Quinaretic Side Effects

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

Quinaretic

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 Quinaretic:

Diarrhea; difficulty breathing, dizziness, or lightheadedness when sitting up or standing; fatigue; headache; loss of appetite; nausea; persistent dry cough; tiredness.

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); chest pain; darkening of urine; decrease in the amount of urine; drowsiness; dry mouth; fainting; fast, slow, or irregular heartbeat; fever, chills, or sore throat; prolonged nausea, vomiting, or diarrhea; restlessness; severe dizziness or lightheadedness; unusual joint pain; unusual muscle pain, cramps, or weakness; unusual or severe stomach pain; unusual thirst; unusual tiredness or weakness; unusual weight gain; yellowing of the skin or eyes.

Quinaretic Side Effects - for the Professional

Quinaretic

Quinaretic has been evaluated for safety in 1571 patients in controlled and uncontrolled studies. Of these, 498 were given quinapril plus hydrochlorothiazide for at least 1 year, with 153 patients extending combination therapy for over 2 years. In clinical trials with Quinaretic, no adverse experience specific to the combination has been observed. Adverse experiences that have occurred have been limited to those that have been previously reported with quinapril or hydrochlorothiazide.

Adverse experiences were usually mild and transient, and there was no relationship between side effects and age, sex, race, or duration of therapy. Discontinuation of therapy because of adverse effects was required in 2.1% in patients in controlled studies. The most common reasons for discontinuation of therapy with Quinaretic were cough (1.0%; see PRECAUTIONS) and headache (0.7%).

Adverse experiences probably or possibly related to therapy or of unknown relationship to therapy occurring in 1% or more of the 943 patients treated with quinapril plus hydrochlorothiazide in controlled trials are shown below.

Clinical adverse experiences probably, possibly, or definitely related or of uncertain relationship to therapy occurring in ≥0.5% to <1.0% (except as noted) of the patients treated with quinapril/HCTZ in controlled and uncontrolled trials (N=1571) and less frequent, clinically significant events seen in clinical trials or postmarketing experience (the rarer events are in italics) include (listed by body system):

Postmarketing Experience

The following serious nonfatal adverse events, regardless of their relationship to quinapril and HCTZ combination tablets, have been reported during extensive postmarketing experience:

BODY AS A WHOLE: Shock, accidental injury, neoplasm, cellulites, ascites, generalized edema, hernia and anaphylactoid reaction.

CARDIOVASCULAR SYSTEM: Bradycardia, cor pulmonale, vasculitis, and deep thrombosis.

DIGESTIVE SYSTEM: Gastrointestinal carcinoma, cholestatic jaundice, hepatitis, esophagitis, vomiting, and diarrhea.

HEMIC SYSTEM: Anemia.

METABOLIC AND NUTRITIONAL DISORDERS: Weight loss.

MUSCULOSKELETAL SYSTEM: Myopathy, myositis, and arthritis.

NERVOUS SYSTEM: Paralysis, hemiplegia, speech disorder, abnormal gait, meningism, and amnesia.

RESPIRATORY SYSTEM: Pneumonia, asthma, respiratory infiltration, and lung disorder.

SKIN AND APPENDAGES: Urticaria, macropapular rash, and petechiases.

SPECIAL SENSES: Abnormal vision.

UROGENITAL SYSTEM: Kidney function abnormal, albuminuria, pyuria, hematuria, and nephrosis.

Quinapril monotherapy has been evaluated for safety in 4960 patients. In clinical trials adverse events which occurred with quinapril were also seen with Quinaretic. In addition, the following were reported for quinapril at an incidence >0.5%: depression, back pain, constipation, syncope, and amblyopia.

Hydrochlorothiazide has been extensively prescribed for many years, but there has not been enough systematic collection of data to support an estimate of the frequency of the observed adverse reactions. Within organ-system groups, the reported reactions are listed here in decreasing order of severity, without regard to frequency.

Clinical Laboratory Test Findings

Serum Electrolytes: See PRECAUTIONS.

Creatinine, Blood Urea Nitrogen: Increases (>1.25 times the upper limit of normal) in serum creatinine and blood urea nitrogen were observed in 3% and 4%, respectively, of patients treated with Quinaretic. Most increases were minor and reversible, which can occur in patients with essential hypertension but most frequently in patients with renal artery stenosis.

PBI and Tests of Parathyroid Function: See PRECAUTIONS.

Hematology: See WARNINGS.

Other (causal relationships unknown): Other clinically important changes in standard laboratory tests were rarely associated with Quinaretic administration. Elevations in uric acid, glucose, magnesium, cholesterol, triglyceride, and calcium have been reported.

Side Effects by Body System

General

Hydrochlorothiazide-quinapril has been evaluated for safety in more than 1,571 patients with hypertension with 153 treated for more than one year prior to its approval by the FDA. Adverse side effects were usually mild and transient, with no relationship to gender, race, age, or total daily dosage. In controlled trials, discontinuation of therapy was reported in 2.1% of patients due to adverse side effects.

Respiratory

Respiratory side effects including reversible, dry cough has been reported in 3.2% of patients presumably due to the inhibition of the degradation of endogenous bradykinin. Cough appears to be as common in women as men, but women have, in some reviews, reported cough more often than men. Less frequently reported respiratory side effects include rhinitis (2%), upper respiratory infection (1.3%), bronchitis (1.2%) and pharyngitis (1.1%). These side effects occurred more often with placebo than with HCTZ-quinapril. Rare respiratory system side effects have included pneumonia, asthma, respiratory infiltration, lung disorder, and acute noncardiogenic pulmonary edema.

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%).

Renal

Patients with renal artery stenosis maintain glomerular filtration rate (GFR) by efferent arteriolar vasoconstriction, which is blocked by quinapril.

Although quinapril may be associated with a rise in serum creatinine and BUN, GFR has been shown to remain unchanged or improve in most patients.

HCTZ has been used to treat nephrogenic diabetes insipidus. However, a case in which the drug was believed to have caused this condition has been reported.

Renal side effects including new or worsened renal insufficiency may develop especially in patients with preexisting renal insufficiency or in patients who are angiotensin-dependent, such as those with CHF. Patients with renal artery stenosis should not receive quinapril or any other ACE inhibitor since it may precipitate acute renal failure. While there is a growing body of literature describing decreased proteinuria in some patients, new onset proteinuria may develop during ACE inhibition. Rare cases of interstitial nephritis have been associated with HCTZ.

Cardiovascular

Cardiovascular side effects reported include vasodilatation, vertigo, and chest pain in 1% of patients. Palpitations and tachycardia were reported in less than 1% of patients. Rarely reported side effects include heart failure, myocardial infarction, cerebrovascular accident, hypertensive crisis, orthostatic hypotension, and cardiac rhythm disturbance. Additional postmarketing side effects include bradycardia, cor pulmonale, vasculitis, and deep thrombosis. HCTZ-induced hypokalemia can predispose some patients to various cardiac arrhythmias, such as ventricular ectopy and complete AV heart block. Hypokalemia is much less likely with the addition of quinapril, since ACE inhibitors may decrease serum aldosterone.

Hypotension is most likely in patients who are sodium and intravascular volume depleted.

Hypersensitivity

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.

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.

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.

Nervous system

Nervous system side effects have included headache (5.7%), dizziness (4.8%), fatigue (2.9%), insomnia (1.2%), somnolence (1.2%), and asthenia (1.1%). Rare cases of cerebrovascular insufficiency have been associated with HCTZ-induced plasma volume contraction. Postmarketing side effects include paralysis, hemiplegia, speech disorder, abnormal gait, meningism, and amnesia.

Metabolic

HCTZ may increase total serum cholesterol by 11%, LDL lipoprotein cholesterol by 12%, and VLDL lipoprotein cholesterol levels by 50%, as well as reduce insulin secretion. It should be used with caution in patients with diabetes or hypercholesterolemia.

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

Metabolic side effects including hypokalemia associated with HCTZ is much less likely with the addition of quinapril because ACE inhibitors may decrease serum aldosterone levels. By the same token, the mild hyperkalemia, although clinically insignificant, that often accompanies the use of quinapril, 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.

Hematologic

Hematologic side effects are rare. Neutropenia and bone marrow depression have rarely been associated with quinapril and other ACE inhibitors. Isolated cases of immune-complex hemolytic anemia, aplastic anemia, and thrombocytopenia have been associated with HCTZ.

There are rare case reports of HCTZ-induced immune hemolytic anemia. The following illustrates a fatal case:

A 53-year-old man with hypertension developed nausea, vomiting, diarrhea, and progressive anorexia and weakness associated with scleral icterus, anemia with spherocytosis, dark red urine with proteinuria, bilirubinuria, hemoglobinuria, and elevated lactic dehydrogenase levels 18 months after beginning HCTZ and methyldopa. Haptoglobin was less than 50 mg/dL. Direct and indirect Coombs tests were positive. The patient died suddenly. Autopsy revealed no obvious cause of death, left ventricular hypertrophy, and mild coronary atherosclerosis.

Gastrointestinal

Gastrointestinal disturbances have included nausea and vomiting (1.8%), abdominal pain (1.7%), diarrhea (1.4%), and dyspepsia (1.2%). Dry mouth and gastrointestinal hemorrhage have been reported in less than 1% of patients. Rare cases of pancreatitis and acute cholecystitis have been associated with HCTZ.

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).

Dermatologic

A 67-year-old white woman with hypothyroidism, hypercalcemia, depression, and hypertension developed facial erythema, headaches, tremors, confusion, and personality changes associated with a new positive ANA and anti-nRNP, and skin biopsy consistent with lupus erythematosus while taking HCTZ, levothyroxine, and amitriptyline. The eruption resolved upon discontinuation of HCTZ, but she later developed a higher ANA titer associated with symptomatic diffuse interstitial pulmonary infiltrates. She was successfully treated with corticosteroids.

Dermatologic reactions associated with HCTZ include erythema annular centrifugum, acute eczematous dermatitis, and morbilliform or 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 HCTZ. Rare instances of pruritus, increased sweating, erythema, alopecia, and pemphigus have been reported in 1% or less of patients. Postmarketing side effects reported include urticaria, maculopapular rash, and petechiae.

Endocrine

A prospective study of 34 patients who received oral thiazide diuretics for 14 years without interruption revealed an increased mean fasting blood glucose level after treatment. Withdrawal of thiazide therapy for seven months in 10 of the patients resulted in mean reductions of 10% in fasting blood glucose and 25% in the 2-hour glucose tolerance test value. A control group was not reported.

Endocrinologic problems associated with thiazide diuretics include glucose intolerance and a potentially deleterious effect on the lipid profile, either of which may be important in some patients with or at risk for diabetes or coronary artery disease.

Musculoskeletal

Musculoskeletal side effects have rarely been reported and include myalgias, chills, myopathy, myositis, muscle spasm, back pain, and arthritis.

Genitourinary

Genitourinary complaints are limited to impotence in less than 1% of male patients.

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