Bisoprolol fumarate/Hydrochlorothiazide

Description

Bisoprolol fumarate, USP is chemically described as (±)-1-[4-[2-(1‑methylethoxy)ethoxymethyl]phenoxy]-3-(1-methylethyl)amino-2-propanol(E)-2-butenedioate (2:1) (salt). It possesses an asymmetric carbon atom in its structure and is provided as a racemic mixture, with the S(-) enantiomer responsible for most of the beta-blocking activity. The empirical formula is (C18H31NO4)2•C4H4O4, and it has a molecular weight of 766.96 g/mol. Bisoprolol fumarate is a white crystalline powder, approximately equally hydrophilic and lipophilic, and is very soluble in water and methanol. It is freely soluble in alcohol, glacial acetic acid, and chloroform, and slightly soluble in acetone and ethyl acetate.

Hydrochlorothiazide (HCTZ), USP is 6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. It is a white, or almost white, almost odorless crystalline powder. Hydrochlorothiazide is very slightly soluble in water, soluble in acetone, freely soluble in n-butylamine, N,N-dimethylformamide, and diluted solutions of alkali hydroxides. It is sparingly soluble in methanol and ethanol, and practically insoluble in ether, chloroform, and dilute mineral acids. Its empirical formula is C7H8ClN3O4S2, and it has a molecular weight of 297.7 g/mol.

Each Bisoprolol Fumarate and Hydrochlorothiazide Tablet, USP is available in three strengths for oral administration: 2.5 mg of bisoprolol fumarate and 6.25 mg of hydrochlorothiazide; 5 mg of bisoprolol fumarate and 6.25 mg of hydrochlorothiazide; and 10 mg of bisoprolol fumarate and 6.25 mg of hydrochlorothiazide. Inactive ingredients include Colloidal Silicon Dioxide, Corn Starch, Dibasic Calcium Phosphate Dihydrate, Hypromellose, Magnesium Stearate, Microcrystalline Cellulose, Polyethylene Glycol, Polysorbate 80, 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. This combination therapy is intended for use in patients requiring blood pressure control.

Dosage and Administration

Bisoprolol is indicated for the management of hypertension, with a recommended dosage range of 2.5 mg to 40 mg administered orally once daily. Hydrochlorothiazide is also prescribed for hypertension, with a dosage range of 12.5 mg to 50 mg, taken orally once daily.

For patients requiring combination therapy with bisoprolol and hydrochlorothiazide, the bisoprolol dosage should be between 2.5 mg and 20 mg, while hydrochlorothiazide should be dosed between 6.25 mg and 25 mg. The initial therapy for this combination is one tablet containing 2.5 mg of bisoprolol and 6.25 mg of hydrochlorothiazide, taken orally once daily. The maximum recommended dose for the combination therapy is 20 mg of bisoprolol and 12.5 mg of hydrochlorothiazide, which can be achieved by administering two tablets of 10 mg bisoprolol and 6.25 mg hydrochlorothiazide once daily.

All doses should be taken orally, and it is advised that the medication be administered at the same time each day to maintain consistent blood levels.

Contraindications

Bisoprolol fumarate and hydrochlorothiazide tablets are contraindicated in patients with cardiogenic shock, overt cardiac failure, second or third degree AV block, marked sinus bradycardia, anuria, and hypersensitivity to either component of this product or to other sulfonamide-derived drugs. The use of this medication in these conditions poses significant health risks and should be avoided.

Warnings and Precautions

Beta-blocking agents, including bisoprolol fumarate and hydrochlorothiazide tablets, carry several important warnings and precautions that healthcare professionals must consider when prescribing these medications.

Cardiac Failure Beta-blockers should be avoided in patients with overt congestive heart failure. In individuals with compensated cardiac failure, these agents must be used with caution. Continued myocardial depression from beta-blockers can precipitate heart failure; therefore, at the first signs or symptoms of heart failure, discontinuation of bisoprolol fumarate and hydrochlorothiazide tablets should be considered.

Abrupt Cessation of Therapy Patients should be advised against the abrupt discontinuation of beta-blockers, as this may lead to exacerbations of angina pectoris and, in some cases, myocardial infarction or ventricular arrhythmias. It is crucial that any changes to therapy be made under the guidance of a physician.

Peripheral Vascular Disease In patients with peripheral vascular disease, beta-blockers may precipitate or worsen symptoms of arterial insufficiency. Caution is advised when prescribing these medications to such individuals.

Bronchospastic Disease Beta-blockers are generally contraindicated in patients with bronchospastic pulmonary disease. However, bisoprolol fumarate and hydrochlorothiazide tablets may be used with caution in these patients, with careful monitoring for any adverse effects.

Major Surgery Patients on chronic beta-blocking therapy should not routinely discontinue their medication prior to major surgery. Nevertheless, it is important to recognize that the heart's impaired ability to respond to reflex adrenergic stimuli may increase the risks associated with general anesthesia and surgical procedures.

Hypoglycemia Beta-blockers can mask the early warning signs of hypoglycemia. Patients experiencing severe hypoglycemia should be instructed to seek emergency medical treatment.

Thyrotoxicosis Beta-adrenergic blockade may obscure clinical signs of hyperthyroidism. Abrupt withdrawal of beta-blockade can lead to an exacerbation of hyperthyroid symptoms.

Renal Disease In patients with impaired renal function, the cumulative effects of thiazides may develop. If progressive renal impairment is observed, bisoprolol fumarate and hydrochlorothiazide tablets should be discontinued.

Hepatic Disease Caution is warranted when prescribing bisoprolol fumarate and hydrochlorothiazide tablets to patients with impaired hepatic function or progressive liver disease.

Acute Angle-Closure Glaucoma Hydrochlorothiazide may cause an idiosyncratic reaction leading to acute angle-closure glaucoma. In such cases, the primary treatment is the rapid discontinuation of hydrochlorothiazide.

Electrolyte and Fluid Balance Status Periodic monitoring of serum electrolytes is recommended, and patients should be observed for signs of fluid or electrolyte disturbances. Warning signs of fluid and electrolyte imbalance include dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances.

Laboratory Test Interactions Bisoprolol fumarate and hydrochlorothiazide tablets may reduce serum levels of protein-bound iodine. It is advisable to discontinue these medications prior to conducting tests for parathyroid function.

Healthcare professionals should ensure that patients are informed about the potential risks associated with these medications and the importance of monitoring for adverse effects. In the event of severe hypoglycemia or signs of heart failure, patients should be instructed to seek emergency medical assistance promptly.

Side Effects

Patients may experience a range of adverse reactions associated with the use of this medication, which can be categorized by seriousness and frequency.

Serious adverse reactions include cardiovascular events such as bradycardia, arrhythmia, peripheral ischemia, and chest pain. Additionally, patients may experience respiratory complications, including bronchospasm, dyspnea on exertion, and other respiratory distress symptoms. There are also reports of hematological issues such as agranulocytosis and thrombocytopenia, as well as gastrointestinal complications like mesenteric arterial thrombosis and ischemic colitis.

Common adverse reactions reported in clinical trials and postmarketing experiences include fatigue, asthenia, dizziness, headache, and muscle cramps. Patients may also report gastrointestinal symptoms such as diarrhea, nausea, and dyspepsia. Other frequently observed reactions include psychiatric effects like insomnia, somnolence, and decreased libido or impotence.

Additional adverse reactions that may occur, though less frequently, encompass a wide array of symptoms. These include unsteadiness, vertigo, syncope, paresthesia, and hypoesthesia. Patients may also experience skin reactions such as rash, acne, and pruritus, as well as visual disturbances and tinnitus. Musculoskeletal complaints, including myalgia and arthralgia, have also been noted.

Patients should be aware of the potential for more severe reactions, including hypotension, orthostatic hypotension, and angioedema. There are also reports of psychiatric disturbances, such as reversible mental depression and hallucinations, as well as metabolic changes like hyperglycemia and electrolyte imbalances.

In summary, while many patients tolerate the medication well, it is important to monitor for both common and serious adverse reactions, as well as to consider individual patient factors that may influence the occurrence and severity of these effects.

Drug Interactions

Bisoprolol fumarate and hydrochlorothiazide tablets have several notable drug interactions that may affect their efficacy and safety profile. These interactions can be categorized into pharmacodynamic and pharmacokinetic effects.

Pharmacodynamic Interactions

• The concomitant use of bisoprolol fumarate and hydrochlorothiazide tablets with other antihypertensive agents may enhance their antihypertensive effects. Clinicians should monitor blood pressure closely and consider dosage adjustments of the antihypertensive agents as necessary.

• The combination of bisoprolol fumarate and hydrochlorothiazide tablets with other beta-blocking agents is contraindicated due to the potential for additive effects and increased risk of adverse reactions.

• Alcohol, barbiturates, or narcotics may exacerbate orthostatic hypotension when used alongside hydrochlorothiazide. Patients should be advised to use caution when engaging in activities that require alertness.

• The use of antidiabetic drugs in conjunction with hydrochlorothiazide may necessitate dosage adjustments to maintain glycemic control.

• Nonsteroidal anti-inflammatory agents (NSAIDs) may diminish the diuretic, natriuretic, and antihypertensive effects of hydrochlorothiazide. Monitoring of blood pressure and renal function is recommended when these agents are used together.

• The concurrent administration of digitalis glycosides and beta-blockers, such as bisoprolol, may heighten the risk of bradycardia. Patients should be monitored for heart rate and rhythm.

Pharmacokinetic Interactions

• The co-administration of rifampin is known to increase the metabolic clearance of bisoprolol fumarate, resulting in a shortened elimination half-life. Clinicians should consider monitoring the therapeutic effects of bisoprolol and adjusting the dosage if necessary.

• Hydrochlorothiazide may have impaired absorption when taken with cholestyramine or colestipol resins, leading to a significant reduction in its gastrointestinal absorption (up to 85% and 43%, respectively). It is advisable to separate the administration of these agents to optimize the therapeutic effect of hydrochlorothiazide.

Other Considerations

• Bisoprolol fumarate and hydrochlorothiazide tablets may lower serum levels of protein-bound iodine without causing thyroid disturbances.

• Prior to conducting tests for parathyroid function, it is recommended that bisoprolol fumarate and hydrochlorothiazide tablets be discontinued to avoid potential interference with test results.

Healthcare providers should remain vigilant regarding these interactions and adjust treatment regimens as necessary to ensure patient safety and therapeutic efficacy.

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 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 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 of bisoprolol fumarate and hydrochlorothiazide tablets in pregnant women. The use of this drug combination during pregnancy should be considered only if the potential benefit justifies the risk to the fetus.

Animal studies have shown 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 B5.7/H14.3 (mg/kg/day) and higher, the combination was found to be maternotoxic, resulting in decreased body weight and food consumption, and fetotoxic, indicated by increased late resorptions at doses of B17.1/H42.9 (mg/kg/day) and higher. In rabbits, the B/H combination was not teratogenic at doses of B10/H25 (mg/kg/day) but exhibited maternotoxic effects at B1/H2.5 (mg/kg/day) and higher, and fetotoxic effects at B10/H25 (mg/kg/day).

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, without 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.

It is important to note that thiazides, including hydrochlorothiazide, cross the placental barrier and can appear in cord blood. The anticipated benefits of thiazide use in pregnant women must be weighed against potential hazards to the fetus, which may include fetal or neonatal jaundice, pancreatitis, thrombocytopenia, and possibly other adverse reactions that have been observed in adults.

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 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, bisoprolol fumarate and hydrochlorothiazide tablets should be discontinued. Monitoring of renal function is essential in these patients to ensure safety and efficacy.

Hepatic Impairment

Patients with hepatic impairment should use bisoprolol fumarate and hydrochlorothiazide tablets 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, which are components of this combination, may disrupt fluid and electrolyte balance, potentially leading to serious complications such as hepatic coma. Therefore, careful monitoring of liver function and electrolyte levels is recommended in patients with hepatic impairment. Adjustments to dosage may be necessary based on the severity of liver dysfunction and the patient's clinical status.

Overdosage

In cases of overdose with bisoprolol fumarate and hydrochlorothiazide tablets, limited data are available; however, several instances of bisoprolol fumarate overdose have been documented, with a maximum reported dose of 2000 mg. The clinical manifestations of overdose primarily include bradycardia and hypotension, which are the most frequently observed symptoms associated with beta-blocker overdosage. Additional symptoms may encompass lethargy, cardiovascular disturbances (such as tachycardia, hypotension, and shock), neuromuscular effects (including weakness, confusion, dizziness, cramps, paresthesia, and fatigue), gastrointestinal issues (nausea, vomiting, and thirst), and renal complications (polyuria, oliguria, or anuria).

Severe overdoses can lead to more critical conditions, including delirium, coma, convulsions, and respiratory arrest. Patients with pre-existing conditions may be at increased risk for complications such as congestive heart failure, bronchospasm, and hypoglycemia. Laboratory findings in overdose cases may reveal hypokalemia, hyponatremia, hypochloremia, metabolic alkalosis, and elevated blood urea nitrogen (BUN), particularly in individuals with renal insufficiency.

If an overdose is suspected, it is imperative to discontinue therapy with bisoprolol fumarate and hydrochlorothiazide tablets and closely monitor the patient. Management of overdose is primarily symptomatic and supportive, as there is no specific antidote available. General measures for managing overdose may include the induction of emesis, gastric lavage, and the administration of activated charcoal. Respiratory support and correction of fluid and electrolyte imbalances are also critical components of care.

Specific interventions for managing symptoms include the following:

• Bradycardia: This may be treated with intravenous atropine. If the response is inadequate, isoproterenol or another agent with positive chronotropic properties may be administered cautiously.

• Hypotension or Shock: Elevating the patient's legs, administering intravenous fluids, and replacing lost electrolytes are recommended. Intravenous glucagon may also be beneficial in these cases.

• Heart Block: Patients should be monitored closely and may require treatment with isoproterenol infusion or transvenous cardiac pacemaker insertion as appropriate.

• Congestive Heart Failure: Initiation of conventional therapy, including digitalis, diuretics, vasodilators, and inotropic agents, is advised.

• Bronchospasm: The administration of a bronchodilator, such as isoproterenol and/or aminophylline, is recommended.

• Hypoglycemia: Intravenous glucose should be administered to address this condition.

Continuous monitoring of fluid and electrolyte balance, particularly serum potassium levels, and renal function is essential until normalization is achieved in overdose cases.

Nonclinical Toxicology

No teratogenic effects have been observed in the studies conducted. Reproduction studies in rats demonstrated that the bisoprolol fumarate/hydrochlorothiazide combination, at doses of up to 30 mg/kg/day of bisoprolol fumarate in conjunction with 75 mg/kg/day of hydrochlorothiazide, did not impair fertility. These doses correspond to 75 and 300 times the maximum recommended human dose (MRHD) of bisoprolol fumarate and hydrochlorothiazide, respectively, based on body weight, and 15 and 62 times the MRHD based on body surface area. Additionally, no impairment of fertility was noted at doses up to 150 mg/kg/day of bisoprolol fumarate, which equates to 375 and 77 times the MRHD on a body weight and body surface area basis, respectively. Hydrochlorothiazide also showed no adverse effects on the fertility of mice and rats of either sex when administered via diet at doses of up to 100 and 4 mg/kg/day, respectively, prior to mating and throughout gestation. These doses represent 400 (mice) and 16 (rats) times the MRHD based on body weight, and 38 (mice) and 3.3 (rats) times the MRHD based on body surface area.

Long-term studies have not been conducted with the bisoprolol fumarate/hydrochlorothiazide combination. However, long-term studies with oral bisoprolol fumarate administered in the feed of mice (20 and 24 months) and rats (26 months) revealed no evidence of carcinogenic potential at doses of up to 250 mg/kg/day in mice and 125 mg/kg/day in rats. These doses correspond to 625 and 312 times the MRHD of 20 mg, or 0.4 mg/kg/day, based on a 50 kg individual, and 59 times (mice) and 64 times (rats) the MRHD based on body surface area. Two-year feeding studies conducted under the National Toxicology Program (NTP) evaluated hydrochlorothiazide at doses of up to 600 and 100 mg/kg/day in mice and rats, respectively. These doses are 2400 times (mice) and 400 times (rats) the MRHD of hydrochlorothiazide (12.5 mg/day) in the combination tablets, and 226 times (mice) and 82 times (rats) the MRHD based on body surface area. The studies found no evidence of carcinogenic potential for hydrochlorothiazide 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 identified in these in vitro and in vivo assays. Similarly, bisoprolol fumarate was evaluated in the same assays, with no evidence of mutagenicity found. Hydrochlorothiazide was not genotoxic in in vitro assays using several strains of Salmonella typhimurium, the Chinese Hamster Ovary test for chromosomal aberrations, or in vivo assays involving mouse germinal cell chromosomes and Chinese hamster bone marrow chromosomes. However, positive results were obtained in the in vitro CHO Sister Chromatid Exchange test and the mouse Lymphoma Cell assays at specific concentrations, as well as in the Aspergillus nidulans non-disjunction assay.

Postmarketing Experience

Postmarketing experience has identified an association between hydrochlorothiazide and an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC). Data derived from a study conducted within the Sentinel System indicate that this increased risk is predominantly observed in white patients who are administered large cumulative doses of the medication. Specifically, the overall population exhibits an approximate increase of 1 additional case of SCC per 16,000 patients per year. In contrast, white patients receiving a cumulative dose of ≥50,000 mg demonstrate a more pronounced risk, with an estimated increase of 1 additional SCC case for every 6,700 patients per year.

Patient Counseling

Healthcare providers should emphasize to patients, particularly those with coronary artery disease, the importance of not discontinuing bisoprolol fumarate and hydrochlorothiazide tablets without prior consultation with a physician. It is crucial for patients to understand that abrupt cessation of this medication can have serious consequences.

Patients should be advised to seek medical attention if they experience any difficulty in breathing or develop other signs or symptoms indicative of congestive heart failure or excessive bradycardia. This awareness is essential for early intervention and management of potential complications.

It is important to 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 should also be made aware of how this medication may affect their alertness. They should be advised to understand their individual response to the medication before operating automobiles, machinery, or engaging in other activities that require full attention.

Healthcare providers should inform patients that photosensitivity reactions have been reported with thiazide medications. Patients taking hydrochlorothiazide should be instructed to protect their skin from sun exposure and to undergo regular skin cancer screenings as a precautionary measure.

Finally, patients taking hydrochlorothiazide should be advised to immediately consult their healthcare provider if they experience any 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 tight, light-resistant containers to ensure its integrity and efficacy. 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. For dispensing, it is essential to use a tight container to maintain the product's quality during handling and storage.

Additional Clinical Information

Periodic determination of serum electrolytes is recommended for patients undergoing treatment, as it is essential for monitoring potential imbalances. Clinicians should be vigilant for warning signs or symptoms of fluid and electrolyte imbalance, which may include dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

Patients are at risk for hypokalemia, particularly with brisk diuresis in severe cirrhosis, during the use of corticosteroids or adrenocorticotropic hormone (ACTH), or following prolonged therapy. To mitigate this risk, potassium supplementation or increased intake of potassium-rich foods is advisable. Additionally, dilutional hyponatremia may occur in edematous patients during hot weather, where water restriction is the preferred management strategy, except in rare cases of life-threatening hyponatremia. In instances of actual salt depletion, appropriate replacement therapy is recommended.

FDA Insert (PDF)

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

View full prescribing information (PDF)