Bisoprolol fumarate/Hydrochlorothiazide

Description

Bisoprolol fumarate and hydrochlorothiazide tablets, USP, are indicated for the treatment of hypertension. 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) and is provided as a racemic mixture containing an asymmetric carbon atom. The S(-) enantiomer of bisoprolol fumarate is responsible for most of the beta-blocking activity. The empirical formula of bisoprolol fumarate is (C18H31NO4)2•C4H4O4, and it has a molecular weight of 766.97 g/mol. It appears as a white crystalline powder, is approximately equally hydrophilic and lipophilic, 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, sparingly soluble in methanol, and insoluble in ether, chloroform, and dilute mineral acids. The empirical formula of hydrochlorothiazide is C7H8ClN3O4S2, with a molecular weight of 297.73 g/mol.

Each bisoprolol fumarate and hydrochlorothiazide tablet for oral administration is available in three strengths: 2.5 mg bisoprolol fumarate and 6.25 mg hydrochlorothiazide, 5 mg bisoprolol fumarate and 6.25 mg hydrochlorothiazide, and 10 mg bisoprolol fumarate and 6.25 mg hydrochlorothiazide. Inactive ingredients include Anhydrous Lactose, Crospovidone, Hypromellose, Microcrystalline Cellulose, Polyethylene Glycol, Polysorbate 80, Pregelatinized Starch, Stearic Acid, and Titanium Dioxide. The 5 mg/6.25 mg tablet also contains D&C Red #30, while the 2.5 mg/6.25 mg tablet contains D&C Yellow #10 Aluminum Lake and FD&C Yellow #6.

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 administered orally at a dosage range of 2.5 mg to 40 mg once daily. Hydrochlorothiazide is also taken orally, with a recommended dosage of 12.5 mg to 50 mg once daily. For patients requiring combination therapy with bisoprolol and hydrochlorothiazide, the dosages are as follows: bisoprolol at 2.5 mg to 20 mg and hydrochlorothiazide at 6.25 mg to 25 mg.

For initial therapy, it is recommended to prescribe one 2.5/6.25 mg tablet once daily. The maximum recommended dose for the combination therapy is 20/12.5 mg, which can be achieved by administering two 10/6.25 mg tablets once daily.

Administration should occur orally, with a frequency of once daily. Titration of the dosage may be performed at intervals of 14 days, allowing for adjustments based on patient response and tolerability.

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.

Additionally, caution is advised in patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, due to the potential for excessive reduction of sympathetic activity from the combined effects of bisoprolol fumarate. The use of bisoprolol fumarate and hydrochlorothiazide tablets in conjunction with other beta-blocking agents is also contraindicated. Furthermore, the concomitant use of lithium with diuretics is generally not recommended, as diuretics can reduce the renal clearance of lithium, increasing the risk of lithium toxicity.

Warnings and Precautions

Beta-blocking agents, including bisoprolol fumarate and hydrochlorothiazide tablets, carry significant warnings and precautions that healthcare professionals must consider to ensure patient safety.

Cardiac Failure Beta-blockers are contraindicated in patients with overt congestive heart failure. In individuals with compensated cardiac failure, these agents should be administered with caution. It is imperative to monitor for any signs or symptoms of heart failure, and if such symptoms arise, discontinuation of therapy should be considered.

Abrupt Cessation of Therapy Patients should be advised against the abrupt discontinuation of beta-blockers, as this can lead to exacerbations of angina pectoris and, in some cases, myocardial infarction or ventricular arrhythmias. Any changes to therapy should be made under the guidance of a healthcare provider.

Peripheral Vascular Disease Caution is warranted when prescribing beta-blockers to patients with peripheral vascular disease, as these medications may exacerbate symptoms of arterial insufficiency.

Bronchospastic Disease In patients with bronchospastic pulmonary disease, beta-blockers are generally not recommended. However, bisoprolol fumarate and hydrochlorothiazide tablets may be used cautiously in this population, with close monitoring for respiratory symptoms.

Major Surgery Patients on chronic beta-blocker therapy should not routinely discontinue their medication prior to major surgical procedures due to the potential risks associated with general anesthesia and surgical stress.

Hypoglycemia Beta-blockers can mask the early warning signs of hypoglycemia, increasing the risk of severe or prolonged hypoglycemic episodes. Patients should be instructed to seek emergency medical assistance if they experience severe hypoglycemia.

Thyrotoxicosis Beta-adrenergic blockade may obscure clinical signs of hyperthyroidism. Abrupt withdrawal of beta-blockers in these patients can exacerbate symptoms or precipitate a thyroid storm.

Renal and Hepatic Disease Thiazide diuretics may induce azotemia in patients with impaired renal function; therefore, bisoprolol fumarate and hydrochlorothiazide tablets should be discontinued if progressive renal impairment is observed. Caution is also advised in patients with hepatic impairment, as thiazides can disrupt fluid and electrolyte balance, potentially leading to hepatic coma.

Acute Angle-Closure Glaucoma Hydrochlorothiazide has been associated with an idiosyncratic reaction that can result in acute angle-closure glaucoma. Symptoms may include a sudden decrease in visual acuity or ocular pain, necessitating the rapid discontinuation of hydrochlorothiazide.

Electrolyte and Fluid Balance Healthcare providers should periodically assess serum electrolytes and monitor patients for signs of fluid or electrolyte disturbances. Warning signs include dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle cramps, hypotension, oliguria, tachycardia, and gastrointestinal disturbances. Hypokalemia may develop, particularly with brisk diuresis or prolonged therapy, and can lead to ventricular arrhythmias or increase the risk of digitalis toxicity. Dilutional hyponatremia may occur in edematous patients during hot weather, and appropriate management includes water restriction. Additionally, hyperuricemia or acute gout may be precipitated in certain patients receiving thiazide diuretics.

Laboratory Tests Regular monitoring of serum electrolytes is recommended. It is important to note that bisoprolol fumarate and hydrochlorothiazide tablets may lower serum levels of protein-bound iodine without causing thyroid dysfunction. Furthermore, these medications should be discontinued prior to conducting tests for parathyroid function.

Patients should be instructed to seek emergency medical help if they experience severe hypoglycemia. At the first signs or symptoms of heart failure, discontinuation of bisoprolol fumarate and hydrochlorothiazide tablets should be considered, and the patient should contact their healthcare provider promptly.

Side Effects

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

Serious adverse reactions include cardiovascular events such as bradycardia, hypotension, and congestive heart failure. Additionally, patients may experience central nervous system effects, including severe depression, hallucinations, and a reversible acute syndrome characterized by disorientation and emotional lability. Other serious reactions noted include agranulocytosis and thrombocytopenia, as well as mesenteric arterial thrombosis and ischemic colitis.

Common adverse reactions reported in clinical trials and postmarketing experiences include central nervous system effects such as dizziness, headache, and sleep disturbances. Cardiovascular reactions may manifest as palpitations, cold extremities, and dyspnea on exertion. Gastrointestinal issues such as nausea, abdominal pain, and constipation are also frequently observed. Patients may report musculoskeletal pain, skin reactions including rash and pruritus, and general symptoms such as fatigue and malaise.

Hydrochlorothiazide is associated with its own set of adverse reactions. Serious reactions may include orthostatic hypotension, which can be exacerbated by alcohol or narcotics, and hypersensitive reactions such as anaphylaxis and severe skin conditions like Stevens-Johnson syndrome.

Common adverse reactions for hydrochlorothiazide include weakness, vertigo, and gastrointestinal disturbances such as anorexia and cramping. Patients may also experience transient blurred vision and musculoskeletal muscle spasms. Notably, hydrochlorothiazide has been linked to an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma in white patients taking large cumulative doses.

Laboratory abnormalities associated with bisoprolol fumarate include increases in serum triglycerides and sporadic liver test abnormalities. Hydrochlorothiazide may lead to hyperglycemia, hypokalemia, and other electrolyte imbalances, as well as leukopenia and various forms of anemia.

Healthcare providers should monitor patients for these adverse reactions and consider them when prescribing bisoprolol fumarate and hydrochlorothiazide.

Drug Interactions

Concurrent administration of bisoprolol fumarate and hydrochlorothiazide tablets with other antihypertensive agents may enhance their effects. Clinicians should monitor blood pressure closely to avoid excessive hypotension.

The co-administration of rifampin is known to increase the metabolic clearance of bisoprolol fumarate, resulting in a reduced elimination half-life. However, initial dose modification is generally not required.

When hydrochlorothiazide is used alongside alcohol, barbiturates, or narcotics, there is an increased risk of orthostatic hypotension. Caution is advised, and patients should be monitored for signs of hypotension.

Antidiabetic medications may necessitate dosage adjustments when prescribed with hydrochlorothiazide, as the diuretic can affect glycemic control. Regular monitoring of blood glucose levels is recommended.

Cholestyramine and colestipol resins can significantly impair the absorption of hydrochlorothiazide, with reductions of up to 85% and 43%, respectively. It is advisable to separate the administration of these resins from hydrochlorothiazide to minimize interaction.

The use of corticosteroids and adrenocorticotropic hormone (ACTH) in conjunction with hydrochlorothiazide may exacerbate electrolyte depletion, particularly hypokalemia. Monitoring of electrolyte levels is recommended during concurrent therapy.

Nonsteroidal anti-inflammatory drugs (NSAIDs) may diminish the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics, including hydrochlorothiazide. Clinicians should consider this interaction when prescribing NSAIDs to patients on hydrochlorothiazide.

Additionally, bisoprolol fumarate and hydrochlorothiazide tablets may lower serum levels of protein-bound iodine without causing thyroid dysfunction. It is important to note that these tablets 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 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 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 effects and adverse reactions.

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 only be considered if the potential benefits justify the risks to the fetus.

Animal studies have shown that the bisoprolol fumarate/hydrochlorothiazide (B/H) combination is not teratogenic 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 has been associated with maternotoxic effects, including decreased body weight and food consumption, and at doses of B17.1/H42.9 (mg/kg/day) and higher, it has been fetotoxic, leading to increased late resorptions. 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).

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, resulting in increased late resorptions, and maternotoxic at 150 mg/kg/day, causing 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, leading to increased early resorptions.

Hydrochlorothiazide has been administered orally to pregnant mice and rats during critical periods of organogenesis at doses up to 3000 and 1000 mg/kg/day, respectively, without evidence of harm to the fetus. Nonetheless, due to the lack of adequate and well-controlled studies in pregnant women, hydrochlorothiazide should also be used during pregnancy only if clearly needed.

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

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. In studies involving 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 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, it is essential to monitor renal function closely in these patients. If progressive renal impairment is observed, bisoprolol fumarate and hydrochlorothiazide tablets should be discontinued to prevent further complications.

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 therapy, 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 impaired hepatic function or progressive liver disease. Adjustments to dosage may be necessary based on the severity of hepatic impairment and the patient's clinical status.

Overdosage

In cases of overdose with bisoprolol fumarate, several instances have been documented, with the maximum reported dose reaching 2000 mg. The most commonly observed symptoms associated with overdose include bradycardia, hypotension, lethargy, delirium, coma, convulsions, and respiratory arrest.

Acute intoxication with thiazide diuretics, while rare, can result in significant complications. Overdose may lead to acute loss of fluid and electrolytes, manifesting as tachycardia, hypotension, shock, weakness, confusion, and gastrointestinal disturbances.

Upon suspicion of an overdose, it is imperative to discontinue therapy with bisoprolol fumarate and hydrochlorothiazide immediately. The patient should be closely monitored for any adverse effects. Management of overdose is primarily symptomatic and supportive, as there is no specific antidote available for either bisoprolol fumarate or hydrochlorothiazide.

Recommended management strategies include the induction of emesis, gastric lavage, and the administration of activated charcoal to limit further absorption of the drugs. Respiratory support may be necessary, along with the correction of any fluid and electrolyte imbalances.

In cases of bradycardia, intravenous atropine may be administered; if the response is inadequate, the use of isoproterenol or the placement of a transvenous pacemaker may be warranted. For patients experiencing hypotension or shock, elevating the legs, administering intravenous fluids, and replacing lost electrolytes are crucial steps. Additionally, intravenous glucagon and vasopressors may be beneficial in managing these conditions.

Patients presenting with heart block should be monitored closely and may require treatment with isoproterenol infusion or the insertion of a transvenous cardiac pacemaker, depending on the severity of the block. Continuous monitoring of fluid and electrolyte balance, particularly serum potassium levels and renal function, is essential until normalization is achieved in cases of overdose.

Nonclinical Toxicology

No teratogenic effects have been reported in the available studies. Reproductive studies conducted in rats demonstrated that the bisoprolol fumarate/hydrochlorothiazide combination, at doses of bisoprolol fumarate up to 30 mg/kg/day in conjunction with hydrochlorothiazide at 75 mg/kg/day, did not impair fertility. Additionally, no impairment of fertility was observed at doses of bisoprolol fumarate up to 150 mg/kg/day, which corresponds to 375 and 77 times the maximum recommended human dose (MRHD) based on body weight and body surface area, respectively. Hydrochlorothiazide also showed no adverse effects on the fertility of both male and female mice and rats when administered via diet at doses of up to 100 mg/kg/day and 4 mg/kg/day, respectively, prior to mating and throughout gestation.

Long-term studies involving the bisoprolol fumarate/hydrochlorothiazide combination have not been conducted. 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 bisoprolol fumarate up to 250 mg/kg/day in mice and up to 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. Similarly, bisoprolol fumarate was evaluated in the same assays, yielding no evidence of mutagenicity. Hydrochlorothiazide was also found to be non-genotoxic in in vitro assays using various strains of Salmonella typhimurium and in Chinese Hamster Ovary (CHO) tests for chromosomal aberrations. 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 at an unspecified concentration.

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 who have received 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 or more, 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. They should be advised to monitor for symptoms of hypoglycemia.

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 take precautions to protect their skin from sun exposure. Regular skin cancer screenings should also be encouraged.

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° to 25°C (68° 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

Periodic determination of serum electrolytes is recommended for patients undergoing treatment. Clinicians should be aware of warning signs or symptoms indicative 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.

To prevent or manage hypokalemia, potassium supplementation or increased intake of potassium-rich foods is advised. In edematous patients, dilutional hyponatremia may occur, particularly in hot weather; in such cases, water restriction is the preferred therapy, except in rare instances of life-threatening hyponatremia. For 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 Edenbridge Pharmaceuticals LLC.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)