Bisoprolol fumarate/Hydrochlorothiazide

Description

Bisoprolol fumarate and hydrochlorothiazide tablets, USP are indicated for the treatment of hypertension. This formulation combines two antihypertensive agents for once-daily administration: bisoprolol fumarate, a synthetic beta1-selective (cardioselective) adrenoceptor blocking agent, and hydrochlorothiazide, a benzothiadiazine diuretic.

Bisoprolol fumarate is chemically defined as 1-[α-(2-Isopropoxyethoxy)-4-tolyoxy]-3-(isopropylamino)-2-propanol fumarate (2:1) (salt), featuring an asymmetric carbon atom and provided as a racemic mixture, with the S(-) enantiomer contributing predominantly to its beta-blocking activity. Its empirical formula is (C18H31NO4)2•C4H4O4, and it has a molecular weight of 766.97. The structural formula is as follows:

Bisoprolol fumarate appears as a white crystalline powder, exhibiting approximately equal hydrophilicity and lipophilicity, and is readily soluble in water, methanol, ethanol, and chloroform.

Hydrochlorothiazide (HCTZ) is identified as 6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. It is a white or practically white, odorless crystalline powder, with slight solubility in water, sparing solubility in dilute sodium hydroxide solution, and is freely soluble in n-butylamine and dimethylformamide. Its empirical formula is C7H8ClN3O4S2, and it has a molecular weight of 297.73. The structural formula is as follows:

Each bisoprolol fumarate and hydrochlorothiazide tablet for oral administration contains one of the following combinations: 2.5 mg/6.25 mg, 5 mg/6.25 mg, or 10 mg/6.25 mg. Inactive ingredients include anhydrous lactose, colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, pregelatinized starch (corn), sodium lauryl sulfate, and titanium dioxide. The 2.5 mg/6.25 mg tablets also contain FD&C Yellow No. 6 Aluminum Lake, while the 5 mg/6.25 mg tablets contain FD&C Blue No. 2 Aluminum Lake and FD&C Yellow No. 6 Aluminum Lake.

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 is administered orally once daily, with effective dosing ranging from 2.5 mg to 40 mg. Hydrochlorothiazide is also administered orally, with effective doses between 12.5 mg and 50 mg.

For combination therapy involving bisoprolol and hydrochlorothiazide, clinical trials have demonstrated efficacy with bisoprolol doses of 2.5 mg to 20 mg and hydrochlorothiazide doses of 6.25 mg to 25 mg. Antihypertensive therapy may be initiated with the lowest dose of bisoprolol fumarate and hydrochlorothiazide tablets, specifically one 2.5/6.25 mg tablet once daily.

Titration of the dosage may be performed as clinically indicated, with the maximum recommended dose being 20/12.5 mg, which corresponds to two 10/6.25 mg tablets taken once daily.

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

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. Continued myocardial depression from beta-blockers can precipitate cardiac failure; therefore, at the first signs or symptoms of heart failure, discontinuation of bisoprolol fumarate and hydrochlorothiazide tablets should be considered. 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, and in some instances, myocardial infarction or ventricular arrhythmia may occur following abrupt cessation of beta-blocker therapy. Consequently, these patients should be advised against interrupting or discontinuing therapy without consulting their physician. For patients without overt coronary artery disease, it is advisable to taper the dosage of bisoprolol fumarate and hydrochlorothiazide tablets over approximately one week, with careful observation. Should withdrawal symptoms arise, reinstitution of beta-blocker therapy may be necessary, at least temporarily.

Beta-blockers can exacerbate symptoms of arterial insufficiency in patients with peripheral vascular disease, necessitating caution in this population. Additionally, patients with bronchospastic pulmonary disease should generally avoid beta-blockers. However, due to the relative beta1-selectivity of bisoprolol, 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 employed, and a beta2 agonist (bronchodilator) should be readily available.

Chronic beta-blocking therapy should not routinely be withdrawn prior to major surgery, as the heart's impaired ability to respond to reflex adrenergic stimuli may increase the risks associated with general anesthesia and surgical procedures. Furthermore, beta-blockers may mask early warning signs of hypoglycemia, such as tachycardia, thereby increasing the risk for severe or prolonged hypoglycemia, particularly in patients with diabetes mellitus, children, or those who are fasting. Patients experiencing severe hypoglycemia should seek emergency medical treatment.

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 creatinine clearance 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 noted, bisoprolol fumarate and hydrochlorothiazide tablets should be discontinued.

Caution is warranted when using bisoprolol fumarate and hydrochlorothiazide tablets in 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, may cause an idiosyncratic reaction leading to acute angle-closure glaucoma and elevated intraocular pressure, which can occur within hours to weeks of initiation. Symptoms may include acute onset of decreased visual acuity or ocular pain. If untreated, acute angle-closure glaucoma may result in permanent visual field loss. The primary treatment is to discontinue hydrochlorothiazide promptly, and if intraocular pressure remains uncontrolled, medical or surgical intervention may be necessary. Risk factors for developing acute angle-closure glaucoma include a history of sulfonamide or penicillin allergy.

Although the likelihood of developing hypokalemia is reduced with bisoprolol fumarate and hydrochlorothiazide tablets due to the low dose of hydrochlorothiazide, periodic serum electrolyte determinations are recommended. Patients should be monitored for signs of fluid or electrolyte disturbances, including hyponatremia, hypochloremic alkalosis, hypokalemia, and hypomagnesemia. Warning signs of fluid and electrolyte imbalance may include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

Hypokalemia may develop, particularly with brisk diuresis in severe cirrhosis, during concomitant use of corticosteroids or adrenocorticotropic hormone (ACTH), or after prolonged therapy. Inadequate oral electrolyte intake can also contribute to hypokalemia, which may provoke ventricular arrhythmias or exacerbate the heart's response to digitalis toxicity. Hypokalemia can be managed with potassium supplementation or increased intake of potassium-rich foods. Dilutional hyponatremia may occur in edematous patients during hot weather; appropriate management involves water restriction rather than salt administration, except in rare cases of life-threatening hyponatremia. In instances of actual salt depletion, appropriate replacement is the preferred treatment.

Periodic determination of serum electrolytes is essential, and patients should be closely monitored for signs of fluid or electrolyte disturbances. In the event of severe hypoglycemia, patients must be instructed to seek emergency medical assistance. At the first signs or symptoms of heart failure, discontinuation of bisoprolol fumarate and hydrochlorothiazide tablets should be considered.

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, chest pain, hypotension, and congestive heart failure. Respiratory complications may manifest as bronchospasm, laryngospasm, and respiratory distress, including pneumonitis and pulmonary edema. Additionally, patients may experience severe skin reactions such as erythema multiforme, including Stevens-Johnson syndrome, and exfoliative dermatitis, which occurs very rarely. Other serious reactions include renal dysfunction, interstitial nephritis, and hematological disorders such as agranulocytosis, thrombocytopenia, and aplastic anemia.

Common adverse reactions reported in clinical trials and postmarketing experiences include central nervous system effects such as dizziness, headache, unsteadiness, vertigo, syncope, and various sensory disturbances including paresthesia and hypoesthesia. Patients may also report sleep disturbances, including insomnia and vivid dreams, as well as symptoms of depression and anxiety/restlessness.

Gastrointestinal adverse reactions are frequently observed and may include nausea, vomiting, diarrhea, constipation, dyspepsia, and abdominal pain. Other gastrointestinal issues such as peptic ulcer, gastritis, and dry mouth have also been reported.

Musculoskeletal symptoms, including muscle cramps, myalgia, and arthralgia, are noted, along with general body reactions such as asthenia, fatigue, and peripheral edema.

Skin reactions can range from mild to severe, including rash, acne, eczema, and pruritus. More serious skin conditions such as necrotizing angiitis and photosensitivity have also been documented.

Metabolic adverse reactions include hyperglycemia, hyperlipidemia, hyperuricemia, and electrolyte imbalances such as hypokalemia. Patients may also experience gout and various blood dyscrasias, including leukopenia and hemolytic anemia.

In the genitourinary system, decreased libido and impotence are common, with rare occurrences of Peyronie’s disease.

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

Overall, while many adverse reactions are manageable, healthcare providers should monitor patients closely for both common and serious reactions to ensure timely intervention when necessary.

Drug Interactions

Bisoprolol fumarate and hydrochlorothiazide tablets may enhance the effects of other antihypertensive agents when used concurrently. Therefore, careful monitoring of blood pressure is recommended to avoid excessive hypotension.

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

Patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, should be closely monitored. The beta-adrenergic blocking action of bisoprolol fumarate may lead to an excessive reduction in sympathetic activity, necessitating dosage adjustments or careful observation for signs of hypotension or bradycardia.

In cases where patients are undergoing concurrent therapy with clonidine, it is advisable to discontinue bisoprolol fumarate and hydrochlorothiazide tablets several days prior to the withdrawal of clonidine to mitigate the risk of rebound hypertension.

Caution is warranted when bisoprolol fumarate and hydrochlorothiazide tablets are used alongside myocardial depressants or agents that inhibit atrioventricular conduction, such as certain calcium antagonists (notably verapamil and diltiazem) and antiarrhythmic medications like disopyramide. The combination may exacerbate bradycardia or other conduction disturbances.

The concomitant use of digitalis glycosides and beta-blockers, including bisoprolol fumarate, can lead to an increased risk of bradycardia due to their shared effects on atrioventricular conduction and heart rate. Monitoring of heart rate and rhythm is recommended in these patients to ensure safety.

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

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 therapy 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 indicate that the bisoprolol fumarate/hydrochlorothiazide 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 higher doses (B5.7/H14.3 mg/kg/day and above), the combination was found to be maternotoxic, resulting in decreased body weight and food consumption, and fetotoxic, leading to increased late resorptions at doses of B17.1/H42.9 mg/kg/day and higher.

In rabbits, the combination was not teratogenic at doses of B10/H25 mg/kg/day but exhibited maternotoxic effects (decreased body weight) at doses of B1/H2.5 mg/kg/day and higher, and fetotoxic effects (increased resorptions) at B10/H25 mg/kg/day. Hydrochlorothiazide, when administered orally to pregnant mice and rats during periods of major organogenesis at doses up to 3000 and 1000 mg/kg/day, respectively, showed no evidence of harm to the fetus. However, there are no adequate and well-controlled studies in pregnant women for hydrochlorothiazide, and its use should be considered only if clearly needed.

Thiazides, including hydrochlorothiazide, cross the placental barrier and can be detected in cord blood. Therefore, the use of thiazides in pregnant women necessitates careful consideration of the anticipated benefits against potential hazards to the fetus, which may include fetal or neonatal jaundice, pancreatitis, thrombocytopenia, and possibly other adverse reactions.

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 is observed, bisoprolol fumarate and hydrochlorothiazide tablets should be discontinued to prevent potential adverse effects. Monitoring of renal function is recommended in these patients to ensure safe and effective use of the medication.

Hepatic Impairment

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

Additionally, thiazides, including hydrochlorothiazide, may alter fluid and electrolyte balance, potentially precipitating hepatic coma in individuals with compromised liver function. 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 severity of hepatic impairment and the patient's clinical status.

Overdosage

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

The thiazide component, hydrochlorothiazide, is associated with rare occurrences of acute intoxication, primarily characterized by significant fluid and electrolyte loss. Symptoms of this type of overdose may present as cardiovascular disturbances (such as tachycardia, hypotension, and shock), neuromuscular issues (including weakness, confusion, dizziness, calf muscle cramps, paresthesia, and fatigue), gastrointestinal complaints (nausea, vomiting, and thirst), and renal complications (polyuria, oliguria, or anuria due to hemoconcentration). Laboratory findings may reveal hypokalemia, hyponatremia, hypochloremia, alkalosis, and increased blood urea nitrogen (BUN), particularly in patients with renal insufficiency.

Upon suspicion of overdosage, it is imperative to discontinue therapy with bisoprolol fumarate and hydrochlorothiazide tablets and closely monitor the patient. Management is primarily symptomatic and supportive, as there is no specific antidote available. Current evidence suggests that bisoprolol fumarate is not dialyzable, and similarly, hydrochlorothiazide does not appear to be amenable to dialysis.

General measures to consider in the management of overdose include the induction of emesis and/or gastric lavage, administration of activated charcoal, provision of respiratory support, correction of fluid and electrolyte imbalances, and treatment of convulsions. Clinicians should also consider additional interventions based on the pharmacologic actions of beta-blockers and hydrochlorothiazide, as well as the specific clinical scenario presented.

Nonclinical Toxicology

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

Non-teratogenic effects associated with thiazides include their ability to cross the placental barrier and appear in cord blood. The use of thiazides in pregnant women necessitates careful consideration of the anticipated benefits against potential hazards to the fetus, which may include fetal or neonatal jaundice, pancreatitis, thrombocytopenia, and other adverse reactions observed in adults.

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 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 also showed 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 not found to be genotoxic in in vitro assays using multiple strains of Salmonella typhimurium (Ames test), the Chinese Hamster Ovary (CHO) 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. 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 shows an approximate 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 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 side effects is crucial for timely intervention.

Inform patients or their caregivers about the risk of hypoglycemia associated with bisoprolol fumarate and hydrochlorothiazide tablets, particularly in those who 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. It is important for them to assess their individual response to the medication.

Advise patients that photosensitivity reactions have been reported with thiazide medications. Therefore, it is prudent for patients taking hydrochlorothiazide to protect their skin from sun exposure and to undergo regular skin cancer screenings.

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 medical attention.

Storage and Handling

The product is supplied in a tight, light-resistant container, as defined by the United States Pharmacopeia (USP), and features a child-resistant closure to ensure safety. It should be stored at a controlled room temperature of 20° to 25°C (68° to 77°F), in accordance with USP guidelines.

Additional Clinical Information

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

Patient counseling is essential, particularly for those with coronary artery disease, as abrupt discontinuation of the medication should only occur under physician supervision. Patients must be advised to seek medical attention if they experience breathing difficulties or symptoms indicative 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, thiazide-related photosensitivity reactions have been reported, 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 linked to an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC), in white patients receiving high cumulative doses. The overall risk for SCC is approximately one additional case per 16,000 patients per year, with a significantly higher risk for white patients taking a cumulative dose of ≥ 50,000 mg, estimated at one additional case for every 6,700 patients per year.

FDA Insert (PDF)

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

View full prescribing information (PDF)