Ziac (bisoprolol and hydrochlorothiazide) Side Effects, Warnings, and Drug Interactions

Ziac (bisoprolol and hydrochlorothiazide) is a combination of a beta-adrenergic receptor blocking agent (beta-blocker) and a diuretic (water pill) used to treat high blood pressure and heart pain (angina). 

Bisoprolol prevents the neurotransmitters norepinephrine and epinephrine (adrenaline), from binding to beta-adrenergic receptors on nerves. By blocking the effect of norepinephrine and epinephrine on the nerves reaching the heart and blood vessels, beta-blockers reduce heart rate and the force with which the heart contracts and reduce blood pressure by dilating blood vessels. It also may constrict air passages by stimulating the muscles that surround the air passages. 

Hydrochlorothiazide works by blocking salt and fluid reabsorption in the kidneys, causing increased urine output (diuresis). The combination of bisoprolol and hydrochlorothiazide reduces blood pressure better than either drug alone.

Common side effects of Ziac include:

• fatigue,
• headache,
• diarrhea,
• low potassium,
• low blood pressure,
• impotence,
• reduced heart rate, and
• increased blood glucose.

Serious side effects of Ziac include:

• congestive heart failure,
• heart block,
• severely reduced heart rate,
• bronchospasms,
• abnormal heart rhythms, and
• serious skin reactions.

Drug interactions of Ziac include rifampin, which when taken with Ziac may make Ziac less effective. 

Other beta-blockers when taken with Ziac may produce excessive reduction of sympathetic activity. 

Certain calcium channel blockers (CCBs) may enhance the effect of Ziac on the heart. 

The use of digoxin with Ziac also may cause an excessive reduction in heart rate. Nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce the blood pressure lowering effects of beta-blockers. 

Blood sugar levels can be elevated by hydrochlorothiazide, necessitating adjustment in the doses of medications that are used for treating diabetes. 

Combining hydrochlorothiazide with corticosteroids may increase the risk for low levels of blood potassium and other electrolytes. 

The most common side effects are:

• fatigue,
• headache,
• diarrhea,
• low potassium,
• low blood pressure,
• impotence,
• reduced heart rate, and
• increased blood glucose.

Serious side effects of Ziac include:

• congestive heart failure,
• heart block,
• severely reduced heart rate,
• bronchospasms,
• abnormal heart rhythms, and
• serious skin reactions.

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 rumarate 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:

% of Patients with Adverse Experiences^a

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.

Central Nervous System

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

Cardiovascular

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

Gastrointestinal

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

Musculoskeletal

• arthralgia,
• muscle/joint pain,
• back/neck pain,
• muscle cramps,
• twitching/tremor.

Skin

• rash,
• acne,
• eczema,
• psoriasis,
• skin irritation,
• pruritus,
• purpura,
• flushing,
• sweating,
• alopecia,
• dermatitis,
• exfoliative dermatitis (very rarely),
• cutaneous vasculitis.

Special Senses

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

Metabolic

gout.

Respiratory

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

Genitourinary

• decreased libido/impotence,
• Peyronie's disease (very rarely),
• cystitis,
• renal colic,
• polyuria.

General

• 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:

Central Nervous System

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

Allergic

• fever,
• combined with aching and sore throat,
• laryngospasm, and
• respiratory distress.

Hematologic

• agranulocytosis,
• thrombocytopenia.

Gastrointestinal

• mesenteric arterial thrombosis and
• ischemic colitis.

Miscellaneous

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).

General

Weakness.

Central Nervous System

• vertigo,
• paresthesia,
• restlessness.

Cardiovascular

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

Gastrointestinal

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

Musculoskeletal

Muscle spasm.

Hypersensitive Reactions

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

Special Senses

Transient blurred vision, xanthopsia.

Metabolic

Gout.

Genitourinary

• sexual dysfunction,
• renal failure,
• renal dysfunction,
• interstitial nephritis.

Skin

• Erythema multiforme, including Stevens-Johnson syndrome,
• exfoliative dermatitis including toxic epidermal necrolysis.

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:

Serum Potassium Data from U.S. Placebo Controlled Studies

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.

Ziac may potentiate the action of other antihypertensive agents used concomitantly. Ziac should not be combined with other beta-blocking agents. Patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, should be closely monitored because the added beta-adrenergic blocking action of bisoprolol fumarate may produce excessive reduction of sympathetic activity. In patients receiving concurrent therapy with clonidine, if therapy is to be discontinued, it is suggested that Ziac be discontinued for several days before the withdrawal of clonidine.

Ziac should be used with caution when myocardial depressants or inhibitors of AV conduction, such as certain calcium antagonists (particularly of the phenylalkylamine [verapamil] and benzothiazepine [diltiazem] classes), or antiarrhythmic agents, such as disopyramide, are used concurrently.

Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.

Bisoprolol Fumarate

Concurrent use of rifampin increases the metabolic clearance of bisoprolol fumarate, shortening its elimination half-life. However, initial dose modification is generally not necessary.

Pharmacokinetic studies document no clinically relevant interactions with other agents given concomitantly, including thiazide diuretics and cimetidine. There was no effect of bisoprolol fumarate on prothrombin times in patients on stable doses of warfarin.

Risk of Anaphylactic Reaction

While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.

Hydrochlorothiazide

When given concurrently the following drugs may interact with thiazide diuretics.

Alcohol, barbiturates, or narcotics - potentiation of orthostatic hypotension may occur.

Antidiabetic drugs (oral agents and insulin) - dosage adjustment of the antidiabetic drug may be required.

Other antihypertensive drugs - additive effect or potentiation.

Cholestyramine and colestipol resins - Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of cholestyramine and colestipol resins bind the hydrochlorothiazide and reduce its absorption in the gastrointestinal tract by up to 85 percent and 43 percent, respectively.

Corticosteroids, ACTH - Intensified electrolyte depletion, particularly hypokalemia.

Pressor amines (e.g., norepinephrine) - possible decreased response to pressor amines but not sufficient to preclude their use.

Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine) - possible increased responsiveness to the muscle relaxant.

Lithium - generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Refer to the package insert for lithium preparations before use of such preparations with ZLAC.

Nonsteroidal anti-inflammatory drugs - In some patients, the administration of a nonsteroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium sparing, and thiazide diuretics. Therefore, when ZLAC and nonsteroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.

In patients receiving thiazides, sensitivity reactions may occur with or without a history of allergy or bronchial asthma. Photosensitivity reactions and possible exacerbation or activation of systemic lupus erythematosus have been reported in patients receiving thiazides. The antihypertensive effects of thiazides may be enhanced in the post-sympathectomy patient.

Laboratory Test Interactions

Based on reports involving thiazides, Ziac (bisoprolol fumarate and hydrochlorothiazide) may decrease serum levels of protein-bound iodine without signs of thyroid disturbance.

Because it includes a thiazide, Ziac should be discontinued before carrying out tests for parathyroid function.