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
| N=760 || N=554 || N=475 || N=408 |
*Edema refers to all edema, such as dependent edema, angioedema, facial edema.
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
| N=329 || N=431 || N=269 || N=285 || N=277 || N=198 || N=217 || N=191 |
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.
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.