Bisoprolol fumarate/Hydrochlorothiazide

Description

Bisoprolol fumarate and hydrochlorothiazide tablets, USP are indicated for the management of hypertension. This formulation combines two antihypertensive agents for once-daily administration: bisoprolol fumarate, a synthetic beta 1-selective (cardioselective) adrenoceptor blocking agent, and hydrochlorothiazide, a benzothiadiazine diuretic.

Bisoprolol fumarate, USP is chemically defined as (±)-1-[4-[2-(1-methylethoxy)ethoxymethyl]phenoxy]-3-(1-methylethyl)amino-2-propanol(E)-2-butenedioate (2:1) (salt). It is a racemic mixture with an asymmetric carbon atom, where the S(-) enantiomer predominantly contributes to the beta-blocking activity. The molecular formula is (C18H31NO4)2•C4H4O4, and it has a molecular weight of 766.96. Bisoprolol fumarate appears as a white crystalline powder, exhibiting approximately equal hydrophilicity and lipophilicity, and is very soluble in water and methanol, freely soluble in chloroform, glacial acetic acid, and ethanol, and slightly soluble in ethyl acetate and acetone.

Hydrochlorothiazide (HCTZ), USP is identified as 6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide, 1,1-dioxide. It is a white or practically white crystalline powder, very slightly soluble in methanol, sparingly soluble in acetonitrile, soluble in 1% NaOH solution, and practically insoluble in water and ethanol. The molecular formula for hydrochlorothiazide is C7H8ClN3O4S2, with a molecular weight of 297.74.

Each bisoprolol fumarate and hydrochlorothiazide tablet, USP is available in three strengths for oral administration: 2.5 mg/6.25 mg, 5 mg/6.25 mg, and 10 mg/6.25 mg. The 2.5 mg/6.25 mg tablet contains 2.5 mg of bisoprolol fumarate and 6.25 mg of hydrochlorothiazide; the 5 mg/6.25 mg tablet contains 5 mg of bisoprolol fumarate and 6.25 mg of hydrochlorothiazide; and the 10 mg/6.25 mg tablet contains 10 mg of bisoprolol fumarate and 6.25 mg of hydrochlorothiazide.

Inactive ingredients in each tablet include butylated hydroxyanisole, colloidal silicon dioxide, crospovidone, dibasic calcium phosphate anhydrous, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, and titanium dioxide. The 2.5 mg/6.25 mg tablet also contains iron oxide red and iron oxide yellow, while the 5 mg/6.25 mg tablet includes FD&C red #40 Aluminum Lake and D&C yellow #10 Aluminum Lake.

Uses and Indications

Bisoprolol fumarate and hydrochlorothiazide tablets are indicated for the management of hypertension.

Limitations of Use: There are no teratogenic or nonteratogenic effects associated with this medication as per the available data.

Dosage and Administration

Bisoprolol is indicated for once-daily administration in doses ranging from 2.5 mg to 40 mg. Hydrochlorothiazide is effective in doses between 12.5 mg and 50 mg. In clinical trials involving the combination therapy of bisoprolol and hydrochlorothiazide, bisoprolol was administered in doses of 2.5 mg to 20 mg, while hydrochlorothiazide was given in doses of 6.25 mg to 25 mg.

Antihypertensive therapy may be initiated with one tablet of bisoprolol fumarate and hydrochlorothiazide, containing 2.5 mg of bisoprolol and 6.25 mg of hydrochlorothiazide, taken once daily. Subsequent titration of the dosage may be performed, allowing for the administration of bisoprolol fumarate and hydrochlorothiazide tablets up to a maximum recommended dose of 20 mg of bisoprolol and 12.5 mg of hydrochlorothiazide (equivalent to two 10 mg/6.25 mg tablets) once daily, as deemed appropriate.

It is important to consider therapy with the combination of bisoprolol and hydrochlorothiazide only after a patient has not achieved the desired therapeutic effect with monotherapy.

Contraindications

Bisoprolol fumarate and hydrochlorothiazide tablets are contraindicated in patients with the following conditions:

• Cardiogenic shock

• Overt cardiac failure

• Second or third degree AV block

• Marked sinus bradycardia

• Anuria

• Hypersensitivity to either component of this product or to other sulfonamide-derived drugs

These contraindications are based on the potential for exacerbating existing conditions or causing adverse reactions in susceptible individuals.

Warnings and Precautions

In patients with overt congestive heart failure, the use of beta-blocking agents is generally contraindicated. However, in select cases of compensated cardiac failure, these agents may be necessary but should be administered with caution. Continuous monitoring of cardiac function is essential in these patients.

For individuals without a prior history of cardiac failure, it is important to note that beta-blockers can lead to myocardial depression, potentially precipitating heart failure. At the first indication of heart failure symptoms, healthcare professionals should consider discontinuing bisoprolol fumarate and hydrochlorothiazide. In certain instances, it may be appropriate to continue therapy while managing heart failure with alternative medications.

Abrupt cessation of beta-blocker therapy can result in exacerbations of angina pectoris and, in some cases, myocardial infarction or ventricular arrhythmias, particularly in patients with coronary artery disease. Therefore, patients should be advised against discontinuing therapy without consulting their physician. For those without overt coronary artery disease, a gradual tapering of bisoprolol fumarate and hydrochlorothiazide over approximately one week is recommended, with careful patient observation. Should withdrawal symptoms arise, reinitiating beta-blocker therapy may be necessary.

Patients with peripheral vascular disease should be monitored closely, as beta-blockers can exacerbate symptoms of arterial insufficiency. Caution is advised in this population.

In patients with bronchospastic pulmonary disease, beta-blockers are generally contraindicated. However, due to the relative beta 1-selectivity of bisoprolol fumarate, it may be used cautiously in patients who do not respond to or cannot tolerate other antihypertensive treatments. The lowest effective dose should be utilized, and a beta 2 agonist (bronchodilator) should be readily available.

For patients undergoing major surgery, it is not routinely necessary to withdraw chronically administered beta-blocking therapy. However, clinicians should be aware that the heart's impaired response to reflex adrenergic stimuli may increase the risks associated with general anesthesia and surgical procedures.

Beta-blockers can mask early warning signs of hypoglycemia, such as tachycardia, thereby increasing the risk of severe or prolonged hypoglycemia, particularly in patients with diabetes mellitus, children, or those who are fasting. Patients experiencing severe hypoglycemia should be instructed to seek emergency medical attention.

In cases of thyrotoxicosis, beta-adrenergic blockade may obscure clinical signs of hyperthyroidism, including tachycardia. Abrupt withdrawal of beta-blockade can lead to exacerbation of hyperthyroid symptoms or precipitate a thyroid storm.

Patients with renal impairment may experience cumulative effects from thiazides, potentially leading to azotemia. In individuals with a creatinine clearance of less than 40 mL/min, the plasma half-life of bisoprolol fumarate may increase significantly. If progressive renal impairment is observed, discontinuation of bisoprolol fumarate and hydrochlorothiazide is warranted.

Caution is also advised in patients with hepatic impairment or progressive liver disease, as thiazides can disrupt fluid and electrolyte balance, potentially leading to hepatic coma. The elimination of bisoprolol fumarate is notably slower in patients with cirrhosis compared to healthy individuals.

Hydrochlorothiazide, a sulfonamide, has been associated with idiosyncratic reactions that can result in acute angle-closure glaucoma and elevated intraocular pressure, with or without acute myopia and choroidal effusions. Symptoms may manifest as a sudden decrease in visual acuity or ocular pain, typically occurring within hours to weeks of initiating treatment. If left untreated, acute angle-closure glaucoma can lead to permanent visual field loss. The primary course of action is to discontinue hydrochlorothiazide promptly, and if intraocular pressure remains uncontrolled, immediate medical or surgical intervention may be necessary. Patients with a history of sulfonamide or penicillin allergy may be at increased risk for developing this condition.

Side Effects

Adverse reactions associated with Bisoprolol Fumarate and Hydrochlorothiazide have been observed in clinical trials and postmarketing experiences. These reactions can be categorized by seriousness and frequency.

Serious Adverse Reactions Patients may experience serious cardiovascular effects, including hypotension, orthostatic hypotension, and congestive heart failure. Additionally, hypersensitive reactions such as anaphylaxis, necrotizing angiitis, and respiratory distress, including pneumonitis and pulmonary edema, have been reported. Hydrochlorothiazide has been linked to an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC), in white patients receiving large cumulative doses, with an estimated risk of approximately 1 additional case per 16,000 patients per year.

Common Adverse Reactions In clinical trials, the following common adverse reactions were reported:

• Cardiovascular: Bradycardia (1.1% in the treatment group vs. 0.7% in placebo), arrhythmia (0.4% vs. 1.4%), peripheral ischemia (0.7% vs. 0.9%), and chest pain (1.8% vs. 0.7%).

• Respiratory: Cough (2.2% vs. 1%), rhinitis (0.7% vs. 2%), and upper respiratory infections (2.1% vs. 2.3%).

• Body as a Whole: Fatigue (4.6% vs. 2.7%) and peripheral edema (1.1% vs. 0.7%).

• Central Nervous System: Dizziness (5.1% vs. 1.8%) and headache (4.5% vs. 4.7%).

• Musculoskeletal: Myalgia (2.4% vs. 1.4%) and muscle cramps (1.2% vs. 0.7%).

• Psychiatric: Insomnia (1.1% vs. 2.4%), somnolence (1.1% vs. 0.7%), loss of libido (0.4% vs. 1.2%), and impotence (1.1% vs. 0.7%).

• Gastrointestinal: Diarrhea (4.3% vs. 1.4%), nausea (1.1% vs. 0.9%), and dyspepsia (1.2% vs. 0.7%).

Additional Adverse Reactions Beyond the common reactions, other adverse effects have been noted. Bisoprolol Fumarate may cause central nervous system effects such as unsteadiness, vertigo, syncope, and sleep disturbances. Gastrointestinal issues may include gastric pain, constipation, and dry mouth. Musculoskeletal complaints can involve arthralgia and muscle pain. Skin reactions may manifest as rash, eczema, and pruritus. Hydrochlorothiazide may lead to gastrointestinal disturbances, including anorexia and jaundice, as well as transient blurred vision and sexual dysfunction.

Patients should be monitored for these adverse reactions, and any serious or concerning symptoms should be reported to a healthcare provider promptly.

Drug Interactions

Bisoprolol fumarate and hydrochlorothiazide may interact with various medications, necessitating careful consideration of concomitant therapies.

Antihypertensive Agents The combination of bisoprolol fumarate and hydrochlorothiazide may enhance the effects of other antihypertensive agents. Caution is advised when using these agents together, as they may lead to an additive hypotensive effect. Additionally, bisoprolol fumarate and hydrochlorothiazide should not be used in conjunction with other beta-blockers due to the potential for increased adverse effects.

Catecholamine-Depleting Drugs Patients receiving catecholamine-depleting medications, such as reserpine or guanethidine, should be closely monitored. The use of bisoprolol fumarate in these patients may result in an excessive reduction of sympathetic activity.

Clonidine For patients undergoing treatment with clonidine, it is recommended that bisoprolol fumarate and hydrochlorothiazide be discontinued several days prior to the withdrawal of clonidine to mitigate the risk of rebound hypertension.

Myocardial Depressants and AV Conduction Inhibitors Caution is warranted when bisoprolol fumarate and hydrochlorothiazide are used alongside myocardial depressants or agents that inhibit atrioventricular (AV) conduction, such as certain calcium antagonists (e.g., verapamil, diltiazem) and antiarrhythmic drugs (e.g., disopyramide).

Digitalis Glycosides The concurrent use of digitalis glycosides with beta-blockers may increase the risk of bradycardia, necessitating careful monitoring of heart rate.

Rifampin The co-administration of rifampin may enhance the metabolic clearance of bisoprolol fumarate, resulting in a shortened elimination half-life. However, initial dose adjustments are generally not required.

Hydrochlorothiazide Interactions Hydrochlorothiazide may interact with several classes of drugs. Alcohol, barbiturates, and narcotics can potentiate orthostatic hypotension when used concurrently. Antidiabetic medications, including oral agents and insulin, may require dosage adjustments due to the potential for altered glycemic control. Other antihypertensive drugs may also exhibit additive effects when used with hydrochlorothiazide.

Absorption Impairment Cholestyramine and colestipol resins can significantly impair the gastrointestinal absorption of hydrochlorothiazide, reducing its bioavailability by up to 85% and 43%, respectively.

Electrolyte Depletion Corticosteroids and adrenocorticotropic hormone (ACTH) may exacerbate electrolyte depletion, particularly hypokalemia, when administered with hydrochlorothiazide.

Pressor Amines The response to pressor amines, such as norepinephrine, may be diminished when used in conjunction with hydrochlorothiazide; however, this does not contraindicate their use.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) NSAIDs may attenuate the diuretic, natriuretic, and antihypertensive effects of hydrochlorothiazide. Patients should be monitored closely to ensure the desired therapeutic outcomes are achieved.

Thyroid Function Tests Bisoprolol fumarate and hydrochlorothiazide may lower serum levels of protein-bound iodine without causing thyroid dysfunction. It is advisable to discontinue these medications prior to conducting tests for parathyroid function.

No clinically significant interactions have been observed with other agents, including thiazide diuretics and cimetidine.

Packaging & NDC

The table below lists all NDC Code configurations of Bisoprolol Fumarate and Hydrochlorothiazide, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Safety and effectiveness of bisoprolol fumarate and hydrochlorothiazide in pediatric patients have not been established. Therefore, caution is advised when considering the use of this medication in children and adolescents. Further studies are necessary to determine appropriate dosing and therapeutic outcomes in this population.

Geriatric Use

In clinical trials, at least 270 patients aged 60 years and older were treated with bisoprolol fumarate in combination with hydrochlorothiazide (HCTZ). The addition of HCTZ significantly enhanced the antihypertensive effect of bisoprolol in elderly hypertensive patients.

No overall differences in effectiveness or safety were observed between geriatric patients and their younger counterparts. However, it is important to note that while clinical experience has not identified significant differences in responses between elderly and younger patients, greater sensitivity in some older individuals cannot be ruled out.

Healthcare providers should exercise caution when prescribing this combination to elderly patients, considering the potential for increased sensitivity and the need for careful monitoring of therapeutic responses and adverse effects.

Pregnancy

There are no adequate and well-controlled studies with bisoprolol fumarate and hydrochlorothiazide in pregnant women. The use of bisoprolol fumarate and hydrochlorothiazide during pregnancy should be considered only if the potential benefit justifies the risk to the fetus. Hydrochlorothiazide should be used during pregnancy only if clearly needed, as animal reproduction studies are not always predictive of human response.

Thiazides, including hydrochlorothiazide, cross the placental barrier and can be detected in cord blood. Therefore, the anticipated benefit of thiazide use in pregnant women must be weighed against possible hazards to the fetus. Potential risks associated with thiazide use during pregnancy include fetal or neonatal jaundice, pancreatitis, thrombocytopenia, and possibly other adverse reactions that have been observed in adults.

Animal studies have demonstrated that the drug combination of bisoprolol fumarate and hydrochlorothiazide is maternotoxic, resulting in decreased body weight and food consumption, and fetotoxic, leading to increased late resorptions at high doses. Bisoprolol fumarate alone has also shown fetotoxic effects, including increased late resorptions, and maternotoxic effects, such as decreased food intake and body weight gain, in animal studies at high doses. Hydrochlorothiazide was administered to pregnant mice and rats during major organogenesis without evidence of harm to the fetus at very high doses; however, there are no adequate studies in pregnant women to confirm safety.

Lactation

Bisoprolol fumarate, whether used alone or in combination with hydrochlorothiazide (HCTZ), has not been studied in nursing mothers. Thiazides, including HCTZ, are known to be excreted in human breast milk. In lactating rats, small amounts of bisoprolol fumarate (less than 2% of the dose) have been detected in breast milk.

Due to the potential for serious adverse reactions in breastfed infants, healthcare professionals should consider the importance of the drug to the mother when making a decision to either discontinue nursing or discontinue the medication.

Renal Impairment

Patients with renal impairment may experience cumulative effects of thiazides, which can precipitate azotemia. In individuals with a creatinine clearance of less than 40 mL/min, the plasma half-life of bisoprolol fumarate is increased up to threefold compared to healthy subjects. Therefore, if progressive renal impairment is observed, it is recommended that bisoprolol fumarate and hydrochlorothiazide be discontinued to mitigate potential risks. Monitoring of renal function is essential in this patient population to ensure appropriate management and dosing adjustments.

Hepatic Impairment

Patients with hepatic impairment should use bisoprolol fumarate and hydrochlorothiazide with caution. The pharmacokinetics of bisoprolol fumarate are notably affected in individuals with compromised liver function, particularly in those with cirrhosis, where the elimination of the drug is significantly slower compared to healthy subjects.

Additionally, thiazides, including hydrochlorothiazide, may alter fluid and electrolyte balance, potentially precipitating hepatic coma in susceptible patients. Therefore, careful monitoring of liver function and electrolyte levels is recommended in patients with hepatic impairment to mitigate the risk of adverse effects. Adjustments to dosing may be necessary based on the severity of liver dysfunction and the clinical response of the patient.

Overdosage

In cases of suspected overdosage with bisoprolol fumarate and hydrochlorothiazide, it is essential to recognize the potential symptoms and implement appropriate management strategies.

Limited data are available regarding overdose incidents involving bisoprolol fumarate; however, several cases have been documented, with the maximum reported dose reaching 2,000 mg. The most frequently observed symptoms associated with bisoprolol overdose include bradycardia and hypotension. Additional symptoms may encompass lethargy, and in severe cases, patients may experience delirium, coma, convulsions, and respiratory arrest. Furthermore, individuals with pre-existing conditions may be at risk for congestive heart failure, bronchospasm, and hypoglycemia.

Overdose with thiazide diuretics, such as hydrochlorothiazide, is rare; however, acute intoxication can lead to significant fluid and electrolyte loss. Symptoms may manifest across various systems, including cardiovascular (tachycardia, hypotension, shock), neuromuscular (weakness, confusion, dizziness, calf muscle cramps, paresthesia, fatigue, and impaired consciousness), gastrointestinal (nausea, vomiting, and thirst), and renal (polyuria, oliguria, or anuria due to hemoconcentration). Laboratory findings may reveal hypokalemia, hyponatremia, hypochloremia, alkalosis, and increased blood urea nitrogen (BUN), particularly in patients with renal insufficiency.

Upon suspicion of overdosage, it is crucial to discontinue therapy with bisoprolol fumarate and hydrochlorothiazide and closely monitor the patient. Management should be symptomatic and supportive, as there is no specific antidote available. Current evidence suggests that bisoprolol fumarate is not dialyzable, and similarly, hydrochlorothiazide does not appear to be amenable to dialysis.

General measures for managing overdosage may include the induction of emesis and/or gastric lavage, administration of activated charcoal, provision of respiratory support, correction of fluid and electrolyte imbalances, and treatment of convulsions. These interventions aim to stabilize the patient and mitigate the effects of the overdose.

Nonclinical Toxicology

In nonclinical studies, the teratogenic effects of the bisoprolol fumarate/hydrochlorothiazide (B/H) combination were evaluated in rats and rabbits. In rats, the combination was not teratogenic at doses up to 51.4 mg/kg/day of bisoprolol fumarate and 128.6 mg/kg/day of hydrochlorothiazide. Similarly, in rabbits, the B/H combination did not demonstrate teratogenic effects at doses of B10/H25 (mg/kg/day). However, there are no adequate and well-controlled studies in pregnant women, and the use of bisoprolol fumarate and hydrochlorothiazide during pregnancy should only occur if the potential benefit justifies the risk to the fetus. Bisoprolol fumarate alone was not teratogenic at doses up to 150 mg/kg/day in rats. Hydrochlorothiazide was administered orally to pregnant mice and rats during major organogenesis at doses up to 3,000 mg/kg/day and 1,000 mg/kg/day, respectively, with no evidence of fetal harm observed at these doses.

The non-teratogenic effects of thiazides in pregnant women necessitate careful consideration of the anticipated benefits against potential hazards to the fetus. These hazards may include fetal or neonatal jaundice, pancreatitis, thrombocytopenia, and possibly other adverse reactions that have been reported in adults.

Long-term studies with the bisoprolol fumarate/hydrochlorothiazide combination have not been conducted. However, long-term studies with oral bisoprolol fumarate administered in the feed of mice (20 months and 24 months) and rats (26 months) revealed no evidence of carcinogenic potential at doses up to 250 mg/kg/day in mice and 125 mg/kg/day in rats. Two-year feeding studies conducted under the National Toxicology Program (NTP) with hydrochlorothiazide at doses up to 600 mg/kg/day in mice and 100 mg/kg/day in rats found no evidence of carcinogenic potential in rats or female mice, although equivocal evidence of hepatocarcinogenicity was noted in male mice.

The mutagenic potential of the bisoprolol fumarate/hydrochlorothiazide combination was assessed through various assays, including the microbial mutagenicity (Ames) test, point mutation and chromosomal aberration assays in Chinese hamster V79 cells, and the micronucleus test in mice. No evidence of mutagenic potential was observed in these in vitro and in vivo assays. Additionally, reproduction studies in rats indicated no impairment of fertility with the bisoprolol fumarate/hydrochlorothiazide combination at doses of up to 30 mg/kg/day of bisoprolol fumarate and 75 mg/kg/day of hydrochlorothiazide.

Postmarketing Experience

Postmarketing experience has identified several adverse events associated with hydrochlorothiazide and bisoprolol fumarate/hydrochlorothiazide.

Hydrochlorothiazide has been linked to an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC), as observed in a study within the Sentinel System. The overall risk for SCC was estimated at approximately 1 additional case per 16,000 patients per year, with a higher risk in white patients taking cumulative doses of ≥ 50,000 mg, where the risk increased to about 1 additional case per 6,700 patients per year.

Laboratory abnormalities have been reported, indicating that the lower dose of hydrochlorothiazide in bisoprolol fumarate/hydrochlorothiazide (6.25 mg) is associated with fewer and less severe adverse metabolic effects compared to higher doses (25 mg). Increases in uric acid levels were noted with the combination of beta blockers and thiazide diuretics, although the changes were less pronounced in patients receiving the lower dose. Mean increases in serum triglycerides were observed, while total cholesterol levels remained generally stable, with minor decreases in HDL cholesterol.

A range of other adverse experiences has been reported in clinical trials and postmarketing settings. These include:

Central Nervous System: Unsteadiness, dizziness, vertigo, headache, syncope, paresthesia, hypoesthesia, hyperesthesia, sleep disturbances, vivid dreams, insomnia, somnolence, depression, anxiety, restlessness, and decreased concentration or memory.

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

Gastrointestinal: Gastric, epigastric, or abdominal pain, peptic ulcer, gastritis, dyspepsia, nausea, vomiting, diarrhea, constipation, and dry mouth.

Musculoskeletal: Arthralgia, muscle or joint pain, back or neck pain, muscle cramps, and twitching or tremor.

Skin: Rash, acne, eczema, psoriasis, skin irritation, pruritus, purpura, flushing, sweating, alopecia, dermatitis, and very rarely, exfoliative dermatitis and cutaneous vasculitis.

Special Senses: Visual disturbances, ocular pain or pressure, abnormal lacrimation, tinnitus, decreased hearing, earache, and taste abnormalities.

Metabolic: Gout.

Respiratory: Asthma, bronchospasm, bronchitis, dyspnea, pharyngitis, rhinitis, sinusitis, and upper respiratory infections.

Genitourinary: Decreased libido, impotence, Peyronie's disease (very rarely), cystitis, renal colic, and polyuria.

General: Fatigue, asthenia, chest pain, malaise, edema, weight gain, and angioedema.

Additionally, adverse effects specifically associated with hydrochlorothiazide (generally at doses of 25 mg or greater) include weakness, vertigo, paresthesia, restlessness, orthostatic hypotension (potentially exacerbated by alcohol, barbiturates, or narcotics), anorexia, gastric irritation, cramping, constipation, jaundice, pancreatitis, cholecystitis, sialadenitis, and dry mouth. Musculoskeletal effects such as muscle spasms, hypersensitive reactions including purpura, photosensitivity, rash, urticaria, necrotizing angiitis, fever, respiratory distress (including pneumonitis and pulmonary edema), and anaphylactic reactions have also been reported. Special senses may experience transient blurred vision, choroidal effusion, and xanthopsia. Metabolic effects include gout, while genitourinary issues may involve sexual dysfunction, renal failure, renal dysfunction, and interstitial nephritis. Skin reactions can include erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, and toxic epidermal necrolysis.

Patient Counseling

Healthcare providers should emphasize the importance of not discontinuing bisoprolol fumarate and hydrochlorothiazide without physician supervision, particularly for patients with coronary artery disease. It is crucial to advise patients to consult their physician if they experience any difficulty in breathing or develop other signs or symptoms indicative of congestive heart failure or excessive bradycardia.

Patients and their caregivers should be informed about the risk of hypoglycemia associated with bisoprolol fumarate and hydrochlorothiazide, especially in situations where patients are fasting or experiencing vomiting. Monitoring for symptoms of hypoglycemia is essential.

Patients should be made aware of how this medication affects their alertness before operating automobiles, machinery, or engaging in other tasks that require concentration. Additionally, healthcare providers should inform patients that photosensitivity reactions have been reported with thiazides, and therefore, patients taking hydrochlorothiazide should be instructed to protect their skin from sun exposure and to undergo regular skin cancer screenings.

Finally, patients taking hydrochlorothiazide should be advised to immediately consult their healthcare provider if they experience visual field defects, decreased visual acuity, or ocular pain.

Storage and Handling

The product is supplied in a tight container to ensure integrity and stability. It should be stored at a temperature range of 20°C to 25°C (68°F to 77°F), with permissible excursions between 15°C to 30°C (59°F to 86°F) as defined by USP Controlled Room Temperature guidelines. Proper adherence to these storage conditions is essential for maintaining the product's efficacy and safety.

Additional Clinical Information

Bisoprolol fumarate and hydrochlorothiazide may lead to a decrease in serum levels of protein-bound iodine without causing thyroid disturbances. It is recommended that these medications be discontinued prior to conducting tests for parathyroid function.

Clinicians should counsel patients, particularly those with coronary artery disease, against discontinuing bisoprolol fumarate and hydrochlorothiazide without medical supervision. Patients should be advised to seek medical attention if they experience difficulty breathing or symptoms indicative of congestive heart failure or excessive bradycardia. There is a risk of hypoglycemia in patients who are fasting or vomiting, necessitating monitoring for symptoms. Patients should be aware of their response to the medication before engaging in activities requiring alertness, such as operating vehicles or machinery. Additionally, photosensitivity reactions have been reported with thiazides, and patients taking hydrochlorothiazide should protect their skin from sun exposure and undergo regular skin cancer screenings. They should also consult their healthcare provider immediately if they experience visual field defects, decreased visual acuity, or ocular pain.

Postmarketing data indicate that hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC), especially in white patients receiving high cumulative doses. The overall risk for SCC is approximately one additional case per 16,000 patients per year, with a significantly higher risk for white patients taking cumulative doses of 50,000 mg or more, estimated at one additional case for every 6,700 patients per year.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Bisoprolol Fumarate and Hydrochlorothiazide as submitted by Viona Pharmaceuticals Inc. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)