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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, lisinopril should be discontinued as soon as possible. Women of child-bearing age should be made aware of the potential risk and lisinopril should only be given after careful counseling and consideration of individual risks and benefits. When used during the second and third trimesters, drugs that affect the renin-angiotensin system (e.g., ACE inhibitors, angiotensin II receptor antagonists) reduce fetal renal function and increase fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Other potential neonatal adverse effects include skull hypoplasia, anuria, and hypotension. Retrospective data indicate that first trimester use of ACE inhibitors has been associated with a potential risk of birth defects. However, a large 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. In rare cases when another antihypertensive agent cannot be used to treat a pregnant patient, serial ultrasound examinations should be performed to assess the intraamniotic environment. If oligohydramnios is observed, discontinue lisinopril unless it is considered life-saving for the mother. It should be noted that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe neonates with histories of in utero exposure to lisinopril 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. Lisinopril crosses the placenta and 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

    Long-acting, oral ACE inhibitor
    Used for hypertension, congestive heart failure, post-myocardial infarction, and diabetic nephropathy
    Can be dosed once daily; slower onset and a longer duration of action than either captopril or enalapril

    COMMON BRAND NAMES

    Prinivil, QBRELIS, Zestril

    HOW SUPPLIED

    Lisinopril/Prinivil/Zestril Oral Tab: 2.5mg, 5mg, 10mg, 20mg, 30mg, 40mg
    QBRELIS Oral Sol: 1mg, 1mL

    DOSAGE & INDICATIONS

    For the treatment of hypertension.
    Oral dosage
    Adults

    Initially, 10 mg PO once daily. The usual dosage range is 20 to 40 mg PO once daily. Lower dosage may be necessary in patients with impaired renal function, the elderly, and in those receiving diuretics. In patients with a creatinine clearance of less than 30 mL/minute, initiate therapy with 5 mg PO once daily. Max: 80 mg/day.

    Children and Adolescents 6 to 17 years

    0.07 mg/kg (Max: 5 mg) PO once daily initially; adjust dosage according to clinical response. Max: 0.6 mg/kg/day or 40 mg/day PO, whichever is less.

    Children† 2 to 5 years

    Limited data available. A initial dose of 0.07 to 0.1 mg/kg (Max: 5 mg) PO once daily has been recommended; adjust according to clinical response. Max: 0.6 mg/kg/day or 40 mg/day, whichever is less. An initial dose of 0.1 mg/kg PO once daily, adjusted according to clinical response (Max: 0.5 mg/kg/day) was reported in a retrospective chart review (n = 123) including 13 children 2 to 5 years, 7 of whom were hypertensive. Mean maximum dose in this age group was 0.17 +/- 0.2 mg/kg/day PO; this was similar to the mean dose in the older age groups. The first dose was almost always administered in the hospital with the patient under close observation for 4 to 8 hours.

    Children† 12 to 23 months

    Limited data available. An initial dose of 0.07 to 0.1 mg/kg PO once daily has been recommended; adjust according to clinical response (Max: 0.6 mg/kg/day). An initial dose of 0.1 mg/kg PO once daily, adjusted according to clinical response (Max: 0.5 mg/kg/day) was reported in a retrospective chart review (n = 123) including 13 pediatric patients 2 to 23 months, 9 of whom were hypertensive. Mean maximum dose in this age group was 0.33 +/- 0.39 mg/kg/day PO; this was higher in comparison to the older age groups. The first dose was almost always administered in the hospital with the patient under close observation for 4 to 8 hours.

    Infants†

    Limited data available. An initial dose of 0.1 mg/kg PO once daily, adjusted according to clinical response (Max: 0.5 mg/kg/day) was reported in a retrospective chart review (n = 123) including 13 pediatric patients 2 to 23 months, 9 of which were hypertensive. Mean maximum dose in this age group was 0.33 +/- 0.39 mg/kg/day PO; this was higher in comparison to the older age groups. The first dose was almost always administered in the hospital with the patient under close observation for 4 to 8 hours.

    For the treatment of heart failure.
    Oral dosage
    Adults

    Initially, 2.5 to 5 mg PO once daily. The initial dose should be administered under medical observation, especially in patients with low blood pressure. Consider lowering the dose of concomitant diuretic therapy to minimize hypovolemia. Hypotension after the initial dose does not preclude further titration. In patients who have hyponatremia (serum sodium less than 130 mEq/L) or with a creatinine clearance of less than 30 mL/minute, initiate therapy with 2.5 mg PO once daily. Increase as tolerated, adjusting to the clinical response of the patient up to the maximum of 40 mg/day PO. A suggested rate of dose adjustment for tolerance is to adjust by 10 mg/day or less at intervals of approximately 2 weeks. Based on the ATLAS study in heart failure patients, high doses (32.5 to 35 mg/day) did not significantly change overall mortality rate compared to low doses (2.5 to 5 mg/day PO); however, the high dose group had a lower hospitalization rate for heart failure. To reduce morbidity and mortality associated with heart failure, clinical practice guidelines recommend treatment with angiotensin converting enzyme (ACE) inhibitors for all patients with current or prior symptoms of heart failure and reduced left ventricular ejection fraction, unless contraindicated. ACE inhibitors also should be used to prevent symptomatic heart failure and reduce mortality in all patients with a recent or remote history of myocardial infarction or acute coronary syndrome who have reduced ejection fraction and in patients with a reduced ejection fraction and no symptoms of heart failure, even if they have not experienced myocardial infarction.

    To reduce cardiovascular morbidity and mortality postmyocardial infarction† or to improve survival of hemodynamically stable patients when administered within 24 hours of acute myocardial infarction (AMI).
    Oral dosage
    Adults who are hemodynamically stable

    Initiate therapy within 24 hours of onset of symptoms. Administer one 5 mg PO dose, followed by 5 mg PO after 24 hours, 10 mg PO after 48 hours, and then 10 mg PO once daily. In patients without complications and no evidence of symptomatic or asymptomatic LV dysfunction by 6 weeks after AMI, ACE inhibitor therapy can be stopped.

    Adults who develop low systolic blood pressure (<= 120 mmHg) either prior to therapy or during the first three days of therapy after the infarct

    Initiate therapy within 24 hours of onset of symptoms. If patients are hypotensive prior to therapy, initiate therapy with 2.5 mg/day PO. If not hypotensive prior to therapy, 5 mg PO once daily may be given with dosage reductions to 2.5 mg/day when needed. If systolic blood pressure falls below 90 mm Hg for more than 1 hour, lisinopril should be withdrawn.

    Geriatric

    Initiate therapy at the lower end of the adult dosage range. Peak lisinopril serum concentrations and AUC are approximately doubled in elderly patients. Adjust dosage based on clinical response.

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

    Doses vary, but are within the usual adult dose range for lisinopril. Up to 10 mg PO once daily has been studied in normotensive diabetic patients with microalbuminuria and up to 20 mg PO once daily has been studied in nondiabetic hypertensive patients with microalbuminuria. Lisinopril has been shown to reduce the albumin excretion rate in diabetic patients with or without microalbuminuria. 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.

    To control the rate of progression of diabetic retinopathy† in patients with normotensive type I diabetes mellitus.
    Oral dosage
    Adults

    10 to 20 mg/day PO has been studied. The EUCLID trial evaluated normotensive patients with type 1 diabetes mellitus. Retinal photography was performed at baseline and after 2 years of therapy with lisinopril. Over the course of the study, retinopathy worsened by one stage in only 13% of lisinopril subjects compared to 23% of placebo subjects (p = 0.02). Progression by at least 2 stages was also less in the lisinopril group.

    Geriatric

    Initiate therapy at the lower end of the adult dosage range. Peak lisinopril serum concentrations and AUC are approximately doubled in elderly patients. Adjust dosage based on clinical response.

    For migraine prophylaxis†.
    Oral dosage
    Adults

    10 mg PO once daily for 1 week, then 20 mg PO once daily. Or alternately, 2.5 mg PO once daily for 1 week followed by 5 mg PO once daily. Clinical practice guidelines classify lisinopril as possibly effective for migraine prophylaxis.

    For the treatment of proteinuria† in pediatric patients with IgA nephropathy†.
    Oral dosage
    Children and Adolescents 4 to 17 years

    Limited data available. An initial dose of 0.2 mg/kg (Max: 10 mg/day) PO once daily for 1 week, then increased to 0.4 mg/kg (Max: 20 mg/day) PO once daily was effective for the resolution of proteinuria (morning urine protein/creatinine ratio less than 0.2 g/g) in 83% of patients during a 2-year pilot study of pediatric patients with mild IgA nephropathy (n = 40; mean age: 11.4 years). Five patients developed dizziness and 4 of those required dose reduction (to between 50% to 75% of the maximum dose); no other adverse effects were reported.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    80 mg/day PO for hypertension; 40 mg/day PO for heart failure.

    Geriatric

    80 mg/day PO for hypertension; 40 mg/day PO for heart failure.

    Adolescents

    0.6 mg/kg/day (Max: 40 mg/day) PO.

    Children

    6 to 12 years: 0.6 mg/kg/day (Max: 40 mg/day) PO.
    2 to 5 years: Safety and efficacy have not been established; however, clinical guidelines recommend 0.6 mg/kg/day (Max: 40 mg/day) PO and a mean maximum dose of 0.17 +/- 0.2 mg/kg/day PO has been reported with off-label use.
    12 to 23 months: Safety and efficacy have not been established; however, clinical guidelines recommend 0.6 mg/kg/day PO and a mean maximum dose of 0.33 +/- 0.39 mg/kg/day PO has been reported with off-label use.

    Infants

    Safety and efficacy have not been established; however, a mean maximum dose of 0.33 +/- 0.39 mg/kg/day PO has been reported with off-label use.

    Neonates

    Safety and efficacy have not been established.

    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

    Adult patients
    CrCl more than 30 mL/minute: No dosage adjustment needed.
    CrCl 10 to 30 mL/minute: Reduce initial recommended dose by 50% for adults (i.e., 5 mg PO once daily for hypertension, 2.5 mg PO once daily for heart failure and acute myocardial infarction). Max: 40 mg/day.
    CrCl less than 10 mL/minute: Reduce initial dosage to 2.5 mg PO once daily. Max: 40 mg/day.
     
    Pediatric patients (6 years and older)
    FDA-approved labeling does not recommend use in pediatric patients with a GFR less than 30 mL/minute/1.73 m2. Alternatively, the following adjustments have been recommended:
    GFR more than 50 mL/minute/1.73 m2: No dosage adjustment necessary.
    GFR 10 to 50 mL/minute/1.73 m2: Administer 50% of the usual dose.
    GFR less than 10 mL/minute/1.73 m2: Administer 25% of the usual dose.
     
    Intermittent hemodialysis
    Lisinopril is removed by hemodialysis. For adult patients receiving dialysis, the initial recommended dosage is 2.5 mg PO once daily. Max: 40 mg/day. In pediatric patients, administer 25% of the usual dose after dialysis.
     
    Peritoneal dialysis
    In pediatric patients, administer 25% of the usual dose after dialysis.
     
    Continuous renal replacement therapy (CRRT)
    In pediatric patients, administer 50% of the usual dose (assuming a dialysis dose of 2,000 mL/minute/1.73 m2).

    ADMINISTRATION

    Oral Administration

    May administer without regard to food.

    Oral Liquid Formulations

    Measure with a calibrated oral syringe prior to administration.

    Extemporaneous Compounding-Oral

    Extemporaneous compounding instructions for lisinopril oral suspension
    NOTE: There is a FDA-approved oral solution of lisinopril (1 mg/mL) commercially available.
     
    An oral suspension yielding 2 mg/mL may be prepared using the following procedure:
    Crush forty-eight (48) 5-mg tablets in a mortar and grind to a fine powder.
    Measure out 20 mL of distilled water in a graduated cylinder. 
    Wet the powder with the smallest amount of distilled water as possible, forming a smooth uniform paste.
    Add the remaining distilled water and Simple Syrup vehicle geometrically until a volume slightly short of 120 mL, mixing well.
    Transfer the suspension to a graduated cylinder.
    Rinse the mortar with vehicle and add rinse to the graduated cylinder.
    Add Simple Syrup quantity sufficient to make a final volume of 120 mL.
    Shake well prior to each administration.
    Storage: Stable at room temperature or refrigerated for 30 days.
     
    The manufacturer of Prinivil tablets recommends the following procedure to prepare a 1 mg/mL suspension:
    Add 10 mL of Purified Water USP to a polyethylene terephthalate (PET) bottle containing ten (10) 20-mg tablets.
    Shake for at least 1 minute.
    Add 30 mL of Sodium Citrate and Citric Acid Oral Solution or Cytra-2 diluent and 160 mL Ora-Sweet SF to the concentrate in the PET bottle.
    Shake gently for several seconds to disperse the ingredients.
    Shake well prior to each administration.
    Storage: Stable at room temperature or refrigerated (at or below 25 degrees C [77 degrees F]) for up to 4 weeks.

    STORAGE

    Prinivil:
    - Protect from freezing
    - Protect from light
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)
    QBRELIS:
    - Avoid excessive heat (above 104 degrees F)
    - Protect from freezing
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Zestril:
    - Protect from freezing
    - Protect from light
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    ACE-inhibitor induced angioedema, angioedema, Angiotensin-converting enzyme inhibitors (ACE inhibitors) hypersensitivity, Black patients, hereditary 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. Lisinopril is contraindicated in patients with a history of ACE-inhibitor induced angioedema, hereditary angioedema, or idiopathic angioedema. If angioedema occurs, ACE inhibitor therapy should be halted and appropriate treatment instituted (see Adverse Reactions). 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.

    Diabetes mellitus, hyperkalemia, renal artery stenosis, renal disease, renal failure, renal impairment

    Lisinopril should be used with caution in patients with risk factors for hyperkalemia. ACE inhibitors can elevate serum potassium concentrations and could worsen pre-existing conditions. In clinical trials, hyperkalemia (serum potassium greater than 5.7 mEq/L) occurred in 2.2% and 4.8% of patients receiving lisinopril for high blood pressure and cardiac failure, respectively. 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 very cautiously, if at all, with lisinopril. Monitor renal function and serum potassium. Dosage adjustment of lisinopril 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 lisinopril 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 lisinopril are insufficient to show that the drug does not cause agranulocytosis. Therefore, complete blood counts should be established prior to and during lisinopril therapy whenever the drug is administered to patients with pre-existing renal disease or autoimmune disease. Lisinopril should be used with caution in patients with pre-existing bone marrow suppression.

    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 lisinopril 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.

    Acute myocardial infarction, aortic stenosis, cardiomyopathy, cerebrovascular disease, coronary artery disease, heart failure, hyponatremia, hypotension, hypovolemia

    Lisinopril should be used cautiously in patients who exhibit hyponatremia or hypovolemia, in part because inhibition of aldosterone production would be expected to exacerbate both conditions. Excessive hypotension may occur in patients undergoing dialysis or in patients treated vigorously with diuretics (e.g., patients with congestive heart failure). Lisinopril should be used cautiously in patients with congestive heart failure with systolic blood pressure below 100 mmHg (initial doses should be lower than in the treatment of hypertension); these patients are at greater risk of developing hypotension. Patients with severe heart failure are at increased risk for development of renal complications. Avoid lisinopril use in hemodynamically unstable patients after an acute myocardial infarction. Hypotension may aggravate ischemia in patients with coronary artery disease or cerebrovascular disease precipitating a myocardial infarction or cerebrovascular accident. Lisinopril 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.

    Surgery

    In patients undergoing major surgery or during anesthesia with agents that produce hypotension, lisinopril may block angiotensin II formation secondary to compensatory renin release. Hypotension considered to be due to this mechanism can be corrected by volume expansion.

    Jaundice

    ACE inhibitors such as lisinopril have been associated with a syndrome that starts with cholestatic jaundice or hepatitis 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 treatment.

    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, lisinopril should be discontinued as soon as possible. Women of child-bearing age should be made aware of the potential risk and lisinopril should only be given after careful counseling and consideration of individual risks and benefits. When used during the second and third trimesters, drugs that affect the renin-angiotensin system (e.g., ACE inhibitors, angiotensin II receptor antagonists) reduce fetal renal function and increase fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Other potential neonatal adverse effects include skull hypoplasia, anuria, and hypotension. Retrospective data indicate that first trimester use of ACE inhibitors has been associated with a potential risk of birth defects. However, a large 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. In rare cases when another antihypertensive agent cannot be used to treat a pregnant patient, serial ultrasound examinations should be performed to assess the intraamniotic environment. If oligohydramnios is observed, discontinue lisinopril unless it is considered life-saving for the mother. It should be noted that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe neonates with histories of in utero exposure to lisinopril 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. Lisinopril crosses the placenta and 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

    No data are available regarding the presence of lisinopril in human milk or the effects of lisinopril on the breast-fed infant or on milk production. Lisinopril is present in rat milk. Because of the potential for severe adverse reactions in the breast-fed infant, advise women to discontinue breast-feeding during treatment with lisinopril. Captopril and enalapril have been considered usually compatible with breast-feeding. Benazepril and quinapril are excreted in human breast milk in very small quantities ; therefore, a clinically significant risk to a breast-feeding infant is not expected. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children, infants

    Lisinopril is not recommended for infants and children less than 6 years of age or in any pediatric patient with an estimated glomerular filtration rate (eGFR) less than 30 mL/minute/1.732. Infants and neonates may be especially susceptible to prolonged, excessive, and unpredictable decreases in blood pressure. Oliguria and seizures have been reported in this age group with other ACE inhibitor therapy. Antihypertensive effects and safety of lisinopril have been established in pediatric patients aged 6 to 16 years; trial data support efficacy and safety profiles similar to adult patients in this age group.

    Geriatric

    Greater sensitivity to the hypotensive effects of lisinopril 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 have 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.

    ADVERSE REACTIONS

    Severe

    hyperkalemia / Delayed / 2.2-6.0
    visual impairment / Early / 1.0
    pancreatitis / Delayed / 1.0
    Stevens-Johnson syndrome / Delayed / 1.0
    toxic epidermal necrolysis / Delayed / 1.0
    hemolytic anemia / Delayed / 1.0
    SIADH / Delayed / 1.0
    laryngeal edema / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    hepatic failure / Delayed / Incidence not known
    hepatic necrosis / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    oliguria / Early / Incidence not known
    azotemia / Delayed / Incidence not known
    teratogenesis / Delayed / Incidence not known

    Moderate

    hypotension / Rapid / 3.8-11.0
    chest pain (unspecified) / Early / 2.1-2.1
    orthostatic hypotension / Delayed / 1.0
    impotence (erectile dysfunction) / Delayed / 1.0
    photophobia / Early / 1.0
    blurred vision / Early / 1.0
    constipation / Delayed / 1.0
    erythema / Early / 1.0
    thrombocytopenia / Delayed / 1.0
    neutropenia / Delayed / 1.0
    leukopenia / Delayed / 1.0
    diabetes mellitus / Delayed / 1.0
    gout / Delayed / 1.0
    confusion / Early / Incidence not known
    depression / Delayed / Incidence not known
    hallucinations / Early / Incidence not known
    jaundice / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    psoriasis / Delayed / Incidence not known
    eosinophilia / Delayed / Incidence not known
    anemia / Delayed / Incidence not known
    hypoglycemia / Early / Incidence not known
    hyponatremia / Delayed / Incidence not known

    Mild

    dizziness / Early / 3.5-19.0
    syncope / Early / 7.0-7.0
    headache / Early / 3.8-3.8
    cough / Delayed / 2.5-2.5
    fatigue / Early / 1.0
    dysosmia / Delayed / 1.0
    dysgeusia / Early / 1.0
    tinnitus / Delayed / 1.0
    diplopia / Early / 1.0
    flatulence / Early / 1.0
    xerostomia / Early / 1.0
    diarrhea / Early / 1.0
    asthenia / Delayed / 1.0
    photosensitivity / Delayed / 1.0
    diaphoresis / Early / 1.0
    alopecia / Delayed / 1.0
    urticaria / Rapid / 1.0
    flushing / Rapid / 1.0
    pruritus / Rapid / 1.0
    myalgia / Early / Incidence not known
    arthralgia / Delayed / Incidence not known
    leukocytosis / Delayed / Incidence not known
    vertigo / Early / Incidence not known
    rash (unspecified) / Early / Incidence not known
    paresthesias / Delayed / Incidence not known
    fever / Early / 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) Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ACE inhibitors in patients with diabetes mellitus. 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) Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ACE inhibitors in patients with diabetes mellitus. 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) Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ACE inhibitors in patients with diabetes mellitus. 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) Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ACE inhibitors in patients with diabetes mellitus. 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) Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ACE inhibitors in patients with diabetes mellitus. 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. In general, avoid combined use of these drugs together. Closely monitor blood pressure, renal function, and electrolytes. 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 the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), the combination of ramipril 10 mg/day and telmisartan 80 mg/day did not provide a significant benefit in the prevention of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure compared to ramipril alone. There was, however, a significantly increased rate of renal dysfunction associated with combination therapy (13.5%) compared to ramipril (10.2%) or telmisartan (10.6%) alone and a significantly increased rate of hyperkalemia with combination therapy compared to ramipril (5.6% vs. 3.3%; p<0.001). Additionally, there was a significantly higher number of patients who discontinued therapy due to adverse reactions, including hypotensive symptoms (4.8% vs. 1.7%; p<0.001), syncope (0.3% vs. 0.2%; p=0.03), diarrhea (0.5% vs. 0.1%; p<0.001), and renal impairment (1.1% vs. 0.7%; p<0.001), from combination therapy compared to ramipril alone. In a separate analysis of the ONTARGET renal outcomes, the rate of the composite primary renal outcome of dialysis, doubling of serum creatinine, and death was similar with ramipril and telmisartan alone (13.5% vs. 13.6%, respectively), but was significantly higher with combination therapy (14.5%) compared to ramipril (p=0.037). In the CHARM-Added program, the combination of candesartan and an ACE-inhibitor resulted in an increased incidence of hypotension (22.6% vs. 13.8%), renal dysfunction (15% vs. 9%), and hyperkalemia (9.5% vs. 3.5%) compared to placebo combined with an ACE inhibitor. 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. Patients receiving concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia.
    Alkalinizing Agents: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as ACE inhibitors. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function.
    Alogliptin: (Moderate) ACE inhibitors may enhance the hypoglycemic effects antidiabetic agents, such as alogliptin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. In addition, coadministration may increase the risk for angioedema.
    Alogliptin; Metformin: (Moderate) ACE inhibitors may enhance the hypoglycemic effects antidiabetic agents, such as alogliptin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. In addition, coadministration may increase the risk for angioedema. (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.
    Alogliptin; Pioglitazone: (Moderate) ACE inhibitors may enhance the hypoglycemic effects antidiabetic agents, such as alogliptin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. In addition, coadministration may increase the risk for angioedema.
    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. In general, avoid combined use of these drugs together. Closely monitor blood pressure, renal function, and electrolytes. 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 the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), the combination of ramipril 10 mg/day and telmisartan 80 mg/day did not provide a significant benefit in the prevention of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure compared to ramipril alone. There was, however, a significantly increased rate of renal dysfunction associated with combination therapy (13.5%) compared to ramipril (10.2%) or telmisartan (10.6%) alone and a significantly increased rate of hyperkalemia with combination therapy compared to ramipril (5.6% vs. 3.3%; p<0.001). Additionally, there was a significantly higher number of patients who discontinued therapy due to adverse reactions, including hypotensive symptoms (4.8% vs. 1.7%; p<0.001), syncope (0.3% vs. 0.2%; p=0.03), diarrhea (0.5% vs. 0.1%; p<0.001), and renal impairment (1.1% vs. 0.7%; p<0.001), from combination therapy compared to ramipril alone. In a separate analysis of the ONTARGET renal outcomes, the rate of the composite primary renal outcome of dialysis, doubling of serum creatinine, and death was similar with ramipril and telmisartan alone (13.5% vs. 13.6%, respectively), but was significantly higher with combination therapy (14.5%) compared to ramipril (p=0.037). In the CHARM-Added program, the combination of candesartan and an ACE-inhibitor resulted in an increased incidence of hypotension (22.6% vs. 13.8%), renal dysfunction (15% vs. 9%), and hyperkalemia (9.5% vs. 3.5%) compared to placebo combined with an ACE inhibitor. 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. Patients receiving concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia.
    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. In general, avoid combined use of these drugs together. Closely monitor blood pressure, renal function, and electrolytes. 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 the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), the combination of ramipril 10 mg/day and telmisartan 80 mg/day did not provide a significant benefit in the prevention of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure compared to ramipril alone. There was, however, a significantly increased rate of renal dysfunction associated with combination therapy (13.5%) compared to ramipril (10.2%) or telmisartan (10.6%) alone and a significantly increased rate of hyperkalemia with combination therapy compared to ramipril (5.6% vs. 3.3%; p<0.001). Additionally, there was a significantly higher number of patients who discontinued therapy due to adverse reactions, including hypotensive symptoms (4.8% vs. 1.7%; p<0.001), syncope (0.3% vs. 0.2%; p=0.03), diarrhea (0.5% vs. 0.1%; p<0.001), and renal impairment (1.1% vs. 0.7%; p<0.001), from combination therapy compared to ramipril alone. In a separate analysis of the ONTARGET renal outcomes, the rate of the composite primary renal outcome of dialysis, doubling of serum creatinine, and death was similar with ramipril and telmisartan alone (13.5% vs. 13.6%, respectively), but was significantly higher with combination therapy (14.5%) compared to ramipril (p=0.037). In the CHARM-Added program, the combination of candesartan and an ACE-inhibitor resulted in an increased incidence of hypotension (22.6% vs. 13.8%), renal dysfunction (15% vs. 9%), and hyperkalemia (9.5% vs. 3.5%) compared to placebo combined with an ACE inhibitor. 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. Patients receiving concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia.
    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. In general, avoid combined use of these drugs together. Closely monitor blood pressure, renal function, and electrolytes. 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 the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), the combination of ramipril 10 mg/day and telmisartan 80 mg/day did not provide a significant benefit in the prevention of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure compared to ramipril alone. There was, however, a significantly increased rate of renal dysfunction associated with combination therapy (13.5%) compared to ramipril (10.2%) or telmisartan (10.6%) alone and a significantly increased rate of hyperkalemia with combination therapy compared to ramipril (5.6% vs. 3.3%; p<0.001). Additionally, there was a significantly higher number of patients who discontinued therapy due to adverse reactions, including hypotensive symptoms (4.8% vs. 1.7%; p<0.001), syncope (0.3% vs. 0.2%; p=0.03), diarrhea (0.5% vs. 0.1%; p<0.001), and renal impairment (1.1% vs. 0.7%; p<0.001), from combination therapy compared to ramipril alone. In a separate analysis of the ONTARGET renal outcomes, the rate of the composite primary renal outcome of dialysis, doubling of serum creatinine, and death was similar with ramipril and telmisartan alone (13.5% vs. 13.6%, respectively), but was significantly higher with combination therapy (14.5%) compared to ramipril (p=0.037). In the CHARM-Added program, the combination of candesartan and an ACE-inhibitor resulted in an increased incidence of hypotension (22.6% vs. 13.8%), renal dysfunction (15% vs. 9%), and hyperkalemia (9.5% vs. 3.5%) compared to placebo combined with an ACE inhibitor. 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. Patients receiving concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia.
    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. In general, avoid combined use of these drugs together. Closely monitor blood pressure, renal function, and electrolytes. 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 the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), the combination of ramipril 10 mg/day and telmisartan 80 mg/day did not provide a significant benefit in the prevention of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure compared to ramipril alone. There was, however, a significantly increased rate of renal dysfunction associated with combination therapy (13.5%) compared to ramipril (10.2%) or telmisartan (10.6%) alone and a significantly increased rate of hyperkalemia with combination therapy compared to ramipril (5.6% vs. 3.3%; p<0.001). Additionally, there was a significantly higher number of patients who discontinued therapy due to adverse reactions, including hypotensive symptoms (4.8% vs. 1.7%; p<0.001), syncope (0.3% vs. 0.2%; p=0.03), diarrhea (0.5% vs. 0.1%; p<0.001), and renal impairment (1.1% vs. 0.7%; p<0.001), from combination therapy compared to ramipril alone. In a separate analysis of the ONTARGET renal outcomes, the rate of the composite primary renal outcome of dialysis, doubling of serum creatinine, and death was similar with ramipril and telmisartan alone (13.5% vs. 13.6%, respectively), but was significantly higher with combination therapy (14.5%) compared to ramipril (p=0.037). In the CHARM-Added program, the combination of candesartan and an ACE-inhibitor resulted in an increased incidence of hypotension (22.6% vs. 13.8%), renal dysfunction (15% vs. 9%), and hyperkalemia (9.5% vs. 3.5%) compared to placebo combined with an ACE inhibitor. 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. Patients receiving concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia.
    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. In general, avoid combined use of these drugs together. Closely monitor blood pressure, renal function, and electrolytes. 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 the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), the combination of ramipril 10 mg/day and telmisartan 80 mg/day did not provide a significant benefit in the prevention of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure compared to ramipril alone. There was, however, a significantly increased rate of renal dysfunction associated with combination therapy (13.5%) compared to ramipril (10.2%) or telmisartan (10.6%) alone and a significantly increased rate of hyperkalemia with combination therapy compared to ramipril (5.6% vs. 3.3%; p<0.001). Additionally, there was a significantly higher number of patients who discontinued therapy due to adverse reactions, including hypotensive symptoms (4.8% vs. 1.7%; p<0.001), syncope (0.3% vs. 0.2%; p=0.03), diarrhea (0.5% vs. 0.1%; p<0.001), and renal impairment (1.1% vs. 0.7%; p<0.001), from combination therapy compared to ramipril alone. In a separate analysis of the ONTARGET renal outcomes, the rate of the composite primary renal outcome of dialysis, doubling of serum creatinine, and death was similar with ramipril and telmisartan alone (13.5% vs. 13.6%, respectively), but was significantly higher with combination therapy (14.5%) compared to ramipril (p=0.037). In the CHARM-Added program, the combination of candesartan and an ACE-inhibitor resulted in an increased incidence of hypotension (22.6% vs. 13.8%), renal dysfunction (15% vs. 9%), and hyperkalemia (9.5% vs. 3.5%) compared to placebo combined with an ACE inhibitor. 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. Patients receiving concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia.
    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: (Major) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as angiotensin-converting enzyme inhibitors. Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed.
    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. In general, avoid combined use of these drugs together. Closely monitor blood pressure, renal function, and electrolytes. 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 the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), the combination of ramipril 10 mg/day and telmisartan 80 mg/day did not provide a significant benefit in the prevention of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure compared to ramipril alone. There was, however, a significantly increased rate of renal dysfunction associated with combination therapy (13.5%) compared to ramipril (10.2%) or telmisartan (10.6%) alone and a significantly increased rate of hyperkalemia with combination therapy compared to ramipril (5.6% vs. 3.3%; p<0.001). Additionally, there was a significantly higher number of patients who discontinued therapy due to adverse reactions, including hypotensive symptoms (4.8% vs. 1.7%; p<0.001), syncope (0.3% vs. 0.2%; p=0.03), diarrhea (0.5% vs. 0.1%; p<0.001), and renal impairment (1.1% vs. 0.7%; p<0.001), from combination therapy compared to ramipril alone. In a separate analysis of the ONTARGET renal outcomes, the rate of the composite primary renal outcome of dialysis, doubling of serum creatinine, and death was similar with ramipril and telmisartan alone (13.5% vs. 13.6%, respectively), but was significantly higher with combination therapy (14.5%) compared to ramipril (p=0.037). In the CHARM-Added program, the combination of candesartan and an ACE-inhibitor resulted in an increased incidence of hypotension (22.6% vs. 13.8%), renal dysfunction (15% vs. 9%), and hyperkalemia (9.5% vs. 3.5%) compared to placebo combined with an ACE inhibitor. 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. Patients receiving concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia.
    Apomorphine: (Moderate) Patients receiving apomorphine may experience orthostatic hypotension, hypotension, and/or syncope. Extreme caution should be exercised if apomorphine is used concurrently with antihypertensive agents, or vasodilators such as nitrates.
    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.
    Azelaic Acid; Copper; Folic Acid; Nicotinamide; Pyridoxine; Zinc: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. (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.
    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. In general, avoid combined use of these drugs together. Closely monitor blood pressure, renal function, and electrolytes. 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 the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), the combination of ramipril 10 mg/day and telmisartan 80 mg/day did not provide a significant benefit in the prevention of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure compared to ramipril alone. There was, however, a significantly increased rate of renal dysfunction associated with combination therapy (13.5%) compared to ramipril (10.2%) or telmisartan (10.6%) alone and a significantly increased rate of hyperkalemia with combination therapy compared to ramipril (5.6% vs. 3.3%; p<0.001). Additionally, there was a significantly higher number of patients who discontinued therapy due to adverse reactions, including hypotensive symptoms (4.8% vs. 1.7%; p<0.001), syncope (0.3% vs. 0.2%; p=0.03), diarrhea (0.5% vs. 0.1%; p<0.001), and renal impairment (1.1% vs. 0.7%; p<0.001), from combination therapy compared to ramipril alone. In a separate analysis of the ONTARGET renal outcomes, the rate of the composite primary renal outcome of dialysis, doubling of serum creatinine, and death was similar with ramipril and telmisartan alone (13.5% vs. 13.6%, respectively), but was significantly higher with combination therapy (14.5%) compared to ramipril (p=0.037). In the CHARM-Added program, the combination of candesartan and an ACE-inhibitor resulted in an increased incidence of hypotension (22.6% vs. 13.8%), renal dysfunction (15% vs. 9%), and hyperkalemia (9.5% vs. 3.5%) compared to placebo combined with an ACE inhibitor. 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. Patients receiving concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia.
    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. In general, avoid combined use of these drugs together. Closely monitor blood pressure, renal function, and electrolytes. 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 the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), the combination of ramipril 10 mg/day and telmisartan 80 mg/day did not provide a significant benefit in the prevention of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure compared to ramipril alone. There was, however, a significantly increased rate of renal dysfunction associated with combination therapy (13.5%) compared to ramipril (10.2%) or telmisartan (10.6%) alone and a significantly increased rate of hyperkalemia with combination therapy compared to ramipril (5.6% vs. 3.3%; p<0.001). Additionally, there was a significantly higher number of patients who discontinued therapy due to adverse reactions, including hypotensive symptoms (4.8% vs. 1.7%; p<0.001), syncope (0.3% vs. 0.2%; p=0.03), diarrhea (0.5% vs. 0.1%; p<0.001), and renal impairment (1.1% vs. 0.7%; p<0.001), from combination therapy compared to ramipril alone. In a separate analysis of the ONTARGET renal outcomes, the rate of the composite primary renal outcome of dialysis, doubling of serum creatinine, and death was similar with ramipril and telmisartan alone (13.5% vs. 13.6%, respectively), but was significantly higher with combination therapy (14.5%) compared to ramipril (p=0.037). In the CHARM-Added program, the combination of candesartan and an ACE-inhibitor resulted in an increased incidence of hypotension (22.6% vs. 13.8%), renal dysfunction (15% vs. 9%), and hyperkalemia (9.5% vs. 3.5%) compared to placebo combined with an ACE inhibitor. 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. Patients receiving concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia.
    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: (Major) Benzphetamine can increase both systolic and diastolic blood pressure and may counteract the activity of angiotensin-converting enzyme inhibitors. This represents a pharmacodynamic, and not a pharmacokinetic, interaction. Close monitoring of blood pressure, especially in patients who are taking antihypertensive agents, may be needed.
    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.
    Bromocriptine: (Minor) Bromocriptine has only minimal affinity for adrenergic receptors; however, hypotension can occur during bromocriptine administration. Orthostatic hypotension occurs in 6% of acromegaly patients receiving the drug. Hypotension occurred frequently (approximately 30%) in postpartum studies, which in rare cases approached a decline in supine pressure of almost 60 mmHg. It is unknown if bromocriptine is the exact cause of this effect. However, the drug should be used cautiously with other medications known to lower blood pressure such as antihypertensive agents. Monitoring of blood pressure should be considered, especially during the initial weeks of concomitant therapy.
    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; 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: (Minor) Cabergoline has minimal affinity for adrenergic receptors; however, it has been associated with hypotension in some instances. Cabergoline should be used cautiously in those receiving antihypertensive agents.
    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: (Moderate) When canagliflozin is initiated in patients already receiving angiotensin-converting enzyme inhibitors (ACE inhibitors), symptomatic hypotension can occur. Patients with impaired renal function (eGFR < 60 ml/min/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Before initiating canagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, canagliflozin can lead to hyperkalemia. Patients treated with canagliflozin 300 mg/day were more likely to experience increases in potassium. Patients with moderate renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically after initiating canagliflozin in patients with impaired renal function and in patients predisposed to hyperkalemia due to medications or other medical conditions.
    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. (Moderate) When canagliflozin is initiated in patients already receiving angiotensin-converting enzyme inhibitors (ACE inhibitors), symptomatic hypotension can occur. Patients with impaired renal function (eGFR < 60 ml/min/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Before initiating canagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, canagliflozin can lead to hyperkalemia. Patients treated with canagliflozin 300 mg/day were more likely to experience increases in potassium. Patients with moderate renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically after initiating canagliflozin in patients with impaired renal function and in patients predisposed to hyperkalemia due to medications or other medical conditions.
    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. In general, avoid combined use of these drugs together. Closely monitor blood pressure, renal function, and electrolytes. 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 the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), the combination of ramipril 10 mg/day and telmisartan 80 mg/day did not provide a significant benefit in the prevention of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure compared to ramipril alone. There was, however, a significantly increased rate of renal dysfunction associated with combination therapy (13.5%) compared to ramipril (10.2%) or telmisartan (10.6%) alone and a significantly increased rate of hyperkalemia with combination therapy compared to ramipril (5.6% vs. 3.3%; p<0.001). Additionally, there was a significantly higher number of patients who discontinued therapy due to adverse reactions, including hypotensive symptoms (4.8% vs. 1.7%; p<0.001), syncope (0.3% vs. 0.2%; p=0.03), diarrhea (0.5% vs. 0.1%; p<0.001), and renal impairment (1.1% vs. 0.7%; p<0.001), from combination therapy compared to ramipril alone. In a separate analysis of the ONTARGET renal outcomes, the rate of the composite primary renal outcome of dialysis, doubling of serum creatinine, and death was similar with ramipril and telmisartan alone (13.5% vs. 13.6%, respectively), but was significantly higher with combination therapy (14.5%) compared to ramipril (p=0.037). In the CHARM-Added program, the combination of candesartan and an ACE-inhibitor resulted in an increased incidence of hypotension (22.6% vs. 13.8%), renal dysfunction (15% vs. 9%), and hyperkalemia (9.5% vs. 3.5%) compared to placebo combined with an ACE inhibitor. 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. Patients receiving concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia.
    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. In general, avoid combined use of these drugs together. Closely monitor blood pressure, renal function, and electrolytes. 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 the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), the combination of ramipril 10 mg/day and telmisartan 80 mg/day did not provide a significant benefit in the prevention of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure compared to ramipril alone. There was, however, a significantly increased rate of renal dysfunction associated with combination therapy (13.5%) compared to ramipril (10.2%) or telmisartan (10.6%) alone and a significantly increased rate of hyperkalemia with combination therapy compared to ramipril (5.6% vs. 3.3%; p<0.001). Additionally, there was a significantly higher number of patients who discontinued therapy due to adverse reactions, including hypotensive symptoms (4.8% vs. 1.7%; p<0.001), syncope (0.3% vs. 0.2%; p=0.03), diarrhea (0.5% vs. 0.1%; p<0.001), and renal impairment (1.1% vs. 0.7%; p<0.001), from combination therapy compared to ramipril alone. In a separate analysis of the ONTARGET renal outcomes, the rate of the composite primary renal outcome of dialysis, doubling of serum creatinine, and death was similar with ramipril and telmisartan alone (13.5% vs. 13.6%, respectively), but was significantly higher with combination therapy (14.5%) compared to ramipril (p=0.037). In the CHARM-Added program, the combination of candesartan and an ACE-inhibitor resulted in an increased incidence of hypotension (22.6% vs. 13.8%), renal dysfunction (15% vs. 9%), and hyperkalemia (9.5% vs. 3.5%) compared to placebo combined with an ACE inhibitor. 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. Patients receiving concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia.
    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.
    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.
    Cod Liver Oil: (Moderate) Fish oil supplements may cause mild, dose-dependent reductions in systolic or diastolic blood pressure in untreated hypertensive patients. Relatively high doses of fish oil are required to produce any blood pressure lowering effect. Additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents. (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.
    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: (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 (i.e., captopril or enalapril) are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Dapagliflozin; Metformin: (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 (i.e., captopril or enalapril) 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.
    Dapagliflozin; Saxagliptin: (Moderate) ACE inhibitors may enhance the hypoglycemic effects antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. In addition, coadministration may increase the risk for angioedema. (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 (i.e., captopril or enalapril) are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in 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; 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: (Moderate) Angiotensin-converting enzyme inhibitors (ACE inhibitors) may enhance the hypoglycemic effects antidiabetic agents, such as empagliflozin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Empagliflozin; Linagliptin: (Moderate) ACE inhibitors may enhance the hypoglycemic effects antidiabetic agents, such as linagliptin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. In addition, coadministration may increase the risk for angioedema. (Moderate) Angiotensin-converting enzyme inhibitors (ACE inhibitors) may enhance the hypoglycemic effects antidiabetic agents, such as empagliflozin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in 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. (Moderate) Angiotensin-converting enzyme inhibitors (ACE inhibitors) may enhance the hypoglycemic effects antidiabetic agents, such as empagliflozin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in 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. In general, avoid combined use of these drugs together. Closely monitor blood pressure, renal function, and electrolytes. 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 the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), the combination of ramipril 10 mg/day and telmisartan 80 mg/day did not provide a significant benefit in the prevention of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure compared to ramipril alone. There was, however, a significantly increased rate of renal dysfunction associated with combination therapy (13.5%) compared to ramipril (10.2%) or telmisartan (10.6%) alone and a significantly increased rate of hyperkalemia with combination therapy compared to ramipril (5.6% vs. 3.3%; p<0.001). Additionally, there was a significantly higher number of patients who discontinued therapy due to adverse reactions, including hypotensive symptoms (4.8% vs. 1.7%; p<0.001), syncope (0.3% vs. 0.2%; p=0.03), diarrhea (0.5% vs. 0.1%; p<0.001), and renal impairment (1.1% vs. 0.7%; p<0.001), from combination therapy compared to ramipril alone. In a separate analysis of the ONTARGET renal outcomes, the rate of the composite primary renal outcome of dialysis, doubling of serum creatinine, and death was similar with ramipril and telmisartan alone (13.5% vs. 13.6%, respectively), but was significantly higher with combination therapy (14.5%) compared to ramipril (p=0.037). In the CHARM-Added program, the combination of candesartan and an ACE-inhibitor resulted in an increased incidence of hypotension (22.6% vs. 13.8%), renal dysfunction (15% vs. 9%), and hyperkalemia (9.5% vs. 3.5%) compared to placebo combined with an ACE inhibitor. 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. Patients receiving concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia.
    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. In general, avoid combined use of these drugs together. Closely monitor blood pressure, renal function, and electrolytes. 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 the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), the combination of ramipril 10 mg/day and telmisartan 80 mg/day did not provide a significant benefit in the prevention of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure compared to ramipril alone. There was, however, a significantly increased rate of renal dysfunction associated with combination therapy (13.5%) compared to ramipril (10.2%) or telmisartan (10.6%) alone and a significantly increased rate of hyperkalemia with combination therapy compared to ramipril (5.6% vs. 3.3%; p<0.001). Additionally, there was a significantly higher number of patients who discontinued therapy due to adverse reactions, including hypotensive symptoms (4.8% vs. 1.7%; p<0.001), syncope (0.3% vs. 0.2%; p=0.03), diarrhea (0.5% vs. 0.1%; p<0.001), and renal impairment (1.1% vs. 0.7%; p<0.001), from combination therapy compared to ramipril alone. In a separate analysis of the ONTARGET renal outcomes, the rate of the composite primary renal outcome of dialysis, doubling of serum creatinine, and death was similar with ramipril and telmisartan alone (13.5% vs. 13.6%, respectively), but was significantly higher with combination therapy (14.5%) compared to ramipril (p=0.037). In the CHARM-Added program, the combination of candesartan and an ACE-inhibitor resulted in an increased incidence of hypotension (22.6% vs. 13.8%), renal dysfunction (15% vs. 9%), and hyperkalemia (9.5% vs. 3.5%) compared to placebo combined with an ACE inhibitor. 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. Patients receiving concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia.
    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) 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. (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.
    Hawthorn, Crataegus laevigata: (Moderate) Hawthorn, Crataegus laevigata (also known as C. oxyacantha) may potentially interact with antihypertensive, heart failure, or arrhythmia medications such as the Angiotensin-converting enzyme inhibitors (ACE inhibitors). Following hawthorn administration, the cardiac action potential duration is increased and the refractory period is prolonged. Hawthorn may also lower peripheral vascular resistance. Patients with hypertension or heart failure should be advised to only use hawthorn with their prescribed medications after discussion with their prescriber. Patients who choose to take hawthorn should receive periodic blood pressure and heart rate monitoring.
    Heparin: (Moderate) Angiotensin-converting enzyme inhibitors decrease aldosterone secretion, leading to small increases in serum potassium levels. Due to the risk of hyperkalemia, drugs that increase serum potassium concentration, such as potassium-sparing diuretics, potassium salts, and heparin, should be given cautiously, if at all, to patients receiving lisinopril, with frequent serum potassium monitoring. 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. In general, avoid combined use of these drugs together. Closely monitor blood pressure, renal function, and electrolytes. 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 the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), the combination of ramipril 10 mg/day and telmisartan 80 mg/day did not provide a significant benefit in the prevention of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure compared to ramipril alone. There was, however, a significantly increased rate of renal dysfunction associated with combination therapy (13.5%) compared to ramipril (10.2%) or telmisartan (10.6%) alone and a significantly increased rate of hyperkalemia with combination therapy compared to ramipril (5.6% vs. 3.3%; p<0.001). Additionally, there was a significantly higher number of patients who discontinued therapy due to adverse reactions, including hypotensive symptoms (4.8% vs. 1.7%; p<0.001), syncope (0.3% vs. 0.2%; p=0.03), diarrhea (0.5% vs. 0.1%; p<0.001), and renal impairment (1.1% vs. 0.7%; p<0.001), from combination therapy compared to ramipril alone. In a separate analysis of the ONTARGET renal outcomes, the rate of the composite primary renal outcome of dialysis, doubling of serum creatinine, and death was similar with ramipril and telmisartan alone (13.5% vs. 13.6%, respectively), but was significantly higher with combination therapy (14.5%) compared to ramipril (p=0.037). In the CHARM-Added program, the combination of candesartan and an ACE-inhibitor resulted in an increased incidence of hypotension (22.6% vs. 13.8%), renal dysfunction (15% vs. 9%), and hyperkalemia (9.5% vs. 3.5%) compared to placebo combined with an ACE inhibitor. 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. Patients receiving concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia.
    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. In general, avoid combined use of these drugs together. Closely monitor blood pressure, renal function, and electrolytes. 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 the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), the combination of ramipril 10 mg/day and telmisartan 80 mg/day did not provide a significant benefit in the prevention of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure compared to ramipril alone. There was, however, a significantly increased rate of renal dysfunction associated with combination therapy (13.5%) compared to ramipril (10.2%) or telmisartan (10.6%) alone and a significantly increased rate of hyperkalemia with combination therapy compared to ramipril (5.6% vs. 3.3%; p<0.001). Additionally, there was a significantly higher number of patients who discontinued therapy due to adverse reactions, including hypotensive symptoms (4.8% vs. 1.7%; p<0.001), syncope (0.3% vs. 0.2%; p=0.03), diarrhea (0.5% vs. 0.1%; p<0.001), and renal impairment (1.1% vs. 0.7%; p<0.001), from combination therapy compared to ramipril alone. In a separate analysis of the ONTARGET renal outcomes, the rate of the composite primary renal outcome of dialysis, doubling of serum creatinine, and death was similar with ramipril and telmisartan alone (13.5% vs. 13.6%, respectively), but was significantly higher with combination therapy (14.5%) compared to ramipril (p=0.037). In the CHARM-Added program, the combination of candesartan and an ACE-inhibitor resulted in an increased incidence of hypotension (22.6% vs. 13.8%), renal dysfunction (15% vs. 9%), and hyperkalemia (9.5% vs. 3.5%) compared to placebo combined with an ACE inhibitor. 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. Patients receiving concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia.
    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. In general, avoid combined use of these drugs together. Closely monitor blood pressure, renal function, and electrolytes. 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 the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), the combination of ramipril 10 mg/day and telmisartan 80 mg/day did not provide a significant benefit in the prevention of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure compared to ramipril alone. There was, however, a significantly increased rate of renal dysfunction associated with combination therapy (13.5%) compared to ramipril (10.2%) or telmisartan (10.6%) alone and a significantly increased rate of hyperkalemia with combination therapy compared to ramipril (5.6% vs. 3.3%; p<0.001). Additionally, there was a significantly higher number of patients who discontinued therapy due to adverse reactions, including hypotensive symptoms (4.8% vs. 1.7%; p<0.001), syncope (0.3% vs. 0.2%; p=0.03), diarrhea (0.5% vs. 0.1%; p<0.001), and renal impairment (1.1% vs. 0.7%; p<0.001), from combination therapy compared to ramipril alone. In a separate analysis of the ONTARGET renal outcomes, the rate of the composite primary renal outcome of dialysis, doubling of serum creatinine, and death was similar with ramipril and telmisartan alone (13.5% vs. 13.6%, respectively), but was significantly higher with combination therapy (14.5%) compared to ramipril (p=0.037). In the CHARM-Added program, the combination of candesartan and an ACE-inhibitor resulted in an increased incidence of hypotension (22.6% vs. 13.8%), renal dysfunction (15% vs. 9%), and hyperkalemia (9.5% vs. 3.5%) compared to placebo combined with an ACE inhibitor. 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. Patients receiving concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia.
    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. In general, avoid combined use of these drugs together. Closely monitor blood pressure, renal function, and electrolytes. 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 the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), the combination of ramipril 10 mg/day and telmisartan 80 mg/day did not provide a significant benefit in the prevention of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure compared to ramipril alone. There was, however, a significantly increased rate of renal dysfunction associated with combination therapy (13.5%) compared to ramipril (10.2%) or telmisartan (10.6%) alone and a significantly increased rate of hyperkalemia with combination therapy compared to ramipril (5.6% vs. 3.3%; p<0.001). Additionally, there was a significantly higher number of patients who discontinued therapy due to adverse reactions, including hypotensive symptoms (4.8% vs. 1.7%; p<0.001), syncope (0.3% vs. 0.2%; p=0.03), diarrhea (0.5% vs. 0.1%; p<0.001), and renal impairment (1.1% vs. 0.7%; p<0.001), from combination therapy compared to ramipril alone. In a separate analysis of the ONTARGET renal outcomes, the rate of the composite primary renal outcome of dialysis, doubling of serum creatinine, and death was similar with ramipril and telmisartan alone (13.5% vs. 13.6%, respectively), but was significantly higher with combination therapy (14.5%) compared to ramipril (p=0.037). In the CHARM-Added program, the combination of candesartan and an ACE-inhibitor resulted in an increased incidence of hypotension (22.6% vs. 13.8%), renal dysfunction (15% vs. 9%), and hyperkalemia (9.5% vs. 3.5%) compared to placebo combined with an ACE inhibitor. 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. Patients receiving concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia.
    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. In general, avoid combined use of these drugs together. Closely monitor blood pressure, renal function, and electrolytes. 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 the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), the combination of ramipril 10 mg/day and telmisartan 80 mg/day did not provide a significant benefit in the prevention of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure compared to ramipril alone. There was, however, a significantly increased rate of renal dysfunction associated with combination therapy (13.5%) compared to ramipril (10.2%) or telmisartan (10.6%) alone and a significantly increased rate of hyperkalemia with combination therapy compared to ramipril (5.6% vs. 3.3%; p<0.001). Additionally, there was a significantly higher number of patients who discontinued therapy due to adverse reactions, including hypotensive symptoms (4.8% vs. 1.7%; p<0.001), syncope (0.3% vs. 0.2%; p=0.03), diarrhea (0.5% vs. 0.1%; p<0.001), and renal impairment (1.1% vs. 0.7%; p<0.001), from combination therapy compared to ramipril alone. In a separate analysis of the ONTARGET renal outcomes, the rate of the composite primary renal outcome of dialysis, doubling of serum creatinine, and death was similar with ramipril and telmisartan alone (13.5% vs. 13.6%, respectively), but was significantly higher with combination therapy (14.5%) compared to ramipril (p=0.037). In the CHARM-Added program, the combination of candesartan and an ACE-inhibitor resulted in an increased incidence of hypotension (22.6% vs. 13.8%), renal dysfunction (15% vs. 9%), and hyperkalemia (9.5% vs. 3.5%) compared to placebo combined with an ACE inhibitor. 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. Patients receiving concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia.
    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.
    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. In general, avoid combined use of these drugs together. Closely monitor blood pressure, renal function, and electrolytes. 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 the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), the combination of ramipril 10 mg/day and telmisartan 80 mg/day did not provide a significant benefit in the prevention of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure compared to ramipril alone. There was, however, a significantly increased rate of renal dysfunction associated with combination therapy (13.5%) compared to ramipril (10.2%) or telmisartan (10.6%) alone and a significantly increased rate of hyperkalemia with combination therapy compared to ramipril (5.6% vs. 3.3%; p<0.001). Additionally, there was a significantly higher number of patients who discontinued therapy due to adverse reactions, including hypotensive symptoms (4.8% vs. 1.7%; p<0.001), syncope (0.3% vs. 0.2%; p=0.03), diarrhea (0.5% vs. 0.1%; p<0.001), and renal impairment (1.1% vs. 0.7%; p<0.001), from combination therapy compared to ramipril alone. In a separate analysis of the ONTARGET renal outcomes, the rate of the composite primary renal outcome of dialysis, doubling of serum creatinine, and death was similar with ramipril and telmisartan alone (13.5% vs. 13.6%, respectively), but was significantly higher with combination therapy (14.5%) compared to ramipril (p=0.037). In the CHARM-Added program, the combination of candesartan and an ACE-inhibitor resulted in an increased incidence of hypotension (22.6% vs. 13.8%), renal dysfunction (15% vs. 9%), and hyperkalemia (9.5% vs. 3.5%) compared to placebo combined with an ACE inhibitor. 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. Patients receiving concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia.
    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.
    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: (Major) 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.
    Levomilnacipran: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin-converting enzyme inhibitors may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Linagliptin: (Moderate) ACE inhibitors may enhance the hypoglycemic effects antidiabetic agents, such as linagliptin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. In addition, coadministration may increase the risk for angioedema.
    Linagliptin; Metformin: (Moderate) ACE inhibitors may enhance the hypoglycemic effects antidiabetic agents, such as linagliptin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. In addition, coadministration may increase the risk for angioedema. (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: (Major) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents. Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed.
    Lithium: (Major) ACE inhibitors (ACEIs) should be used very cautiously, if at all, in patients already receiving lithium. The risk of lithium toxicity is increased in patients receiving medications that may affect kidney function, such as ACEIs. These drug classes decrease lithium clearance, possibly as a result of sodium depletion which leads to increased renal tubular reabsorption of lithium. If combination therapy cannot be avoided, begin with lower doses of lithium and be alert for evidence of lithium toxicity (e.g., nausea, vomiting, anorexia, drowsiness, dysarthria, tremor, confusion, lethargy, ECG changes, etc.). Consider reducing the lithium dosage in previously established patients and monitor lithium concentrations and patient response and tolerability. Conversely, clinicians should be alert to the possibility of loss of lithium effectiveness if ACEIs are discontinued in a patient stabilized on lithium. According to the Beers Criteria, concurrent use of lithium and ACE inhibitors may result in a clinically important drug interaction particularly in older adults; the panel recommends avoiding concurrent use 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. In general, avoid combined use of these drugs together. Closely monitor blood pressure, renal function, and electrolytes. 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 the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), the combination of ramipril 10 mg/day and telmisartan 80 mg/day did not provide a significant benefit in the prevention of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure compared to ramipril alone. There was, however, a significantly increased rate of renal dysfunction associated with combination therapy (13.5%) compared to ramipril (10.2%) or telmisartan (10.6%) alone and a significantly increased rate of hyperkalemia with combination therapy compared to ramipril (5.6% vs. 3.3%; p<0.001). Additionally, there was a significantly higher number of patients who discontinued therapy due to adverse reactions, including hypotensive symptoms (4.8% vs. 1.7%; p<0.001), syncope (0.3% vs. 0.2%; p=0.03), diarrhea (0.5% vs. 0.1%; p<0.001), and renal impairment (1.1% vs. 0.7%; p<0.001), from combination therapy compared to ramipril alone. In a separate analysis of the ONTARGET renal outcomes, the rate of the composite primary renal outcome of dialysis, doubling of serum creatinine, and death was similar with ramipril and telmisartan alone (13.5% vs. 13.6%, respectively), but was significantly higher with combination therapy (14.5%) compared to ramipril (p=0.037). In the CHARM-Added program, the combination of candesartan and an ACE-inhibitor resulted in an increased incidence of hypotension (22.6% vs. 13.8%), renal dysfunction (15% vs. 9%), and hyperkalemia (9.5% vs. 3.5%) compared to placebo combined with an ACE inhibitor. 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. Patients receiving concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia.
    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) ACE inhibitors may enhance the hypoglycemic effects antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. In addition, coadministration may increase the risk for angioedema. (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) ACE inhibitors may enhance the hypoglycemic effects antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. In addition, coadministration may increase the risk for angioedema. (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: (Major) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, including ACE Inhibitors. Monitor blood pressure and/or consider alternative therapeutic agents.
    Methohexital: (Moderate) Concurrent use of methohexital and antihypertensive agents increases the risk of developing hypotension.
    Methylphenidate: (Moderate) Methylphenidate can reduce the hypotensive effect of antihypertensive agents such as angiotensin-converting enzyme inhibitors. 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.
    Milnacipran: (Moderate) Milnacipran has been associated with an increase in blood pressure. The effectiveness of antihypertensive agents may be diminished during concurrent use of milnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    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. In general, avoid combined use of these drugs together. Closely monitor blood pressure, renal function, and electrolytes. 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 the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), the combination of ramipril 10 mg/day and telmisartan 80 mg/day did not provide a significant benefit in the prevention of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure compared to ramipril alone. There was, however, a significantly increased rate of renal dysfunction associated with combination therapy (13.5%) compared to ramipril (10.2%) or telmisartan (10.6%) alone and a significantly increased rate of hyperkalemia with combination therapy compared to ramipril (5.6% vs. 3.3%; p<0.001). Additionally, there was a significantly higher number of patients who discontinued therapy due to adverse reactions, including hypotensive symptoms (4.8% vs. 1.7%; p<0.001), syncope (0.3% vs. 0.2%; p=0.03), diarrhea (0.5% vs. 0.1%; p<0.001), and renal impairment (1.1% vs. 0.7%; p<0.001), from combination therapy compared to ramipril alone. In a separate analysis of the ONTARGET renal outcomes, the rate of the composite primary renal outcome of dialysis, doubling of serum creatinine, and death was similar with ramipril and telmisartan alone (13.5% vs. 13.6%, respectively), but was significantly higher with combination therapy (14.5%) compared to ramipril (p=0.037). In the CHARM-Added program, the combination of candesartan and an ACE-inhibitor resulted in an increased incidence of hypotension (22.6% vs. 13.8%), renal dysfunction (15% vs. 9%), and hyperkalemia (9.5% vs. 3.5%) compared to placebo combined with an ACE inhibitor. 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. Patients receiving concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia.
    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. In general, avoid combined use of these drugs together. Closely monitor blood pressure, renal function, and electrolytes. 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 the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), the combination of ramipril 10 mg/day and telmisartan 80 mg/day did not provide a significant benefit in the prevention of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure compared to ramipril alone. There was, however, a significantly increased rate of renal dysfunction associated with combination therapy (13.5%) compared to ramipril (10.2%) or telmisartan (10.6%) alone and a significantly increased rate of hyperkalemia with combination therapy compared to ramipril (5.6% vs. 3.3%; p<0.001). Additionally, there was a significantly higher number of patients who discontinued therapy due to adverse reactions, including hypotensive symptoms (4.8% vs. 1.7%; p<0.001), syncope (0.3% vs. 0.2%; p=0.03), diarrhea (0.5% vs. 0.1%; p<0.001), and renal impairment (1.1% vs. 0.7%; p<0.001), from combination therapy compared to ramipril alone. In a separate analysis of the ONTARGET renal outcomes, the rate of the composite primary renal outcome of dialysis, doubling of serum creatinine, and death was similar with ramipril and telmisartan alone (13.5% vs. 13.6%, respectively), but was significantly higher with combination therapy (14.5%) compared to ramipril (p=0.037). In the CHARM-Added program, the combination of candesartan and an ACE-inhibitor resulted in an increased incidence of hypotension (22.6% vs. 13.8%), renal dysfunction (15% vs. 9%), and hyperkalemia (9.5% vs. 3.5%) compared to placebo combined with an ACE inhibitor. 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. Patients receiving concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia.
    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 and thus enhance the hypotensive effects of antihypertensive agents. Lower initial doses of paliperidone may be necessary in patients receiving antihypertensive agents concomitantly.
    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).
    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: (Major) 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.
    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. In general, avoid combined use of these drugs together. Closely monitor blood pressure, renal function, and electrolytes. 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 the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), the combination of ramipril 10 mg/day and telmisartan 80 mg/day did not provide a significant benefit in the prevention of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure compared to ramipril alone. There was, however, a significantly increased rate of renal dysfunction associated with combination therapy (13.5%) compared to ramipril (10.2%) or telmisartan (10.6%) alone and a significantly increased rate of hyperkalemia with combination therapy compared to ramipril (5.6% vs. 3.3%; p<0.001). Additionally, there was a significantly higher number of patients who discontinued therapy due to adverse reactions, including hypotensive symptoms (4.8% vs. 1.7%; p<0.001), syncope (0.3% vs. 0.2%; p=0.03), diarrhea (0.5% vs. 0.1%; p<0.001), and renal impairment (1.1% vs. 0.7%; p<0.001), from combination therapy compared to ramipril alone. In a separate analysis of the ONTARGET renal outcomes, the rate of the composite primary renal outcome of dialysis, doubling of serum creatinine, and death was similar with ramipril and telmisartan alone (13.5% vs. 13.6%, respectively), but was significantly higher with combination therapy (14.5%) compared to ramipril (p=0.037). In the CHARM-Added program, the combination of candesartan and an ACE-inhibitor resulted in an increased incidence of hypotension (22.6% vs. 13.8%), renal dysfunction (15% vs. 9%), and hyperkalemia (9.5% vs. 3.5%) compared to placebo combined with an ACE inhibitor. 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. Patients receiving concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia.
    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.
    Saxagliptin: (Moderate) ACE inhibitors may enhance the hypoglycemic effects antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. In addition, coadministration may increase the risk for angioedema.
    Selegiline: (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.
    Sevoflurane: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    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.
    Simvastatin; Sitagliptin: (Moderate) ACE inhibitors may enhance the hypoglycemic effects antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. In addition, coadministration may increase the risk for angioedema.
    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.
    Sitagliptin: (Moderate) ACE inhibitors may enhance the hypoglycemic effects antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. In addition, coadministration may increase the risk for angioedema.
    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: (Major) Avoid the concomitant use of trimethoprim and ACE inhibitors. Concurrent use may result in additive hyperkalemia. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially with pre-existing risk factors for hyperkalemia. Patients, especially those with renal dysfunction, should be monitored for hyperkalemia if concomitant use of ACE inhibitors and trimethoprim is necessary.
    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. In general, avoid combined use of these drugs together. Closely monitor blood pressure, renal function, and electrolytes. 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 the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), the combination of ramipril 10 mg/day and telmisartan 80 mg/day did not provide a significant benefit in the prevention of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure compared to ramipril alone. There was, however, a significantly increased rate of renal dysfunction associated with combination therapy (13.5%) compared to ramipril (10.2%) or telmisartan (10.6%) alone and a significantly increased rate of hyperkalemia with combination therapy compared to ramipril (5.6% vs. 3.3%; p<0.001). Additionally, there was a significantly higher number of patients who discontinued therapy due to adverse reactions, including hypotensive symptoms (4.8% vs. 1.7%; p<0.001), syncope (0.3% vs. 0.2%; p=0.03), diarrhea (0.5% vs. 0.1%; p<0.001), and renal impairment (1.1% vs. 0.7%; p<0.001), from combination therapy compared to ramipril alone. In a separate analysis of the ONTARGET renal outcomes, the rate of the composite primary renal outcome of dialysis, doubling of serum creatinine, and death was similar with ramipril and telmisartan alone (13.5% vs. 13.6%, respectively), but was significantly higher with combination therapy (14.5%) compared to ramipril (p=0.037). In the CHARM-Added program, the combination of candesartan and an ACE-inhibitor resulted in an increased incidence of hypotension (22.6% vs. 13.8%), renal dysfunction (15% vs. 9%), and hyperkalemia (9.5% vs. 3.5%) compared to placebo combined with an ACE inhibitor. 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. Patients receiving concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia.
    Temsirolimus: (Moderate) Use caution if coadministration with temsirolimus and lisinopril is necessary, and monitor for a possible risk of angioedema. Angioneurotic edema-type reactions have been observed in some patients who received temsirolimus and angiotensin-converting enzyme inhibitors (ACE inhibitors) such as lisinopril concomitantly. Of note, the active metabolite of temsirolimus, sirolimus, has also been associated with the development of angioedema.
    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: (Major) Avoid the concomitant use of trimethoprim and ACE inhibitors. Concurrent use may result in additive hyperkalemia. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially with pre-existing risk factors for hyperkalemia. Patients, especially those with renal dysfunction, should be monitored for hyperkalemia if concomitant use of ACE inhibitors and trimethoprim is necessary.
    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. In general, avoid combined use of these drugs together. Closely monitor blood pressure, renal function, and electrolytes. 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 the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), the combination of ramipril 10 mg/day and telmisartan 80 mg/day did not provide a significant benefit in the prevention of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure compared to ramipril alone. There was, however, a significantly increased rate of renal dysfunction associated with combination therapy (13.5%) compared to ramipril (10.2%) or telmisartan (10.6%) alone and a significantly increased rate of hyperkalemia with combination therapy compared to ramipril (5.6% vs. 3.3%; p<0.001). Additionally, there was a significantly higher number of patients who discontinued therapy due to adverse reactions, including hypotensive symptoms (4.8% vs. 1.7%; p<0.001), syncope (0.3% vs. 0.2%; p=0.03), diarrhea (0.5% vs. 0.1%; p<0.001), and renal impairment (1.1% vs. 0.7%; p<0.001), from combination therapy compared to ramipril alone. In a separate analysis of the ONTARGET renal outcomes, the rate of the composite primary renal outcome of dialysis, doubling of serum creatinine, and death was similar with ramipril and telmisartan alone (13.5% vs. 13.6%, respectively), but was significantly higher with combination therapy (14.5%) compared to ramipril (p=0.037). In the CHARM-Added program, the combination of candesartan and an ACE-inhibitor resulted in an increased incidence of hypotension (22.6% vs. 13.8%), renal dysfunction (15% vs. 9%), and hyperkalemia (9.5% vs. 3.5%) compared to placebo combined with an ACE inhibitor. 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. Patients receiving concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia.
    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

    No data are available regarding the presence of lisinopril in human milk or the effects of lisinopril on the breast-fed infant or on milk production. Lisinopril is present in rat milk. Because of the potential for severe adverse reactions in the breast-fed infant, advise women to discontinue breast-feeding during treatment with lisinopril. Captopril and enalapril have been considered usually compatible with breast-feeding. Benazepril and quinapril are excreted in human breast milk in very small quantities ; therefore, a clinically significant risk to a breast-feeding infant is not expected. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Mechanism of Action: Lisinopril competes with angiotensin I for its binding site on the angiotensin-converting enzyme (ACE). As a result, the drug blocks the conversion of angiotensin I to angiotensin II. Angiotensin II is a potent vasoconstrictor and a negative feedback mediator for renin activity. Thus, when lisinopril 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, thus decreasing vascular sensitivity to vasopressor activity; however, this action may not be clinically evident at usual doses. Decreases in plasma angiotensin II levels also result in a reduction in 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.Lisinopril 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. Both standing and supine blood pressure are reduced following administration of lisinopril, and although symptomatic hypotension is rare, it occurs more commonly in patients who are hypovolemic or hyponatremic.The mechanism by which lisinopril improves the outcome following an acute MI involves reduced peripheral vascular resistance, improved perfusion and a direct action on the myocardium. Addition of an ACE inhibitor within the initial 24 hour period after an acute MI, attenuates LV dilatation, improves perfusion and reduces peripheral vascular resistance. Inhibition of angiotensin II production reduces the workload on the heart, and inhibits collagen production. Plasma has a lower concentration of ACE than tissue (primarily vascular endothelial cells, but also present in other organs including the heart.) It has been postulated that short-term cardiovascular effects of ACE inhibitors are due to plasma ACE, whereas their long-term effects are due to action on tissue ACE.

    PHARMACOKINETICS

    Lisinopril is administered orally. The drug distributes widely throughout the body tissues, with only minimal amounts crossing the blood-brain barrier. Lisinopril is not metabolized, and the majority of an oral dose is excreted unchanged in the urine. Because of this, the half-life depends on renal function. In patients with normal renal function, multiple dosing of lisinopril results in a half-life of 12 hours.
     
    Affected cytochrome P450 isoenzymes and drug transporters: none

    Oral Route

    Lisinopril is poorly absorbed from the GI tract following oral administration; bioavailability is approximately 25%. After oral administration, noticeable cardiovascular effects begin within 1 hour, with peak effects occurring within 6 hours.