Lotrel Side Effects

Please note - some side effects for Lotrel may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

Side Effects of Lotrel - for the Consumer

Lotrel

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Lotrel:

Dizziness or lightheadedness when sitting or standing; headache; persistent, dry cough; swelling of the hands or feet.

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); chest pain; infection (fever, sore throat); irregular or slow heartbeat; yellowing of the skin or eyes.

Lotrel Side Effects - for the Professional

Lotrel

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.

*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.

      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.

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.

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.

Side Effects by Body System

General

Amlodipine-benazepril is generally well-tolerated. Reported side effects are generally mild and transient, and are apparently unrelated to age, sex, race, or duration of therapy. Discontinuation of therapy has been reported in 4% of patients treated with the drug, compared to 3% of patients treated with placebo.

Cardiovascular

ACE inhibitors, in general, are more likely to cause hypotension in sodium depleted or dehydrated patients.

Cardiovascular side effects including dose-dependent peripheral edema have been associated with amlodipine monotherapy in 2% to 5% of patients, but has been observed significantly less often (in only 2% of patients) taking amlodipine in combination with benazepril. Palpitations, postural hypotension, and dizziness have each been reported in approximately 1% of patients receiving either drug alone. Angioneurotic edema is a rare, but potentially serious side effect associated with ACE inhibitors. The occurrence of angioneurotic edema generally requires discontinuation of therapy.

Nervous system

Nervous system side effects include headache in 2%, dizziness in 1%, and sleep disturbances, nervousness, anxiety, tremor, and decreased libido, each in less than 1% of patients.

Respiratory

Respiratory side effects are unusual. An increase in cough or rhinitis occurs in 2% to 3% of patients who receive benazepril or amlodipine-benazepril.

A retrospective study has revealed a significantly higher incidence of discontinuation of angiotensin converting enzyme inhibitor therapy due to cough among black patients compared to non-black patients (9.6% vs. 2.4%).

Gastrointestinal

Gastrointestinal side effects are unusual, and include nausea, general abdominal pain, dry mouth, constipation, diarrhea, dyspepsia, and esophagitis, each in approximately 1% of patients. As with some other calcium channel blockers, rare cases of gingival hyperplasia have been associated with amlodipine.

Hypersensitivity

Hypersensitivity reactions to angiotensin converting enzyme (ACE) inhibitors may be life threatening. Angioedema of the face, extremities, lips, tongue, glottis and/or pharynx have been reported rarely in patients receiving ACE inhibitors. In addition, intestinal angioedema has been reported in patients treated with ACE inhibitors. It is recommended that any patient with dyspnea, dysphagia, or significant facial angioedema stop therapy immediately and avoid ACE inhibitor therapy in general. Other hypersensitivity reactions associated with ACE inhibitors have included dermatitis, rash, flushing, and pruritus.

A single case of erythema multiforme has been associated with amlodipine.

A 62-year-old man with hypertension and psoriasis developed erythema multiforme within three days after starting amlodipine. The rash resolved upon substitution with nifedipine.

Patients with intestinal angioedema generally present with abdominal pain (with or without nausea or vomiting) and in some cases there was no prior history of facial angioedema, and C-1 esterase levels were normal. These symptoms resolve after stopping the ACE inhibitor.

Renal

Renal side effects including new or worsened renal insufficiency (defined as an increase in serum creatinine by 150% above pretreatment values) have been reported in 2% of patients who have received benazepril monotherapy. ACE inhibitor-associated renal dysfunction is more likely in patients with renal artery stenosis, hypovolemia, or sodium depletion.

Metabolic

Metabolic side effects including hypokalemia have been reported in less than 1% of patients. Typically, however, hyperkalemia has been associated with ACE inhibitors due to their ability to decrease serum aldosterone concentrations.

Endocrine

Endocrine side effects including a single case of gynecomastia have been associated with the use of amlodipine. The gynecomastia resolved upon substitution of amlodipine with an unrelated antihypertensive agent. No other endocrinologic side effects have been reported.

Hematologic

Hematologic side effects are rare. There have been rare reports of hemolytic anemia in patients receiving ACE inhibitors.

In two studies, 1 of 2,014 and 1 of 1,357 patients developed decreased hemoglobin concentrations during benazepril monotherapy. Neither patient required discontinuation of the drug.

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