Bisoprolol fumarate/Hydrochlorothiazide

Description

Bisoprolol fumarate and hydrochlorothiazide tablets are indicated for the treatment of hypertension, combining two antihypertensive agents in a once-daily dosage. The formulation includes bisoprolol fumarate, a synthetic beta 1-selective (cardioselective) adrenoceptor blocking agent, and hydrochlorothiazide, a benzothiadiazine diuretic.

Bisoprolol fumarate is chemically defined as (±)-1-[4-[2-(1-methylethoxy)ethoxymethyl]phenoxy]-3-(1-methylethyl)amino-2-propanol (E)-2-butenedioate (2:1) (salt), existing as a racemic mixture with an asymmetric carbon atom. The S(-) enantiomer is primarily responsible for the beta-blocking activity. Its empirical formula is (C18H31NO4)2•C4H4O4, and it has a molecular weight of 766.97. Bisoprolol fumarate appears as a white crystalline powder, exhibiting approximately equal hydrophilicity and lipophilicity, and is readily soluble in water, methanol, ethanol, and chloroform.

Hydrochlorothiazide (HCTZ) 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, practically odorless crystalline powder. Hydrochlorothiazide is slightly soluble in water, sparingly soluble in dilute sodium hydroxide solution, freely soluble in n-butylamine and dimethylformamide, and sparingly soluble in methanol, while being insoluble in ether, chloroform, and dilute mineral acids. Its empirical formula is C7H8ClN3O4S2, with a molecular weight of 297.73.

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

Inactive ingredients in the tablets include corn starch, dibasic calcium phosphate, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, and titanium dioxide. The 10 mg/6.25 mg tablet also contains colloidal silicon dioxide. The 5 mg/6.25 mg tablet includes colloidal silicon dioxide, red iron oxide, and yellow iron oxide, while the 2.5 mg/6.25 mg tablet contains crospovidone, pregelatinized starch, and yellow iron oxide.

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 the treatment of hypertension, with recommended once-daily doses ranging from 2.5 mg to 40 mg. Hydrochlorothiazide is also effective in managing hypertension, with dosing options between 12.5 mg and 50 mg.

For patients initiating antihypertensive therapy, it is advisable to start with the lowest dose of bisoprolol fumarate and hydrochlorothiazide combination therapy, specifically one 2.5/6.25 mg tablet taken once daily. In clinical trials, bisoprolol doses of 2.5 mg to 20 mg and hydrochlorothiazide doses of 6.25 mg to 25 mg were utilized effectively.

Following the initial dose, healthcare professionals may titrate the dosage of bisoprolol fumarate and hydrochlorothiazide tablets as needed, up to the maximum recommended dose of 20/12.5 mg (equivalent to two 10/6.25 mg tablets) once daily. It is important to note that therapy with this combination is generally associated with minimal dose-dependent adverse effects when low doses are employed.

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 bisoprolol, hydrochlorothiazide, or other sulfonamide-derived drugs

Use in these situations is contraindicated due to the potential for exacerbating the underlying condition or causing severe adverse effects.

Warnings and Precautions

In general, beta-blocking agents should be avoided in patients with overt congestive heart failure. However, in select patients with compensated cardiac failure, the use of these agents may be necessary, albeit with caution. Continuous depression of the myocardium due to beta-blockers can precipitate cardiac failure; therefore, at the first signs or symptoms of heart failure, discontinuation of bisoprolol fumarate and hydrochlorothiazide tablets should be considered.

Patients with coronary artery disease are at risk for exacerbations of angina pectoris, and in some cases, myocardial infarction or ventricular arrhythmia may occur following abrupt cessation of beta-blocker therapy. It is imperative that these patients are advised against interrupting or discontinuing therapy without consulting their physician.

Caution is also warranted in patients with peripheral vascular disease, as beta-blockers can precipitate or exacerbate symptoms of arterial insufficiency. Additionally, patients with bronchospastic pulmonary disease should generally avoid beta-blockers. However, due to the relative beta 1-selectivity of bisoprolol fumarate, it may be used cautiously in patients with bronchospastic disease who do not respond to or cannot tolerate other antihypertensive treatments.

For patients undergoing major surgery, chronically administered beta-blocking therapy should not be routinely withdrawn. Nevertheless, the impaired ability of the heart to respond to reflex adrenergic stimuli may increase the risks associated with general anesthesia and surgical procedures.

Beta-blockers may mask early warning signs of hypoglycemia, such as tachycardia, thereby increasing the risk for severe or prolonged hypoglycemia, particularly in patients with diabetes mellitus, children, and those who are fasting. Furthermore, beta-adrenergic blockade may obscure clinical signs of hyperthyroidism, such as tachycardia, and abrupt withdrawal of beta-blockade can lead to exacerbation of hyperthyroid symptoms or precipitate a thyroid storm.

In patients with impaired renal function, cumulative effects of thiazides may develop, potentially leading to azotemia. Bisoprolol fumarate and hydrochlorothiazide tablets should be used with caution in individuals with impaired hepatic function or progressive liver disease. Hydrochlorothiazide, a sulfonamide, carries the risk of idiosyncratic reactions, which may result in acute angle-closure glaucoma and elevated intraocular pressure, with or without a noticeable acute myopic shift and/or choroidal effusions.

Periodic determination of serum electrolytes is recommended, and patients should be monitored for signs of fluid or electrolyte disturbances, including hyponatremia, hypochloremic alkalosis, hypokalemia, and hypomagnesemia. In the event of severe hypoglycemia, patients should be instructed to seek emergency medical assistance.

Side Effects

Patients receiving bisoprolol fumarate and hydrochlorothiazide tablets may experience a range of adverse reactions, which can be categorized by seriousness and frequency.

Serious adverse reactions associated with bisoprolol fumarate include cardiovascular events such as bradycardia, arrhythmia, peripheral ischemia, and chest pain. Additionally, patients may experience hypotension, orthostatic hypotension, and exacerbations of congestive heart failure. Respiratory complications, including bronchospasm and dyspnea on exertion, have also been reported. In rare cases, patients may experience severe skin reactions such as exfoliative dermatitis and necrotizing angiitis.

Common adverse reactions observed in clinical trials and postmarketing experiences include fatigue, asthenia, dizziness, headache, and gastrointestinal disturbances such as diarrhea, nausea, and dyspepsia. Patients may also report musculoskeletal symptoms, including muscle cramps and myalgia, as well as psychiatric effects such as insomnia, somnolence, and sexual dysfunction, including loss of libido and impotence.

Additional adverse reactions specific to bisoprolol fumarate encompass a variety of central nervous system effects, including unsteadiness, vertigo, syncope, and sleep disturbances. Cardiovascular effects may also include palpitations, cold extremities, and claudication. Gastrointestinal issues can extend to gastric pain, vomiting, and constipation. Skin reactions may involve rash, pruritus, and flushing, while special senses may be affected by visual disturbances and tinnitus.

Hydrochlorothiazide has been associated with its own set of adverse reactions, including orthostatic hypotension, which may be exacerbated by alcohol or narcotics. Patients may also experience gastrointestinal symptoms such as anorexia and cramping, as well as hypersensitive reactions like purpura and photosensitivity. Serious skin reactions, including erythema multiforme and exfoliative dermatitis, have been reported. Additionally, metabolic effects such as gout and renal dysfunction may occur.

Patients should be monitored for these adverse reactions, particularly those with a history of cardiac failure, bronchospastic disease, or peripheral vascular disease, as beta-blockers can exacerbate these conditions. Abrupt cessation of therapy may lead to serious cardiovascular events, including angina exacerbation and myocardial infarction.

Drug Interactions

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

Antihypertensive Agents The use of bisoprolol fumarate and hydrochlorothiazide tablets may enhance the effects of other antihypertensive agents when administered together. Clinicians should monitor blood pressure closely and consider dosage adjustments of the antihypertensive agents as needed.

Beta-Blockers Concomitant use of bisoprolol fumarate and hydrochlorothiazide tablets with other beta-blocking agents is contraindicated due to the potential for additive effects, which may lead to excessive bradycardia or hypotension.

Catecholamine-Depleting Drugs Patients receiving catecholamine-depleting medications, such as reserpine or guanethidine, should be monitored closely. The beta-adrenergic blocking action of bisoprolol fumarate may lead to an excessive reduction in sympathetic activity, necessitating careful observation and possible dosage adjustments.

Clonidine In patients undergoing treatment with clonidine, it is recommended that bisoprolol fumarate and hydrochlorothiazide tablets 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 advised when bisoprolol fumarate and hydrochlorothiazide tablets are used in conjunction with myocardial depressants or agents that inhibit atrioventricular conduction, such as certain calcium antagonists (notably verapamil and diltiazem) and antiarrhythmic drugs like disopyramide. The combination may exacerbate bradycardia or other cardiac conduction issues.

Digitalis Glycosides The concurrent use of digitalis glycosides and beta-blockers, including bisoprolol fumarate and hydrochlorothiazide tablets, may increase the risk of bradycardia due to their combined effects on atrioventricular conduction and heart rate. Monitoring of heart rate and rhythm is recommended.

Thyroid Function Tests Bisoprolol fumarate and hydrochlorothiazide tablets may reduce serum levels of protein-bound iodine without causing thyroid disturbances. It is advisable to discontinue the medication prior to conducting tests for parathyroid function to avoid potential interference with test results.

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

The safety and effectiveness of bisoprolol fumarate and hydrochlorothiazide tablets 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 received treatment with bisoprolol fumarate in combination with hydrochlorothiazide (HCTZ). The addition of HCTZ was found to significantly enhance the antihypertensive effect of bisoprolol in elderly hypertensive patients.

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

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

Pregnancy

There is no specific information regarding the use of this drug during pregnancy, including safety concerns, dosage modifications, or special precautions. Healthcare professionals should consider the lack of data when prescribing this medication to pregnant patients. It is advisable to weigh the potential benefits against any unknown risks to fetal outcomes. Women of childbearing potential should be counseled on the importance of effective contraception during treatment and should be informed of the absence of established safety data in pregnancy.

Lactation

Bisoprolol fumarate, either 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. Small amounts of bisoprolol fumarate, specifically less than 2% of the dose, have been detected in the milk of lactating rats. Due to the potential for serious adverse reactions in breastfed infants, healthcare professionals should consider whether to discontinue nursing or to discontinue the drug, weighing the importance of the medication to the mother.

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 tablets be discontinued to mitigate potential risks associated with reduced kidney function.

Hepatic Impairment

Patients with hepatic impairment should use bisoprolol fumarate and hydrochlorothiazide tablets with caution. The pharmacokinetics of bisoprolol fumarate are notably affected in this population, as its elimination is significantly slower in patients with cirrhosis compared to healthy individuals.

Additionally, thiazides, including hydrochlorothiazide, may alter fluid and electrolyte balance, potentially precipitating hepatic coma in patients with compromised liver function. Therefore, careful monitoring of liver function and electrolyte levels is recommended for patients with hepatic impairment receiving this combination therapy.

It is advisable to consider dosage adjustments and closely observe these patients for any signs of adverse effects related to their liver condition.

Overdosage

In cases of suspected overdosage with bisoprolol fumarate and hydrochlorothiazide tablets, it is essential to recognize the potential symptoms and implement appropriate management strategies. Although data on overdose incidents are limited, several cases involving bisoprolol fumarate have been documented, with the maximum reported dose reaching 2000 mg. The most frequently observed clinical manifestations include bradycardia and hypotension. Additional symptoms may encompass lethargy, and in severe instances, delirium, coma, convulsions, and respiratory arrest have been reported. Patients with pre-existing conditions may also experience congestive heart failure, bronchospasm, and hypoglycemia.

The thiazide component, hydrochlorothiazide, is associated with rare occurrences of acute intoxication. The primary concern in such cases is the acute loss of fluid and electrolytes. Symptoms indicative of this condition may include cardiovascular manifestations such as tachycardia, hypotension, and shock; neuromuscular symptoms including weakness, confusion, dizziness, calf muscle cramps, paresthesia, and fatigue; gastrointestinal symptoms such as nausea, vomiting, and thirst; and renal symptoms like polyuria, oliguria, or anuria, particularly due to hemoconcentration. Laboratory findings may reveal hypokalemia, hyponatremia, hypochloremia, alkalosis, and increased blood urea nitrogen (BUN), especially in patients with renal insufficiency.

Upon suspicion of overdose, it is crucial to discontinue therapy with bisoprolol fumarate and hydrochlorothiazide tablets and closely monitor the patient. Management is primarily 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 dialyzable.

Recommended general measures for managing overdose 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. Clinicians should consider these interventions based on the pharmacologic actions of beta-blockers and hydrochlorothiazide, as well as the clinical context of the patient.

Nonclinical Toxicology

In nonclinical studies, the teratogenic potential of the bisoprolol fumarate/hydrochlorothiazide (B/H) combination was evaluated in both rats and rabbits. In rats, the combination did not demonstrate teratogenic effects at doses up to 51.4 mg/kg/day of bisoprolol fumarate in conjunction with 128.6 mg/kg/day of hydrochlorothiazide. Similarly, in rabbits, the B/H combination was not teratogenic at doses of B10/H25 (mg/kg/day). Individual components also showed no teratogenic effects, with bisoprolol fumarate not being teratogenic at doses up to 150 mg/kg/day in rats and up to 12.5 mg/kg/day in rabbits. However, there are no adequate and well-controlled studies in pregnant women, and the use of bisoprolol fumarate and hydrochlorothiazide tablets during pregnancy should only occur if the potential benefits justify the risks to the fetus.

The non-teratogenic effects of thiazides, including hydrochlorothiazide, indicate that these agents cross the placental barrier and can be detected in cord blood. The use of thiazides in pregnant women necessitates careful consideration of the anticipated benefits against potential risks to the fetus, which may include fetal or neonatal jaundice, pancreatitis, thrombocytopenia, and other adverse reactions observed in adults.

Maternotoxicity was observed with the B/H combination, characterized by decreased body weight and food consumption at doses of B5.7/H14.3 (mg/kg/day) and higher. Fetotoxicity, indicated by increased late resorptions, was noted at doses of B17.1/H42.9 (mg/kg/day) and higher. Maternotoxicity was evident at 14/57 times the maximum recommended human dose (MRHD) of B/H on a body weight basis and 3/12 times the MRHD based on body surface area. Fetotoxicity was present at 43/172 times the MRHD on a body weight basis and 9/35 times the MRHD on the basis of body surface area. Bisoprolol fumarate alone was fetotoxic at 50 mg/kg/day, leading to increased late resorptions, and exhibited maternotoxicity at 150 mg/kg/day, with decreased food intake and body weight gain. The fetotoxicity in rats occurred at 125 times the MRHD on a body weight basis and 26 times the MRHD on the basis of body surface area, while maternotoxicity was observed at 375 times the MRHD on a body weight basis and 77 times the MRHD on the basis of body surface area. Additionally, bisoprolol fumarate was found to be embryolethal, resulting in increased early resorptions at a dose of 12.5 mg/kg/day.

Hydrochlorothiazide was administered orally to pregnant mice and rats during critical periods of organogenesis at doses up to 3000 mg/kg/day and 1000 mg/kg/day, respectively. At these doses, no evidence of harm to the fetus was observed.

Postmarketing Experience

Postmarketing experience has identified an association between hydrochlorothiazide and an increased risk of non-melanoma skin cancer. Data from a study conducted within the Sentinel System indicate that this increased risk is primarily observed for squamous cell carcinoma (SCC), particularly among white patients receiving large cumulative doses of the medication. The overall population exhibits an approximate risk increase of 1 additional case of SCC per 16,000 patients per year. Notably, for white patients who have taken a cumulative dose of ≥50,000 mg, the risk escalates to approximately 1 additional case of SCC for every 6,700 patients per year.

Patient Counseling

Healthcare providers should warn patients, particularly those with coronary artery disease, against discontinuing the use of bisoprolol fumarate and hydrochlorothiazide tablets without the supervision of a physician. It is essential for patients to understand the importance of consulting 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 tablets, especially in situations where patients are fasting or experiencing vomiting. Monitoring for symptoms of hypoglycemia is crucial.

Patients should be advised to assess how this medication affects their alertness before operating automobiles, machinery, or engaging in other activities that require concentration. Additionally, healthcare providers should inform patients that photosensitivity reactions have been reported with thiazides, and therefore, patients taking hydrochlorothiazide should take precautions to protect their skin from sun exposure. Regular skin cancer screenings are also recommended.

Finally, patients taking hydrochlorothiazide should be instructed 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), in accordance with USP Controlled Room Temperature guidelines. Proper storage conditions are essential to maintain the product's efficacy and safety.

Additional Clinical Information

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

Clinicians should counsel patients, particularly those with coronary artery disease, against abruptly stopping the medication without medical supervision. Patients should be advised to seek medical attention if they experience difficulty breathing or exhibit symptoms 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, patients taking hydrochlorothiazide should be informed about the potential for photosensitivity reactions and the importance of sun protection and regular skin cancer screenings. They should also be instructed to 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), in white patients receiving high cumulative doses. The overall risk for SCC is approximately 1 additional case per 16,000 patients per year, with a significantly higher risk for white patients taking a cumulative dose of ≥50,000 mg, estimated at 1 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 Teva Pharmaceuticals USA, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)