ADVERSE REACTIONS
Enalapril maleate and hydrochlorothiazide tablets has been evaluated for safety in more than 1500 patients, including over 300 patients treated for one year or more. In clinical trials with enalapril maleate and hydrochlorothiazide tablets no adverse experiences peculiar to this combination drug have been observed. Adverse experiences that have occurred, have been limited to those that have been previously reported with enalapril or hydrochlorothiazide.
The most frequent clinical adverse experiences in controlled trials were: dizziness (8.6 percent), headache (5.5 percent), fatigue (3.9 percent) and cough (3.5 percent). Generally, adverse experiences were mild and transient in nature. Adverse experiences occurring in greater than two percent of patients treated with enalapril maleate and hydrochlorothiazide tablets in controlled clinical trials are shown below.
|
Percent of Patients
in Controlled Studies |
|
Enalapril maleate and hydrochlorothiazide tablets
(n = 1580)
Incidence
(discontinuation) |
Placebo
(n=230)
Incidence |
| Dizziness |
8.6 (0.7) |
4.3 |
| Headache |
5.5 (0.4) |
9.1 |
| Fatigue |
3.9 (0.8) |
2.6 |
| Cough |
3.5 (0.4) |
0.9 |
| Muscle Cramps |
2.7 (0.2) |
0.9 |
| Nausea |
2.5 (0.4) |
1.7 |
| Asthenia |
2.4 (0.3) |
0.9 |
| Orthostatic Effects |
2.3 (<0.1) |
0.0 |
| Impotence |
2.2 (0.5) |
0.5 |
| Diarrhea |
2.1 (<0.1) |
1.7 |
Clinical adverse experiences occurring in 0.5 to 2.0 percent of patients in controlled trials included: Body As A Whole: Syncope, chest pain, abdominal pain; Cardiovascular: Orthostatic hypotension, palpitation, tachycardia; Digestive: Vomiting, dyspepsia, constipation, flatulence, dry mouth; Nervous/Psychiatric: Insomnia, nervousness, paresthesia, somnolence, vertigo; Skin: Pruritus, rash; Other: Dyspnea, gout, back pain, arthralgia, diaphoresis, decreased libido, tinnitus, urinary tract infection.
Angioedema
Angioedema has been reported in patients receiving enalapril maleate and hydrochlorothiazide tablets, with an incidence higher in black than in non-black patients. Angioedema associated with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis and/or larynx occurs, treatment with enalapril maleate and hydrochlorothiazide tablets should be discontinued and appropriate therapy instituted immediately. (See
WARNINGS.)
Hypotension
In clinical trials, adverse effects relating to hypotension occurred as follows: hypotension (0.9 percent), orthostatic hypotension (1.5 percent), other orthostatic effects (2.3 percent). In addition syncope occurred in 1.3 percent of patients. (See
WARNINGS.)
Cough
See
PRECAUTIONS, Cough.
Clinical Laboratory Test Findings
Serum Electrolytes
See
PRECAUTIONS.
Creatinine, Blood Urea Nitrogen
In controlled clinical trials minor increases in blood urea nitrogen and serum creatinine, reversible upon discontinuation of therapy, were observed in about 0.6 percent of patients with essential hypertension treated with enalapril maleate and hydrochlorothiazide tablets. More marked increases have been reported in other enalapril experience. Increases are more likely to occur in patients with renal artery stenosis. (See
PRECAUTIONS.)
Serum Uric Acid, Glucose, Magnesium, and Calcium
See
PRECAUTIONS.
Hemoglobin and Hematocrit
Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.3 g percent and 1.0 vol percent, respectively) occur frequently in hypertensive patients treated with enalapril maleate and hydrochlorothiazide tablets but are rarely of clinical importance unless another cause of anemia coexists. In clinical trials, less than 0.1 percent of patients discontinued therapy due to anemia.
Liver Function Tests
Rarely, elevations of liver enzymes and/or serum bilirubin have occurred (see
WARNINGS, Hepatic Failure).
Other adverse reactions that have been reported with the individual components are listed below and, within each category, are in order of decreasing severity.
Enalapril Maleate
Enalapril has been evaluated for safety in more than 10,000 patients. In clinical trials adverse reactions which occurred with enalapril were also seen with enalapril maleate and hydrochlorothiazide tablets. However, since enalapril has been marketed, the following adverse reactions have been reported: Body As A Whole: Anaphylactoid reactions (see
WARNINGS, Anaphylactoid reactions during membrane exposure
); Cardiovascular: Cardiac arrest; myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients (see
WARNINGS, Hypotension); pulmonary embolism and infarction; pulmonary edema; rhythm disturbances including atrial tachycardia and bradycardia; atrial fibrillation; hypotension; angina pectoris, Raynaud's phenomenon; Digestive: Ileus, pancreatitis, hepatic failure, hepatitis (hepatocellular [proven on rechallenge] or cholestatic jaundice) (see
WARNINGS, Hepatic Failure), melena, anorexia, glossitis, stomatitis, dry mouth; Hematologic: Rare cases of neutropenia, thrombocytopenia and bone marrow depression. Hemolytic anemia, including cases of hemolysis in patients with G-6-PD deficiency, has been reported; a causal relationship to enalapril cannot be excluded. Nervous System/Psychiatric: Depression, confusion, ataxia, peripheral neuropathy (e.g., paresthesia, dysesthesia), dream abnormality; Urogenital: Renal failure, oliguria, renal dysfunction, (see
PRECAUTIONS
and
DOSAGE AND ADMINISTRATION), flank pain, gynecomastia; Respiratory: Pulmonary infiltrates, eosinophilic pneumonitis, bronchospasm, pneumonia, bronchitis, rhinorrhea, sore throat and hoarseness, asthma, upper respiratory infection; Skin: Exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, herpes zoster, erythema multiforme, urticaria, pemphigus, alopecia, flushing, photosensitivity; Special Senses: Blurred vision, taste alteration, anosmia, conjunctivitis, dry eyes, tearing.
Miscellaneous
A symptom complex has been reported 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.
Fetal/Neonatal Morbidity and Mortality
See
WARNINGS, Pregnancy, Enalapril Maleate, Fetal/Neonatal Morbidity and Mortality.
Hydrochlorothiazide
Body as a Whole: Weakness; Digestive: Pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, gastric irritation, anorexia; Hematologic: Aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia; Hypersensitivity: Purpura, photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), fever, respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions; Musculoskeletal: Muscle spasm; Nervous System/Psychiatric: Restlessness; Renal: Renal failure, renal dysfunction, interstitial nephritis (see
WARNINGS); Skin: Erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis, alopecia; Special Senses: Transient blurred vision, xanthopsia.
|
