Hydrochlorothiazide/Bisoprolol fumarate

Description

Bisoprolol fumarate and hydrochlorothiazide tablets USP 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 described as (±)-1-[4-[2-(1-methylethoxy)ethoxymethyl]phenoxy]-3-(1-methylethyl)amino-2-propanol(E)-2-butenedioate(2:1)(salt), with a molecular formula of (C18H31NO4)2•C4H4O4 and a molecular weight of 766.97. It is a white crystalline powder, exhibiting approximately equal hydrophilicity and lipophilicity, and is readily soluble in water, methanol, ethanol, and chloroform. The S(-) enantiomer of bisoprolol fumarate is primarily responsible for its beta-blocking activity.

Hydrochlorothiazide (HCTZ) is identified as 6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, presenting as a white or practically white, odorless crystalline powder. Its molecular formula is C7H8ClN3O4S2, with a molecular weight of 297.73. Hydrochlorothiazide is slightly soluble in water, sparingly soluble in dilute sodium hydroxide solution, and freely soluble in n-butylamine and dimethylformamide, while being insoluble in ether, chloroform, and dilute mineral acids.

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 the tablets include pregelatinized starch, dibasic calcium phosphate anhydrous, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, colloidal silicon dioxide, copovidone, and titanium dioxide. The 5 mg/6.25 mg tablet also contains red and yellow iron oxide, while the 2.5 mg/6.25 mg tablet contains yellow iron oxide.

Uses and Indications

Bisoprolol fumarate and hydrochlorothiazide tablets are indicated for the management of hypertension. There are no reported teratogenic or nonteratogenic effects associated with this medication.

Dosage and Administration

Bisoprolol is administered in once-daily doses ranging from 2.5 mg to 40 mg, while hydrochlorothiazide is effective in doses between 12.5 mg and 50 mg. In clinical trials involving the combination therapy of bisoprolol and hydrochlorothiazide, bisoprolol doses of 2.5 mg to 20 mg and hydrochlorothiazide doses of 6.25 mg to 25 mg were utilized, demonstrating enhanced antihypertensive effects at higher doses.

Antihypertensive therapy may be initiated with one tablet of bisoprolol fumarate and hydrochlorothiazide at a dosage of 2.5/6.25 mg once daily. Following initiation, titration of the dosage may occur at 14-day intervals, with the maximum recommended dose being 20/12.5 mg (equivalent to two 10/6.25 mg tablets) once daily, as deemed appropriate by the healthcare provider.

Contraindications

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

• Patients with cardiogenic shock due to the risk of exacerbating cardiac function.

• Patients with overt cardiac failure, as the medication may worsen the condition.

• Patients with second or third degree AV block, which can lead to severe bradycardia or asystole.

• Patients with marked sinus bradycardia, where further reduction in heart rate could be dangerous.

• Patients with anuria, as the drug's diuretic component may not be effective or safe.

• Patients with hypersensitivity to either component of this product or to other sulfonamide-derived drugs, due to the risk of severe allergic reactions.

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 from beta-blockers can precipitate cardiac failure; therefore, at the first signs or symptoms of heart failure, discontinuation of bisoprolol fumarate and hydrochlorothiazide should be considered. In certain cases, therapy may be continued while heart failure is managed with alternative medications.

Patients with coronary artery disease are at risk for exacerbations of angina pectoris, myocardial infarction, or ventricular arrhythmias following abrupt cessation of beta-blocker therapy. It is crucial that these patients are advised against interrupting or discontinuing therapy without consulting their physician. For patients without overt coronary artery disease, a gradual tapering of bisoprolol fumarate and hydrochlorothiazide over approximately one week is recommended, with careful observation. Should withdrawal symptoms arise, it is advisable to reinstate beta-blocking agent therapy temporarily.

Beta-blockers may exacerbate symptoms of arterial insufficiency in patients with peripheral vascular disease; therefore, caution is warranted in this population. 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. The lowest effective dose should be utilized, and a beta 2 agonist (bronchodilator) should be readily available.

Chronic beta-blocking therapy should not be routinely withdrawn prior to major surgical procedures, as the heart's impaired ability to respond to reflex adrenergic stimuli may increase the risks associated with general anesthesia and surgery. Furthermore, 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, and those who are fasting. Patients experiencing severe hypoglycemia should seek emergency medical assistance.

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.

In patients with impaired renal function, cumulative effects of thiazides may develop, 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 up to threefold compared to healthy subjects. If progressive renal impairment is observed, bisoprolol fumarate and hydrochlorothiazide should be discontinued.

Caution is also advised when prescribing bisoprolol fumarate and hydrochlorothiazide to patients with impaired hepatic function or progressive liver disease, as thiazides can disrupt fluid and electrolyte balance, potentially precipitating hepatic coma. The elimination of bisoprolol fumarate is significantly slower in patients with cirrhosis than in healthy individuals.

Hydrochlorothiazide, a sulfonamide, carries the risk of idiosyncratic reactions, which may result in acute angle-closure glaucoma and elevated intraocular pressure, with or without an acute myopic shift and/or choroidal effusions. Symptoms may include 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 may lead to permanent visual field loss. The primary course of action is to discontinue hydrochlorothiazide as quickly as possible, and prompt medical or surgical intervention may be necessary if intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma include a history of sulfonamide or penicillin allergy.

In summary, healthcare professionals should exercise caution in prescribing bisoprolol fumarate and hydrochlorothiazide, particularly in patients with the aforementioned conditions, and monitor for any adverse effects or signs of complications.

Side Effects

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

Serious adverse reactions include cardiovascular events such as bradycardia, arrhythmia, peripheral ischemia, and chest pain. Patients may also experience respiratory issues, including bronchospasm and dyspnea on exertion. Other serious reactions noted include hypotension, orthostatic hypotension, and congestive heart failure. Additionally, there have been reports of agranulocytosis and thrombocytopenia, as well as mesenteric arterial thrombosis and ischemic colitis.

Common adverse reactions reported in clinical trials and postmarketing experiences include dizziness, headache, fatigue, and asthenia. Patients may also report gastrointestinal disturbances such as diarrhea, nausea, and dyspepsia. Musculoskeletal symptoms, including muscle cramps and myalgia, have been observed, along with psychiatric effects such as insomnia, somnolence, and decreased libido or impotence.

Other notable adverse reactions include respiratory symptoms like cough, rhinitis, and upper respiratory infections. Dermatological reactions such as rash, pruritus, and photosensitivity have also been documented. Patients may experience visual disturbances, tinnitus, and taste abnormalities. Hydrochlorothiazide has been associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma in white patients taking large cumulative doses.

In addition to these reactions, patients may report unsteadiness, vertigo, syncope, paresthesia, and sleep disturbances. Gastrointestinal issues may extend to gastric pain, vomiting, and constipation. There are also reports of muscle spasms, arthralgia, and various skin conditions, including eczema and dermatitis.

It is important for healthcare providers to monitor patients for these adverse reactions and manage them appropriately.

Drug Interactions

Concomitant use of bisoprolol fumarate and hydrochlorothiazide with other antihypertensive agents may enhance their effects, necessitating careful monitoring of blood pressure and potential dosage adjustments. It is advised that bisoprolol fumarate and hydrochlorothiazide not be used in combination with other beta-blocking agents due to the risk of additive effects.

Patients receiving catecholamine-depleting medications, such as reserpine or guanethidine, should be closely monitored for excessive sympathetic activity reduction when bisoprolol fumarate is administered. In cases where clonidine is being used concurrently, it is recommended that bisoprolol fumarate and hydrochlorothiazide be discontinued several days prior to the withdrawal of clonidine to mitigate withdrawal effects.

Caution is warranted when bisoprolol fumarate and hydrochlorothiazide are used alongside myocardial depressants or agents that inhibit atrioventricular conduction, including certain calcium antagonists (notably verapamil and diltiazem) and antiarrhythmic drugs like disopyramide. The concomitant use of digitalis glycosides with beta-blockers may elevate the risk of bradycardia, necessitating careful patient monitoring.

The co-administration of rifampin has been shown to increase the metabolic clearance of bisoprolol fumarate, thereby shortening its elimination half-life; however, initial dose adjustments are typically not required. No clinically significant interactions have been observed with other agents, including thiazide diuretics and cimetidine.

Hydrochlorothiazide may potentiate orthostatic hypotension when used with alcohol, barbiturates, or narcotics. Additionally, dosage adjustments of antidiabetic medications, including both oral agents and insulin, may be necessary when hydrochlorothiazide is administered. The use of hydrochlorothiazide with other antihypertensive drugs may result in additive effects.

Cholestyramine and colestipol resins can significantly impair the gastrointestinal absorption of hydrochlorothiazide, reducing its bioavailability by up to 85% and 43%, respectively. Concurrent use of corticosteroids or adrenocorticotropic hormone (ACTH) may exacerbate electrolyte depletion, particularly hypokalemia.

The response to pressor amines, such as norepinephrine, may be diminished when used with hydrochlorothiazide; however, this interaction does not contraindicate their use. Nonsteroidal anti-inflammatory drugs may attenuate the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazide diuretics, warranting close observation of patients for the desired diuretic effect.

Sensitivity reactions may occur in patients receiving thiazides, regardless of prior allergy or bronchial asthma history. It is important to note that bisoprolol fumarate and hydrochlorothiazide may lower serum levels of protein-bound iodine without causing thyroid disturbances. Furthermore, these medications should be discontinued prior to conducting tests for parathyroid function to avoid 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 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 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, greater sensitivity in some older individuals cannot be ruled out.

Healthcare providers should exercise caution when prescribing this combination to geriatric patients, considering potential variations in drug response and the need for careful monitoring.

Pregnancy

There are no adequate and well-controlled studies of bisoprolol fumarate and hydrochlorothiazide in pregnant women. The combination of bisoprolol fumarate and hydrochlorothiazide should be used during pregnancy only if the potential benefit justifies the risk to the fetus.

Animal studies indicate that the bisoprolol fumarate/hydrochlorothiazide (B/H) combination is not teratogenic in rats at doses up to 51.4 mg/kg/day of bisoprolol fumarate combined with 128.6 mg/kg/day of hydrochlorothiazide. However, at doses of B 5.7/H 14.3 mg/kg/day and higher, the combination was associated with maternotoxic effects, including decreased body weight and food consumption, and at doses of B 17.1/H 42.9 mg/kg/day and higher, it was fetotoxic, leading to increased late resorptions. In rabbits, the B/H combination was not teratogenic at doses of B 10/H 25 mg/kg/day but exhibited maternotoxic effects at B 1/H 2.5 mg/kg/day and higher, and fetotoxic effects at B 10/H 25 mg/kg/day, resulting in increased resorptions.

Bisoprolol fumarate alone has been shown to be non-teratogenic in rats at doses up to 150 mg/kg/day; however, it was fetotoxic at 50 mg/kg/day, leading to increased late resorptions, and maternotoxic at 150 mg/kg/day, resulting in decreased food intake and body weight gain. In rabbits, bisoprolol fumarate was not teratogenic at doses up to 12.5 mg/kg/day but was embryolethal at this same dose, causing increased early resorptions.

Hydrochlorothiazide has been administered orally to pregnant mice and rats during major organogenesis at doses up to 3000 mg/kg/day and 1000 mg/kg/day, respectively, with no evidence of harm to the fetus. Nonetheless, there are no adequate and well-controlled studies in pregnant women, and hydrochlorothiazide should be used during pregnancy only if clearly needed.

Healthcare professionals should weigh the potential benefits against the risks when considering the use of bisoprolol fumarate and hydrochlorothiazide in pregnant patients.

Lactation

Bisoprolol fumarate, either alone or in combination with hydrochlorothiazide (HCTZ), has not been studied in nursing mothers. Thiazides 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 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 lead to the precipitation of 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, careful monitoring is advised in this population. If progressive renal impairment is observed, it is recommended that bisoprolol fumarate and hydrochlorothiazide be discontinued to mitigate potential risks associated with reduced kidney function.

Hepatic Impairment

Patients with hepatic impairment should use bisoprolol fumarate and hydrochlorothiazide with caution. It is important to monitor these patients closely due to the potential for altered fluid and electrolyte balance associated with thiazide use, which may precipitate hepatic coma.

In patients with cirrhosis, the elimination of bisoprolol fumarate is significantly slower compared to healthy subjects. Therefore, dosage adjustments may be necessary, and careful monitoring of liver function is recommended to ensure safety and efficacy in this population.

Overdosage

In cases of suspected overdosage with bisoprolol fumarate and hydrochlorothiazide, 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 highest reported dose reaching 2000 mg. The most frequently observed clinical manifestations include bradycardia and hypotension. Additional symptoms may encompass lethargy, and in severe instances, 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.

Clinical Manifestations

The signs and symptoms associated with an overdose of bisoprolol fumarate and hydrochlorothiazide can be categorized as follows:

• Cardiovascular: Tachycardia, hypotension, and shock.

• Neuromuscular: Weakness, confusion, dizziness, calf muscle cramps, paresthesia, fatigue, and impaired consciousness.

• Gastrointestinal: Nausea, vomiting, and increased thirst.

• Renal: Polyuria, oliguria, or anuria, particularly due to hemoconcentration.

• Laboratory Findings: Hypokalemia, hyponatremia, hypochloremia, metabolic alkalosis, and increased blood urea nitrogen (BUN), especially in patients with renal insufficiency.

Management

Upon suspicion of overdose, it is imperative 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.

Recommended general measures include:

• Induction of emesis and/or gastric lavage, if appropriate.

• Administration of activated charcoal to limit further absorption.

• Provision of respiratory support as needed.

• Correction of fluid and electrolyte imbalances.

• Treatment of convulsions, if they occur.

In light of the pharmacologic actions of beta-blockers and hydrochlorothiazide, healthcare professionals should consider these measures when clinically warranted to ensure optimal patient care during an overdose situation.

Nonclinical Toxicology

Thiazides are known to cross the placental barrier and can be detected in cord blood. The administration of thiazides in pregnant women necessitates a careful evaluation of the anticipated benefits against potential risks to the fetus. These risks may encompass fetal or neonatal jaundice, pancreatitis, thrombocytopenia, and possibly other adverse reactions that have been observed in adult populations.

Postmarketing Experience

Hydrochlorothiazide has been associated with an increased risk of non-melanoma skin cancer, as reported in postmarketing surveillance. Data from a study conducted within the Sentinel System indicate that the elevated risk is primarily linked to 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 without the supervision of a physician. It is essential for patients to understand the importance of adhering to their prescribed regimen and to seek medical advice before making any changes.

Patients should be advised 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. Awareness of these potential complications is crucial for timely intervention.

Inform patients or their caregivers about the risk of hypoglycemia associated with bisoprolol fumarate and hydrochlorothiazide, especially in situations where patients are fasting or experiencing vomiting. Patients should be encouraged to monitor for symptoms of hypoglycemia and report any concerns to their healthcare provider.

Patients must be made aware of how this medication affects their alertness before operating automobiles, machinery, or engaging in other tasks that require concentration. Understanding their individual response to the medication is vital for their safety.

Advise patients that photosensitivity reactions have been reported with thiazide diuretics. It is important for patients to protect their skin from sun exposure and to undergo regular skin cancer screenings while on hydrochlorothiazide.

Additionally, instruct patients taking hydrochlorothiazide to immediately consult their healthcare provider if they experience visual field defects, decreased visual acuity, or ocular pain, as these may indicate serious side effects that require prompt evaluation.

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 quality and efficacy of the product.

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 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, 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), in white patients receiving large cumulative doses. The overall risk for SCC is approximately 1 additional case per 16,000 patients per year, with a higher risk of 1 additional case for every 6,700 patients per year among white patients taking a cumulative dose of ≥50,000 mg.

FDA Insert (PDF)

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

View full prescribing information (PDF)