Ziac Side Effects

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

Ziac

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 Ziac:

Cough; dizziness; lightheadedness; tiredness.

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); chest pain; irregular heartbeat; muscle pain or weakness; swelling of ankles or feet; unusual thirst or fatigue; unusually slow or irregular heartbeat.

Ziac Side Effects - for the Professional

Ziac

Ziac

Bisoprolol fumarate/HCTZ 6.25 mg is well tolerated in most patients. Most adverse effects (AEs) have been mild and transient. In more than 65,000 patients treated worldwide with bisoprolol fumarate, occurrences of bronchospasm have been rare. Discontinuation rates for AEs were similar for bisoprolol fumarate/HCTZ 6.25 mg and placebo-treated patients.

In the United States, 252 patients received bisoprolol fumarate (2.5, 5, 10, or 40 mg)/HCTZ 6.25 mg and 144 patients received placebo in two controlled trials. In Study 1, bisoprolol fumarate 5/HCTZ 6.25 mg was administered for 4 weeks. In Study 2, bisoprolol fumarate 2.5, 10, or 40/HCTZ 6.25 mg was administered for 12 weeks. All adverse experiences, whether drug related or not, and drug related adverse experiences in patients treated with bisoprolol fumarate 2.5-10/HCTZ 6.25 mg, reported during comparable, 4 week treatment periods by at least 2% of bisoprolol fumarate/HCTZ 6.25 mg-treated patients (plus additional selected adverse experiences) are presented in the following table:

Other adverse experiences that have been reported with the individual components are listed below.

Bisoprolol Fumarate

In clinical trials worldwide, or in postmarketing experience, a variety of other AEs, in addition to those listed above, have been reported. While in many cases it is not known whether a causal relationship exists between bisoprolol and these AEs, they are listed to alert the physician to a possible relationship.

Unsteadiness, dizziness, vertigo, headache, syncope, paresthesia, hypoesthesia, hyperesthesia, sleep disturbance/vivid dreams, insomnia, somnolence, depression, anxiety/restlessness, decreased concentration/memory.

Bradycardia, palpitations and other rhythm disturbances, cold extremities, claudication, hypotension, orthostatic hypotension, chest pain, congestive heart failure, dyspnea on exertion.

Gastric/epigastric/abdominal pain, peptic ulcer, gastritis, dyspepsia, nausea, vomiting, diarrhea, constipation, dry mouth.

Arthralgia, muscle/joint pain, back/neck pain, muscle cramps, twitching/tremor.

Rash, acne, eczema, psoriasis, skin irritation, pruritus, purpura, flushing, sweating, alopecia, dermatitis, exfoliative dermatitis (very rarely), cutaneous vaculitis.

Visual disturbances, ocular pain/pressure, abnormal lacrimation, tinnitus, decreased hearing, earache, taste abnormalities.

Gout.

Asthma, bronchospasm, bronchitis, dyspnea, pharyngitis, rhinitis, sinusitis, URI (upper respiratory infection).

Decreased libido/impotence, Peyronie’s disease (very rarely), cystitis, renal colic, polyuria.

Fatigue, asthenia, chest pain, malaise, edema, weight gain, angioedema.

In addition, a variety of adverse effects have been reported with other beta-adrenergic blocking agents and should be considered potential adverse effects:

Reversible mental depression progressing to catatonia, hallucinations, an acute reversible syndrome characterized by disorientation to time and place, emotional lability, slightly clouded sensorium.

Fever, combined with aching and sore throat, laryngospasm, and respiratory distress.

Agranulocytosis, thrombocytopenia.

Mesenteric arterial thrombosis and ischemic colitis.

The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with bisoprolol fumarate during investigational use or extensive foreign marketing experience.

Hydrochlorothiazide

The following adverse experiences, in addition to those listed in the above table, have been reported with hydrochlorothiazide (generally with doses of 25 mg or greater).

Weakness.

Vertigo, paresthesia, restlessness.

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

Anorexia, gastric irritation, cramping, constipation, jaundice (intrahepatic cholestatic jaundice), pancreatitis, cholecystitis, sialadenitis, dry mouth.

Muscle spasm.

Purpura, photosensitivity, rash, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), fever, respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions.

Transient blurred vision, xanthopsia.

Gout.

Sexual dysfunction, renal failure, renal dysfunction, interstitial nephritis.

Laboratory Abnormalities

Ziac

Because of the low dose of hydrochlorothiazide in Ziac (bisoprolol fumarate and hydrochlorothiazide), adverse metabolic effects with bisoprolol fumarate/HCTZ 6.25 mg are less frequent and of smaller magnitude than with HCTZ 25 mg. Laboratory data on serum potassium from the U.S. placebo-controlled trials are shown in the following table:

Treatment with both beta blockers and thiazide diuretics is associated with increases in uric acid. However, the magnitude of the change in patients treated with B/H 6.25 mg was smaller than in patients treated with HCTZ 25 mg. Mean increases in serum triglycerides were observed in patients treated with bisoprolol fumarate and hydrochlorothiazide 6.25 mg. Total cholesterol was generally unaffected, but small decreases in HDL cholesterol were noted.

Other laboratory abnormalities that have been reported with the individual components are listed below.

Bisoprolol Fumarate

In clinical trials, the most frequently reported laboratory change was an increase in serum triglycerides, but this was not a consistent finding.

Sporadic liver test abnormalities have been reported. In the U.S. controlled trials experience with bisoprolol fumarate treatment for 4-12 weeks, the incidence of concomitant elevations in SGOT and SGPT from 1 to 2 times normal was 3.9%, compared to 2.5% for placebo. No patient had concomitant elevations greater than twice normal.

In the long-term, uncontrolled experience with bisoprolol fumarate treatment for 6-18 months, the incidence of one or more concomitant elevations in SGOT and SGPT from 1 to 2 times normal was 6.2%. The incidence of multiple occurrences was 1.9%. For concomitant elevations in SGOT and SGPT of greater than twice normal, the incidence was 1.5%. The incidence of multiple occurrences was 0.3%. In many cases these elevations were attributed to underlying disorders, or resolved during continued treatment with bisoprolol fumarate.

Other laboratory changes included small increases in uric acid, creatinine, BUN, serum potassium, glucose, and phosphorus and decreases in WBC and platelets. There have been occasional reports of eosinophilia. These were generally not of clinical importance and rarely resulted in discontinuation of bisoprolol fumarate.

As with other beta-blockers, ANA conversions have also been reported on bisoprolol fumarate. About 15% of patients in long-term studies converted to a positive titer, although about one-third of these patients subsequently reconverted to a negative titer while on continued therapy.

Hydrochlorothiazide

Hyperglycemia, glycosuria, hyperuricemia, hypokalemia and other electrolyte imbalances, hyperlipidemia, hypercalcemia, leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia, and hemolytic anemia have been associated with HCTZ therapy.

Side Effects by Body System

General

Experience with this combination product is limited. Due to the relatively low doses of each drug in the combination tablets, side effects are unlikely.

Cardiovascular

The incidence of premature ventricular depolarizations associated with HCTZ, as measured by 48-hour ECG monitoring, is the same in patients with and without left ventricular hypertrophy despite a similar fall in serum potassium concentrations.

Cardiovascular side effects include bradycardia, dizziness, and dyspnea. Like other beta-blockers, bisoprolol may decrease myocardial contractility, which may be important in some patients with poor left ventricular systolic function. The drug has, however, been used safely in patients with chronic stable heart failure.

Unusual side effects include palpitations, mild heart rhythm disturbances, and orthostatic hypotension. Claudication is reported, and may be more likely in patients with peripheral vascular disease.

Metabolic

Metabolic changes are common during HCTZ therapy, but are not expected due to the relatively low dose (6.25 mg) in each combination tablet. Mild hypokalemia (decrease of 0.5 mEq/L) occurs in up to 50% of patients who are receiving at least 50 mg per day of HCTZ. This may predispose some patients to develop cardiac arrhythmias. Metabolic alkalosis, hyponatremia, hypomagnesemia, hypercalcemia, hyperglycemia, hypercholesterolemia, and hyperuricemia are also relatively common with these higher doses.

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, it should be used with caution in diabetic patients and in those with hypercholesterolemia.

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.

Hypersensitivity

Hypersensitivity reactions are reported in 1% of patients who are taking HCTZ. These may present as nausea, vomiting, diarrhea, or rash. Rare cases of acute pulmonary edema, interstitial cystitis, and interstitial nephritis, and anaphylaxis have been associated with HCTZ.

A 68-year-old man with a history of myocardial infarction (MI) developed dyspnea, chest tightness, a low grade fever, dizziness, sweating, and vomiting associated with cyanosis, a mild leukocytosis, radiographic evidence of pulmonary edema, clinical evidence of hypovolemia, and respiratory acidosis. MI and infection were ruled out; the patient recovered after restoration of this intravascular volume with saline and albumin. The only precipitating factor per history was the ingestion of HCTZ, which the patient had taken without incidence for two years. Rechallenge resulted in recurrent acute pulmonary edema. Other signs of hypersensitivity, such as rash and eosinophilia, were absent.

Nervous system

Nervous system side effects include dizziness, vertigo, headache, paresthesias, somnolence, decreased concentration or memory, and anxiety. One case of ischemic stroke is associated with HCTZ-induced plasma volume contraction.

Respiratory

Wheezing is a rare respiratory system side effect that is associated with beta-blockers. This is due to beta-blockade of bronchial dilation, and may be important in patients with reactive airways disease. Approximately 30 case reports of acute noncardiogenic pulmonary edema have been associated with HCTZ.

Dermatologic

Dermatologic problems associated with bisoprolol include rash, acne, eczema, skin irritation, pruritus, flushing, sweating, alopecia, angioedema, and exfoliative dermatitis. Reactions associated with HCTZ include erythema annular centrifugum, acute eczematous dermatitis, 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 HCTZ.

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.

Endocrine

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

Endocrinologic changes associated with both bisoprolol and HCTZ include hyperglycemia and hyperlipidemia. In one study, patients treated with the combination had an average increase of 32.6 mg/dl in serum triglycerides and an average decrease of 3.3 mg in HDL cholesterol. This may be important in patients with or at risk of diabetes or coronary artery disease. Thyroid function tests are unaffected by bisoprolol. This may be relevant if bisoprolol is used to treat the symptoms of hyperthyroidism.

Hepatic

The incidence of elevated liver function tests (SGOT and SGPT) of between one and two times normal is approximately 6%, of greater than two times normal is approximately 2%.

Renal

Renal insufficiency may develop due to HCTZ-induced intravascular volume depletion, but is unlikely due to the relative small doses of drug in the combination tablet. Rare cases of interstitial nephritis have been associated with 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.

Gastrointestinal

Gastrointestinal side effects are unusual. Diarrhea has been reported in up to 5% and 6% of patients taking bisoprolol alone and bisoprolol-HCTZ, respectively. Rare cases of pancreatitis and acute cholecystitis have been associated with HCTZ.

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

Genitourinary

Genitourinary problems include decreased libido, impotence, Peyronie's disease, cystitis, and renal colic.

Psychiatric

Psychiatric problems associated with bisoprolol include vivid dreams, hallucinations, and insomnia. Rare cases of catatonia or depression have been associated with bisoprolol.

Hematologic

Hematologic side effects are rare. Purpura, agranulocytosis, and thrombocytopenia have been associated with bisoprolol, and rare cases of immune-complex hemolytic anemia, aplastic anemia, and thrombocytopenia have been associated with HCTZ.

Musculoskeletal

Musculoskeletal pain is reported in rare cases. Gout and elevated serum uric acid levels are reported in at least 1% of patients. Myalgias and chills are rarely reported in patients who are receiving HCTZ.

Immunologic

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, and hemoglobinuria, and elevated serum lactic dehydrogenase levels 18 months after beginning HCTZ and methyldopa. Haptoglobin was less than 50 mg per 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.

Clinically significant immunologic changes are rare. Approximately 15% of patients on long-term bisoprolol therapy develop a positive ANA titer. Rare cases of allergic vasculitis and hemolytic anemia are associated with HCTZ.

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