal function, and electrolytes if aliskiren must be combined with another RAAS inhibitor. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury. (Major) Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor antagonists (ARBs) do not obtain any additional benefit compared to monotherapy. Combination therapy has been associated with an increased risk of diarrhea, hypotension, syncope, hyperkalemia, and renal dysfunction resulting in dialysis, doubling of serum creatinine, and death in clinical studies. The risk of hyperkalemia is particularly high in patients with renal impairment (stage 3a or higher kidney disease). In general, avoid combined use of these drugs together. Patients who must receive concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia. Closely monitor blood pressure, renal function, and electrolytes.
    Alogliptin; Metformin: (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Alpha-glucosidase Inhibitors: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Alprostadil: (Minor) The concomitant use of systemic alprostadil injection and antihypertensive agents, such as angiotensin-converting enzyme inhibitors (ACE inhibitors), may cause additive hypotension. Caution is advised with this combination. Systemic drug interactions with the urethral suppository (MUSE) or alprostadil intracavernous injection are unlikely in most patients because low or undetectable amounts of the drug are found in the peripheral venous circulation following administration. In those men with significant corpora cavernosa venous leakage, hypotension might be more likely. Use caution with in-clinic dosing for erectile dysfunction (ED) and monitor for the effects on blood pressure. However, in clinical trials with alprostadil intracavernous injection, anti-hypertensive agents had no apparent effect on the safety and efficacy of alprostadil.
    Amifostine: (Major) Patients receiving angiotensin-converting enzyme inhibitors should be closely monitored during amifostine infusions due to additive effects. Patients receiving amifostine at doses recommended for chemotherapy should have antihypertensive therapy interrupted 24 hours preceding administration of amifostine. If the antihypertensive cannot be stopped, patients should not receive amifostine.
    Amiloride: (Major) Amiloride should be used very cautiously with agents that have potential to induce hyperkalemia; serum potassium levels monitored when such agents are coadministered with amiloride. Simultaneous use of a potassium-sparing diuretic (e.g., amiloride) with angiotensin-converting enzyme inhibitors (ACE inhibitors) can increase the risk of hyperkalemia, especially in the presence of renal impairment (renal disease, elderly patients). These agents should be used with caution and serum potassium levels monitored when the substances are coadministered. The Beers Criteria recommends avoiding routine use of this combination in older adults; reserve this combination for patients with demonstrated hypokalemia while taking an ACE inhibitor.
    Amiloride; Hydrochlorothiazide, HCTZ: (Major) Amiloride should be used very cautiously with agents that have potential to induce hyperkalemia; serum potassium levels monitored when such agents are coadministered with amiloride. Simultaneous use of a potassium-sparing diuretic (e.g., amiloride) with angiotensin-converting enzyme inhibitors (ACE inhibitors) can increase the risk of hyperkalemia, especially in the presence of renal impairment (renal disease, elderly patients). These agents should be used with caution and serum potassium levels monitored when the substances are coadministered. The Beers Criteria recommends avoiding routine use of this combination in older adults; reserve this combination for patients with demonstrated hypokalemia while taking an ACE inhibitor.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Major) Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor antagonists (ARBs) do not obtain any additional benefit compared to monotherapy. Combination therapy has been associated with an increased risk of diarrhea, hypotension, syncope, hyperkalemia, and renal dysfunction resulting in dialysis, doubling of serum creatinine, and death in clinical studies. The risk of hyperkalemia is particularly high in patients with renal impairment (stage 3a or higher kidney disease). In general, avoid combined use of these drugs together. Patients who must receive concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia. Closely monitor blood pressure, renal function, and electrolytes.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Major) Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor antagonists (ARBs) do not obtain any additional benefit compared to monotherapy. Combination therapy has been associated with an increased risk of diarrhea, hypotension, syncope, hyperkalemia, and renal dysfunction resulting in dialysis, doubling of serum creatinine, and death in clinical studies. The risk of hyperkalemia is particularly high in patients with renal impairment (stage 3a or higher kidney disease). In general, avoid combined use of these drugs together. Patients who must receive concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia. Closely monitor blood pressure, renal function, and electrolytes.
    Amlodipine; Olmesartan: (Major) Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor antagonists (ARBs) do not obtain any additional benefit compared to monotherapy. Combination therapy has been associated with an increased risk of diarrhea, hypotension, syncope, hyperkalemia, and renal dysfunction resulting in dialysis, doubling of serum creatinine, and death in clinical studies. The risk of hyperkalemia is particularly high in patients with renal impairment (stage 3a or higher kidney disease). In general, avoid combined use of these drugs together. Patients who must receive concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia. Closely monitor blood pressure, renal function, and electrolytes.
    Amlodipine; Telmisartan: (Major) Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor antagonists (ARBs) do not obtain any additional benefit compared to monotherapy. Combination therapy has been associated with an increased risk of diarrhea, hypotension, syncope, hyperkalemia, and renal dysfunction resulting in dialysis, doubling of serum creatinine, and death in clinical studies. The risk of hyperkalemia is particularly high in patients with renal impairment (stage 3a or higher kidney disease). In general, avoid combined use of these drugs together. Patients who must receive concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia. Closely monitor blood pressure, renal function, and electrolytes.
    Amlodipine; Valsartan: (Major) Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor antagonists (ARBs) do not obtain any additional benefit compared to monotherapy. Combination therapy has been associated with an increased risk of diarrhea, hypotension, syncope, hyperkalemia, and renal dysfunction resulting in dialysis, doubling of serum creatinine, and death in clinical studies. The risk of hyperkalemia is particularly high in patients with renal impairment (stage 3a or higher kidney disease). In general, avoid combined use of these drugs together. Patients who must receive concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia. Closely monitor blood pressure, renal function, and electrolytes.
    Amobarbital: (Moderate) Concurrent use of amobarbital with antihypertensive agents may lead to hypotension. Monitor for decreases in blood pressure during times of coadministration.
    Amphetamine; Dextroamphetamine Salts: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like angiotensin-converting enzyme inhibitors (ACE inhibitors). Close monitoring of blood pressure is advised.
    Amyl Nitrite: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Angiotensin II receptor antagonists: (Major) Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor antagonists (ARBs) do not obtain any additional benefit compared to monotherapy. Combination therapy has been associated with an increased risk of diarrhea, hypotension, syncope, hyperkalemia, and renal dysfunction resulting in dialysis, doubling of serum creatinine, and death in clinical studies. The risk of hyperkalemia is particularly high in patients with renal impairment (stage 3a or higher kidney disease). In general, avoid combined use of these drugs together. Patients who must receive concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia. Closely monitor blood pressure, renal function, and electrolytes.
    Angiotensin II: (Moderate) Angiotensin converting enzyme inhibitors (ACE inhibitors) may increase the response to angiotensin II. Angiotensin II is a naturally occurring peptide hormone of the renin-angiotensin-aldosterone system (RAAS) that causes vasoconstriction and an increase in blood pressure. ACE inhibitors reduce the breakdown of angiotensin II.
    Apomorphine: (Moderate) Use of angiotensin-converting enzyme inhibitors (ACE inhibitors) and apomorphine together can increase the hypotensive effects of apomorphine. Monitor blood pressure regularly during use of this combination.
    Apraclonidine: (Minor) Alpha blockers as a class may reduce heart rate and blood pressure. While no specific drug interactions have been identified with systemic agents and apraclonidine during clinical trials, it is theoretically possible that additive blood pressure reductions could occur when apraclonidine is combined with the use of antihypertensive agents. Patients using cardiovascular drugs concomitantly with apraclonidine should have their pulse and blood pressure monitored periodically.
    Aprotinin: (Moderate) The manufacturer recommends using aprotinin cautiously in patients that are receiving drugs that can affect renal function, such as ACE inhibitors, as the risk of renal impairment may be increased.
    Aripiprazole: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents.
    Asenapine: (Moderate) Secondary to alpha-blockade, asenapine can produce vasodilation that may result in additive effects during concurrent use of antihypertensive agents. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use of asenapine and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
    Azathioprine: (Major) The use of ACE inhibitors in hypertensive patients receiving azathioprine has been reported to induce anemia and severe leukopenia. This combination should be avoided where possible. When concurrent azathioprine and ACE inhibitor therapy is necessary, the patient should be monitored cautiously for potential myelosuppression.
    Azilsartan: (Major) Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor antagonists (ARBs) do not obtain any additional benefit compared to monotherapy. Combination therapy has been associated with an increased risk of diarrhea, hypotension, syncope, hyperkalemia, and renal dysfunction resulting in dialysis, doubling of serum creatinine, and death in clinical studies. The risk of hyperkalemia is particularly high in patients with renal impairment (stage 3a or higher kidney disease). In general, avoid combined use of these drugs together. Patients who must receive concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia. Closely monitor blood pressure, renal function, and electrolytes.
    Azilsartan; Chlorthalidone: (Major) Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor antagonists (ARBs) do not obtain any additional benefit compared to monotherapy. Combination therapy has been associated with an increased risk of diarrhea, hypotension, syncope, hyperkalemia, and renal dysfunction resulting in dialysis, doubling of serum creatinine, and death in clinical studies. The risk of hyperkalemia is particularly high in patients with renal impairment (stage 3a or higher kidney disease). In general, avoid combined use of these drugs together. Patients who must receive concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia. Closely monitor blood pressure, renal function, and electrolytes.
    Baclofen: (Moderate) Baclofen has been associated with hypotension. Concurrent use with baclofen and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required
    Benzphetamine: (Minor) Benzphetamine may increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like angiotensin-converting enzyme inhibitors (ACE inhibitors). Close monitoring of blood pressure is advised.
    Bosentan: (Moderate) Although no specific interactions have been documented, bosentan has vasodilatory effects and may contribute additive hypotensive effects when given with angiotensin-converting enzyme inhibitors (ACE inhibitors).
    Brexpiprazole: (Moderate) Due to brexpiprazole's antagonism at alpha 1-adrenergic receptors, the drug may enhance the hypotensive effects of alpha-blockers and other antihypertensive agents.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Monitor heart rate and blood pressure.
    Brompheniramine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Monitor heart rate and blood pressure.
    Cabergoline: (Moderate) Cabergoline should be used cautiously with antihypertensive agents, including angiotensin-converting enzyme inhibitors. Cabergoline has been associated with hypotension. Initial doses of cabergoline higher than 1 mg may produce orthostatic hypotension. It may be advisable to monitor blood pressure.
    Calcium Phosphate, Supersaturated: (Moderate) Concomitant use of medicines with potential to alter renal perfusion or function such as angiotensin-converting enzyme inhibitors, may increase the risk of acute phosphate nephropathy in patients taking sodium phosphate monobasic monohydrate; sodium phosphate dibasic anhydrous.
    Canagliflozin; Metformin: (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Candesartan: (Major) Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor antagonists (ARBs) do not obtain any additional benefit compared to monotherapy. Combination therapy has been associated with an increased risk of diarrhea, hypotension, syncope, hyperkalemia, and renal dysfunction resulting in dialysis, doubling of serum creatinine, and death in clinical studies. The risk of hyperkalemia is particularly high in patients with renal impairment (stage 3a or higher kidney disease). In general, avoid combined use of these drugs together. Patients who must receive concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia. Closely monitor blood pressure, renal function, and electrolytes.
    Candesartan; Hydrochlorothiazide, HCTZ: (Major) Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor antagonists (ARBs) do not obtain any additional benefit compared to monotherapy. Combination therapy has been associated with an increased risk of diarrhea, hypotension, syncope, hyperkalemia, and renal dysfunction resulting in dialysis, doubling of serum creatinine, and death in clinical studies. The risk of hyperkalemia is particularly high in patients with renal impairment (stage 3a or higher kidney disease). In general, avoid combined use of these drugs together. Patients who must receive concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia. Closely monitor blood pressure, renal function, and electrolytes.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Carbetapentane; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Carbetapentane; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Monitor heart rate and blood pressure.
    Carbidopa; Levodopa: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Carbidopa; Levodopa; Entacapone: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Monitor heart rate and blood pressure.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Monitor heart rate and blood pressure.
    Carbinoxamine; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Carbinoxamine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Monitor heart rate and blood pressure.
    Cariprazine: (Moderate) Orthostatic vital signs should be monitored in patients who are at risk for hypotension, such as those receiving cariprazine in combination with antihypertensive agents. Atypical antipsychotics may cause orthostatic hypotension and syncope, most commonly during treatment initiation and dosage increases. Patients should be informed about measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning, or rising slowly from a seated position. Consider a cariprazine dose reduction if hypotension occurs.
    Carvedilol: (Moderate) Consider separating the time of dosing of carvedilol from that of an angiotensin-converting enzyme (ACE) inhibitor or temporarily reducing the ACE inhibitor dosage if vasodilatory symptoms (e.g., dizziness, lightheadedness, syncope) occur with concomitant use.
    Cetirizine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Monitor heart rate and blood pressure.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Monitor heart rate and blood pressure.
    Chlophedianol; Guaifenesin; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Chloroprocaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Monitor heart rate and blood pressure.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Monitor heart rate and blood pressure.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Monitor heart rate and blood pressure.
    Chlorpheniramine; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Chlorpheniramine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Monitor heart rate and blood pressure.
    Clozapine: (Moderate) Lisinopril may decrease the renal elimination of clozapine and metabolites. Clozapine toxicity, including irritability, anger, insomnia, nightmares and sialorrhea may occur. The mechanism of this interaction is unclear; however, as lisinopril does not undergo metabolism, cytochrome P450 enzyme involvement is unlikely. It is speculated that a decrease in renal elimination of clozapine occurs due to a lisinopril-induced reduction in glomerular filtration rate (GFR). Plasma clozapine concentrations should be measured carefully during concomitant lisinopril therapy; another antihypertensive class may need to be selected. In addition, clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Cocaine: (Major) Use of cocaine with antihypertensive agents may increase the antihypertensive effects of the antihypertensive medications or may potentiate cocaine-induced sympathetic stimulation.
    Codeine; Phenylephrine; Promethazine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Co-Enzyme Q10, Ubiquinone: (Moderate) Co-enzyme Q10, ubiquinone (CoQ10) may lower blood pressure. CoQ10 use in combination with antihypertensive agents may lead to additional reductions in blood pressure in some individuals. Patients who choose to take CoQ10 concurrently with antihypertensive medications should receive periodic blood pressure monitoring. Patients should be advised to inform their prescriber of their use of CoQ10.
    Conivaptan: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Cyclophosphamide: (Moderate) Use caution if cyclophosphamide is used concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors), as increased or additive leukopenia may occur.
    Cyclosporine: (Moderate) Several cases of acute renal failure have been associated with the addition of angiotensin-converting enzyme (ACE) inhibitors to cyclosporine therapy in renal transplant patients. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of ACE could reduce renal function acutely. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with ACE inhibitors or potassium salts.
    Dapagliflozin; Metformin: (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Desloratadine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Monitor heart rate and blood pressure.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Monitor heart rate and blood pressure.
    Dexmethylphenidate: (Moderate) Dexmethylphenidate can reduce the hypotensive effect of antihypertensive agents, including angiotensin-converting enzyme inhibitors (ACE inhibitors). Periodic evaluation of blood pressure is advisable during concurrent use of dexmethylphenidate and antihypertensive agents, particularly during initial coadministration and after dosage increases of dexmethylphenidate.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Monitor heart rate and blood pressure.
    Dextromethorphan; Quinidine: (Moderate) Quinidine can decrease blood pressure and should be used cautiously in patients receiving antihypertensive agents due to the potential for additive hypotension.
    Diazoxide: (Moderate) Additive hypotensive effects can occur with the concomitant administration of diazoxide with other antihypertensive agents. This interaction can be therapeutically advantageous, but dosages must be adjusted accordingly. The manufacturer advises that IV diazoxide should not be administered to patients within 6 hours of receiving other antihypertensive agents.
    Diethylpropion: (Major) Diethylpropion has vasopressor effects and may limit the benefit of angiotensin-converting enzyme inhibitors. Although leading drug interaction texts differ in the potential for an interaction between diethylpropion and this group of antihypertensive agents, these effects are likely to be clinically significant and have been described in hypertensive patients on these medications.
    Digoxin: (Moderate) Caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin-converting enzyme inhibitors (ACE inhibitors). A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Monitor heart rate and blood pressure.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Diphenhydramine; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Drospirenone: (Moderate) Drospirenone has antimineralocorticoid effects and may increase serum potassium. The concurrent use of ACE inhibitors may increase the risk of hyperkalemia, especially in the presence of renal impairment. Monitor serum potassium during the 1st month of drospirenone treatment if an Angiotensin-Converting Enzyme inhibitor (ACE inhibitor) is used concurrently and thereafter as clinically indicated. Also monitor for any changes in blood pressure, fluid retention, or renal function.
    Drospirenone; Estradiol: (Moderate) Drospirenone has antimineralocorticoid effects and may increase serum potassium. The concurrent use of ACE inhibitors may increase the risk of hyperkalemia, especially in the presence of renal impairment. Monitor serum potassium during the 1st month of drospirenone treatment if an Angiotensin-Converting Enzyme inhibitor (ACE inhibitor) is used concurrently and thereafter as clinically indicated. Also monitor for any changes in blood pressure, fluid retention, or renal function.
    Drospirenone; Ethinyl Estradiol: (Moderate) Drospirenone has antimineralocorticoid effects and may increase serum potassium. The concurrent use of ACE inhibitors may increase the risk of hyperkalemia, especially in the presence of renal impairment. Monitor serum potassium during the 1st month of drospirenone treatment if an Angiotensin-Converting Enzyme inhibitor (ACE inhibitor) is used concurrently and thereafter as clinically indicated. Also monitor for any changes in blood pressure, fluid retention, or renal function.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Drospirenone has antimineralocorticoid effects and may increase serum potassium. The concurrent use of ACE inhibitors may increase the risk of hyperkalemia, especially in the presence of renal impairment. Monitor serum potassium during the 1st month of drospirenone treatment if an Angiotensin-Converting Enzyme inhibitor (ACE inhibitor) is used concurrently and thereafter as clinically indicated. Also monitor for any changes in blood pressure, fluid retention, or renal function.
    Duloxetine: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
    Empagliflozin; Linagliptin; Metformin: (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Empagliflozin; Metformin: (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Enflurane: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Entecavir: (Moderate) Because entecavir is primarily eliminated by the kidneys and ACE inhibitors can affect renal function, concurrent administration with ACE inhibitors may increase the serum concentrations of entecavir and adverse events. Monitor for adverse effects when these drugs are coadministered.
    Ephedrine: (Major) The cardiovascular effects of sympathomimetics, such as ephedrine, may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Eplerenone: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin-converting enzyme (ACE) inhibitors. Hyperkalemia risk is increased when eplerenone is used with ACE inhibitors. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Eprosartan: (Major) Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor antagonists (ARBs) do not obtain any additional benefit compared to monotherapy. Combination therapy has been associated with an increased risk of diarrhea, hypotension, syncope, hyperkalemia, and renal dysfunction resulting in dialysis, doubling of serum creatinine, and death in clinical studies. The risk of hyperkalemia is particularly high in patients with renal impairment (stage 3a or higher kidney disease). In general, avoid combined use of these drugs together. Patients who must receive concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia. Closely monitor blood pressure, renal function, and electrolytes.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Major) Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor antagonists (ARBs) do not obtain any additional benefit compared to monotherapy. Combination therapy has been associated with an increased risk of diarrhea, hypotension, syncope, hyperkalemia, and renal dysfunction resulting in dialysis, doubling of serum creatinine, and death in clinical studies. The risk of hyperkalemia is particularly high in patients with renal impairment (stage 3a or higher kidney disease). In general, avoid combined use of these drugs together. Patients who must receive concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia. Closely monitor blood pressure, renal function, and electrolytes.
    Ertugliflozin; Metformin: (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Estradiol Cypionate; Medroxyprogesterone: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Estradiol: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Etomidate: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Everolimus: (Moderate) The risk of angioedema, with or without respiratory impairment, may be increased if everolimus is given with other drugs known to cause angioedema such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). In a pooled analysis of randomized, double-blind oncology clinical trials, angioedema was reported in 6.8% of patients receiving concomitant everolimus and ACE inhibitor therapy, compared to 1.3% of patients with an ACE inhibitor alone. If coadministration is necessary, educate patients regarding signs and symptoms of angioedema and monitor therapy closely.
    Fexofenadine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Monitor heart rate and blood pressure.
    Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Fluorescein: (Moderate) Patients on angiotensin-converting enzyme inhibitors are at an increased risk of adverse reactions when administered fluorescein injection. If fluorescein injection is deemed necessary in a patient on ACE inhibitor therapy, monitor as appropriate during and after the procedure.
    Fluoxetine; Olanzapine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Fospropofol: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    General anesthetics: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Glipizide; Metformin: (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Glyburide; Metformin: (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Gold: (Minor) Nitritoid reactions (facial flushing, diaphoresis, dizziness, nausea/vomiting, hypotension, tachycardia, syncope, and anaphylactic type reactions) or vasomotor reactions have been reported rarely in patients receiving injectable gold and concomitant ACE inhibitor therapy. Monitor closely for nitritoid reactions during co-therapy with gold and ACE inhibitor agents.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Monitor heart rate and blood pressure.
    Guaifenesin; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Guaifenesin; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Monitor heart rate and blood pressure.
    Haloperidol: (Moderate) In general, haloperidol should be used cautiously with antihypertensive agents due to the possibility of additive hypotension.
    Halothane: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Heparin: (Moderate) Angiotensin-converting enzyme (ACE) inhibitors decrease aldosterone secretion, leading to small increases in serum potassium levels. Drugs that increase serum potassium concentration, such as heparin, should be given cautiously to patients taking ACE inhibitors. Frequently monitor serum potassium. Hyperkalemia can cause serious, sometimes fatal, arrhythmias.
    Hydralazine; Isosorbide Dinitrate, ISDN: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Hydrochlorothiazide, HCTZ; Irbesartan: (Major) Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor antagonists (ARBs) do not obtain any additional benefit compared to monotherapy. Combination therapy has been associated with an increased risk of diarrhea, hypotension, syncope, hyperkalemia, and renal dysfunction resulting in dialysis, doubling of serum creatinine, and death in clinical studies. The risk of hyperkalemia is particularly high in patients with renal impairment (stage 3a or higher kidney disease). In general, avoid combined use of these drugs together. Patients who must receive concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia. Closely monitor blood pressure, renal function, and electrolytes.
    Hydrochlorothiazide, HCTZ; Losartan: (Major) Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor antagonists (ARBs) do not obtain any additional benefit compared to monotherapy. Combination therapy has been associated with an increased risk of diarrhea, hypotension, syncope, hyperkalemia, and renal dysfunction resulting in dialysis, doubling of serum creatinine, and death in clinical studies. The risk of hyperkalemia is particularly high in patients with renal impairment (stage 3a or higher kidney disease). In general, avoid combined use of these drugs together. Patients who must receive concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia. Closely monitor blood pressure, renal function, and electrolytes.
    Hydrochlorothiazide, HCTZ; Olmesartan: (Major) Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor antagonists (ARBs) do not obtain any additional benefit compared to monotherapy. Combination therapy has been associated with an increased risk of diarrhea, hypotension, syncope, hyperkalemia, and renal dysfunction resulting in dialysis, doubling of serum creatinine, and death in clinical studies. The risk of hyperkalemia is particularly high in patients with renal impairment (stage 3a or higher kidney disease). In general, avoid combined use of these drugs together. Patients who must receive concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia. Closely monitor blood pressure, renal function, and electrolytes.
    Hydrochlorothiazide, HCTZ; Spironolactone: (Major) Spironolactone should not be used concomitantly with ACE inhibitors, especially in the presence of renal impairment (renal disease, elderly patients). Coadministration of ACE inhibitors and spironolactone, even in the presence of a diuretic, has been associated with severe hyperkalemia. Use together with extreme caution and monitor serum potassium concentrations.
    Hydrochlorothiazide, HCTZ; Telmisartan: (Major) Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor antagonists (ARBs) do not obtain any additional benefit compared to monotherapy. Combination therapy has been associated with an increased risk of diarrhea, hypotension, syncope, hyperkalemia, and renal dysfunction resulting in dialysis, doubling of serum creatinine, and death in clinical studies. The risk of hyperkalemia is particularly high in patients with renal impairment (stage 3a or higher kidney disease). In general, avoid combined use of these drugs together. Patients who must receive concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia. Closely monitor blood pressure, renal function, and electrolytes.
    Hydrochlorothiazide, HCTZ; Triamterene: (Major) ACE inhibitors can increase the risk of hyperkalemia developing in patients receiving triamterene, especially in the presence of renal impairment. This combination should be used with caution and serum potassium levels monitored. The Beers Criteria recommends avoiding routine use of this combination in older adults; reserve this combination for patients with demonstrated hypokalemia while taking an ACE inhibitor.
    Hydrochlorothiazide, HCTZ; Valsartan: (Major) Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor antagonists (ARBs) do not obtain any additional benefit compared to monotherapy. Combination therapy has been associated with an increased risk of diarrhea, hypotension, syncope, hyperkalemia, and renal dysfunction resulting in dialysis, doubling of serum creatinine, and death in clinical studies. The risk of hyperkalemia is particularly high in patients with renal impairment (stage 3a or higher kidney disease). In general, avoid combined use of these drugs together. Patients who must receive concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia. Closely monitor blood pressure, renal function, and electrolytes.
    Hydrocodone; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Monitor heart rate and blood pressure.
    Hydrocodone; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Monitor heart rate and blood pressure.
    Ibritumomab Tiuxetan: (Major) Avoid coadministration of potassium phosphate and angiotensin-converting enzyme inhibitors as concurrent use may increase the risk of severe and potentially fatal hyperkalemia, particularly in high-risk patients (renal impairment, cardiac disease, adrenal insufficiency). If concomitant use is necessary, closely monitor serum potassium concentrations.
    Ibuprofen; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Monitor heart rate and blood pressure.
    Icatibant: (Minor) Although clinical data are lacking, icatibant is a bradykinin B2 receptor antagonist and may theoretically potentiate the antihypertensive effect of ACE inhibitors.
    Iloperidone: (Moderate) Secondary to alpha-blockade, iloperidone can produce vasodilation that may result in additive effects during concurrent use with antihypertensive agents. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use of iloperidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
    Iloprost: (Moderate) Further reductions in blood pressure may occur when inhaled iloprost is administered to patients receiving other antihypertensive agents.
    Incretin Mimetics: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Indapamide: (Moderate) The effects of indapamide may be additive when administered with other antihypertensive agents or diuretics. In some patients, this may be desirable, but orthostatic hypotension may occur. Patients with hyponatremia or hypovolemia are more susceptible to developing reversible renal insufficiency when given an angiotensin-converting enzyme inhibitors (ACE Inhibitors) and diuretic therapy concomitantly.
    Insulins: (Moderate) Monitor patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors) concomitantly with insulin for changes in glycemic control. ACE inhibitors may enhance the hypoglycemic effects of insulin by improving insulin sensitivity. In addition, ACE inhibitors have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease.
    Intravenous Lipid Emulsions: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Iohexol: (Moderate) Because the use of other nephrotoxic drugs, including ACE inhibitors, is an additive risk factor for nephrotoxicity in patients receiving radiopaque contrast agents, ACE inhibitor therapy should be withheld, when possible, during radiopaque contrast agent administration.
    Iopamidol: (Moderate) Because the use of other nephrotoxic drugs, including ACE inhibitors, is an additive risk factor for nephrotoxicity in patients receiving radiopaque contrast agents, ACE inhibitor therapy should be withheld, when possible, during radiopaque contrast agent administration.
    Iopromide: (Moderate) Because the use of other nephrotoxic drugs, including ACE inhibitors, is an additive risk factor for nephrotoxicity in patients receiving radiopaque contrast agents, ACE inhibitor therapy should be withheld, when possible, during radiopaque contrast agent administration.
    Ioversol: (Moderate) Because the use of other nephrotoxic drugs, including ACE inhibitors, is an additive risk factor for nephrotoxicity in patients receiving radiopaque contrast agents, ACE inhibitor therapy should be withheld, when possible, during radiopaque contrast agent administration.
    Irbesartan: (Major) Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor antagonists (ARBs) do not obtain any additional benefit compared to monotherapy. Combination therapy has been associated with an increased risk of diarrhea, hypotension, syncope, hyperkalemia, and renal dysfunction resulting in dialysis, doubling of serum creatinine, and death in clinical studies. The risk of hyperkalemia is particularly high in patients with renal impairment (stage 3a or higher kidney disease). In general, avoid combined use of these drugs together. Patients who must receive concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia. Closely monitor blood pressure, renal function, and electrolytes.
    Iron Dextran: (Moderate) The concomitant use of angiotensin-converting enzyme inhibitors (ACE inhibitors) with iron dextran may increase the risk for anaphylactic-type reactions. The factors that affect the risk for anaphylactic-type reactions to iron dextran products are not fully known but limited clinical data suggest the risk may be increased among patients with a history of drug allergy or multiple drug allergies. Patients should be monitored for signs and symptoms of anaphylactic-type reactions during all iron dextran administrations.
    Isocarboxazid: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Isoflurane: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Concomitant use of rifampin and enalapril may result in decreased concentrations of enalaprilat, the active metabolite of enalapril. Dosage adjustments of enalapril may be required.
    Isoniazid, INH; Rifampin: (Moderate) Concomitant use of rifampin and enalapril may result in decreased concentrations of enalaprilat, the active metabolite of enalapril. Dosage adjustments of enalapril may be required.
    Isoproterenol: (Moderate) The pharmacologic effects of isoproterenol may cause an increase in blood pressure. If isoproterenol is used concomitantly with antihypertensives, the blood pressure should be monitored as the administration of isoproterenol can compromise the effectiveness of antihypertensive agents.
    Isosorbide Dinitrate, ISDN: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Isosorbide Mononitrate: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Isosulfan Blue: (Moderate) Because the use of other nephrotoxic drugs, including ACE inhibitors, is an additive risk factor for nephrotoxicity in patients receiving radiopaque contrast agents, ACE inhibitor therapy should be withheld, when possible, during radiopaque contrast agent administration.
    Kanamycin: (Moderate) Kanamycin is a nephrotoxic drug. Additive nephrotoxicity is possible if kanamycin is administered with other nephrotoxic medications such as angiotensin-converting enzyme inhibitors (ACE inhibitors). The manufacturer of kanamycin indicates that such combinations should be avoided.
    Ketamine: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Lanthanum Carbonate: (Moderate) ACE Inhibitors should not be taken within 2 hours of dosing with lanthanum carbonate. Oral compounds known to interact with cationic antacids may similarly be bound with lanthanum carbonate and have their absorption reduced. If these agents are used concomitantly, separate the dosing intervals appropriately. Monitor the clinical condition of the patient to ensure the proper clinical response to the ACE inhibitor is obtained.
    Levodopa: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Linagliptin; Metformin: (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Lisdexamfetamine: (Minor) Lisdexamfetamine may increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like angiotensin-converting enzyme inhibitors (ACE inhibitors). Close monitoring of blood pressure is advised.
    Lithium: (Moderate) ACE inhibitors (ACEIs) should be used very cautiously in patients receiving lithium. The risk of lithium toxicity may be increased in patients receiving ACEIs. ACE inhibitors decrease lithium clearance, possibly as a result of sodium depletion which leads to increased renal tubular reabsorption of lithium. Start with lower doses of lithium or reduce dosage, while frequently monitoring serum lithium concentrations and for signs/symptoms of lithium toxicity. According to the Beers Criteria, this drug interaction may be particularly relevant for older adults; the panel recommends avoiding concurrent use if possible due to an increased risk of lithium toxicity. If the combination is medically necessary, monitoring of lithium concentrations is recommended.
    Loop diuretics: (Moderate) Coadministration of loop diuretics and Angiotensin-converting enzyme inhibitors (ACE inhibitors) may result in severe hypotension and deterioration in renal function, including renal failure. Hyponatremia or hypovolemia predisposes patients to acute hypotensive episodes following initiation of ACE inhibitor therapy. While ACE inhibitors and loop diuretics are routinely administered together in the treatment of heart failure, if an ACE inhibitor is to be administered to a patient receiving furosemide, initial doses should be conservative.
    Loratadine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Monitor heart rate and blood pressure.
    Losartan: (Major) Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor antagonists (ARBs) do not obtain any additional benefit compared to monotherapy. Combination therapy has been associated with an increased risk of diarrhea, hypotension, syncope, hyperkalemia, and renal dysfunction resulting in dialysis, doubling of serum creatinine, and death in clinical studies. The risk of hyperkalemia is particularly high in patients with renal impairment (stage 3a or higher kidney disease). In general, avoid combined use of these drugs together. Patients who must receive concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia. Closely monitor blood pressure, renal function, and electrolytes.
    Lovastatin; Niacin: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
    Lurasidone: (Moderate) Due to the antagonism of lurasidone at alpha-1 adrenergic receptors, the drug may enhance the hypotensive effects of alpha-blockers and other antihypertensive agents. If concurrent use of lurasidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
    Magnesium Salts: (Moderate) Use caution when prescribing sulfate salt bowel preparation in patients taking concomitant medications that may affect renal function such as angiotensin-converting enzyme inhibitors (ACE inhibitors).
    Magnesium Sulfate; Potassium Sulfate; Sodium Sulfate: (Moderate) Use caution when prescribing sulfate salt bowel preparation in patients taking concomitant medications that may affect renal function such as angiotensin-converting enzyme inhibitors (ACE inhibitors).
    Meglitinides: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Mestranol; Norethindrone: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients; monitor patients receiving concurrent therapy to confirm that the desired antihypertensive effect is being obtained.
    Metformin: (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Metformin; Pioglitazone: (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Metformin; Repaglinide: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Metformin; Rosiglitazone: (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Metformin; Saxagliptin: (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Metformin; Sitagliptin: (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Methamphetamine: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like angiotensin-converting enzyme inhibitors (ACE inhibitors). Close monitoring of blood pressure is advised.
    Methohexital: (Moderate) Concurrent use of methohexital and antihypertensive agents increases the risk of developing hypotension.
    Methylphenidate: (Minor) Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate. Methylphenidate can reduce the hypotensive effect of antihypertensive agents such as angiotensin-converting enzyme inhibitors.
    Milrinone: (Moderate) Concurrent administration of antihypertensive agents could lead to additive hypotension when administered with milrinone. Titrate milrinone dosage according to hemodynamic response.
    Naproxen; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Monitor heart rate and blood pressure.
    Nateglinide: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Nebivolol; Valsartan: (Major) Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor antagonists (ARBs) do not obtain any additional benefit compared to monotherapy. Combination therapy has been associated with an increased risk of diarrhea, hypotension, syncope, hyperkalemia, and renal dysfunction resulting in dialysis, doubling of serum creatinine, and death in clinical studies. The risk of hyperkalemia is particularly high in patients with renal impairment (stage 3a or higher kidney disease). In general, avoid combined use of these drugs together. Patients who must receive concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia. Closely monitor blood pressure, renal function, and electrolytes.
    Nefazodone: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Nesiritide, BNP: (Major) The potential for hypotension may be increased when coadministering nesiritide with antihypertensive agents.
    Niacin, Niacinamide: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
    Niacin; Simvastatin: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
    Nitrates: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Nitroglycerin: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Nitroprusside: (Moderate) Additive hypotensive effects may occur when nitroprusside is used concomitantly with other antihypertensive agents. Dosages should be adjusted carefully, according to blood pressure.
    Non-Ionic Contrast Media: (Moderate) Because the use of other nephrotoxic drugs, including ACE inhibitors, is an additive risk factor for nephrotoxicity in patients receiving radiopaque contrast agents, ACE inhibitor therapy should be withheld, when possible, during radiopaque contrast agent administration.
    Nonsteroidal antiinflammatory drugs: (Moderate) In the low-renin or volume-dependent hypertensive patient, prostaglandins play an important role in the hypotensive effects of ACE inhibitors. NSAIDs may attenuate the antihypertensive effects of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of ACE inhibitors may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking an ACE inhibitor. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. The potential clinical effects of selective or preferential COX-2 inhibitors are not known. Mean arterial blood pressure increased 3 mmHg in patients receiving ACE inhibitor (benazepril 10 to 40 mg daily for 4 weeks) with rofecoxib 25 mg once daily compared to the ACE inhibitor regimen alone.
    Olanzapine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Olmesartan: (Major) Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor antagonists (ARBs) do not obtain any additional benefit compared to monotherapy. Combination therapy has been associated with an increased risk of diarrhea, hypotension, syncope, hyperkalemia, and renal dysfunction resulting in dialysis, doubling of serum creatinine, and death in clinical studies. The risk of hyperkalemia is particularly high in patients with renal impairment (stage 3a or higher kidney disease). In general, avoid combined use of these drugs together. Patients who must receive concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia. Closely monitor blood pressure, renal function, and electrolytes.
    Oxymetazoline: (Major) The vasoconstricting actions of oxymetazoline, an alpha adrenergic agonist, may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. If these drugs are used together, closely monitor for changes in blood pressure.
    Paliperidone: (Moderate) Paliperidone may cause orthostatic hypotension, thereby enhancing the hypotensive effects of antihypertensive agents. Orthostatic vital signs should be monitored in patients receiving paliperidone and angiotensin-converting enzyme inhibitors who are susceptible to hypotension.
    Pentoxifylline: (Moderate) Pentoxifylline has been used concurrently with antihypertensive drugs (beta blockers, diuretics) without observed problems. Small decreases in blood pressure have been observed in some patients treated with pentoxifylline; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensives. If indicated, dosage of the antihypertensive agents should be reduced.
    Phenelzine: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Phenylephrine; Promethazine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Polyethylene Glycol; Electrolytes: (Moderate) Use caution when prescribing sulfate salt bowel preparation in patients taking concomitant medications that may affect renal function such as angiotensin-converting enzyme inhibitors (ACE inhibitors).
    Polyethylene Glycol; Electrolytes; Ascorbic Acid: (Moderate) Use caution when prescribing sulfate salt bowel preparation in patients taking concomitant medications that may affect renal function such as angiotensin-converting enzyme inhibitors (ACE inhibitors).
    Potassium Phosphate: (Major) Avoid coadministration of potassium phosphate and angiotensin-converting enzyme inhibitors as concurrent use may increase the risk of severe and potentially fatal hyperkalemia, particularly in high-risk patients (renal impairment, cardiac disease, adrenal insufficiency). If concomitant use is necessary, closely monitor serum potassium concentrations.
    Potassium Phosphate; Sodium Phosphate: (Major) Avoid coadministration of potassium phosphate and angiotensin-converting enzyme inhibitors as concurrent use may increase the risk of severe and potentially fatal hyperkalemia, particularly in high-risk patients (renal impairment, cardiac disease, adrenal insufficiency). If concomitant use is necessary, closely monitor serum potassium concentrations.
    Potassium: (Major) Potassium supplements should be used with caution in patients taking drugs that may increase serum potassium levels, such as ACE inhibitors. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Also, use caution when prescribing sulfate salt bowel preparation in patients taking concomitant medications that may affect renal function such as angiotensin-converting enzyme inhibitors (ACE inhibitors).
    Pramlintide: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Prazosin: (Moderate) Prazosin is well-known to produce a 'first-dose' phenomenon. Some patients develop significant hypotension shortly after administration of the first dose. The first dose response (acute postural hypotension) of prazosin may be exaggerated in patients who are receiving beta-adrenergic blockers, diuretics, or other antihypertensive agents. Concomitant administration of prazosin with other antihypertensive agents is not prohibited, however. This can be therapeutically advantageous, but lower dosages of each agent should be used.
    Pregabalin: (Moderate) Concomitant use of pregabalin with angiotensin converting enzyme (ACE) inhibitors should be closely monitored. Life-threatening angioedema with respiratory compromise has been reported with use of pregabalin. Angioedema of the face, mouth (lips, tongue, gums), throat, and larynx has occurred. The risk of developing this complication may be increased when pregabalin is used with ACE inhibitors or other drugs known to cause angioedema.
    Procainamide: (Moderate) Procainamide can decrease blood pressure and should be used cautiously in patients receiving antihypertensive agents. Intravenous administration of procainamide is more likely to cause hypotensive effects.
    Procaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Propofol: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Monitor heart rate and blood pressure.
    Quinidine: (Moderate) Quinidine can decrease blood pressure and should be used cautiously in patients receiving antihypertensive agents due to the potential for additive hypotension.
    Rasagiline: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Repaglinide: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Rifampin: (Moderate) Concomitant use of rifampin and enalapril may result in decreased concentrations of enalaprilat, the active metabolite of enalapril. Dosage adjustments of enalapril may be required.
    Risperidone: (Moderate) Risperidone may induce orthostatic hypotension and thus enhance the hypotensive effects of antihypertensive agents. Lower initial doses or slower dose titration of risperidone may be necessary in patients receiving antihypertensive agents concomitantly.
    Sacubitril; Valsartan: (Severe) Sacubitril; valsartan is contraindicated with the concomitant use of angiotensin-converting enzyme inhibitors (ACE inhibitors) due to the increased risk of angioedema. Do not administer sacubitril; valsartan within 36 hours of switching to or from an ACE inhibitor. (Major) Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor antagonists (ARBs) do not obtain any additional benefit compared to monotherapy. Combination therapy has been associated with an increased risk of diarrhea, hypotension, syncope, hyperkalemia, and renal dysfunction resulting in dialysis, doubling of serum creatinine, and death in clinical studies. The risk of hyperkalemia is particularly high in patients with renal impairment (stage 3a or higher kidney disease). In general, avoid combined use of these drugs together. Patients who must receive concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia. Closely monitor blood pressure, renal function, and electrolytes.
    Salicylates: (Moderate) Aspirin, ASA may reduce the vasodilatory efficacy of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. This interaction has been documented primarily in heart failure patients. However, the established benefits of using aspirin in combination with an ACE inhibitor in patients with ischemic heart disease and left ventricular dysfunction generally outweigh this concern. Patients receiving concurrent salicylates and ACE inhibitor therapy should be monitored for antihypertensive or vasodilatory efficacy; the dose of the ACE inhibitor can be adjusted if indicated based on clinical evaluation.
    Sevoflurane: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    SGLT2 Inhibitors: (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium, and glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ACE inhibitors may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity.
    Silodosin: (Moderate) During clinical trials with silodosin, the incidence of dizziness and orthostatic hypotension was higher in patients receiving concomitant antihypertensive treatment. Thus, caution is advisable when silodosin is administered with antihypertensive agents.
    Sirolimus: (Moderate) Sirolimus has been associated with the development of angioedema. The use of sirolimus with other drugs known to cause angioedema, such as angiotensin-converting enzyme inhibitors may increase the risk of developing angioedema. Patients should be monitored for angioedema if any of these drugs are coadministered with sirolimus.
    Sodium Phosphate Monobasic Monohydrate; Sodium Phosphate Dibasic Anhydrous: (Moderate) Concomitant use of medicines with potential to alter renal perfusion or function such as angiotensin-converting enzyme inhibitors, may increase the risk of acute phosphate nephropathy in patients taking sodium phosphate monobasic monohydrate; sodium phosphate dibasic anhydrous.
    Sodium picosulfate; Magnesium oxide; Anhydrous citric acid: (Moderate) Use caution when prescribing sodium picosulfate; magnesium oxide; anhydrous citric acid in patients taking concomitant medications that may affect renal function such as angiotensin-converting enzyme inhibitors (ACE inhibitors). In addition, use caution in patients receiving drugs where hypokalemia is a particular risk.
    Spironolactone: (Major) Spironolactone should not be used concomitantly with ACE inhibitors, especially in the presence of renal impairment (renal disease, elderly patients). Coadministration of ACE inhibitors and spironolactone, even in the presence of a diuretic, has been associated with severe hyperkalemia. Use together with extreme caution and monitor serum potassium concentrations.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin-converting enzyme (ACE) inhibitors and trimethoprim is necessary. Hyperkalemia may be more signficant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Sulfonylureas: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Tacrolimus: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, including ACE inhibitors.
    Telavancin: (Moderate) Concurrent or sequential use of telavancin with other potentially nephrotoxic drugs such as Angiotensin-converting enzyme inhibitors (ACE inhibitors) may lead to additive nephrotoxicity. Closely monitor renal function and adjust telavancin doses based on calculated creatinine clearance.
    Telbivudine: (Moderate) Drugs that alter renal function such as angiotensin-converting enzyme inhibitors may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Telmisartan: (Major) Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor antagonists (ARBs) do not obtain any additional benefit compared to monotherapy. Combination therapy has been associated with an increased risk of diarrhea, hypotension, syncope, hyperkalemia, and renal dysfunction resulting in dialysis, doubling of serum creatinine, and death in clinical studies. The risk of hyperkalemia is particularly high in patients with renal impairment (stage 3a or higher kidney disease). In general, avoid combined use of these drugs together. Patients who must receive concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia. Closely monitor blood pressure, renal function, and electrolytes.
    Temsirolimus: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with enalapril. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with another ACE inhibitor.
    Tetrabenazine: (Moderate) Tetrabenazine may induce orthostatic hypotension and thus enhance the hypotensive effects of antihypertensive agents. Lower initial doses or slower dose titration of tetrabenazine may be necessary in patients receiving antihypertensive agents concomitantly.
    Tetracaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of tetracaine and antihypertensive agents.
    Thiazide diuretics: (Moderate) Patients with hyponatremia or hypovolemia are more susceptible to developing reversible renal insufficiency when given angiotensin converting enzyme (ACE) inhibitors and diuretics concomitantly.
    Thiazolidinediones: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Thiopental: (Moderate) Concurrent use of thiopental and alpha-blockers or antihypertensive agents increases the risk of developing hypotension.
    Thiothixene: (Moderate) Thiothixene should be used cautiously in patients receiving antihypertensive agents. Additive hypotensive effects are possible.
    Tizanidine: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Tolvaptan: (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors). Hyperkalemia was reported at a rate 1 to 2% higher when tolvaptan was administered with angiotensin converting enzyme inhibitors than when angiotensin converting enzyme inhibitors were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors).
    Tranylcypromine: (Severe) The use of hypotensive agents and tranylcypromine is contraindicated by the manufacturer of tranylcypromine because the effects of hypotensive agents may be markedly potentiated.
    Trazodone: (Minor) Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.
    Triamterene: (Major) ACE inhibitors can increase the risk of hyperkalemia developing in patients receiving triamterene, especially in the presence of renal impairment. This combination should be used with caution and serum potassium levels monitored. The Beers Criteria recommends avoiding routine use of this combination in older adults; reserve this combination for patients with demonstrated hypokalemia while taking an ACE inhibitor.
    Trimethoprim: (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin-converting enzyme (ACE) inhibitors and trimethoprim is necessary. Hyperkalemia may be more signficant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Valsartan: (Major) Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor antagonists (ARBs) do not obtain any additional benefit compared to monotherapy. Combination therapy has been associated with an increased risk of diarrhea, hypotension, syncope, hyperkalemia, and renal dysfunction resulting in dialysis, doubling of serum creatinine, and death in clinical studies. The risk of hyperkalemia is particularly high in patients with renal impairment (stage 3a or higher kidney disease). In general, avoid combined use of these drugs together. Patients who must receive concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia. Closely monitor blood pressure, renal function, and electrolytes.
    Vasopressin, ADH: (Minor) Use of vasopressin with drugs suspected of causing syndrome of inappropriate antidiuretic hormone secretion (SIADH), such as enalapril, may increase the pressor and antidiuretic effects of vasopressin.
    Yohimbine: (Moderate) Yohimbine can increase blood pressure and therefore can antagonize the therapeutic action of antihypertensive agents. Use with particular caution in hypertensive patients with high or uncontrolled blood pressure.
    Ziprasidone: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.

    PREGNANCY AND LACTATION

    Pregnancy

    When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, enalapril should be discontinued as soon as possible. Women of child-bearing age should be made aware of the potential risk and ACE inhibitors should only be given after careful counseling and consideration of individual risks and benefits. Rarely (probably less often than once per 1,000 pregnancies), no alternative to ACE inhibitors will be found. In these rare cases, the pregnant women should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intraamniotic environment. The reported adverse fetal and neonatal effects (e.g., hypotension, neonatal skull hypoplasia and craniofacial deformation, fetal limb contractures, hypoplastic lung development, anuria, oligohydramnios, reversible or irreversible renal failure, and death) have been reported during ACE inhibitor exposure during the second and third trimesters. An observational study based on Tennessee Medicaid data reported that the risk of congenital malformations is significantly increased during first-trimester exposure to ACE inhibitors as well. However, a much larger observational study (n = 465,754) found that the risk of birth defects was similar in babies exposed to ACE inhibitors during the first trimester, in those exposed to other antihypertensives during the first trimester, and in those whose mothers were hypertensive but were not treated. Newborns born to mothers with hypertension, either treated or untreated, had a higher risk of birth defects than those born to mothers without hypertension. The authors concluded that the presence of hypertension likely contributed to the development of birth defects rather than the use of medications. Further evaluation of teratogenicity data associated with ACE inhibitor exposure during pregnancy is ongoing. Closely observe neonates with histories of in utero exposure to enalapril for hypotension, oliguria, and hyperkalemia. If oliguria or hypotension occurs, blood pressure and renal perfusion support may be required, as well as exchange transfusion or dialysis to reverse hypotension and/or support decreased renal function. Enalapril, which crosses the placenta, has been removed from neonatal circulation by peritoneal dialysis with some clinical benefit, and theoretically may be removed by exchange transfusion, although there is no experience with the latter procedure.

    MECHANISM OF ACTION

    Enalapril competes with the natural substrate, angiotensin I, thereby inhibiting its conversion to angiotensin II. Angiotensin II is a potent vasoconstrictor and a negative feedback mediator for renin activity. Thus, when enalapril lowers angiotensin II plasma levels, blood pressure decreases and plasma renin activity increases. In addition, baroreceptor reflex mechanisms are stimulated in response to the fall in blood pressure. Kininase II, identical to ACE, is an enzyme that degrades bradykinin, a potent vasodilator, to inactive peptides. Whether increased bradykinin levels play a part in the therapeutic effects of ACE inhibitors is presently unclear. Bradykinin-induced vasodilation is thought to be of secondary importance in the blood-pressure lowering effect of ACE inhibitors. A bradykinin mechanism may, however, contribute to ACE-inhibitor-induced angioneurotic edema.
     
    ACE-inhibiting drugs can act locally to reduce vascular tone by decreasing local angiotensin II-induced sympathetic and/or vasoconstrictive activity. ACE inhibitors also can inhibit presynaptic norepinephrine release and postsynaptic adrenergic receptor activity, decreasing vascular sensitivity to vasopressor activity; however, this action may not be clinically evident at usual doses. Decreases in plasma angiotensin II levels also reduce aldosterone secretion, with a subsequent decrease in sodium and water retention. As antihypertensives, ACE inhibitors reduce LVH, do not worsen insulin resistance or hyperlipidemia, and do not cause sexual dysfunction.
     
    Enalapril causes arterial dilation, thereby lowering total peripheral vascular resistance. In hypertensive patients, blood pressure is decreased with little or no change in heart rate, stroke volume, or cardiac output. However, in patients with heart failure, enalapril increases cardiac output, cardiac index, stroke volume, and exercise tolerance. The drug also decreases pulmonary wedge pressure, pulmonary vascular resistance, and mean arterial and right atrial pressures in these patients.

    PHARMACOKINETICS

    Enalapril is administered orally and enalaprilat is administered parenterally. Enalapril maleate is a prodrug; it is converted by hydrolysis of the ethyl ester to enalaprilat, the active drug. Animal studies indicate that enalapril crosses the blood-brain barrier poorly, if at all. Enalaprilat does not enter the brain. Excretion of enalapril and enalaprilat is primarily renal. Approximately 94% of a dose is recovered in the urine and feces as enalaprilat or enalapril. The principal components in urine are enalaprilat (accounting for about 40% of the dose) and intact enalapril. The half-life of enalaprilat after multiple doses of enalapril is about 11 hours.
     
    Affected cytochrome P450 isoenzymes: none

    Oral Route

    After oral administration, peak serum concentrations are achieved within about 1 hour. The extent of absorption is approximately 60%. Peak serum concentrations of enalaprilat occur 3 to 4 hours after an oral dose of enalapril maleate. In most patients, the onset of antihypertensive activity after a single dose of enalapril occurs about 1 hour after administration, with peak reductions in blood pressure achieved by 4 to 6 hours. At recommended doses, the antihypertensive effect of enalapril monotherapy is maintained for at least 24 hours in many patients. However, in some patients, the effect diminishes towards the end of the 24-hour dosing interval. The pharmacokinetics of enalapril oral solution are similar to that of the tablets.

    Intravenous Route

    The onset of antihypertensive activity usually occurs within 15 minutes of administration, with peak reductions in blood pressure achieved within 1 to 4 hours. At recommended doses, the antihypertensive effect of enalaprilat is maintained for approximately 6 hours.