Trandolapril

The recommended starting dose for treating high blood pressure in patients not receiving a diuretic is 1 mg once daily in Caucasian patients and 2 mg in black patients. Doses may be increased at weekly intervals. Most patients require 2 to 4 mg daily, and there is no additional benefit from doses larger than 8 mg daily. Patients receiving a diuretic should start at 0.5 mg daily if the diuretic cannot be stopped for 2 to 3 days before starting trandolapril. For heart failure the starting dose is 1 mg once daily. The dose should be increased to 4 mg once daily or the largest tolerated dose.

Trandolapril is part of the drug class:

• ACE INHIBITORS, PLAIN

Serious side effects have been reported. See "Drug Precautions" section

Common side effects include:

• cough
• dizziness
• diarrhea
• extremely low blood pressure
• indigestion
• muscle pain or cramps

This is not a complete list of trandolapril side effects. Ask your doctor or pharmacist for more information.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

• potassium-sparing diuretics such as:
  • spironolactone (Aldactone)
  • triamterene (Dyrenium)
  • amiloride (Midamor)
• other diuretics such as:
  • furosemide (Lasix)
  • hydrochlorothiazide
  • torsemide (Demadex)
• aliskiren (Tekturna)
• angiotensin receptor blockers such as candesartan (Atacand), losartan (Cozaar), and telmisartan (Micardis, Twynsta)
• aspirin and other NSAIDs (non-steroidal anti-inflammatory drugs) such as:
  • celecoxib (Celebrex)
  • diclofenac (Cambia, Cataflam, Flector, Voltaren, Zipsor and others)
  • etodolac (Lodine)
  • ibuprofen (Advil, Motrin, Nuprin)
  • indomethacin (Indocin, Indocin SR)
  • ketoprofen (Orudis, Actron, Oruvail)
  • ketorolac (Toradol)
  • meloxicam (Mobic)
  • nabumetone (Relafen)
  • naproxen (Naprosyn)
  • naproxen sodium (Aleve, Anaprox, Naprelan)
  • oxaprozin (Daypro)
  • piroxicam (Feldene)
• lithium (Eskalith, Lithobid)
• potassium supplements
• injectable gold (sodium aurothiomalate)

This is not a complete list of trandolapril drug interactions. Ask your doctor or pharmacist for more information.

Before taking trandolapril, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• history of angioedema (swelling under the skin)
• have diabetes (high blood sugar) and you are taking aliskiren (Tekturna; also in Amturnide, Tekamlo, Tekturna HCT). Your doctor will probably tell you not to take trandolapril if you have diabetes and you are also taking aliskiren.
• have or have ever had heart or kidney disease or diabetes
• have liver disease
• are having surgery, including dental surgery. Inform the doctor or dentist that you are taking trandolapril.
• are using salt substitutes containing potassium. If your doctor prescribes a low-salt or low-sodium diet, follow these instructions carefully.
• pregnant or breastfeeding

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

Tell your doctor if you are breastfeeding or plan to breastfeed.

Trandolapril has been detected in human breast milk. Because of the possibility for adverse reactions in nursing infants from trandolapril, a choice should be made whether to stop nursing or to stop use of this medication. Determining the importance of the drug to the mother should be considered.

Trandolapril is an ACE inhibitor. ACE stands for angiotensin converting enzyme.

Trandolapril is used to treat high blood pressure (hypertension), and to improve survival after a heart attack.

Trandolapril may also be used for purposes not listed in this medication guide.

Do not use if you are pregnant. Stop using this medicine and tell your doctor right away if you become pregnant.

If you have diabetes, do not use trandolapril together with any medication that contains aliskiren (Amturnide, Tekturna, Tekamlo).

Nonsulfhydryl ACE inhibitor.1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Storage

Oral

20–25°C.1

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• Avoid driving and doing other tasks or actions that call for you to be alert until you see how trandolapril affects you.
• To lower the chance of feeling dizzy or passing out, rise slowly if you have been sitting or lying down. Be careful going up and down stairs.
• Have your blood pressure checked often. Talk with your doctor.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• If you are taking a salt substitute that has potassium, potassium-sparing diuretics, or potassium, talk with your doctor.
• If you are on a low-salt or salt-free diet, talk with your doctor.
• Low white blood cell counts have happened with captopril, a drug like this one. This may lead to more chance of getting an infection. Most of the time, this has happened in people with kidney problems, mainly if they have certain other health problems. Call your doctor right away if you have signs of infection like fever, chills, or sore throat. Talk with your doctor.
• If you are taking this medicine and have high blood pressure, talk with your doctor before using OTC products that may raise blood pressure. These include cough or cold drugs, diet pills, stimulants, ibuprofen or like products, and some natural products or aids.
• Talk with your doctor before you drink alcohol.
• Be careful in hot weather or while being active. Drink lots of fluids to stop fluid loss.
• Tell your doctor if you have too much sweat, fluid loss, throwing up, or loose stools. This may lead to low blood pressure.
• If you are taking lithium, talk with your doctor. You may need to have your blood work checked more closely while you are taking it with trandolapril.
• This medicine may not work as well in black patients. Talk with the doctor.
• A very bad reaction called angioedema has happened with this medicine. Sometimes, this has been deadly. The chance of angioedema may be higher in black patients. Talk with the doctor.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this medicine, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take trandolapril or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to trandolapril. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

Mechanism of Action

Trandolapril is deesterified to the diacid metabolite, Trandolaprilat, which is approximately eight times more active as an inhibitor of ACE activity. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor, angiotensin II. Angiotensin II is a potent peripheral vasoconstrictor that also stimulates secretion of aldosterone by the adrenal cortex and provides negative feedback for renin secretion. The effect of Trandolapril in hypertension appears to result primarily from the inhibition of circulating and tissue ACE activity thereby reducing angiotensin II formation, decreasing vasoconstriction, decreasing aldosterone secretion, and increasing plasma renin. Decreased aldosterone secretion leads to diuresis, natriuresis, and a small increase of serum potassium. In controlled clinical trials, treatment with Trandolapril alone resulted in mean increases in potassium of 0.1 mEq/L. (see PRECAUTIONS.)

ACE is identical to kininase II, an enzyme that degrades bradykinin, a potent peptide vasodilator; whether increased levels of bradykinin play a role in the therapeutic effect of Trandolapril remains to be elucidated.

While the principal mechanism of antihypertensive effect is thought to be through the renin-angiotensin-aldosterone system, Trandolapril exerts antihypertensive actions even in patients with low-renin hypertension. Trandolapril was an effective antihypertensive in all races studied. Both black patients (usually a predominantly low-renin group) and non-black patients responded to 2 to 4 mg of Trandolapril.

Pharmacokinetics and Metabolism

Trandolapril's ACE-inhibiting activity is primarily due to its diacid metabolite, Trandolaprilat. Cleavage of the ester group of Trandolapril, primarily in the liver, is responsible for conversion. Absolute bioavailability after oral administration of Trandolapril is about 10% as Trandolapril and 70% as Trandolaprilat. After oral Trandolapril under fasting conditions, peak Trandolapril levels occur at about one hour and peak Trandolaprilat levels occur between 4 and 10 hours. The elimination half-life of Trandolapril is about 6 hours. At steady state, the effective half-life of Trandolaprilat is 22.5 hours. Like all ACE inhibitors, Trandolaprilat also has a prolonged terminal elimination phase, involving a small fraction of administered drug, probably representing binding to plasma and tissue ACE. During multiple dosing of Trandolapril, there is no significant accumulation of Trandolaprilat. Food slows absorption of Trandolapril, but does not affect AUC or Cmax of Trandolaprilat or Cmax of Trandolapril.

After oral administration of Trandolapril, about 33% of parent drug and metabolites are recovered in urine, mostly as Trandolaprilat, with about 66% in feces. The extent of the absorbed dose which is biliary excreted has not been determined. Plasma concentrations (Cmax and AUC of Trandolapril and Cmax of Trandolaprilat) are dose proportional over the 1-4 mg range, but the AUC of Trandolaprilat is somewhat less than dose proportional. In addition to Trandolaprilat, at least 7 other metabolites have been found, principally glucuronides or deesterification products.

Serum protein binding of Trandolapril is about 80%, and is independent of concentration. Binding of Trandolaprilat is concentration- dependent, varying from 65% at 1000 ng/mL to 94% at 0.1 ng/mL, indicating saturation of binding with increasing concentration.

The volume of distribution of Trandolapril is about 18 liters. Total plasma clearances of Trandolapril and Trandolaprilat after approximately 2 mg IV doses are about 52 liters/hour and 7 liters/hour respectively. Renal clearance of Trandolaprilat varies from 1- 4 liters/hour, depending on dose.

Special Populations

Trandolapril pharmacokinetics have not been evaluated in patients < 18 years of age.

Geriatric and Gender

Trandolapril pharmacokinetics have been investigated in the elderly (> 65 years) and in both genders. The plasma concentration of Trandolapril is increased in elderly hypertensive patients, but the plasma concentration of Trandolaprilat and inhibition of ACE activity are similar in elderly and young hypertensive patients. The pharmacokinetics of Trandolapril and Trandolaprilat and inhibition of ACE activity are similar in male and female elderly hypertensive patients.

Pharmacokinetic differences have not been evaluated in different races.

Compared to normal subjects, the plasma concentrations of Trandolapril and Trandolaprilat are approximately 2-fold greater and renal clearance is reduced by about 85% in patients with creatinine clearance below 30 ml/min and in patients on hemodialysis. Dosage adjustment is recommended in renally impaired patients. (see DOSAGE AND ADMINISTRATION.)

Following oral administration in patients with mild to moderate alcoholic cirrhosis, plasma concentrations of Trandolapril and Trandolaprilat were, respectively, 9-fold and 2-fold greater than in normal subjects, but inhibition of ACE activity was not affected. Lower doses should be considered in patients with hepatic insufficiency. (see DOSAGE AND ADMINISTRATION.)

Trandolapril did not affect the plasma concentration (pre-dose and 2 hours post-dose) of oral digoxin (0.25 mg). Coadministration of Trandolapril and cimetidine led to an increase of about 44% in Cmax for Trandolapril, but no difference in the pharmacokinetics of Trandolaprilat or in ACE inhibition. Coadministration of Trandolapril and furosemide led to an increase of about 25% in the renal clearance of Trandolaprilat, but no effect was seen on the pharmacokinetics of furosemide or Trandolaprilat or on ACE inhibition.

Pharmacodynamics and Clinical Effects

A single 2-mg dose of Trandolapril produces 70 to 85% inhibition of plasma ACE activity at 4 hours with about 10% decline at 24 hours and about half the effect manifest at 8 days. Maximum ACE inhibition is achieved with a plasma Trandolaprilat concentration of 2 ng/mL. ACE inhibition is a function of Trandolaprilat concentration, not Trandolapril concentration. The effect of Trandolapril on exogenous angiotensin I was not measured.

Hypertension

Four placebo-controlled dose response studies were conducted using once-daily oral dosing of Trandolapril in doses from 0.25 to 16 mg per day in 827 black and non-black patients with mild to moderate hypertension. The minimal effective once-daily dose was 1 mg in non-black patients and 2 mg in black patients. Further decreases in trough supine diastolic blood pressure were obtained in non-black patients with higher doses, and no further response was seen with doses above 4 mg (up to 16 mg). The antihypertensive effect diminished somewhat at the end of the dosing interval, but trough/peak ratios are well above 50% for all effective doses. There was a slightly greater effect on the diastolic pressure, but no difference on systolic pressure with b.i.d. dosing. During chronic therapy, the maximum reduction in blood pressure with any dose is achieved within one week. Following 6 weeks of monotherapy in placebo-controlled trials in patients with mild to moderate hypertension, once-daily doses of 2 to 4 mg lowered supine or standing systolic/diastolic blood pressure 24 hours after dosing by an average 7-10/4-5 mmHg below placebo responses in non-black patients. Once-daily doses of 2 to 4 mg lowered blood pressure 4-6/3-4 mmHg in black patients. Trough to peak ratios for effective doses ranged from 0.5 to 0.9. There were no differences in response between men and women, but responses were somewhat greater in patients under 60 than in patients over 60 years old. Abrupt withdrawal of Trandolapril has not been associated with a rapid increase in blood pressure.

Administration of Trandolapril to patients with mild to moderate hypertension results in a reduction of supine, sitting and standing blood pressure to about the same extent without compensatory tachycardia.

Symptomatic hypotension is infrequent, although it can occur in patients who are salt- and/or volume-depleted. (see WARNINGS.) Use of Trandolapril in combination with thiazide diuretics gives a blood pressure lowering effect greater than that seen with either agent alone, and the additional effect of Trandolapril is similar to the effect of monotherapy.

Heart Failure Post Myocardial Infarction or Left Ventricular Dysfunction Post Myocardial Infarction

The Trandolapril Cardiac Evaluation (TRACE) Trial was a Danish, 27-center, double-blind, placebo controlled, parallel-group study of the effect of Trandolapril on all-cause mortality in stable patients with echocardiographic evidence of left ventricular dysfunction 3 to 7 days after a myocardial infarction. Subjects with residual ischemia or overt heart failure were included. Patients tolerant of a test dose of 1 mg Trandolapril were randomized to placebo (n=873) or Trandolapril (n=876) and followed for 24 months. Among patients randomized to Trandolapril, who began treatment on 1 mg, 62% were successfully titrated to a target dose of 4 mg once daily over a period of weeks. The use of Trandolapril was associated with a 16% reduction in the risk of all-cause mortality (p=0.042), largely cardiovascular mortality. Trandolapril was also associated with a 20% reduction in the risk of progression of heart failure (p=0.047), defined by a time-to-first-event analysis of death attributed to heart failure, hospitalization for heart failure, or requirement for open-label ACE inhibitor for the treatment of heart failure. There was no significant effect of treatment on other end-points: subsequent hospitalization, incidence of recurrent myocardial infarction, exercise tolerance, ventricular function, ventricular dimensions, or NYHA class.

The population in TRACE was entirely Caucasian and had less usage than would be typical in a U.S. population of other post- infarction interventions: 42% thrombolysis, 16% beta-adrenergic blockade, and 6.7% PTCA or CABG during the entire period of follow-up. Blood pressure control, especially in the placebo group, was poor: 47 to 53% of patients randomized to placebo and 32 to 40% of patients randomized to Trandolapril had blood pressures > 140/95 at 90-day follow-up visits.

Trandolapril Tablets USP, 4 mg

Rx Only

100 Tablets

(tran DOE la pril)

Hypertension: Oral:

Patients not receiving a diuretic: Initial: 1 mg once daily (2 mg daily in black patients). Adjust dosage at intervals of ≥1 week according to blood pressure response; usual dosage (ASH/ISH [Weber 2014]): 2 to 8 mg daily. There is little experience with doses >8 mg daily. Patients inadequately treated with once daily dosing at 4 mg may be treated with twice daily dosing. If blood pressure is not adequately controlled with trandolapril monotherapy, a diuretic may be added.

Patients receiving a diuretic: Consider discontinuing diuretic therapy 2 to 3 days before initiating trandolapril if possible; if blood pressure is not controlled by trandolapril alone, diuretic therapy should be resumed; if unable to discontinue diuretic, initiate trandolapril 0.5 mg once daily and monitor closely until blood pressure is stable; titrate to response as tolerated.

Post-MI heart failure or LV dysfunction: Oral: Initial: 1 mg once daily; titrate (as tolerated) toward target dose of 4 mg once daily. If 4 mg dose is not tolerated, patients may continue therapy with the greatest tolerated dose. The American College of Cardiology Foundation/American Heart Association guidelines recommend the use of a 0.5 mg test dose with titration up to 4 mg daily as tolerated (O’Gara 2013).

Heart failure with reduced ejection fraction (HFrEF) (off-label use): Oral: Initial: 1 mg once daily; target dose: 4 mg once daily (ACCF/AHA [Yancy 2013]).

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Aliskiren: May enhance the hyperkalemic effect of ACE Inhibitors. Aliskiren may enhance the hypotensive effect of ACE Inhibitors. Aliskiren may enhance the nephrotoxic effect of ACE Inhibitors. Management: Aliskiren use with ACEIs or ARBs in patients with diabetes is contraindicated. Combined use in other patients should be avoided, particularly when CrCl is less than 60 mL/min. If combined, monitor potassium, creatinine, and blood pressure closely. Consider therapy modification

Allopurinol: ACE Inhibitors may enhance the potential for allergic or hypersensitivity reactions to Allopurinol. Consider therapy modification

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Angiotensin II Receptor Blockers: May enhance the adverse/toxic effect of ACE Inhibitors. Angiotensin II Receptor Blockers may increase the serum concentration of ACE Inhibitors. Management: In US labeling, use of telmisartan and ramipril is not recommended. It is not clear if any other combination of an ACE inhibitor and an ARB would be any safer. Consider alternatives to the combination when possible. Consider therapy modification

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Aprotinin: May diminish the antihypertensive effect of ACE Inhibitors. Monitor therapy

AzaTHIOprine: ACE Inhibitors may enhance the myelosuppressive effect of AzaTHIOprine. Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Brigatinib: May diminish the antihypertensive effect of Antihypertensive Agents. Brigatinib may enhance the bradycardic effect of Antihypertensive Agents. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Canagliflozin: May enhance the hyperkalemic effect of ACE Inhibitors. Canagliflozin may enhance the hypotensive effect of ACE Inhibitors. Monitor therapy

Ciprofloxacin (Systemic): ACE Inhibitors may enhance the arrhythmogenic effect of Ciprofloxacin (Systemic). Monitor therapy

Dapoxetine: May enhance the orthostatic hypotensive effect of ACE Inhibitors. Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

DPP-IV Inhibitors: May enhance the adverse/toxic effect of ACE Inhibitors. Specifically, the risk of angioedema may be increased. Monitor therapy

Drospirenone: ACE Inhibitors may enhance the hyperkalemic effect of Drospirenone. Monitor therapy

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Eplerenone: May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy

Everolimus: May enhance the adverse/toxic effect of ACE Inhibitors. Specifically, the risk of angioedema may be increased. Monitor therapy

Ferric Gluconate: ACE Inhibitors may enhance the adverse/toxic effect of Ferric Gluconate. Monitor therapy

Ferric Hydroxide Polymaltose Complex: ACE Inhibitors may enhance the adverse/toxic effect of Ferric Hydroxide Polymaltose Complex. Specifically, the risk for angioedema or allergic reactions may be increased. Monitor therapy

Gold Sodium Thiomalate: ACE Inhibitors may enhance the adverse/toxic effect of Gold Sodium Thiomalate. An increased risk of nitritoid reactions has been appreciated. Monitor therapy

Grass Pollen Allergen Extract (5 Grass Extract): ACE Inhibitors may enhance the adverse/toxic effect of Grass Pollen Allergen Extract (5 Grass Extract). Specifically, ACE inhibitors may increase the risk of severe allergic reaction to Grass Pollen Allergen Extract (5 Grass Extract). Consider therapy modification

Heparin: May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy

Heparin (Low Molecular Weight): May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy

Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Icatibant: May diminish the antihypertensive effect of ACE Inhibitors. Monitor therapy

Iron Dextran Complex: ACE Inhibitors may enhance the adverse/toxic effect of Iron Dextran Complex. Specifically, patients receiving an ACE inhibitor may be at an increased risk for anaphylactic-type reactions. Management: Follow iron dextran recommendations closely regarding both having resuscitation equipment and trained personnel on-hand prior to iron dextran administration and the use of a test dose prior to the first therapeutic dose. Consider therapy modification

Lanthanum: May decrease the serum concentration of ACE Inhibitors. Management: Administer angiotensin-converting enzyme inhibitors at least two hours before or after lanthanum. Consider therapy modification

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy

Lithium: ACE Inhibitors may increase the serum concentration of Lithium. Management: Lithium dosage reductions will likely be needed following the addition of an ACE inhibitor. Monitor patient response to lithium closely following addition or discontinuation of concurrent ACE inhibitor treatment. Consider therapy modification

Loop Diuretics: May enhance the hypotensive effect of ACE Inhibitors. Loop Diuretics may enhance the nephrotoxic effect of ACE Inhibitors. Monitor therapy

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: ACE Inhibitors may enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the combination may result in a significant decrease in renal function. Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of ACE Inhibitors. Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Potassium Salts: May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy

Potassium-Sparing Diuretics: May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy

Pregabalin: ACE Inhibitors may enhance the adverse/toxic effect of Pregabalin. Specifically, the risk of angioedema may be increased. Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Sacubitril: ACE Inhibitors may enhance the adverse/toxic effect of Sacubitril. Specifically, the risk of angioedema may be increased with this combination. Avoid combination

Salicylates: May enhance the nephrotoxic effect of ACE Inhibitors. Salicylates may diminish the therapeutic effect of ACE Inhibitors. Monitor therapy

Sirolimus: May enhance the adverse/toxic effect of ACE Inhibitors. Monitor therapy

Sodium Phosphates: ACE Inhibitors may enhance the nephrotoxic effect of Sodium Phosphates. Specifically, the risk of acute phosphate nephropathy may be enhanced. Management: Consider avoiding this combination by temporarily suspending treatment with ACEIs, or seeking alternatives to oral sodium phosphate bowel preparation. If the combination cannot be avoided, maintain adequate hydration and monitor renal function closely. Consider therapy modification

Temsirolimus: May enhance the adverse/toxic effect of ACE Inhibitors. Monitor therapy

Thiazide and Thiazide-Like Diuretics: May enhance the hypotensive effect of ACE Inhibitors. Thiazide and Thiazide-Like Diuretics may enhance the nephrotoxic effect of ACE Inhibitors. Monitor therapy

TiZANidine: May enhance the hypotensive effect of ACE Inhibitors. Monitor therapy

Tolvaptan: May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy

Trimethoprim: May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy

Yohimbine: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Severe renal dysfunction (CrCl less than 30 mL/min):
-Initial dose: 0.5 mg orally once a day

US BOXED WARNING: FETAL TOXICITY:
-When pregnancy is detected, discontinue this drug as soon as possible.
-Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

Data not available