Uniretic Side Effects

Please note - some side effects for Uniretic 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 Uniretic - for the Consumer

Uniretic

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 Uniretic:

Coughing; diarrhea; dizziness; headache; lightheadedness; nausea; persistent nonproductive cough; tiredness; vomiting.

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); difficulty swallowing; fainting; fast, slow, or irregular heartbeat; fever; muscle cramps; muscle weakness; severe dizziness or lightheadedness; shortness of breath; sore throat; unusual stomach pain; yellowing of the skin or eyes.

Uniretic Side Effects - for the Professional

Uniretic

Uniretic® has been evaluated for safety in more than 1140 patients with hypertension with more than 120 treated for more than one year. Uniretic® has not demonstrated a potential for causing adverse experiences different from those previously associated with other ACE inhibitor/diuretic combinations. The overall incidence of reported adverse events was slightly less in patients treated with Uniretic® than patients treated with placebo.

Adverse experiences were usually mild and transient, and there was no relationship between adverse experiences and gender, race, age, or total daily dosage (except for serum potassium decreases at 50 mg hydrochlorothiazide) within the moexipril/ hydrochlorothiazide dosage range of 3.75 mg / 3.125 mg to 30 mg / 50 mg. Discontinuation of therapy due to adverse experiences was required in 5.3% of patients treated with Uniretic® and in 8.4% of patients treated with placebo. The most common reasons for discontinuation of therapy with Uniretic® were cough (0.5%) and dizziness (0.5%).

All adverse experiences considered at least possibly related to treatment that occurred at any dose in placebo-controlled trials of once-daily dosing in more than 1% of patients treated with Uniretic® and that were at least as frequent in the Uniretic® group as in the placebo group are shown in the following table.

Other adverse experiences occurring in more than 1% of patients treated with Uniretic® in controlled or uncontrolled trials, some of which were of uncertain drug relationship, listed in decreasing frequency include: upper respiratory infection, headache, pain, flu syndrome, pharyngitis, hyperuricemia, diarrhea, back pain, rhinitis, sinusitis, abnormal ECG, infection, abdominal pain, chest pain, dyspepsia, hyperglycemia, hypokalemia, rash, vertigo, nausea, hypertonia, increased SGPT, urinary tract infection, impotence, peripheral edema, pyuria, bronchitis, and fever. See WARNINGS and PRECAUTIONSfor discussion of anaphylactoid reactions, angioedema, hypotension, neutropenia/agranulocytosis, fetal/neonatal morbidity and mortality, serum electrolyte imbalances, and cough.

 The following adverse experiences, some of which are of uncertain drug relationship, were reported in Uniretic® controlled or uncontrolled clinical trials in less than 1% of patients or have been attributed to other ACE inhibitors. Within each organ system, adverse experiences are listed in decreasing frequency.

Cardiovascular

Palpitation, flushing, syncope, tachycardia, myocardial infarct, hypotension, postural hypotension, arrhythmia, first degree AV block, ventricular extrasystoles, atrial fibrillation, migraine, hemorrhage, sinus bradycardia, bigeminy, bradycardia, bundle branch block, heart arrest, myocardial ischemia, peripheral vascular disorder, prolonged QT interval, inverted T wave, ventricular fibrillation

Dermatologic

Eczema, pruritus, sweating, acne, dry skin, herpes simplex, contact dermatitis, herpes zoster, psoriasis, alopecia, angioedema, erythema nodosum, fungal dermatitis, furunculosis, maculopapular rash, purpuric rash, skin carcinoma, subcutaneous nodule, urticaria, pemphigus

Gastrointestinal

Vomiting, constipation, gastroenteritis, periodontal abscess, cholelithiasis, gastritis, gingivitis, esophagitis, flatulence, anorexia, colitis, dysphagia, tooth caries, cheilitis, enteritis, eructation, gastrointestinal carcinoma, gastrointestinal hemorrhage, glossitis, increased appetite, jaundice, melena, rectal hemorrhage, stomatitis, tongue discoloration, tongue edema

Hematologic

Anemia, hypochromic anemia, leukopenia, abnormal erythrocytes, ecchymosis, lymphocytosis, hemolysis, lymphadenopathy, eosinophilia, petechia, abnormal WBC, hemolytic anemia

Metabolic

Hyperlipemia, increased SGOT, gout, bilirubinemia, increased creatinine, hypercholesterolemia, increased BUN, increased CPK, diabetes mellitus, hyponatremia, thirst, edema, increased alkaline phosphatase, increased amylase, dehydration, decreased glucose tolerance, goiter, hypercalcemia, hyperkalemia, hypocalcemia, hypochloremia, hypoproteinemia, weight gain

Neurologic/Psychiatric

Insomnia, postural dizziness, somnolence, dry mouth, anxiety, nervousness, paresthesia, depression, neuritis, hypesthesia, decreased libido, neuralgia, amnesia, ataxia, cerebral infarct, emotional lability, facial paralysis, hypokinesia, neurosis, vocal cord paralysis

Renal

Albuminuria, urinary frequency, hematuria, glycosuria, cystitis, dysuria, nocturia, polyuria, kidney calculus, pyelonephritis, urate crystalluria, urinary casts, urinary retention

Respiratory

Epistaxis, pneumonia, dyspnea, asthma, lung carcinoma, hemoptysis, laryngitis, voice alteration, eosinophilic pneumonitis

Urogenital

Vaginal hemorrhage, breast carcinoma, scrotal edema, vaginitis, breast enlargement, breast pain, dysmenorrhea, leukorrhea

Other

Asthenia, conjunctivitis, myalgia, arthralgia, arthrosis, hernia, neck pain, cyst, tenosynovitis, abnormal vision, allergic reaction, arthritis, cataract, cellulitis, moniliasis, otitis media, eye hemorrhage, chills, abscess, bursitis, deafness, ear pain, glaucoma, iritis, neck rigidity, photosensitivity, retinal degeneration, tinnitus

Monotherapy with moexipril has been evaluated for safety in over 3000 patients. In clinical trials, the observed adverse experiences with moexipril were similar to those seen in the Uniretic® trials.

Hydrochlorothiazide

The following adverse reactions have been reported with hydrochlorothiazide and, within each organ system, are listed by decreasing severity.

Orthostatic hypotension (may be potentiated by alcohol, barbiturates, or narcotics)

Pancreatitis, jaundice (intrahepatic cholestatic, see WARNINGS), sialadenitis, vomiting, diarrhea, cramping, nausea, gastric irritation, constipation, anorexia

Vertigo, dizziness, transient blurred vision, headache, paresthesia, xanthopsia, weakness, restlessness

Muscle spasm

Aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia

Hyperglycemia, glycosuria, hyperuricemia

Necrotizing angiitis, Stevens-Johnson syndrome, respiratory distress including pneumonitis and pulmonary edema, purpura, urticaria, rash, photosensitivity

Clinical Laboratory Test Findings

See PRECAUTIONS, General.

As with other ACE inhibitors, minor increases in blood urea nitrogen or serum creatinine, reversible upon discontinuation of therapy, were observed in less than 1% of patients with essential hypertension who were treated with Uniretic®. Increases are more likely to occur in patients with compromised renal function.

Clinically important changes in standard laboratory tests were rarely associated with Uniretic® administration.

Side Effects by Body System

General

Moexipril-hydrochlorothiazide (HCTZ) has been evaluated for safety in more than 1,140 patients with hypertension with more than 120 treated for more than 1 year prior to its approval by the FDA. The overall incidence of adverse side effects was slightly less than in comparable patients treated with placebo. Adverse side effects were usually mild and transient, and there was no relationship between them and gender, race, age, or total daily dosage (except for serum potassium decreases associated with daily doses of HCTZ greater than 50 mg). In controlled trials, discontinuation of therapy was reported in 5.3% of treated patients due to adverse side effects, compared with 8.4% of patients who were taking placebo.

Renal

Renal side effects including new or worsened renal insufficiency, defined as an increase in serum creatinine concentration to at least 140% of baseline values, has been reported in 2% of patients taking moexipril-HCTZ. The presence of the following risk factors may significantly increase the likelihood of nephrotoxicity: heart failure, intravascular hypovolemia or dehydration, renal artery stenosis, and underlying renal insufficiency.

Rare cases of interstitial nephritis have been associated with the use of HCTZ. Although HCTZ has been used to treat nephrogenic diabetes insipidus, a case report in which the drug was believed to have caused this condition has been reported.

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.

Urticaria, rash, pemphigus, pruritus, and photosensitivity have also been associated with moexipril.

Hypersensitivity reactions to HCTZ have included nausea, vomiting, diarrhea, and rash in less than 1% of patients. Acute pulmonary edema, interstitial cystitis, interstitial nephritis, and anaphylaxis have rarely been associated with the use of HCTZ.

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..

There have been approximately 34 known cases of thiazide-induced pulmonary edema, encompassing 52 episodes of pulmonary edema, as of 1991 (per a 1996 review). In some cases, doses as small as 12.5 mg were associated with the development of pulmonary edema. The average time to onset of this adverse reaction was 44 minutes, women have a relative risk of 9:1, and the average age was 56 years. The mortality rate was 6%. Some experts consider this side effect grossly underreported.

Metabolic

Since HCTZ may increase total serum cholesterol by 11%, LDL lipoprotein cholesterol by 12%, and VLDL lipoprotein cholesterol levels by 50%, and may reduce insulin secretion, caution is recommended when giving this drug to diabetic patients or those with hypercholesterolemia. Irreversible glucose intolerance may develop in approximately 3% of patients. It is typically reversible within six months after discontinuation of therapy.

Hyperuricemia may be an important consideration in patients with a history of gout. Hypophosphatemia and low serum magnesium concentrations may occur, but are usually clinically insignificant except in malnourished patients.

Metabolic side effects including hypokalemia associated with the use of HCTZ is much less likely with the addition of moexipril because ACE inhibitors decrease serum aldosterone levels. By the same token, the mild hyperkalemia, although clinically insignificant, that often accompanies the use of moexipril, is much less likely due to HCTZ-induced kaliuresis. HCTZ can induce metabolic alkalosis, hyponatremia, hypomagnesemia, hypercalcemia, hyperglycemia, and elevated serum uric acid levels. It may also increase serum cholesterol.

Cardiovascular

Cardiovascular side effects include dizziness, symptomatic hypotension, postural hypotension, or syncope in 0.5% to 1.0% of patients. Angina, myocardial infarction, palpitations, rhythm disturbances, and stroke have rarely been associated with the use of this drug or one of its components.

Hematologic

Hematologic side effects associated with either component of this combination drug have been extremely rare, but very serious in some cases. Rarely, the use of moexipril or other ACE inhibitors has been associated with the development of agranulocytosis, myelosuppression, or hemolytic anemia. Hematologic side effects have only rarely been associated with the use of ACE inhibitors in patients with uncomplicated hypertension, and have been almost exclusively been associated with the use of these drugs in patients with renal impairment and/or collagen-vascular disease (such as lupus erythematosus or scleroderma). Although more data are needed with regard to moexipril, monitoring of white blood cell counts is recommended in cases where these risk factors are present.

Respiratory

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

Respiratory side effects including cough is associated with moexipril and other ACE inhibitors. It has been associated with the use of moexipril and moexipril-HCTZ in up to 6% and 3% of patients, respectively. Cough has been the most common reason patients on moexipril discontinue moexipril therapy. Dyspnea and wheezing have rarely been associated with the use of moexipril, and acute pulmonary edema, presumably due to hypersensitivity, has been associated with the use of HCTZ.

Gastrointestinal

Thiazide diuretics may increase serum cholesterol and triglycerides, resulting in an increased risk of cholesterol gallstone formation. Reports of bowel strictures associated with thiazide ingestion were reported in the 1960's (although patients in these reports were on a combination HCTZ-potassium product).

Gastrointestinal side effects are uncommon, and include abdominal pain, constipation, vomiting, appetite or weight changes, dry mouth, and rare cases of pancreatitis, hepatitis, and cholecystitis.

Dermatologic

Dermatologic reactions to thiazide-type diuretics have rarely included erythema annular centrifugum, acute eczematous dermatitis, and morbilliform and leukocytoclastic vasculitis. Thiazides may induce phototoxic dermatitis. In addition, a rare, distinct entity with clinical and laboratory features indistinguishable from those of subacute cutaneous lupus erythematosus has been associated with the use of HCTZ.

Nervous system

Nervous system side effects associated with the use of moexipril include drowsiness, sleep or taste disturbances, headache, nervousness, mood changes, tinnitus, and anxiety. Rarely, stroke due to cerebrovascular insufficiency and intravascular volume depletion has been associated with the use of HCTZ.

Immunologic

Immunologic side effects associated with the use of HCTZ have been rare, and have included allergic vasculitis and hemolytic anemia. There have been numerous case reports of patients developing a rash histologically identical to subacute cutaneous lupus following HCTZ administration.

Endocrine

A prospective study of 34 patients who received oral thiazide diuretics for 14 years without interruption revealed significantly increased average fasting blood glucose levels. Withdrawal of thiazide therapy for 7 months in 10 of the patients resulted in average reductions of 10% in fasting blood glucose and 25% in 2-hour glucose tolerance test values. A control group was not reported.

Endocrinologic problems associated with the use of thiazide-type diuretics include glucose intolerance and a potentially deleterious effect on the lipid profile. This may be important in some patients with or who are at risk for diabetes or coronary artery disease.

Musculoskeletal

Musculoskeletal side effects have rarely been associated with the use of thiazide-type diuretics and have included myalgias and chills.

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