Bisoprolol fumarate/Hydrochlorothiazide

Description

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). 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 766.97. Bisoprolol fumarate appears as a white crystalline powder, exhibiting approximately equal hydrophilic and lipophilic properties, 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. Its empirical formula is C7H8ClN3O4S2, with a molecular weight of 297.73.

The bisoprolol fumarate and hydrochlorothiazide tablets for oral administration are available in three strengths: 2.5 mg/6.25 mg, 5 mg/6.25 mg, and 10 mg/6.25 mg. Each 2.5 mg/6.25 mg tablet contains 2.5 mg of bisoprolol fumarate and 6.25 mg of hydrochlorothiazide. Each 5 mg/6.25 mg tablet contains 5 mg of bisoprolol fumarate and 6.25 mg of hydrochlorothiazide. Each 10 mg/6.25 mg tablet contains 10 mg of bisoprolol fumarate and 6.25 mg of hydrochlorothiazide. Inactive ingredients include pregelatinized starch, anhydrous dicalcium phosphate, magnesium stearate, microcrystalline cellulose, and colloidal silicon dioxide. The 10 mg/6.25 mg tablet also contains FD&C blue #1 aluminum lake, the 5 mg/6.25 mg tablet contains iron oxide red and ferrosoferric oxide, and the 2.5 mg/6.25 mg tablet contains ferric oxide.

Uses and Indications

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

There are no teratogenic or nonteratogenic effects associated with this medication.

Dosage and Administration

Bisoprolol fumarate and hydrochlorothiazide tablets are administered orally, once daily. The effective dosage range for bisoprolol is 2.5 to 40 mg, while hydrochlorothiazide is effective in doses of 12.5 to 50 mg. In clinical trials, bisoprolol doses of 2.5 to 20 mg and hydrochlorothiazide doses of 6.25 to 25 mg were utilized, demonstrating increased antihypertensive effects at higher doses.

Initial therapy may commence with one tablet containing 2.5 mg of bisoprolol and 6.25 mg of hydrochlorothiazide once daily. Subsequent titration of the dosage may occur at 14-day intervals, with a maximum recommended dose of 20 mg of bisoprolol and 12.5 mg of hydrochlorothiazide (equivalent to two 10/6.25 mg tablets) once daily. The combination therapy may be substituted for the titrated individual components as clinically appropriate.

In cases where therapy cessation is necessary, it is recommended that the process be conducted gradually over a period of approximately 2 weeks, with careful observation of the patient to monitor for any adverse effects.

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. Use in these conditions may exacerbate the patient's clinical status or lead to serious adverse effects.

Warnings and Precautions

Patients with overt congestive heart failure should avoid the use of beta-blocking agents, as they may exacerbate cardiac failure. In individuals with compensated cardiac failure, these agents must be administered with caution. For patients without a history of cardiac failure, it is important to note that continued myocardial depression from beta-blockers can precipitate heart failure. Therefore, discontinuation of bisoprolol fumarate and hydrochlorothiazide tablets should be considered at the first signs or symptoms of heart failure.

Abrupt cessation of therapy with beta-blockers can lead to exacerbations of angina pectoris, myocardial infarction, or ventricular arrhythmias. Patients must be advised against interrupting or discontinuing therapy without consulting their physician. Additionally, caution is warranted in patients with peripheral vascular disease, as beta-blockers may precipitate or worsen symptoms of arterial insufficiency.

In patients with bronchospastic pulmonary disease, beta-blockers are generally contraindicated; however, bisoprolol fumarate and hydrochlorothiazide tablets may be used with caution in these cases. For patients undergoing major surgery, it is recommended that chronically administered beta-blocking therapy not be routinely withdrawn prior to the procedure due to the associated risks with general anesthesia and surgical interventions.

Diabetic patients, particularly those on insulin or oral hypoglycemic agents, should be informed that beta-blockers may mask the symptoms of hypoglycemia. Furthermore, beta-adrenergic blockade can obscure clinical signs of hyperthyroidism in patients with thyrotoxicosis, and abrupt withdrawal may exacerbate symptoms or precipitate a thyroid storm.

In patients with renal impairment, the cumulative effects of thiazides may become pronounced, necessitating the discontinuation of bisoprolol fumarate and hydrochlorothiazide tablets if progressive renal impairment is observed. Caution is also advised in patients with hepatic disease, as thiazides can disrupt fluid and electrolyte balance, potentially leading to hepatic coma.

Hydrochlorothiazide has been associated with acute angle-closure glaucoma, and symptoms such as decreased visual acuity or ocular pain warrant rapid discontinuation of the medication.

To ensure patient safety, periodic determination of serum electrolytes is recommended to monitor electrolyte and fluid balance status. Warning signs of fluid and electrolyte imbalance include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, tachycardia, and gastrointestinal disturbances. Hypokalemia may develop, particularly with brisk diuresis or prolonged therapy, and can lead to ventricular arrhythmias or increase the heart's sensitivity to digitalis toxicity. Dilutional hyponatremia may occur in edematous patients during hot weather, necessitating water restriction as appropriate therapy.

Thiazides have been shown to decrease calcium excretion, and pathologic changes in the parathyroid glands have been observed in some patients on prolonged thiazide therapy. Hyperuricemia may also be precipitated in certain patients receiving thiazide diuretics. Patients with a history of severe anaphylactic reactions should be aware that they may exhibit heightened reactivity to allergens while taking beta-blockers.

Laboratory tests should include periodic serum electrolyte determinations. It is important to note that bisoprolol fumarate and hydrochlorothiazide tablets may lower serum levels of protein-bound iodine without causing thyroid disturbances. Additionally, these tablets should be discontinued prior to conducting tests for parathyroid function.

Patients experiencing symptoms of acute angle-closure glaucoma, such as a sudden decrease in visual acuity or ocular pain, should seek emergency medical assistance, as prompt medical or surgical intervention may be necessary if intraocular pressure remains uncontrolled.

At the first signs or symptoms of heart failure, patients should consider discontinuing bisoprolol fumarate and hydrochlorothiazide tablets. If withdrawal symptoms occur following abrupt cessation of therapy, it is advisable to reinstitute beta-blocking agent therapy, at least temporarily, under medical guidance.

Side Effects

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

Serious adverse reactions include cardiovascular events such as bradycardia, arrhythmia, peripheral ischemia, and chest pain. Hematologic reactions may manifest as agranulocytosis and thrombocytopenia. Additionally, patients may experience allergic reactions characterized by fever, aching, sore throat, laryngospasm, and respiratory distress. There are also reports of 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, insomnia, somnolence, unsteadiness, and vertigo. Patients may also report psychiatric symptoms including anxiety, restlessness, and decreased concentration or memory. Other frequent reactions encompass fatigue, asthenia, and peripheral edema.

Gastrointestinal disturbances such as diarrhea, nausea, and dyspepsia are also noted. Respiratory issues may include bronchospasm, cough, rhinitis, and upper respiratory infections. Dermatological reactions can manifest as rash, acne, eczema, psoriasis, skin irritation, pruritus, and purpura. Rarely, exfoliative dermatitis and cutaneous vasculitis have been observed.

Patients may experience disturbances in special senses, including visual disturbances, ocular pain or pressure, tinnitus, and taste abnormalities. Metabolic reactions such as gout, hyperglycemia, glycosuria, hyperuricemia, and electrolyte imbalances have also been reported.

Postmarketing data indicate an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma, in white patients taking large cumulative doses of hydrochlorothiazide.

Additional adverse reactions may include orthostatic hypotension, which can be exacerbated by alcohol, barbiturates, or narcotics, as well as weakness, muscle cramps, myalgia, and transient blurred vision. Patients may also experience symptoms such as anorexia, gastric irritation, cramping, jaundice, pancreatitis, cholecystitis, sialadenitis, and dry mouth.

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

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 administered 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 dosing 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 interference with test results.

Healthcare providers should remain vigilant regarding these interactions and adjust treatment regimens accordingly 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 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 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, the possibility of greater sensitivity in some older individuals cannot be excluded.

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

Pregnancy

Bisoprolol fumarate and hydrochlorothiazide tablets should be used during pregnancy only if the potential benefit justifies the risk to the fetus. There are no adequate and well-controlled studies with this drug combination in pregnant women. Animal studies have shown that the bisoprolol fumarate/hydrochlorothiazide (B/H) combination was 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, evidenced by 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, with fetotoxicity observed at B10/H25 (mg/kg/day) due to increased resorptions. Additionally, bisoprolol fumarate alone was not teratogenic in rats at doses up to 150 mg/kg/day but was fetotoxic at 50 mg/kg/day and maternotoxic at 150 mg/kg/day. Hydrochlorothiazide has been administered to pregnant mice and rats during major organogenesis at doses up to 3000 and 1000 mg/kg/day, respectively, without evidence of harm to the fetus.

It is important to note that thiazides, including hydrochlorothiazide, cross the placental barrier and can appear in cord blood. Their use in pregnant women necessitates careful consideration of the anticipated benefits against potential hazards to the fetus. Possible risks associated with thiazide use during pregnancy include fetal or neonatal jaundice, pancreatitis, thrombocytopenia, and other adverse reactions that have been reported 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 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 becomes apparent, bisoprolol fumarate and hydrochlorothiazide tablets should be discontinued to avoid potential complications. Monitoring of renal function is advised in these patients to ensure appropriate management and dosing adjustments.

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. This alteration can potentially precipitate hepatic coma in susceptible patients. Therefore, careful monitoring of liver function and electrolyte levels is recommended for patients with impaired hepatic function or progressive liver disease. Adjustments to dosage may be necessary based on the patient's clinical status and laboratory findings.

Overdosage

In cases of suspected overdose with bisoprolol fumarate and hydrochlorothiazide tablets, it is important to note that data on overdose incidents are limited. The maximum reported overdose involved a dosage of 2000 mg, which resulted in bradycardia and/or hypotension.

Symptoms of Overdosage

The most commonly observed symptoms associated with beta-blocker overdose include bradycardia and hypotension. In more severe instances, patients may experience lethargy, delirium, coma, convulsions, and respiratory arrest. Although acute intoxication with thiazide diuretics is rare, an overdose can lead to significant fluid and electrolyte loss. Symptoms may include tachycardia, hypotension, shock, weakness, confusion, and gastrointestinal disturbances.

Recommended Actions

If an overdose is suspected, it is crucial to discontinue the administration of bisoprolol fumarate and hydrochlorothiazide tablets immediately and closely monitor the patient. Management of the overdose is primarily symptomatic and supportive, as there is no specific antidote available.

Management Procedures

Suggested management strategies for overdose include:

• Induction of emesis or gastric lavage, if appropriate.

• Administration of activated charcoal to limit further absorption of the drug.

• Providing respiratory support as needed.

• Correcting any fluid and electrolyte imbalances.

For patients presenting with bradycardia, intravenous atropine should be administered. If the response is inadequate, the use of isoproterenol or the insertion of a transvenous pacemaker may be necessary. In cases of hypotension or shock, elevating the patient's legs, administering intravenous fluids, and replacing lost electrolytes are recommended. Additionally, intravenous glucagon and vasopressors may be beneficial in managing severe hypotension.

Continuous monitoring of fluid and electrolyte balance, particularly serum potassium levels, as well as renal function, is essential until these parameters are normalized in cases of overdose.

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 combination with 75 mg/kg/day of hydrochlorothiazide, did not impair fertility. Additionally, no impairment of fertility was noted at doses up to 150 mg/kg/day of bisoprolol fumarate alone. 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 mg/kg/day and 4 mg/kg/day, respectively, prior to mating and throughout gestation.

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. Two-year feeding studies conducted under the auspices of the National Toxicology Program (NTP) with hydrochlorothiazide at doses of 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 observed 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 found in these in vitro and in vivo assays. Similarly, bisoprolol fumarate was evaluated in the same assays, yielding no evidence of mutagenic potential. Hydrochlorothiazide was also shown to be non-genotoxic in in vitro assays using various strains of Salmonella typhimurium, the Chinese Hamster Ovary test for chromosomal aberrations, and 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

Hydrochlorothiazide has been associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC). Data 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 risk 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 significantly higher risk, with an estimated 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 should be cautioned that beta-blockers, including bisoprolol fumarate, may mask certain manifestations of hypoglycemia, particularly tachycardia. This is especially relevant for patients who are subject to spontaneous hypoglycemia or those with diabetes who are receiving insulin or oral hypoglycemic agents. Therefore, bisoprolol fumarate should be used with caution in these populations.

Patients must be informed about the potential effects of this medication on their alertness. They should be advised to understand how they react to bisoprolol fumarate and hydrochlorothiazide before operating automobiles, machinery, or engaging in other tasks that require full attention.

Additionally, healthcare providers should inform patients that photosensitivity reactions have been reported with thiazides. Patients taking hydrochlorothiazide should be instructed to protect their skin from sun exposure and to undergo regular skin cancer screenings. They should also be advised to immediately consult their healthcare provider if they experience visual field defects, decreased visual acuity, or ocular pain.

Storage and Handling

The product is supplied in a tight container to ensure integrity and stability. It should be stored at a temperature range of 20°C to 25°C (68°F to 77°F), 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, with careful observation for signs of fluid or electrolyte disturbances, including hyponatremia, hypochloremic alkalosis, hypokalemia, and hypomagnesemia. Clinicians should counsel patients on warning signs of fluid and electrolyte imbalance, which may include symptoms such as dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances like nausea and vomiting.

To mitigate hypokalemia, potassium supplementation or increased intake of potassium-rich foods may be beneficial. In cases of dilutional hyponatremia, particularly in edematous patients during hot weather, water restriction is advised rather than salt administration, except in rare life-threatening situations. 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 Marlex Pharmaceuticals, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)