Lotrel has been evaluated for safety in over 2,991 patients with hypertension; over 500 of these patients were treated for at least 6 months, and over 400 were treated for more than 1 year.

In a pooled analysis of 5 placebo-controlled trials involving Lotrel doses up to 5/20, the reported side effects were generally mild and transient, and there was no relationship between side effects and age, sex, race, or duration of therapy. Discontinuation of therapy due to side effects was required in approximately 4% of patients treated with Lotrel and in 3% of patients treated with placebo.

The most common reasons for discontinuation of therapy with Lotrel in these studies were cough and edema.*

The side effects considered possibly or probably related to study drug that occurred in these trials in more than 1% of patients treated with Lotrel are shown in the table below.

PERCENT INCIDENCE IN U.S. PLACEBO-CONTROLLED TRIALS

The incidence of edema was statistically greater in patients treated with amlodipine monotherapy than in patients treated with the combination. Edema and certain other side effects are associated with amlodipine monotherapy in a dose-dependent manner, and appear to affect women more than men. The addition of benazepril resulted in lower incidences as shown in the following table; the protective effect of benazepril was independent of race and (within the range of doses tested) of dose.

PERCENT INCIDENCE BY SEX OF CERTAIN ADVERSE EVENTS

In a trial (n=386) comparing placebo, Lotrel 5/20, and Lotrel 10/20, edema and dizziness were most commonly reported in the Lotrel 10/20 group.

There were no appreciable differences in the safety profile of the 5/40 mg or 10/40 mg doses of Lotrel when studied in two trials (n=329 and n=812) conducted to establish the effectiveness of these doses vs. benazepril monotherapy and amlodipine monotherapy, respectively.

Other side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled trials of patients treated with Lotrel or in postmarketing experience were the following:

Angioedema: Includes edema of the lips or face without other manifestations of angioedema (see WARNINGS, Angioedema).

Body as a Whole: Asthenia and fatigue.

CNS: Insomnia, nervousness, anxiety, tremor, and decreased libido.

Dermatologic: Flushing, hot flashes, rash, skin nodule, and dermatitis.

Digestive: Dry mouth, nausea, abdominal pain, constipation, diarrhea, dyspepsia, and esophagitis.

Metabolic and Nutritional: Hypokalemia.

Musculoskeletal: Back pain, musculoskeletal pain, cramps, and muscle cramps.

Respiratory:Pharyngitis.

Urogenital: Sexual problems such as impotence, and polyuria.

Other infrequently reported events were seen in clinical trials (causal relationship unlikely) or in postmarketing experience. These included chest pain, ventricular extrasystole, gout, neuritis, tinnitus, alopecia and upper respiratory tract infection.

Fetal/Neonatal Morbidity and Mortality: See WARNINGS, Fetal/Neonatal Morbidity and Mortality.

Monotherapies of benazepril and amlodipine have been evaluated for safety in clinical trials in over 6,000 and 11,000 patients, respectively. The observed adverse reactions to the monotherapies in these trials were similar to those seen in trials of Lotrel. In postmarketing experience with benazepril, there have been rare reports of Stevens-Johnson syndrome, pancreatitis, hemolytic anemia, pemphigus, and thrombocytopenia. Jaundice and hepatic enzyme elevations (mostly consistent with cholestasis) severe enough to require hospitalization have been reported in association with use of amlodipine. Other potentially important adverse experiences attributed to other ACE inhibitors and calcium channel blockers include: eosinophilic pneumonitis (ACE inhibitors) and gynecomastia (CCB's).

Clinical Laboratory Test Findings

Serum Electrolytes: See PRECAUTIONS.

Creatinine: Minor reversible increases in serum creatinine were observed in patients with essential hypertension treated with Lotrel. Increases in creatinine are more likely to occur in patients with renal insufficiency or those pretreated with a diuretic and, based on experience with other ACE inhibitors, would be expected to be especially likely in patients with renal artery stenosis (see PRECAUTIONS, General).

Other (causal relationships unknown): Clinically important changes in standard laboratory tests were rarely associated with Lotrel administration. Elevations of serum bilirubin and uric acid have been reported as have scattered incidents of elevations of liver enzymes.

Diuretics: Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with Lotrel. The possibility of hypotensive effects with Lotrel can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with Lotrel.

Potassium Supplements and Potassium-Sparing Diuretics: Benazepril can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia. If concomitant use of such agents is indicated, they should be given with caution, and the patient's serum potassium should be monitored frequently.

Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. Lotrel and lithium should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended.

Other: Benazepril has been used concomitantly with oral anticoagulants, beta-adrenergic-blocking agents, calcium-blocking agents, cimetidine, diuretics, digoxin, hydralazine, and naproxen without evidence of clinically important adverse interactions.

In clinical trials, amlodipine has been safely administered with thiazide diuretics, beta blockers, ACE inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, nonsteroidal anti- inflammatory drugs, antibiotics, and oral hypoglycemic drugs.

In vitro data in human plasma indicate that amlodipine has no effect on the protein binding of drugs tested (digoxin, phenytoin, warfarin, and indomethacin). Special studies have indicated that the coadministration of amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers; that coadministration with cimetidine did not alter the pharmacokinetics of amlodipine; and that coadministration with warfarin did not change the warfarin- induced prothrombin response time.

Bookmark this page: