ENALAPRIL MALEATE (Generic for VASOTEC)

Enalapril is an oral and parenteral angiotensin-converting enzyme (ACE) inhibitor used in the treatment of hypertension and congestive heart failure. It has become a first-line agent for treating heart failure due to its proven reduction of mortality, and, in November 1993, it was approved for use in the early stages of heart failure to slow progression of the disease. Enalapril is longer-acting than captopril but shorter-acting than other ACE inhibitors and is usually dosed twice daily when given orally. In some patients, once-daily dosing may be acceptable. Neither enalapril nor enalaprilat contains a sulfhydryl group, which has implications regarding the drug's adverse reaction profile. In general, ACE inhibitors appear to have a lesser effect on blood pressure in black patients (low renin population) than in non-black patients. Enalapril was originally approved by the FDA in December 1985. Generic enalapril products became available in August 2000.

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-May administer without regard to meals.
Oral Liquid Formulations
-Use a calibrated device to measure the appropriate oral dosage of enalapril.

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

Extemporaneous Compounding-Oral
Extemporaneous Oral Suspension Formulations
NOTE: An FDA-approved oral solution is commercially available; commercially available products are preferred over compounded products when available.

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



Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
-May be administered undiluted or in up to 50 mL of a compatible IV infusion solution.
-Administer by slow, direct IV infusion over a period of at least 5 minutes.

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

Blood dyscrasias have rarely been associated with enalapril/enalaprilat. Rare cases of neutropenia, thrombocytopenia, and bone marrow suppression have been reported with enalapril use. Agranulocytosis has also been associated with ACE-inhibitor use, including enapril. Patients with renal impairment or collagen vascular disease appear to be at highest risk. Hemolytic anemia, including cases of hemolysis in patients with G-6-PD deficiency, has been reported; a causal relationship to enalapril cannot be excluded. Small decreases in hemoglobin and hematocirit occur frequently but are rarely clinically significant unless another cause of anemia is also present. Complete blood counts should be monitored regularly during the first several months of therapy and as needed thereafter.

Renal dysfunction may occur during enalapril treatment, but this effect is usually reversible if therapy is discontinued. Renal failure (unspecified), azotemia, oliguria, and flank pain have been reported during enalapril use. Patients with severe heart failure whose renal function may depend on the renin-angiotensin-aldosterone system are at risk for renal impairment with ACE-inhibitor use. Some patients with hypertension or heart failure and no prior evidence of renal impairment may experience elevations in serum creatinine and blood urea; these elevations are usual mild and transient. Renal insufficiency may be related to hypovolemia, hyponatremia, or preexisting renal artery stenosis. In patients with renal artery stenosis, enalapril therapy must be held. In patients who are either hypovolemic or hyponatremic, correction of these abnormalities may correct the renal dysfunction. Although rare, serious renal effects include ischemic renal tubular necrosis and glomerulonephritis.

Hypotension occurred in 0.9% of patients in clinical trials of enalapril for hypertension and in 6.7% of patients receiving the drug for congestive heart failure. Hypotension occurred in 3.4% of patients who received IV enalaprilat in clinical trials. Syncope was reported in 0.5%-2.2% of patients receiving enalapril for hypertension or heart failure. Chest pain (unspecified) was reported in 2.1% of enalapril-treated patients in clinical trials of patients with heart failure; this is the same incidence as those who received placebo. Orthostatic hypotension (1.6%) and orthostatic effects (1.2%-2.2%), angina pectoris (1.5%, heart failure only), and myocardial infarction (0.5-1.2%) were reported in patients during controlled clinical trials. Of note, angina and myocardial infarction occurred at a lower rate in the enalapril group than in the placebo group during trials of oral enalapril. Other cardiovascular-related adverse reactions occurring in 0.5 to 1% of patients or during post-marketing use include: cardiac arrest, cerebrovascular accident (stroke), pulmonary embolism and infarction, pulmonary edema, arrhythmias (including atrial tachycardia, bradycardia, and atrial fibrillation), palpitations, and Raynaud's phenomenon.

Cough was reported in 1.3%-2.2% of enalapril-treated patients in clinical trials. ACE inhibition can result in the accumulation of kinins in the respiratory tract, sometimes causing a persistent, nonproductive cough. However, accumulation of kinins does not adequately explain the mechanism of ACE inhibitor-induced cough. Kinins have a very short plasma half-life, therapeutic doses of ACE inhibitors are usually not high enough to cause accumulation of circulating bradykinin, and there is a female preponderance of cases. Rather, evidence is growing that ACE inhibitor-induced cough may be related to substance P stimulation of C-fiber receptors in the respiratory tract. This cough may occur more frequently in patients with chronic obstructive pulmonary disease and is often overlooked as a potential adverse effect of enalapril therapy. Dyspnea (1.3%), bronchitis (1.3%), and pneumonia (1%, which was less than placebo) have also have been reported during enalapril clinical trials. Other respiratory-related adverse events occurring in 0.5%-1% or during post-marketing use of enalapril include: eosinophilic pneumonia, pulmonary infiltrates, bronchospasm, rhinorrhea, sore throat and hoarseness, asthma, and upper respiratory infection.

In clinical trials of enalapril for hypertension, approximately 1% of enalapril-treated patients developed elevated serum potassium (> 5.7 mEq/L); 0.28% of these patients discontinued therapy due to hyperkalemia. In heart failure patients, hyperkalemia was observed in 3.8% of patients but was not a cause for discontinuation. Patients with renal impairment, diabetes, heart failure, and those receiving other medications that may increase potassium concentrations are at the highest risk of developing hyperkalemia. Although less common, hyponatremia has also been reported with enalapril use.

Enalapril therapy has been associated with rash (unspecified) in approximately 0.5%-1.4% of enalapril/enalaprilat-treated patients in clinical trials. Enalapril has also been associated with acute generalized exanthematous pustulosis (AGEP). The nonfollicular, pustular, erythematous rash starts suddenly, is associated with fever above 38 degrees C, and is distinct from pustular psoriasis, although biopsy results in each reveal spongiform subcorneal pustules. Drugs are the main cause of AGEP. A period of 2-3 weeks after an inciting drug exposure appears necessary for a first episode of AGEP. Unintentional reexposure may cause a second episode within 2 days. Clinical presentation is diverse with cutaneous lesions beyond erythema and pustules present in half of the cases. For example, bullous lesions, edema, purpura, pruritus, and mucosal erosions are possible. The mean duration of the pustules is 9.7 days followed by an annular desquamation, as long as the causative drug or factor is discontinued. The physiopathological mechanisms of AGEP have not been determined but the pathological criteria of edema, leukocytoclastic vasculitis, eosinophil exocytosis, and keratinocyte focal necrosis are distinctive. Pustule confluence or very small pustules may lead a clinician to make an incorrect diagnosis of TEN, of drug-induced erythroderma, or of staphylococcal scalded skin syndrome. Other dermatologic adverse reactions that have been reported in association with enalapril use include: exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, pemphigus, herpes zoster, erythema multiforme, urticaria, pruritus, alopecia, flushing, diaphoresis, and photosensitivity.

Anaphylactoid reactions and angioedema are uncommon but serious adverse reactions known to be related to enalapril therapy.This is likely due to the inhibitory effect of ACE inhibitors on eicosanoid and polypeptide metabolism, including bradykinin metabolism. Angioedema, or angioneurotic edema, of the face, edema of the extremities, mucous membranes, tongue, lips, larynx (laryngeal edema), and glottis has occurred rarely during ACE inhibitor therapy but is reversible following discontinuance of the drug. Involvement of the upper respiratory tract can induce acute respiratory distress. The onset usually occurs within hours or at most 1 week after starting ACE inhibitor therapy, but may occur at any time during therapy. The mechanism is unknown but may involve drug-induced auto-antibodies, bradykinin accumulation, dysregulation of the complement system, or histamine. Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to non-Black patients. If angioedema occurs during therapy with enalapril, the drug should be discontinued immediately. Appropriate monitoring and therapy should be provided until signs and symptoms have resolved completely. Angioedema associated with laryngeal edema or tongue edema may be fatal. If there is involvement of the tongue, glottis or larynx, appropriate therapy (e.g., 0.3 to 0.5 ml subcutaneous epinephrine 1:1000) and/or measures to ensure a patent airway should be promptly provided. Even in those instances where swelling of only the tongue is involved, without respiratory distress, patients may require prolonged observation since treatment with antihistamines and corticosteroids may not be sufficient. Patients with involvement of the tongue, glottis or larynx are likely to experience airway obstruction, especially those with a history of airway surgery. Rarely, intestinal angioedema has been reported during post-marketing experience with ACE inhibitors. Patients with intestinal angioedema may present with abdominal discomfort (with or without nausea or vomiting). In some cases there is no prior history of facial angioedema and C-1 esterase levels are normal. Intestinal angioedema can be diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery. Symptoms resolve after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients receiving ACE inhibitors who present with abdominal discomfort.

Gastrointestinal-related adverse events reported in enalapril-treated patients in clinical trials include: abdominal pain (1.6%), diarrhea (1.4%-2.1%), nausea (1.3%-1.4%), and vomiting (1.3%). Other less common gastrointestinal-related adverse events reported in enalapril-treated patients include: ileus, pancreatitis, melena, anorexia, dyspepsia, constipation (0.5%-1% for IV, incidence unknown for oral formulation), glossitis, stomatitis, and xerostomia. In addition, abdominal pain (with or without nausea and vomiting) is a presenting symptom of intestinal angioedema; intestinal angioedema should be considered in the differential diagnosis of patients presenting with abdominal pain.

Rarely, hepatitis and hepatic failure have been reported in patients receiving ACE inhibitors such as enalapril. Although not completely understood, hepatotoxicity has included cholestasis with jaundice, fulminant hepatic necrosis, and death. Patients who develop jaundice, hyperbilirubinemia, or significantly elevated hepatic enzymes should discontinue enalapril therapy and receive appropriate follow-up and treatment.

Due to the potential for teratogenesis, enalapril should not be used during pregnancy. Drugs that affect the renin-angiotensin system have been associated with fetal and neonatal abnormalities when administered to women during the second or third trimesters of pregnancy. Adverse fetal and neonatal effects have included hypotension, neonatal skull hypoplasia, anuria, renal failure, oligohydramnios, and death. Oligohydramnios has been associated with fetal lung hypoplasia and skeletal deformations. If oliguria or hypotension occurs in a neonate with a history of in utero exposure to enalapril, blood pressure and renal perfusion support may be required, as well as exchange transfusion or dialysis to reverse hypotension and/or support decreased renal function. Enalapril, which crosses the placenta, has been removed from neonatal circulation by peritoneal dialysis with some clinical benefit, and theoretically may be removed by exchange transfusion, although there is no experience with the latter procedure.

Nervous system/psychiatric-related adverse events occurring in enalapril-treated patients during clinical trials include: fatigue (0.5%-3%), dizziness (0.5%-7.9%), headache (1.8%-5.2%) and vertigo (1.6%). Other less common nervous system/psychiatric-related adverse events include: depression, confusion, ataxia, drowsiness, insomnia, nervousness, peripheral neuropathy (e.g., paresthesias, dysesthesia), and abnormal dreams (e.g., nightmares). Fever has been reported in 0.5%-1% of patients who received IV enalaprilat during clinical trials. Fever may also be a symptom of a more serious condition such as neutropenia or as part of a symptom complex associated enalapril use that includes a variety of symptoms; carefully evaluate patients who present with fever.

Asthenia (1.1%-1.6%) and muscle cramps (incidence unknown) have been reported in enalapril-treated patients.

Blurred vision, dysgeusia, anosmia, tinnitus, conjunctivitis, xerophthalmia, and tearing have been reported in enalapril-treated patients (incidence unknown).

Urinary tract infection was reported in 1.3% of enalapril-treated patients in clinical trials of enalapril for heart failure. Gynecomastia and impotence (erectile dysfunction) have been reported in enalapril-treated patients (incidence unknown).

A symptom complex has been reported in enalapril-treated patients which may include some or all of the following: a positive ANA, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia/myositis, fever, serositis, vasculitis, leukocytosis, eosinophilia, photosensitivity, rash and other dermatologic manifestations.

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

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

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

Enalapril can cause symptomatic hypotension. Persons at risk of excessive hypotension include those with heart failure with systolic blood pressure below 100 mmHg, coronary artery disease, cerebrovascular disease, hyponatremia, high dose diuretic therapy, renal dialysis, or severe hypovolemia and/or salt depletion of any etiology. In these patients, start enalapril under very close medical supervision and follow closely for the first 2 weeks of treatment and whenever the dose of enalapril and/or diuretic is increased. Symptomatic hypotension is also possible in patients with severe aortic stenosis or hypertrophic cardiomyopathy.

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

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

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

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

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

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

Use of enalapril is not recommended in neonates and premature neonates who have not reached a corrected post-conceptual age of 44 weeks. It is unknown whether postnatal use of ACE inhibitors before maturation of renal function is complete has long-term deleterious effects on the kidney. Nephrogenesis is thought to be complete around birth; however, maturation of kidney function (e.g., glomerular filtration, tubular function) may continue until approximately 2 years of age. In addition, for unknown reasons, neonates and infants have an increased sensitivity to ACE inhibitors which makes them susceptible to prolonged or excessive decreases in blood pressure. It has been theorized this may be due to higher renin concentrations in the first few months of life and an increased dependence on the renin-angiotensin system and/or decreased drug clearance due to immature elimination systems.

For the treatment of hypertension:
Oral dosage:
Adults: 5 mg PO once daily, initially. May increase dose if further control is needed. Usual dose range: 5 to 40 mg/day PO in 1 to 2 divided doses.
Adolescents 17 years: 5 mg PO once daily initially. The usual dosage range is 10 to 40 mg/day PO given in 1 to 2 divided doses. In patients with hyponatremia, hypovolemia, moderate-severe congestive heart failure, renal dysfunction (i.e., Scr more than 1.6 mg/dL), or in those receiving diuretics, an initial dose of 2.5 mg is recommended. In patients at risk for hypotension or deterioration of renal function, dosage increases are generally recommended at intervals of 4 days or more. If blood pressure is not controlled with monotherapy, a diuretic may be added.
Infants, Children, and Adolescents 16 years and younger: 0.08 mg/kg/dose PO once daily (Max: 5 mg) initially; adjust dosage based on clinical response. Max: 0.6 mg/kg/day, up to 40 mg/day, given in 1 to 2 divided doses. In patients with hyponatremia, hypovolemia, moderate-severe congestive heart failure, renal dysfunction, or in those receiving diuretics, a lower initial maximum dose of 2.5 mg is recommended. In patients at risk for hypotension or deterioration of renal function, dosage increases are generally recommended at intervals of 4 days or more.
Intravenous dosage (enalaprilat):
Adults: 1.25 mg IV every 6 hours. Higher doses have not been clearly demonstrated to be more effective; however, up to 5 mg IV every 6 hours has been used. Max: 20 mg/day.
Neonates*, Infants*, Children*, and Adolescents*: 5 to 10 mcg/kg/dose (Max: 1.25 mg/dose) IV every 8 to 24 hours. Monitor blood pressure and urine output carefully due to the risk of prolonged hypotension and acute renal failure, especially in neonates; select patients may require higher doses.

For the treatment of hypertensive emergency* or hypertensive urgency*:
Intravenous dosage:
Adults: 0.625 to 1.25 mg IV every 6 hours, initially; may increase dose up to 5 mg IV every 6 hours.
Infants, Children, and Adolescents: 5 to 10 mcg/kg/dose (Max: 1.25 mg/dose) IV every 8 to 24 hours. Monitor blood pressure and urine output carefully due to the risk of prolonged hypotension and acute renal failure; select patients may require higher doses.
Neonates: 5 to 10 mcg/kg/dose (Max: 1.25 mg/dose) IV every 8 to 24 hours. Monitor blood pressure and urine output carefully due to the risk of prolonged hypotension and acute renal failure, especially in neonates; select patients may require higher doses.
Oral dosage:
Infants, Children, and Adolescents: 0.08 mg/kg/dose (Max: 5 mg/dose) PO once daily, initially; adjust dosage based on clinical response. Max: 0.6 mg/kg/day, up to 40 mg/day, in 1 to 2 divided doses.

For the treatment of heart failure:
Oral dosage:
Adults: 2.5 mg PO twice daily, initially. Increase the dose as tolerated over a few days or weeks up to 10 to 20 mg PO twice daily. Guidelines recommend an angiotensin-converting enzyme (ACE) inhibitor in combination with an evidence-based beta blocker and aldosterone antagonist, in select patients, for patients with chronic reduced ejection fraction heart failure (HFrEF) NYHA class I to IV to reduce morbidity and mortality. In patients with prior or current symptoms of chronic HFrEF, use of an ACE inhibitor is recommended. Continued use of an ACE inhibitor is recommended for all classes of HFrEF for those patients for whom subsequent angiotensin receptor-neprilysin inhibitor (ARNI) use is inappropriate. Use of an ACE inhibitor in patients with preserved ejection fraction heart failure (HFpEF) and hypertension is reasonable to control blood pressure.
Infants*, Children*, and Adolescents*: In 39 children, after a test dose, enalapril was titrated to a dose of 0.16 mg/kg/day PO by the end of the first week. Subsequently, the mean dose required for improvement in CHF was 0.36 mg/kg/day PO. In select cases, dosages up to 0.94 mg/kg/day PO have been used. A maximum dose for this indication has not been determined; however, the maximum for pediatric patients with hypertension is 40 mg/day PO.
Neonates*: FDA-approved labeling recommends against use in neonates due to the lack of data. Very limited data describe the use of 0.01 to 0.27 mg/kg/day PO in neonates and infants; however, there are concerns about the risk for adverse events. Cases of acute hypotension and acute renal failure have been reported after doses of 0.1 mg/kg/day PO in hypertensive infants ; therefore, conservative initial dosages and careful monitoring of blood pressure and renal function are recommended. As part of a small pediatric study (total n = 63 patients), 15 infants ages 9 days to 9 months with left-to-right shunts received enalapril; all but 1 patient in this group was less than 4 months old (neonatal-specific data was not reported separately). Four patients improved while receiving enalapril (mean dosage = 0.19 mg/kg/day PO), 6 patients experienced no change in clinical status (mean dosage = 0.27 mg/kg/day PO), and 5 patients discontinued enalapril due to adverse events (mean dosage = 0.11 mg/kg/day PO). Eight patients in the entire cohort developed renal failure within 14 days of initiating enalapril (7 of the 8 developed renal failure within 5 days); 3 of these patients were 4 weeks or younger and all 3 died. In another case series, doses of 0.1 to 0.16 mg/kg/day PO were used in 3 neonatal patients with CHF without adverse events.

For the treatment of asymptomatic left ventricular dysfunction including postmyocardial infarction* patients:
Oral dosage:
Adults: Initially, 2.5 mg PO twice daily. Increase gradually to 20 mg/day PO, given in divided doses. Patients should be observed for hypotension for at least 2 hours following first dose and for at least 1 hour following stabilization of blood pressure.

For the treatment of persistent albuminuria* in patients with diabetic nephropathy* or in at-risk hypertensive patients*:
Oral dosage:
Adults: 10 mg PO once daily. Dose range: 5 to 20 mg/day PO in 1 or 2 divided doses. Usually begin with a low dose and titrate to response and tolerance. Guidelines recommend the use of an angiotensin converting enzyme (ACE) inhibitor to slow the progression of renal disease in selected patients.

For the treatment of proteinuria* in pediatric patients:
Oral dosage (weight-based dosing):
Children and Adolescents: 0.07 to 0.7 mg/kg/day PO given in 1 to 2 divided doses. Begin with a low dose and titrate every 4 to 12 weeks based on clinical response and patient tolerance. Max: 20 to 40 mg/day.
Oral dosage (fixed dosing):
Children and Adolescents 7 to 17 years: 2.5 to 5 mg/day PO decreased proteinuria with no significant effects on blood pressure in a retrospective study in normotensive patients when used with (n = 11) or without (n = 17) prednisone. In a small case study of adolescents with sickle nephropathy (n = 3), initial treatment was 5 mg/day; 1 patient required a dosage increase to 7.5 mg/day due to weight gain during puberty.

Therapeutic Drug Monitoring:
Patients with Hyponatremia Dosing
-Serum sodium less than 130 mEq/L: The recommended initial dose for heart failure is 2.5 mg PO once daily.

Maximum Dosage Limits:
-Adults
40 mg/day PO or 20 mg/day IV.
-Geriatric
40 mg/day PO or 20 mg/day IV.
-Adolescents
17 years: 40 mg/day PO for hypertension; safety and efficacy of IV enalaprilat has not been established; however, doses up to 10 mcg/kg/dose IV (Max: 1.25 mg/dose IV) have been used off-label.
13 to 16 years: 0.6 mg/kg/day PO (Max: 40 mg/day PO) for hypertension; doses of up to 0.94 mg/kg/day PO have been used off-label for congestive heart failure; safety and efficacy of IV enalaprilat has not been established; however, doses up to 10 mcg/kg/dose IV (Max: 1.25 mg/dose IV) have been used off-label.
-Children
0.6 mg/kg/day PO (Max: 40 mg/day PO) for hypertension; doses of up to 0.94 mg/kg/day PO have been used off-label for congestive heart failure; safety and efficacy of IV enalaprilat has not been established; however, doses up to 10 mcg/kg/dose IV (Max: 1.25 mg/dose IV) have been used off-label.
-Infants
0.6 mg/kg/day PO for hypertension; however, doses as high as 0.94 mg/kg/day PO have been used off-label for congestive heart failure; safety and efficacy of IV enalaprilat has not been established; however, doses up to 10 mcg/kg/dose IV have been used off-label.
-Neonates
Safety and efficacy have not been established; however, doses up to 0.27 mg/kg/day PO and 10 mcg/kg/dose IV have been used off-label.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Patients with Renal Impairment Dosing
Adults
CrCl more than 30 mL/minute: No adjustment necessary.
CrCl 30 mL/minute or less: Reduce to 2.5 mg PO once daily initially. For enalaprilat, administer 0.625 mg IV initially; repeat dose if inadequate response after 1 hour. Thereafter, may administer 1.25 mg IV every 6 hours.
Alternatively, the following has been recommended:
GFR more than 50 mL/minute: No adjustment necessary.
GFR 10 to 50 mL/minute: Administer 50% to 100% of usual dose.
GFR less than 10 mL/minute: Administer 25% of usual oral dose and 25% to 50% of usual IV dose.

Pediatrics
Use is not recommended in pediatric patients with a GFR less than 30 mL/minute/1.73 m2, as no data is available per FDA-approved labeling. Alternatively, the following has been recommended:
GFR more than 50 mL/minute/1.73 m2: No adjustment necessary.
GFR 10 to 50 mL/minute/1.73 m2: Administer 75% of usual dose.
GFR less than 10 mL/minute/1.73 m2: Administer 50% of usual dose.

Intermittent hemodialysis (IHD)

Adults
2.5 mg PO on dialysis days; adjust dosage on nondialysis days based on clinical response. For enalaprilat, administer 0.625 mg IV over at least 5 minutes and preferably up to 1 hour every 6 hours. Administer oral and IV doses after hemodialysis.
Pediatrics
Administer 50% of usual dose.

Peritoneal dialysis (PD)
Adults
Administer 25% of usual oral dose and 25% to 50% of usual IV dose.
Pediatrics
Administer 50% of usual dose.

Continuous renal replacement therapy (CRRT)
Adults
Administer 50% to 100% of usual dose.
Pediatrics
Administer 75% of usual dose.

*non-FDA-approved indication

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 : (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; 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.

Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.

Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Monitor heart rate and blood pressure.

Acetaminophen; Dichloralphenazone; Isometheptene: (Major) Isometheptene has sympathomimetic properties. Patients taking antihypertensive agents may need to have their therapy modified. Careful blood pressure monitoring is recommended.

Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.

Acetaminophen; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Monitor heart rate and blood pressure.

Acrivastine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Monitor heart rate and blood pressure.

Aldesleukin, IL-2: (Moderate) Angiotensin converting enzyme inhibitors, like other antihypertensive agents, may potentiate the hypotension seen with aldesleukin, IL 2.

Alemtuzumab: (Moderate) Alemtuzumab may cause hypotension. Careful monitoring of blood pressure and hypotensive symptoms is recommended especially in patients with ischemic heart disease and in patients on antihypertensive agents.

Aliskiren: (Major) Aliskiren-containing products are contraindicated in combination with angiotensin-converting enzyme inhibitors (ACE inhibitors) in patients with diabetes mellitus. In general, avoid combined use of two renin-angiotensin-aldosterone system (RAAS) inhibitors, particularly in patients with CrCl less than 60 mL/minute. Combination therapy increases the risk for hyperkalemia, renal impairment, and other side effects. Most patients receiving a comination of two RAAS inhibitors, such as ACE inhibitors and aliskiren do not obtain any additional benefit compared to monotherapy. Closely monitor blood pressure, renal function, and electrolytes if aliskiren must be combined with another RAAS inhibitor. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.

Aliskiren; Hydrochlorothiazide, HCTZ: (Major) Aliskiren-containing products are contraindicated in combination with angiotensin-converting enzyme inhibitors (ACE inhibitors) in patients with diabetes mellitus. In general, avoid combined use of two renin-angiotensin-aldosterone system (RAAS) inhibitors, particularly in patients with CrCl less than 60 mL/minute. Combination therapy increases the risk for hyperkalemia, renal impairment, and other side effects. Most patients receiving a comination of two RAAS inhibitors, such as ACE inhibitors and aliskiren do not obtain any additional benefit compared to monotherapy. Closely monitor blood pressure, renal function, and electrolytes if aliskiren must be combined with another RAAS inhibitor. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.

Alogliptin; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

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; Olmesartan: (Major) In general, avoid combined use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) due to lack of benefit with concomitant use in most patients. Closely monitor blood pressure, renal function, and electrolytes in patients on ACE inhibitors and ARBs. Dual blockade of the renin-angiotensin system with ACE inhibitors and ARBs is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function, including acute renal failure, compared to monotherapy.

Amlodipine; Valsartan: (Major) In general, avoid combined use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) due to lack of benefit with concomitant use in most patients. Closely monitor blood pressure, renal function, and electrolytes in patients on ACE inhibitors and ARBs. Dual blockade of the renin-angiotensin system with ACE inhibitors and ARBs is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function, including acute renal failure, compared to monotherapy.

Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Major) In general, avoid combined use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) due to lack of benefit with concomitant use in most patients. Closely monitor blood pressure, renal function, and electrolytes in patients on ACE inhibitors and ARBs. Dual blockade of the renin-angiotensin system with ACE inhibitors and ARBs is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function, including acute renal failure, compared to monotherapy.

Amobarbital: (Moderate) Concurrent use of amobarbital with antihypertensive agents may lead to hypotension. Monitor for decreases in blood pressure during times of coadministration.

Amphetamine; Dextroamphetamine Salts: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like angiotensin-converting enzyme inhibitors (ACE inhibitors). Close monitoring of blood pressure is advised.

Amyl Nitrite: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.

Angiotensin II receptor antagonists: (Major) In general, avoid combined use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) due to lack of benefit with concomitant use in most patients. Closely monitor blood pressure, renal function, and electrolytes in patients on ACE inhibitors and ARBs. Dual blockade of the renin-angiotensin system with ACE inhibitors and ARBs is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function, including acute renal failure, compared to monotherapy.

Angiotensin II: (Moderate) Angiotensin converting enzyme inhibitors (ACE inhibitors) may increase the response to angiotensin II. Angiotensin II is a naturally occurring peptide hormone of the renin-angiotensin-aldosterone system (RAAS) that causes vasoconstriction and an increase in blood pressure. ACE inhibitors reduce the breakdown of angiotensin II.

Apomorphine: (Moderate) Use of angiotensin-converting enzyme inhibitors (ACE inhibitors) and apomorphine together can increase the hypotensive effects of apomorphine. Monitor blood pressure regularly during use of this combination.

Apraclonidine: (Minor) Alpha blockers as a class may reduce heart rate and blood pressure. While no specific drug interactions have been identified with systemic agents and apraclonidine during clinical trials, it is theoretically possible that additive blood pressure reductions could occur when apraclonidine is combined with the use of antihypertensive agents. Patients using cardiovascular drugs concomitantly with apraclonidine should have their pulse and blood pressure monitored periodically.

Aprotinin: (Moderate) The manufacturer recommends using aprotinin cautiously in patients that are receiving drugs that can affect renal function, such as ACE inhibitors, as the risk of renal impairment may be increased.

Aripiprazole: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents.

Articaine; Epinephrine: (Moderate) Antihypertensives, including angiotensin-converting enzyme inhibitors, antagonize the vasopressor effects of parenteral epinephrine.

Asenapine: (Moderate) Secondary to alpha-blockade, asenapine can produce vasodilation that may result in additive effects during concurrent use of antihypertensive agents. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use of asenapine and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.

Azathioprine: (Major) The use of ACE inhibitors in hypertensive patients receiving azathioprine has been reported to induce anemia and severe leukopenia. This combination should be avoided where possible. When concurrent azathioprine and ACE inhibitor therapy is necessary, the patient should be monitored cautiously for potential myelosuppression.

Azilsartan: (Major) In general, avoid combined use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) due to lack of benefit with concomitant use in most patients. Closely monitor blood pressure, renal function, and electrolytes in patients on ACE inhibitors and ARBs. Dual blockade of the renin-angiotensin system with ACE inhibitors and ARBs is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function, including acute renal failure, compared to monotherapy.

Azilsartan; Chlorthalidone: (Major) In general, avoid combined use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) due to lack of benefit with concomitant use in most patients. Closely monitor blood pressure, renal function, and electrolytes in patients on ACE inhibitors and ARBs. Dual blockade of the renin-angiotensin system with ACE inhibitors and ARBs is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function, including acute renal failure, compared to monotherapy.

Baclofen: (Moderate) Baclofen has been associated with hypotension. Concurrent use with baclofen and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.

Benzphetamine: (Minor) Benzphetamine may increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like angiotensin-converting enzyme inhibitors (ACE inhibitors). Close monitoring of blood pressure is advised.

Brexpiprazole: (Moderate) Due to brexpiprazole's antagonism at alpha 1-adrenergic receptors, the drug may enhance the hypotensive effects of alpha-blockers and other antihypertensive agents.

Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.

Brompheniramine; 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; 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; Dextromethorphan: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Monitor heart rate and blood pressure.

Bupivacaine; Epinephrine: (Moderate) Antihypertensives, including angiotensin-converting enzyme inhibitors, antagonize the vasopressor effects of parenteral epinephrine.

Cabergoline: (Moderate) Cabergoline should be used cautiously with antihypertensive agents, including angiotensin-converting enzyme inhibitors. Cabergoline has been associated with hypotension. Initial doses of cabergoline higher than 1 mg may produce orthostatic hypotension. It may be advisable to monitor blood pressure.

Calcium Phosphate, Supersaturated: (Moderate) Concomitant use of medicines with potential to alter renal perfusion or function such as angiotensin-converting enzyme inhibitors, may increase the risk of acute phosphate nephropathy in patients taking sodium phosphate monobasic monohydrate; sodium phosphate dibasic anhydrous.

Canagliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

Candesartan: (Major) In general, avoid combined use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) due to lack of benefit with concomitant use in most patients. Closely monitor blood pressure, renal function, and electrolytes in patients on ACE inhibitors and ARBs. Dual blockade of the renin-angiotensin system with ACE inhibitors and ARBs is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function, including acute renal failure, compared to monotherapy.

Candesartan; Hydrochlorothiazide, HCTZ: (Major) In general, avoid combined use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) due to lack of benefit with concomitant use in most patients. Closely monitor blood pressure, renal function, and electrolytes in patients on ACE inhibitors and ARBs. Dual blockade of the renin-angiotensin system with ACE inhibitors and ARBs is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function, including acute renal failure, compared to monotherapy.

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; 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.

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; 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.

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; 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.

Chlorpheniramine; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.

Chlorpheniramine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Monitor heart rate and blood pressure.

Clozapine: (Moderate) Lisinopril may decrease the renal elimination of clozapine and metabolites. Clozapine toxicity, including irritability, anger, insomnia, nightmares and sialorrhea may occur. The mechanism of this interaction is unclear; however, as lisinopril does not undergo metabolism, cytochrome P450 enzyme involvement is unlikely. It is speculated that a decrease in renal elimination of clozapine occurs due to a lisinopril-induced reduction in glomerular filtration rate (GFR). Plasma clozapine concentrations should be measured carefully during concomitant lisinopril therapy; another antihypertensive class may need to be selected. In addition, clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.

Cocaine: (Major) Use of cocaine with antihypertensive agents may increase the antihypertensive effects of the antihypertensive medications or may potentiate cocaine-induced sympathetic stimulation.

Codeine; 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.

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.

Cyclophosphamide: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression.

Cyclosporine: (Moderate) Several cases of acute renal failure have been associated with the addition of angiotensin-converting enzyme (ACE) inhibitors to cyclosporine therapy in renal transplant patients. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of ACE could reduce renal function acutely. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with ACE inhibitors or potassium salts.

Dapagliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

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.

Dexbrompheniramine; 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.

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) Monitor for signs and symptoms of digoxin toxicity during concomitant enalapril use. A decline in GFR or tubular secretion, as from angiotensin-converting enzyme inhibitors, may impair the excretion of digoxin.

Diphenhydramine; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.

Drospirenone: (Moderate) Drospirenone has antimineralocorticoid effects and may increase serum potassium. The concurrent use of ACE inhibitors may increase the risk of hyperkalemia, especially in the presence of renal impairment. Monitor serum potassium during the 1st month of drospirenone treatment if an Angiotensin-Converting Enzyme inhibitor (ACE inhibitor) is used concurrently and thereafter as clinically indicated. Also monitor for any changes in blood pressure, fluid retention, or renal function.

Drospirenone; Estetrol: (Moderate) Drospirenone has antimineralocorticoid effects and may increase serum potassium. The concurrent use of ACE inhibitors may increase the risk of hyperkalemia, especially in the presence of renal impairment. Monitor serum potassium during the 1st month of drospirenone treatment if an Angiotensin-Converting Enzyme inhibitor (ACE inhibitor) is used concurrently and thereafter as clinically indicated. Also monitor for any changes in blood pressure, fluid retention, or renal function.

Drospirenone; Estradiol: (Moderate) Drospirenone has antimineralocorticoid effects and may increase serum potassium. The concurrent use of ACE inhibitors may increase the risk of hyperkalemia, especially in the presence of renal impairment. Monitor serum potassium during the 1st month of drospirenone treatment if an Angiotensin-Converting Enzyme inhibitor (ACE inhibitor) is used concurrently and thereafter as clinically indicated. Also monitor for any changes in blood pressure, fluid retention, or renal function.

Drospirenone; Ethinyl Estradiol: (Moderate) Drospirenone has antimineralocorticoid effects and may increase serum potassium. The concurrent use of ACE inhibitors may increase the risk of hyperkalemia, especially in the presence of renal impairment. Monitor serum potassium during the 1st month of drospirenone treatment if an Angiotensin-Converting Enzyme inhibitor (ACE inhibitor) is used concurrently and thereafter as clinically indicated. Also monitor for any changes in blood pressure, fluid retention, or renal function.

Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Drospirenone has antimineralocorticoid effects and may increase serum potassium. The concurrent use of ACE inhibitors may increase the risk of hyperkalemia, especially in the presence of renal impairment. Monitor serum potassium during the 1st month of drospirenone treatment if an Angiotensin-Converting Enzyme inhibitor (ACE inhibitor) is used concurrently and thereafter as clinically indicated. Also monitor for any changes in blood pressure, fluid retention, or renal function.

Duloxetine: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.

Empagliflozin; Linagliptin; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

Empagliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

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.

Ephedrine; Guaifenesin: (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.

Epinephrine: (Moderate) Antihypertensives, including angiotensin-converting enzyme inhibitors, antagonize the vasopressor effects of parenteral epinephrine.

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) In general, avoid combined use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) due to lack of benefit with concomitant use in most patients. Closely monitor blood pressure, renal function, and electrolytes in patients on ACE inhibitors and ARBs. Dual blockade of the renin-angiotensin system with ACE inhibitors and ARBs is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function, including acute renal failure, compared to monotherapy.

Eprosartan; Hydrochlorothiazide, HCTZ: (Major) In general, avoid combined use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) due to lack of benefit with concomitant use in most patients. Closely monitor blood pressure, renal function, and electrolytes in patients on ACE inhibitors and ARBs. Dual blockade of the renin-angiotensin system with ACE inhibitors and ARBs is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function, including acute renal failure, compared to monotherapy.

Ertugliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

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.

Ethiodized Oil: (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.

Etomidate: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.

Everolimus: (Major) Avoid coadministration of everolimus with angiotensin-converting enzyme inhibitors (ACE inhibitors) as the risk of angioedema, with or without respiratory impairment, may be increased. 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.

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.

Finerenone: (Moderate) Monitor serum potassium concentrations closely if finerenone and angiotensin-converting enzyme inhibitors (ACEI) are used together. Concomitant use may increase the risk of hyperkalemia.

Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.

Fluorescein: (Moderate) Patients on angiotensin-converting enzyme inhibitors are at an increased risk of adverse reactions when administered fluorescein injection. If fluorescein injection is deemed necessary in a patient on ACE inhibitor therapy, monitor as appropriate during and after the procedure.

General anesthetics: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.

Glipizide; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

Glyburide; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

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.

Hydralazine; Isosorbide Dinitrate, ISDN: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.

Hydrocodone; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Monitor heart rate and blood pressure.

Ibritumomab Tiuxetan: (Major) Avoid coadministration of potassium phosphate and angiotensin-converting enzyme inhibitors as concurrent use may increase the risk of severe and potentially fatal hyperkalemia, particularly in high-risk patients (renal impairment, cardiac disease, adrenal insufficiency). If concomitant use is necessary, closely monitor serum potassium concentrations.

Ibuprofen; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Monitor heart rate and blood pressure.

Icatibant: (Minor) Although clinical data are lacking, icatibant is a bradykinin B2 receptor antagonist and may theoretically potentiate the antihypertensive effect of ACE inhibitors.

Iloperidone: (Moderate) Secondary to alpha-blockade, iloperidone can produce vasodilation that may result in additive effects during concurrent use with antihypertensive agents. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use of iloperidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.

Iloprost: (Moderate) Further reductions in blood pressure may occur when inhaled iloprost is administered to patients receiving other antihypertensive agents.

Incretin Mimetics: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

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 blood glucose during concomitant insulin and angiotensin-converting enzyme (ACE) inhibitor use; an insulin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

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.

Iodixanol: (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.

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.

Iomeprol: (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) In general, avoid combined use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) due to lack of benefit with concomitant use in most patients. Closely monitor blood pressure, renal function, and electrolytes in patients on ACE inhibitors and ARBs. Dual blockade of the renin-angiotensin system with ACE inhibitors and ARBs is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function, including acute renal failure, compared to monotherapy.

Irbesartan; Hydrochlorothiazide, HCTZ: (Major) In general, avoid combined use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) due to lack of benefit with concomitant use in most patients. Closely monitor blood pressure, renal function, and electrolytes in patients on ACE inhibitors and ARBs. Dual blockade of the renin-angiotensin system with ACE inhibitors and ARBs is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function, including acute renal failure, compared to monotherapy.

Iron Dextran: (Moderate) The concomitant use of angiotensin-converting enzyme inhibitors (ACE inhibitors) with iron dextran may increase the risk for anaphylactic-type reactions. The factors that affect the risk for anaphylactic-type reactions to iron dextran products are not fully known but limited clinical data suggest the risk may be increased among patients with a history of drug allergy or multiple drug allergies. Patients should be monitored for signs and symptoms of anaphylactic-type reactions during all iron dextran administrations.

Isocarboxazid: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.

Isoflurane: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.

Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Concomitant use of rifampin and enalapril may result in decreased concentrations of enalaprilat, the active metabolite of enalapril. Dosage adjustments of enalapril may be required.

Isoniazid, INH; Rifampin: (Moderate) Concomitant use of rifampin and enalapril may result in decreased concentrations of enalaprilat, the active metabolite of enalapril. Dosage adjustments of enalapril may be required.

Isoproterenol: (Moderate) The pharmacologic effects of isoproterenol may cause an increase in blood pressure. If isoproterenol is used concomitantly with antihypertensives, the blood pressure should be monitored as the administration of isoproterenol can compromise the effectiveness of antihypertensive agents.

Isosorbide Dinitrate, ISDN: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.

Isosorbide Mononitrate: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.

Isosulfan Blue: (Moderate) Because the use of other nephrotoxic drugs, including ACE inhibitors, is an additive risk factor for nephrotoxicity in patients receiving radiopaque contrast agents, ACE inhibitor therapy should be withheld, when possible, during radiopaque contrast agent administration.

Ketamine: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.

Lanthanum Carbonate: (Moderate) ACE Inhibitors should not be taken within 2 hours of dosing with lanthanum carbonate. Oral compounds known to interact with cationic antacids may similarly be bound with lanthanum carbonate and have their absorption reduced. If these agents are used concomitantly, separate the dosing intervals appropriately. Monitor the clinical condition of the patient to ensure the proper clinical response to the ACE inhibitor is obtained.

Levodopa: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.

Lidocaine; Epinephrine: (Moderate) Antihypertensives, including angiotensin-converting enzyme inhibitors, antagonize the vasopressor effects of parenteral epinephrine.

Linagliptin; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

Lisdexamfetamine: (Minor) Lisdexamfetamine may increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like angiotensin-converting enzyme inhibitors (ACE inhibitors). Close monitoring of blood pressure is advised.

Lithium: (Moderate) Monitor serum lithium concentrations during concomitant angiotensin-converting enzyme inhibitor use; reduce the lithium dose based on serum lithium concentration and clinical response. Concomitant use may increase steady-state lithium concentrations.

Loop diuretics: (Major) Discontinue the loop diuretic prior to starting enalapril, if possible, or start enalapril at the lower dose of 2.5 mg/day. Monitor blood pressure and renal function during concomitant use, particularly when doses are increased. Concomitant use may increase the risk for hypotension or renal failure.

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) In general, avoid combined use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) due to lack of benefit with concomitant use in most patients. Closely monitor blood pressure, renal function, and electrolytes in patients on ACE inhibitors and ARBs. Dual blockade of the renin-angiotensin system with ACE inhibitors and ARBs is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function, including acute renal failure, compared to monotherapy.

Losartan; Hydrochlorothiazide, HCTZ: (Major) In general, avoid combined use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) due to lack of benefit with concomitant use in most patients. Closely monitor blood pressure, renal function, and electrolytes in patients on ACE inhibitors and ARBs. Dual blockade of the renin-angiotensin system with ACE inhibitors and ARBs is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function, including acute renal failure, compared to monotherapy.

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) Monitor renal function during concomitant angiotensin-converting enzyme inhibitor and magnesium sulfate; potassium sulfate; sodium sulfate bowel preparation due to risk for renal injury; ensure adequate hydration.

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) Monitor blood glucose during concomitant metformin and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

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) Monitor blood glucose during concomitant metformin and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

Metformin; Rosiglitazone: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

Metformin; Saxagliptin: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

Metformin; Sitagliptin: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

Methamphetamine: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like angiotensin-converting enzyme inhibitors (ACE inhibitors). Close monitoring of blood pressure is advised.

Methohexital: (Moderate) Concurrent use of methohexital and antihypertensive agents increases the risk of developing hypotension.

Methylphenidate Derivatives: (Moderate) Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate derivatives and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate derivatives. Methylphenidate derivatives can reduce the hypotensive effect of antihypertensive agents such as angiotensin-converting enzyme inhibitors.

Milrinone: (Moderate) Concurrent administration of antihypertensive agents could lead to additive hypotension when administered with milrinone. Titrate milrinone dosage according to hemodynamic response.

Nanoparticle Albumin-Bound 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.

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) In general, avoid combined use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) due to lack of benefit with concomitant use in most patients. Closely monitor blood pressure, renal function, and electrolytes in patients on ACE inhibitors and ARBs. Dual blockade of the renin-angiotensin system with ACE inhibitors and ARBs is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function, including acute renal failure, compared to monotherapy.

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) Monitor blood pressure and renal function periodically during concomitant angiotensin-converting enzyme (ACE) inhibitor and nonsteroidal anti-inflammatory drug (NSAID) use. The antihypertensive effect of ACE inhibitors may be diminished by NSAIDs. In persons who are elderly, volume-depleted, or with compromised renal function, coadministration of ACE inhibitors and NSAIDs may result in deterioration of renal function, including possible acute renal failure; these effects are usually reversible.

Olanzapine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.

Olanzapine; Fluoxetine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.

Olanzapine; Samidorphan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.

Olmesartan: (Major) In general, avoid combined use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) due to lack of benefit with concomitant use in most patients. Closely monitor blood pressure, renal function, and electrolytes in patients on ACE inhibitors and ARBs. Dual blockade of the renin-angiotensin system with ACE inhibitors and ARBs is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function, including acute renal failure, compared to monotherapy.

Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Major) In general, avoid combined use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) due to lack of benefit with concomitant use in most patients. Closely monitor blood pressure, renal function, and electrolytes in patients on ACE inhibitors and ARBs. Dual blockade of the renin-angiotensin system with ACE inhibitors and ARBs is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function, including acute renal failure, compared to monotherapy.

Olmesartan; Hydrochlorothiazide, HCTZ: (Major) In general, avoid combined use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) due to lack of benefit with concomitant use in most patients. Closely monitor blood pressure, renal function, and electrolytes in patients on ACE inhibitors and ARBs. Dual blockade of the renin-angiotensin system with ACE inhibitors and ARBs is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function, including acute renal failure, compared to monotherapy.

Oxymetazoline: (Major) The vasoconstricting actions of oxymetazoline, an alpha adrenergic agonist, may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. If these drugs are used together, closely monitor for changes in blood pressure.

Paliperidone: (Moderate) Paliperidone may cause orthostatic hypotension, thereby enhancing the hypotensive effects of antihypertensive agents. Orthostatic vital signs should be monitored in patients receiving paliperidone and angiotensin-converting enzyme inhibitors who are susceptible to hypotension.

Pentoxifylline: (Moderate) Pentoxifylline has been used concurrently with antihypertensive drugs (beta blockers, diuretics) without observed problems. Small decreases in blood pressure have been observed in some patients treated with pentoxifylline; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensives. If indicated, dosage of the antihypertensive agents should be reduced.

Phenelzine: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.

Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.

Pioglitazone; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

Polyethylene Glycol; Electrolytes: (Moderate) Monitor renal function during concomitant angiotensin-converting enzyme inhibitor and magnesium sulfate; potassium sulfate; sodium sulfate bowel preparation due to risk for renal injury; ensure adequate hydration.

Polyethylene Glycol; Electrolytes; Ascorbic Acid: (Moderate) Monitor renal function during concomitant angiotensin-converting enzyme inhibitor and magnesium sulfate; potassium sulfate; sodium sulfate bowel preparation due to risk for renal injury; ensure adequate hydration.

Potassium Phosphate: (Major) Avoid coadministration of potassium phosphate and angiotensin-converting enzyme inhibitors as concurrent use may increase the risk of severe and potentially fatal hyperkalemia, particularly in high-risk patients (renal impairment, cardiac disease, adrenal insufficiency). If concomitant use is necessary, closely monitor serum potassium concentrations.

Potassium Phosphate; Sodium Phosphate: (Major) Avoid coadministration of potassium phosphate and angiotensin-converting enzyme inhibitors as concurrent use may increase the risk of severe and potentially fatal hyperkalemia, particularly in high-risk patients (renal impairment, cardiac disease, adrenal insufficiency). If concomitant use is necessary, closely monitor serum potassium concentrations.

Potassium: (Moderate) Monitor serum potassium concentrations closely if potassium supplements and angiotensin-converting enzyme inhibitors (ACE inhibitors) are used together. Concomitant use may increase the risk of hyperkalemia.

Pramlintide: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.

Prazosin: (Moderate) Prazosin is well-known to produce a 'first-dose' phenomenon. Some patients develop significant hypotension shortly after administration of the first dose. The first dose response (acute postural hypotension) of prazosin may be exaggerated in patients who are receiving beta-adrenergic blockers, diuretics, or other antihypertensive agents. Concomitant administration of prazosin with other antihypertensive agents is not prohibited, however. This can be therapeutically advantageous, but lower dosages of each agent should be used.

Pregabalin: (Moderate) Monitor for signs and symptoms of angioedema during concomitant angiotensin-converting enzyme inhibitor and pregabalin use. Concomitant use may increase the risk of developing angioedema.

Prilocaine; Epinephrine: (Moderate) Antihypertensives, including angiotensin-converting enzyme inhibitors, antagonize the vasopressor effects of parenteral epinephrine.

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.

Promethazine; 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.

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.

Pseudoephedrine; Triprolidine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Monitor heart rate and blood pressure.

Quinidine: (Moderate) Quinidine can decrease blood pressure and should be used cautiously in patients receiving antihypertensive agents due to the potential for additive hypotension.

Rasagiline: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.

Repaglinide: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.

Rifampin: (Moderate) Concomitant use of rifampin and enalapril may result in decreased concentrations of enalaprilat, the active metabolite of enalapril. Dosage adjustments of enalapril may be required.

Risperidone: (Moderate) Risperidone may induce orthostatic hypotension and thus enhance the hypotensive effects of antihypertensive agents. Lower initial doses or slower dose titration of risperidone may be necessary in patients receiving antihypertensive agents concomitantly.

Sacubitril; Valsartan: (Contraindicated) 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) In general, avoid combined use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) due to lack of benefit with concomitant use in most patients. Closely monitor blood pressure, renal function, and electrolytes in patients on ACE inhibitors and ARBs. Dual blockade of the renin-angiotensin system with ACE inhibitors and ARBs is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function, including acute renal failure, compared to monotherapy.

Salicylates: (Moderate) Aspirin, ASA may reduce the vasodilatory efficacy of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. This interaction has been documented primarily in heart failure patients. However, the established benefits of using aspirin in combination with an ACE inhibitor in patients with ischemic heart disease and left ventricular dysfunction generally outweigh this concern. Patients receiving concurrent salicylates and ACE inhibitor therapy should be monitored for antihypertensive or vasodilatory efficacy; the dose of the ACE inhibitor can be adjusted if indicated based on clinical evaluation.

Sevoflurane: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.

SGLT2 Inhibitors: (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

Silodosin: (Moderate) During clinical trials with silodosin, the incidence of dizziness and orthostatic hypotension was higher in patients receiving concomitant antihypertensive treatment. Thus, caution is advisable when silodosin is administered with antihypertensive agents.

Sirolimus: (Moderate) Sirolimus has been associated with the development of angioedema. The use of sirolimus with other drugs known to cause angioedema, such as angiotensin-converting enzyme inhibitors may increase the risk of developing angioedema. Patients should be monitored for angioedema if any of these drugs are coadministered with sirolimus.

Sodium Phosphate Monobasic Monohydrate; Sodium Phosphate Dibasic Anhydrous: (Moderate) Concomitant use of medicines with potential to alter renal perfusion or function such as angiotensin-converting enzyme inhibitors, may increase the risk of acute phosphate nephropathy in patients taking sodium phosphate monobasic monohydrate; sodium phosphate dibasic anhydrous.

Sodium picosulfate; Magnesium oxide; Anhydrous citric acid: (Moderate) Use caution when prescribing sodium picosulfate; magnesium oxide; anhydrous citric acid in patients taking concomitant medications that may affect renal function such as angiotensin-converting enzyme inhibitors (ACE inhibitors). In addition, use caution in patients receiving drugs where hypokalemia is a particular risk.

Sodium Sulfate; Magnesium Sulfate; Potassium Chloride: (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).

Sparsentan: (Moderate) Monitor potassium during concomitant use of sparsentan and angiotensin-converting enzyme inhibitors. Concomitant use increases the risk for hyperkalemia.

Spironolactone: (Moderate) Monitor serum potassium concentrations closely if ACE inhibitors and spironolactone are used together. Concomitant use may increase the risk of hyperkalemia, especially in elderly patients or patients with impaired renal function.

Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations closely if ACE inhibitors and spironolactone are used together. Concomitant use may increase the risk of hyperkalemia, especially in elderly patients or patients with impaired renal function.

Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin-converting enzyme (ACE) inhibitor and trimethoprim is necessary. Avoid concomitant use and consider alternative antibiotic therapy in patients with additional risk factors for hyperkalemia, including patients older than 65 years, those with underlying disorders of potassium metabolism, renal insufficiency, or those requiring high doses of trimethoprim. Amongst patients older than 65 years, concomitant use has been associated with a 2- to 7-fold increased risk of significant hyperkalemia compared to other antibiotics. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.

Sulfonylureas: (Moderate) Monitor blood glucose during concomitant sulfonylurea and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

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) In general, avoid combined use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) due to lack of benefit with concomitant use in most patients. Closely monitor blood pressure, renal function, and electrolytes in patients on ACE inhibitors and ARBs. Dual blockade of the renin-angiotensin system with ACE inhibitors and ARBs is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function, including acute renal failure, compared to monotherapy.

Telmisartan; Amlodipine: (Major) In general, avoid combined use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) due to lack of benefit with concomitant use in most patients. Closely monitor blood pressure, renal function, and electrolytes in patients on ACE inhibitors and ARBs. Dual blockade of the renin-angiotensin system with ACE inhibitors and ARBs is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function, including acute renal failure, compared to monotherapy.

Telmisartan; Hydrochlorothiazide, HCTZ: (Major) In general, avoid combined use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) due to lack of benefit with concomitant use in most patients. Closely monitor blood pressure, renal function, and electrolytes in patients on ACE inhibitors and ARBs. Dual blockade of the renin-angiotensin system with ACE inhibitors and ARBs is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function, including acute renal failure, compared to monotherapy.

Temsirolimus: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with enalapril. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with another ACE inhibitor.

Tenapanor: (Moderate) Consider monitoring for loss of efficacy of enalapril if coadministered with tenapanor. Monitor blood pressure or other treatment parameters and increase the enalapril dosage if clinically indicated. Coadministration may reduce exposure of enalapril. Tenapanor is an inhibitor of intestinal uptake transporter, OATP2B1 and enalapril is an OATP2B1 substrate. Coadministration decreased the exposure of enalapril by 50% to 65%.

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: (Major) Discontinue the thiazide diuretic prior to starting enalapril, if possible, or start enalapril at the lower dose of 2.5 mg/day. Monitor blood pressure, particularly when doses are increased, and renal function during concomitant use. Concomitant use may increase the risk for hypotension or renal failure.

Thiazolidinediones: (Moderate) Monitor blood glucose during concomitant thiazolidinedione and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

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) Monitor serum potassium concentrations closely if tolvaptan and angiotensin-converting enzyme inhibitors (ACE inhibitors) are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with ACE inhibitors compared to administration of these medications with placebo.

Tranylcypromine: (Contraindicated) 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: (Moderate) Monitor serum potassium concentrations closely if ACE inhibitors and triamterene are used together. Concomitant use may increase the risk of hyperkalemia, especially in elderly patients or patients with impaired renal function.

Triamterene; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations closely if ACE inhibitors and triamterene are used together. Concomitant use may increase the risk of hyperkalemia, especially in elderly patients or patients with impaired renal function.

Trimethoprim: (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin-converting enzyme (ACE) inhibitor and trimethoprim is necessary. Avoid concomitant use and consider alternative antibiotic therapy in patients with additional risk factors for hyperkalemia, including patients older than 65 years, those with underlying disorders of potassium metabolism, renal insufficiency, or those requiring high doses of trimethoprim. Amongst patients older than 65 years, concomitant use has been associated with a 2- to 7-fold increased risk of significant hyperkalemia compared to other antibiotics. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.

Valsartan: (Major) In general, avoid combined use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) due to lack of benefit with concomitant use in most patients. Closely monitor blood pressure, renal function, and electrolytes in patients on ACE inhibitors and ARBs. Dual blockade of the renin-angiotensin system with ACE inhibitors and ARBs is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function, including acute renal failure, compared to monotherapy.

Valsartan; Hydrochlorothiazide, HCTZ: (Major) In general, avoid combined use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) due to lack of benefit with concomitant use in most patients. Closely monitor blood pressure, renal function, and electrolytes in patients on ACE inhibitors and ARBs. Dual blockade of the renin-angiotensin system with ACE inhibitors and ARBs is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function, including acute renal failure, compared to monotherapy.

Vasopressin, ADH: (Moderate) Monitor hemodynamics and adjust the dose of vasopressin as needed when used concomitantly with drugs suspected of causing syndrome of inappropriate antidiuretic hormone (SIADH), such as enalapril. Use together may increase the pressor and antidiuretic effects of vasopressin.

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.

Enalapril competes with the natural substrate, angiotensin I, thereby inhibiting its conversion to angiotensin II. Angiotensin II is a potent vasoconstrictor and a negative feedback mediator for renin activity. Thus, when enalapril lowers angiotensin II plasma levels, blood pressure decreases and plasma renin activity increases. In addition, baroreceptor reflex mechanisms are stimulated in response to the fall in blood pressure. Kininase II, identical to ACE, is an enzyme that degrades bradykinin, a potent vasodilator, to inactive peptides. Whether increased bradykinin levels play a part in the therapeutic effects of ACE inhibitors is presently unclear. Bradykinin-induced vasodilation is thought to be of secondary importance in the blood-pressure lowering effect of ACE inhibitors. A bradykinin mechanism may, however, contribute to ACE-inhibitor-induced angioneurotic edema.

ACE-inhibiting drugs can act locally to reduce vascular tone by decreasing local angiotensin II-induced sympathetic and/or vasoconstrictive activity. ACE inhibitors also can inhibit presynaptic norepinephrine release and postsynaptic adrenergic receptor activity, decreasing vascular sensitivity to vasopressor activity; however, this action may not be clinically evident at usual doses. Decreases in plasma angiotensin II levels also reduce aldosterone secretion, with a subsequent decrease in sodium and water retention. As antihypertensives, ACE inhibitors reduce LVH, do not worsen insulin resistance or hyperlipidemia, and do not cause sexual dysfunction.

Enalapril causes arterial dilation, thereby lowering total peripheral vascular resistance. In hypertensive patients, blood pressure is decreased with little or no change in heart rate, stroke volume, or cardiac output. However, in patients with heart failure, enalapril increases cardiac output, cardiac index, stroke volume, and exercise tolerance. The drug also decreases pulmonary wedge pressure, pulmonary vascular resistance, and mean arterial and right atrial pressures in these patients.

Enalapril is administered orally and enalaprilat is administered parenterally. Enalapril maleate is a prodrug; it is converted by hydrolysis of the ethyl ester to enalaprilat, the active drug. Animal studies indicate that enalapril crosses the blood-brain barrier poorly, if at all. Enalaprilat does not enter the brain. Excretion of enalapril and enalaprilat is primarily renal. Approximately 94% of a dose is recovered in the urine and feces as enalaprilat or enalapril. The principal components in urine are enalaprilat (accounting for about 40% of the dose) and intact enalapril. The half-life of enalaprilat after multiple doses of enalapril is about 11 hours.

Affected cytochrome P450 isoenzymes: none


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

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


-Special Populations
Renal Impairment
Renal insufficiency prolongs the elimination of enalaprilat. The disposition of enalapril and enalaprilat in patients with renal insufficiency is similar to that in patients with normal renal function until the glomerular filtration rate is reduced <= 30 mL/minute. With glomerular filtration rate <= 30 mL/minute, peak and trough enalaprilat levels increase, time to peak concentration increases, the time to steady state may be delayed, and the effective elimination half-life of enalaprilat is prolonged. Enalaprilat is hemodialyzable at a rate of 62 mL/minute. Administering enalapril 1 hour after hemodialysis reduces enalaprilat AUC by approximately 50% compared to off-dialysis days. Enalapril can been removed from neonatal circulation by peritoneal dialysis.

Pediatrics
Infants, Children, and Adolescents
The mean half-lives of enalapril and enalaprilat in 11 infants and children 1 month to 6.5 years old with congestive heart failure receiving oral enalapril 0.05 to 0.3 mg/kg/day were 2.7 +/- 1.4 hours and 11.1 +/- 4.3 hours, respectively; this was significantly different than the values seen in healthy adult volunteers for enalapril (1.4 +/- 1 hours) and enalaprilat (5.3 +/- 1.6 hours). The mean AUC per dose normalized for body surface area for enalapril and enalaprilat were 51.1 +/- 30 ng x hour/mL per 1 mg/m2 and 83.1 +/- 47 ng x hour/mL per 1 mg/m2, respectively; this was significantly different than the values seen in healthy adult volunteers for enalapril (21.7 +/- 8.6 ng x hour/mL per 1 mg/m2, p < 0.05) but not for enalaprilat (64.6 +/- 17.8 ng x hour/mL per 1 mg/m2). In a multiple dose pharmacokinetic study in 40 pediatric patients (2 months to 15 years) with hypertension receiving oral enalapril, the median half-life for accumulation was 14.6 to 16.3 hours. Peak serum concentrations of enalapril and enalaprilat were observed at approximately 1 hour and 3 to 4 hours, respectively. Infants and children 2 months to 6 years required slightly higher weight-based doses (0.13 mg/kg and 0.11 mg/kg) compared to the older age group (0.11 mg/kg and 0.07 mg/kg) to achieved a similar AUC at steady state.

Neonates
The mean half-lives of enalapril and enalaprilat in 3 term neonates less than 20 days old with congestive heart failure receiving oral enalapril 0.1 to 0.14 mg/kg/day were 10.3 +/- 5.2 hours and 11.9 +/- 5.3 hours, respectively. The mean AUC per dose normalized for body surface area for enalapril and enalaprilat was 197.6 +/- 123.2 ng x hour/mL per 1 mg/m2 and 497.8 +/- 196.4 ng x hour/mL per 1 mg/m2, respectively. Peak serum concentrations of enalapril and enalaprilat occurred at 12 hours in 2 patients and 8 hours in 1 patient.