Bisoprolol fumarate/Hydrochlorothiazide

Uses and Indications

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

Limitations of Use

No teratogenic or nonteratogenic effects are mentioned in the provided information.

Dosage and Administration

Bisoprolol fumarate and hydrochlorothiazide are administered orally in the form of film-coated tablets. The recommended dosage for bisoprolol is 2.5 mg to 40 mg once daily, while hydrochlorothiazide is effective in doses ranging from 12.5 mg to 50 mg once daily.

For combination therapy, bisoprolol doses of 2.5 mg to 20 mg and hydrochlorothiazide doses of 6.25 mg to 25 mg have been utilized in clinical trials. Initial antihypertensive therapy may be initiated with one 2.5 mg/6.25 mg tablet once daily. Subsequent titration may occur at 14-day intervals, allowing for an increase up to the maximum recommended dose of 20 mg/12.5 mg, which corresponds to two 10 mg/6.25 mg tablets once daily, as appropriate.

It is important to note that therapy with the combination of bisoprolol and hydrochlorothiazide should be considered only after a patient has not achieved the desired effect with monotherapy. If discontinuation of therapy is planned, it should be done gradually over approximately two 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.

Additionally, the use of bisoprolol fumarate and hydrochlorothiazide is not recommended in patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, due to the risk of excessive reduction of sympathetic activity. The combination of bisoprolol fumarate and hydrochlorothiazide with other beta-blocking agents is also contraindicated. Furthermore, lithium should generally not be administered with diuretics, as diuretic agents can reduce the renal clearance of lithium, increasing the risk of lithium toxicity.

Warnings and Precautions

Cardiac Failure Beta-blocking agents should be avoided in patients with overt congestive failure. In patients with compensated cardiac failure, these agents must be used cautiously. Continued depression of the myocardium with beta-blockers can precipitate cardiac failure. At the first signs or symptoms of heart failure, discontinuation of bisoprolol fumarate and hydrochlorothiazide should be considered. In some cases, therapy can be continued while heart failure is treated with other drugs.

Abrupt Cessation of Therapy Exacerbations of angina pectoris, myocardial infarction, or ventricular arrhythmia may occur following abrupt cessation of therapy with beta-blockers. Patients should be cautioned against interruption or discontinuation of therapy without physician’s advice. It may be advisable to taper therapy over approximately one week with careful observation. If withdrawal symptoms occur, beta-blocking agent therapy should be reinstituted, at least temporarily.

Peripheral Vascular Disease Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in such individuals.

Bronchospastic Disease Patients with bronchospastic pulmonary disease should generally not receive beta-blockers. Bisoprolol fumarate and hydrochlorothiazide may be used with caution in these patients, but the lowest possible dose should be utilized, and a beta-2 agonist (bronchodilator) should be made available.

Major Surgery Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery due to the impaired ability of the heart to respond to reflex adrenergic stimuli, which may augment the risks of general anesthesia and surgical procedures.

Hypoglycemia Beta-blockers may mask early warning signs of hypoglycemia, such as tachycardia, and increase the risk for severe or prolonged hypoglycemia, especially in patients with diabetes mellitus or those who are fasting. Patients should be instructed to seek emergency treatment if severe hypoglycemia occurs.

Thyrotoxicosis Beta-adrenergic blockade may mask clinical signs of hyperthyroidism. Abrupt withdrawal may exacerbate symptoms or precipitate thyroid storm.

Renal Disease Cumulative effects of thiazides may develop in patients with impaired renal function, potentially precipitating azotemia. If progressive renal impairment becomes apparent, bisoprolol fumarate and hydrochlorothiazide should be discontinued.

Hepatic Disease Use with caution in patients with impaired hepatic function or progressive liver disease. Thiazides may alter fluid and electrolyte balance, potentially precipitating hepatic coma. Elimination of bisoprolol fumarate is significantly slower in patients with cirrhosis than in healthy subjects.

Acute Angle-Closure Glaucoma Hydrochlorothiazide can cause an idiosyncratic reaction resulting in acute angle-closure glaucoma. Symptoms may include acute onset of decreased visual acuity or ocular pain. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if intraocular pressure remains uncontrolled.

General Precautions Periodic determination of serum electrolytes should be performed, and patients should be observed for signs of fluid or electrolyte disturbances, including hyponatremia, hypochloremic alkalosis, hypokalemia, and hypomagnesemia. 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.

Laboratory Tests Periodic determination of serum electrolytes should be performed. Bisoprolol fumarate and hydrochlorothiazide may decrease serum levels of protein-bound iodine without signs of thyroid disturbance. They should be discontinued before carrying out tests for parathyroid function.

Get Emergency Medical Help Patients should be instructed to seek emergency treatment if severe hypoglycemia occurs or if symptoms of acute angle-closure glaucoma develop, such as acute onset of decreased visual acuity or ocular pain.

Stop Taking and Call Your Doctor Discontinuation of bisoprolol fumarate and hydrochlorothiazide should be considered at the first signs or symptoms of heart failure. If withdrawal symptoms occur, beta-blocking agent therapy should be reinstituted, at least temporarily. If progressive renal impairment becomes apparent, bisoprolol fumarate and hydrochlorothiazide should be discontinued.

Side Effects

Patients receiving Bisoprolol Fumarate and Hydrochlorothiazide may experience a range of adverse reactions, which can be categorized by seriousness and frequency.

Serious Adverse Reactions

• Cardiovascular:

  • Bradycardia, arrhythmia, peripheral ischemia, chest pain, hypotension, orthostatic hypotension (may be potentiated by alcohol, barbiturates, or narcotics), congestive heart failure, dyspnea on exertion.

• Hematologic:

  • Agranulocytosis, thrombocytopenia.

• Respiratory:

  • Bronchospasm, respiratory distress including pneumonitis and pulmonary edema, laryngospasm.

• Skin:

  • Erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis, necrotizing angiitis (vasculitis and cutaneous vasculitis).

• Miscellaneous:

  • Mesenteric arterial thrombosis and ischemic colitis.

Common Adverse Reactions

• Central Nervous System:

  • Dizziness, headache, insomnia, somnolence, unsteadiness, vertigo, syncope, paresthesia, hypoesthesia, hyperesthesia, sleep disturbances/vivid dreams, depression, anxiety/restlessness, decreased concentration/memory.

• Gastrointestinal:

  • Diarrhea, nausea, dyspepsia, gastric/epigastric/abdominal pain, peptic ulcer, gastritis, vomiting, constipation, dry mouth, anorexia, cramping, jaundice (intrahepatic cholestatic jaundice), pancreatitis, cholecystitis, sialadenitis.

• Musculoskeletal:

  • Muscle cramps, myalgia, muscle spasm, arthralgia, muscle/joint pain, back/neck pain, twitching/tremor.

• Psychiatric:

  • Loss of libido, impotence.

• Skin:

  • Rash, acne, eczema, psoriasis, skin irritation, pruritus, purpura, flushing, sweating, alopecia, dermatitis.

• Special Senses:

  • Visual disturbances, ocular pain/pressure, abnormal lacrimation, tinnitus, decreased hearing, earache, taste abnormalities, transient blurred vision, choroidal effusion, xanthopsia.

• Metabolic:

  • Gout, hyperglycemia, glycosuria, hyperuricemia, hypokalemia and other electrolyte imbalances, hyperlipidemia, hypercalcemia.

• General:

  • Asthenia, fatigue, malaise, peripheral edema, weight gain, angioedema, weakness.

Postmarketing Experience

• Hydrochlorothiazide has been associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC) in white patients taking large cumulative doses.

Additional Notes

• Abrupt cessation of therapy may lead to exacerbations of angina pectoris and, in some instances, myocardial infarction or ventricular arrhythmia.

• Patients with bronchospastic pulmonary disease should generally avoid beta-blockers.

• Continued depression of the myocardium with beta-blockers can precipitate cardiac failure in patients without a history of cardiac failure.

• Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease.

Drug Interactions

Bisoprolol fumarate and hydrochlorothiazide tablets may potentiate the action of other antihypertensive agents when used concomitantly. However, these tablets should not be combined with other beta-blocking agents due to the potential for additive effects.

Pharmacokinetic Interactions

Concurrent use of rifampin has been shown to increase the metabolic clearance of bisoprolol fumarate, resulting in a shortened elimination half-life. While initial dose modification is generally not necessary, monitoring may be warranted. Hydrochlorothiazide may also impair absorption when administered with cholestyramine and colestipol resins, reducing its gastrointestinal absorption by up to 85% and 43%, respectively.

Pharmacodynamic Interactions

Patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, should be closely monitored, as the added beta-adrenergic blocking action of bisoprolol fumarate may lead to excessive reduction of sympathetic activity. Caution is advised when bisoprolol fumarate and hydrochlorothiazide are used with myocardial depressants or inhibitors of atrioventricular conduction, such as certain calcium antagonists (notably verapamil and diltiazem) or antiarrhythmic agents like disopyramide.

The concomitant use of digitalis glycosides and beta-blockers can increase the risk of bradycardia, as both classes of drugs slow atrioventricular conduction and decrease heart rate. Additionally, alcohol, barbiturates, or narcotics may potentiate orthostatic hypotension when used with hydrochlorothiazide. Antidiabetic drugs may require dosage adjustments when used alongside hydrochlorothiazide, and nonsteroidal anti-inflammatory agents can reduce the diuretic, natriuretic, and antihypertensive effects of hydrochlorothiazide.

Monitoring Considerations

Bisoprolol fumarate and hydrochlorothiazide tablets may decrease serum levels of protein-bound iodine without signs of thyroid disturbance. It is recommended that these tablets be discontinued prior to conducting tests for parathyroid function. In patients receiving concurrent therapy with clonidine, it is suggested that bisoprolol fumarate and hydrochlorothiazide be discontinued several days before the withdrawal of clonidine to mitigate potential withdrawal effects.

Pediatric Use

Safety and effectiveness of bisoprolol fumarate and hydrochlorothiazide tablets in pediatric patients have not been established. There are no available data to support the use of this medication in children or adolescents. Therefore, caution is advised when considering treatment options for this population.

Geriatric Use

In clinical trials involving bisoprolol fumarate and hydrochlorothiazide (HCTZ), at least 270 patients aged 60 years and older were treated. 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 younger patients. However, clinical experience suggests that greater sensitivity to the drug may occur in some older individuals, although specific differences in responses have not been identified.

Healthcare professionals should monitor geriatric patients closely for any signs of increased sensitivity and consider potential dose adjustments as necessary.

Pregnancy

Bisoprolol fumarate and hydrochlorothiazide 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 (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 higher doses, the combination was found to be maternotoxic, resulting in decreased body weight and food consumption, and fetotoxic, leading to increased late resorptions. In rabbits, the B/H combination was also not teratogenic at doses of 10 mg/kg/day of bisoprolol fumarate and 25 mg/kg/day of hydrochlorothiazide, but it exhibited maternotoxic effects at lower doses and fetotoxic effects at higher doses.

Bisoprolol fumarate alone was not teratogenic in rats at doses up to 150 mg/kg/day but was associated with increased late resorptions at 50 mg/kg/day and maternotoxic effects at 150 mg/kg/day. In rabbits, it was not teratogenic at doses up to 12.5 mg/kg/day but was embryolethal at this same dose.

Hydrochlorothiazide has been administered 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. However, thiazides cross the placental barrier and appear in cord blood, necessitating 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 may occur in adults.

In summary, the use of bisoprolol fumarate and hydrochlorothiazide during pregnancy requires a thorough assessment of the risks and benefits, as there is insufficient data to fully understand the implications for fetal outcomes.

Lactation

Bisoprolol fumarate, whether used 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. Additionally, small amounts of bisoprolol fumarate (less than 2% of the dose) have been detected in the milk of lactating rats.

Due to the potential for serious adverse reactions in breastfed infants, healthcare providers should carefully consider whether to discontinue breastfeeding or to discontinue the medication, weighing the importance of the drug to the mother against the potential risks to the infant.

Renal Impairment

Patients with renal impairment may experience cumulative effects from 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 can increase up to threefold compared to healthy subjects.

It is crucial to monitor renal function closely in these patients. If there is evidence of progressive renal impairment, the use of bisoprolol fumarate and hydrochlorothiazide should be discontinued to prevent further complications. Regular assessment of kidney function is recommended to ensure patient safety and optimal therapeutic outcomes.

Hepatic Impairment

Bisoprolol fumarate and hydrochlorothiazide should be used with caution in patients with impaired hepatic function or progressive liver disease. The elimination of bisoprolol fumarate is significantly slower in patients with cirrhosis compared to healthy subjects. Additionally, thiazides may alter fluid and electrolyte balance, which could precipitate hepatic coma.

Monitoring of liver function and electrolyte levels is recommended in these patients to ensure safety and efficacy. Adjustments to dosage may be necessary based on the severity of hepatic impairment, although specific dosage modifications are not detailed in the available data.

Overdosage

In cases of suspected overdose with bisoprolol fumarate and hydrochlorothiazide, therapy should be discontinued immediately, and the patient must be observed closely. The maximum reported overdose of bisoprolol fumarate is 2000 mg, with bradycardia and/or hypotension frequently noted. Symptoms of overdose may include bradycardia, hypotension, lethargy, delirium, coma, convulsions, and respiratory arrest. Additionally, acute intoxication with thiazide diuretics is rare; however, it may lead to acute loss of fluid and electrolytes, presenting with signs such as tachycardia, hypotension, shock, weakness, confusion, gastrointestinal disturbances, and renal issues like polyuria, oliguria, or anuria.

Management of overdose is symptomatic and supportive, as there is no specific antidote for either bisoprolol fumarate or hydrochlorothiazide. Suggested interventions include:

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

• Administration of activated charcoal to limit further absorption.

• Providing respiratory support as needed.

• Correction of fluid and electrolyte imbalances, with particular attention to serum potassium levels.

• For bradycardia, intravenous atropine may be administered; if the response is inadequate, isoproterenol or 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. Intravenous glucagon and vasopressors may also be beneficial.

• Patients exhibiting heart block should be monitored closely and treated with isoproterenol infusion or transvenous cardiac pacemaker insertion as appropriate.

• For congestive heart failure, conventional therapy should be initiated, including digitalis, diuretics, vasodilating agents, and inotropic agents.

• In instances of bronchospasm, bronchodilators such as isoproterenol and/or aminophylline should be administered.

• For hypoglycemia, intravenous glucose should be provided.

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

Nonclinical Toxicology

Teratogenic Effects

In nonclinical studies, the combination of bisoprolol fumarate and hydrochlorothiazide (B/H) was not found to be teratogenic in rats at doses up to 51.4 mg/kg/day of bisoprolol fumarate combined with 128.6 mg/kg/day of hydrochlorothiazide. Similarly, in rabbits, the B/H combination did not exhibit teratogenic effects at doses of 10 mg/kg/day of bisoprolol fumarate and 25 mg/kg/day of hydrochlorothiazide. 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. However, there are no adequate and well-controlled studies in pregnant women, and the use of bisoprolol fumarate and hydrochlorothiazide during pregnancy should only occur if the potential benefit justifies the risk to the fetus.

Non-Teratogenic Effects

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 other adverse reactions observed in adults. Reproductive studies in rats indicated no impairment of fertility with the B/H combination at doses up to 30 mg/kg/day of bisoprolol fumarate and 75 mg/kg/day of hydrochlorothiazide, as well as at doses up to 150 mg/kg/day of bisoprolol fumarate. Hydrochlorothiazide did not adversely affect fertility in mice and rats at dietary doses of up to 100 mg/kg/day and 4 mg/kg/day, respectively.

Nonclinical Toxicology

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 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 up to 600 mg/kg/day in mice and 100 mg/kg/day in rats showed no evidence of carcinogenic potential in female mice or rats, although equivocal evidence of hepatocarcinogenicity was observed in male mice.

Mutagenicity

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 alone demonstrated no mutagenic potential in the same assays. Hydrochlorothiazide was not genotoxic in in vitro assays using multiple strains of Salmonella typhimurium or in vivo assays involving mouse germinal cell chromosomes and Chinese hamster bone marrow chromosomes. However, positive results were noted in the in vitro CHO Sister Chromatid Exchange test and mouse Lymphoma Cell assays at specific concentrations, as well as in the Aspergillus nidulans non-disjunction assay.

Storage and Handling

Bisoprolol Fumarate and Hydrochlorothiazide is supplied in film-coated tablets and standard tablets.

The product should be stored at a temperature range of 20°C to 25°C (68°F to 77°F), with permissible excursions between 15°C to 30°C (59°F to 86°F) as per USP Controlled Room Temperature guidelines.

It is essential to dispense the tablets in a tight container. For optimal preservation, the product should be kept in tight, light-resistant containers, particularly when specified, and should utilize a child-resistant closure when applicable.