Bisoprolol fumarate/Hydrochlorothiazide

Description

Bisoprolol fumarate and hydrochlorothiazide tablets, USP are indicated for the treatment of hypertension, combining two antihypertensive agents in a once-daily dosage. The formulation includes bisoprolol fumarate, a synthetic beta 1-selective (cardioselective) adrenoceptor blocking agent, and hydrochlorothiazide, a benzothiadiazine diuretic.

Bisoprolol fumarate is chemically defined as (±)-1-[4-[2-(1-methylethoxy)ethoxymethyl]phenoxy]-3-(1-methylethyl)amino-2-propanol(E)-2-butenedioate (2:1) (salt). It is a racemic mixture with an asymmetric carbon atom, where the S(-) enantiomer is primarily responsible for its 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 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. This compound is a white or practically white, odorless crystalline powder. It is slightly soluble in water, sparingly soluble in dilute sodium hydroxide solution, freely soluble in n-butylamine and dimethylformamide, and insoluble in ether, chloroform, and dilute mineral acids. The empirical formula for hydrochlorothiazide is C7H8ClN3O4S2, with a molecular weight of 297.73.

Each bisoprolol fumarate and hydrochlorothiazide tablet, USP for oral administration is available in three strengths: 2.5 mg/6.25 mg, 5 mg/6.25 mg, and 10 mg/6.25 mg. The inactive ingredients include pregelatinized starch, anhydrous dicalcium phosphate, magnesium stearate, microcrystalline cellulose, and colloidal silicon dioxide. The 10 mg/6.25 mg tablet 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. FDA-approved dissolution test specifications for this formulation differ from those of the USP.

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.

Limitations of Use: The available data does not indicate any teratogenic or nonteratogenic effects associated with the use of this medication. However, healthcare professionals should consider individual patient circumstances when prescribing this therapy.

Dosage and Administration

Bisoprolol and hydrochlorothiazide are administered orally, with a recommended frequency of once daily.

For bisoprolol, effective dosing ranges from 2.5 mg to 40 mg. Initial therapy may commence with one 2.5/6.25 mg tablet once daily. Subsequent titration can occur at 14-day intervals, with a maximum recommended dose of 20/12.5 mg (equivalent to two 10/6.25 mg tablets) once daily. In clinical trials, doses of bisoprolol between 2.5 mg and 20 mg were utilized, demonstrating increased antihypertensive effects at higher doses.

Hydrochlorothiazide is effective in doses ranging from 12.5 mg to 50 mg. In conjunction with bisoprolol, hydrochlorothiazide doses of 6.25 mg to 25 mg were employed in clinical studies, also showing enhanced antihypertensive effects at elevated doses.

The combination of bisoprolol and hydrochlorothiazide may be substituted for the titrated individual components as clinically appropriate.

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 may exacerbate the patient's clinical status or lead to serious adverse effects.

Warnings and Precautions

Beta-blocking agents, including bisoprolol fumarate and hydrochlorothiazide tablets, carry several important 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. Continuous myocardial depression from beta-blockers can lead to the onset of heart failure in patients without a prior history. Therefore, at the first signs or symptoms of heart failure, discontinuation of bisoprolol fumarate and hydrochlorothiazide tablets should be considered.

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

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

Bronchospastic Disease Beta-blockers are generally not recommended for patients with bronchospastic pulmonary disease. However, bisoprolol fumarate and hydrochlorothiazide tablets may be used cautiously in these patients, with close monitoring for any adverse effects.

Major Surgery Patients on chronic beta-blocker therapy should not routinely discontinue their medication prior to major surgical procedures, as this may impair the heart's ability to respond to reflex adrenergic stimuli.

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

Thyrotoxicosis Abrupt withdrawal of beta-blockade in patients with thyrotoxicosis may lead to exacerbation of hyperthyroid symptoms or precipitate a thyroid storm.

Renal Disease Thiazide diuretics may induce azotemia in patients with compromised renal function. If progressive renal impairment is observed, bisoprolol fumarate and hydrochlorothiazide tablets should be discontinued.

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

Acute Angle-Closure Glaucoma Hydrochlorothiazide has been associated with an idiosyncratic reaction that can result in acute angle-closure glaucoma. In such cases, the immediate course of action is to discontinue hydrochlorothiazide as quickly as possible.

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

Laboratory Tests It is important to note that bisoprolol fumarate and hydrochlorothiazide tablets may lower serum levels of protein-bound iodine. 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. Additionally, at the first signs or symptoms of heart failure, discontinuation of bisoprolol fumarate and hydrochlorothiazide tablets should be considered.

Side Effects

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

Serious Adverse Reactions Among the serious cardiovascular events, bradycardia was reported in 1.1% of patients receiving the B2.5-40/H6.25 dosage, while arrhythmia occurred in 0.4% of the same group. Peripheral ischemia was noted in 0.7% of patients on B2.5-40/H6.25. Other serious cardiovascular reactions included chest pain, which was reported in 1.8% of patients on B2.5-40/H6.25.

Common Adverse Reactions Common adverse reactions observed in clinical trials included fatigue, which affected 4.6% of patients on B2.5-40/H6.25, and headache, reported by 4.5% of the same group. Dizziness was noted in 5.1% of patients on B2.5-40/H6.25. Gastrointestinal disturbances such as diarrhea were reported in 4.3% of patients on B2.5-40/H6.25, while cough was noted in 2.2% of the same group.

Other Notable Reactions Respiratory adverse reactions included upper respiratory infections (URI), which occurred in 2.3% of patients on placebo, and rhinitis, reported in 2.0% of placebo patients. Psychiatric effects such as insomnia were reported in 2.4% of placebo patients, while somnolence was noted in 1.1% of patients on B2.5-40/H6.25.

Additional Adverse Experiences In addition to the above, other adverse experiences reported with bisoprolol included central nervous system effects such as unsteadiness, vertigo, and sleep disturbances. Cardiovascular reactions included palpitations and hypotension. Gastrointestinal issues such as abdominal pain and constipation were also noted. Musculoskeletal complaints included arthralgia and muscle pain. Skin reactions ranged from rash to pruritus, and special senses disturbances included visual and auditory changes.

Hydrochlorothiazide, when used in conjunction, may also contribute to adverse reactions, including weakness, orthostatic hypotension, and gastrointestinal disturbances such as anorexia and jaundice. Hypersensitive reactions, including rash and respiratory distress, have been reported, as well as metabolic effects such as gout.

Overall, healthcare providers should monitor patients for these adverse reactions and manage them appropriately.

Drug Interactions

Bisoprolol fumarate and hydrochlorothiazide tablets may interact with various medications, necessitating careful consideration of concomitant therapies.

Antihypertensive Agents The combination of bisoprolol fumarate and hydrochlorothiazide tablets with other antihypertensive agents may enhance their effects. Therefore, monitoring blood pressure is advised to avoid excessive hypotension. However, these tablets should not be used in conjunction with other beta-blocking agents due to the potential for additive effects.

Catecholamine-Depleting Drugs Patients receiving catecholamine-depleting medications, 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.

Clonidine In patients undergoing treatment with clonidine, it is recommended that bisoprolol fumarate and hydrochlorothiazide tablets be discontinued several days prior to the withdrawal of clonidine to mitigate the risk of rebound hypertension.

Calcium Antagonists and Antiarrhythmic Agents Caution is advised when bisoprolol fumarate and hydrochlorothiazide tablets are used with myocardial depressants or agents that inhibit atrioventricular conduction, such as certain calcium antagonists (notably verapamil and diltiazem) and antiarrhythmic drugs like disopyramide.

Digitalis Glycosides The concomitant use of digitalis glycosides and beta-blockers may increase the risk of bradycardia due to their combined effects on atrioventricular conduction and heart rate.

Rifampin Concurrent administration of rifampin may increase the metabolic clearance of bisoprolol fumarate, resulting in a shortened elimination half-life. However, initial dose adjustments are generally not required.

Thiazide Diuretics and Cimetidine Pharmacokinetic studies indicate no clinically significant interactions with thiazide diuretics or cimetidine when used alongside bisoprolol fumarate and hydrochlorothiazide tablets.

Warfarin There is no observed effect of bisoprolol fumarate on prothrombin times in patients stabilized on warfarin therapy.

Hydrochlorothiazide Interactions

• Alcohol, Barbiturates, and Narcotics: These substances may enhance the risk of orthostatic hypotension when used with hydrochlorothiazide.

• Antidiabetic Agents: Dosage adjustments of oral antidiabetic drugs or insulin may be necessary when administered with hydrochlorothiazide.

• Other Antihypertensive Drugs: There may be an additive effect when hydrochlorothiazide is used with other antihypertensive medications.

• Cholestyramine and Colestipol: These resins can significantly impair the absorption of hydrochlorothiazide, reducing its gastrointestinal absorption by up to 85% and 43%, respectively.

• Corticosteroids and ACTH: The use of these agents may exacerbate electrolyte depletion, particularly hypokalemia, when combined with hydrochlorothiazide.

• Pressor Amines: The response to pressor amines, such as norepinephrine, may be diminished when used with hydrochlorothiazide, although this does not contraindicate their use.

• Skeletal Muscle Relaxants: Nondepolarizing skeletal muscle relaxants, such as tubocurarine, may exhibit increased responsiveness when used with hydrochlorothiazide.

• Lithium: The use of diuretics, including hydrochlorothiazide, is generally contraindicated with lithium due to the risk of increased lithium toxicity from reduced renal clearance.

• Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): These agents may diminish the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics when used concurrently.

Thyroid Function Tests Bisoprolol fumarate and hydrochlorothiazide tablets may lower serum levels of protein-bound iodine without causing thyroid disturbances. It is advisable to discontinue these tablets prior to conducting tests for parathyroid function.

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, 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 the potential for increased sensitivity and the need for careful monitoring of therapeutic effects and adverse reactions.

Pregnancy

The use of bisoprolol fumarate and hydrochlorothiazide (B/H) during pregnancy should be approached with caution. Animal studies have shown that the 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 higher doses, it has demonstrated maternotoxic effects, such as decreased body weight and food consumption, and fetotoxic effects, including increased late resorptions. Specifically, in rats, fetotoxicity was observed at doses of 17.1 mg/kg/day of bisoprolol fumarate and 42.9 mg/kg/day of hydrochlorothiazide. In rabbits, while no teratogenic effects were noted at doses of 10 mg/kg/day of bisoprolol fumarate and 25 mg/kg/day of hydrochlorothiazide, maternotoxicity and fetotoxicity were evident at lower doses.

Bisoprolol fumarate alone has been shown to be non-teratogenic in rats at doses up to 150 mg/kg/day, but it was fetotoxic at 50 mg/kg/day and maternotoxic at 150 mg/kg/day. In rabbits, it was not teratogenic at doses up to 12.5 mg/kg/day but did exhibit embryolethality 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 fetal harm.

There are no adequate and well-controlled studies in pregnant women regarding the use of bisoprolol fumarate and hydrochlorothiazide tablets. Therefore, these medications should only be used during pregnancy if the potential benefits justify the risks to the fetus. Additionally, thiazides, including hydrochlorothiazide, cross the placental barrier and may lead to adverse effects in the fetus, such as fetal or neonatal jaundice, pancreatitis, and thrombocytopenia. The anticipated benefits of treatment must be carefully weighed against these potential hazards.

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, 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 disrupt fluid and electrolyte balance. This disruption has the potential to 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.

Dosage adjustments may be necessary based on the severity of hepatic impairment, and healthcare providers should consider these factors when prescribing bisoprolol fumarate and hydrochlorothiazide tablets to ensure patient safety and therapeutic efficacy.

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 a maximum reported dose of 2000 mg. The most frequently observed symptoms include bradycardia and hypotension, with additional signs such as lethargy, delirium, coma, convulsions, and respiratory arrest noted in severe cases. Patients with pre-existing conditions may also experience congestive heart failure, bronchospasm, and hypoglycemia.

Clinical Manifestations

The clinical manifestations of overdose can be categorized into several systems:

• Cardiovascular: Symptoms may include tachycardia, hypotension, and shock.

• Neuromuscular: Patients may present with weakness, confusion, dizziness, calf muscle cramps, paresthesia, fatigue, and impaired consciousness.

• Gastrointestinal: Common symptoms include nausea, vomiting, and thirst.

• Renal: Patients may exhibit polyuria, oliguria, or anuria due to hemoconcentration.

• Laboratory Findings: Electrolyte imbalances such as hypokalemia, hyponatremia, hypochloremia, and metabolic alkalosis may be observed, along with increased blood urea nitrogen (BUN), particularly in those with renal insufficiency.

Management

If overdosage is suspected, the administration of bisoprolol fumarate and hydrochlorothiazide tablets should be discontinued immediately, and the patient should be closely monitored. Treatment is primarily symptomatic and supportive, as there is no specific antidote available. Limited evidence suggests that bisoprolol fumarate and hydrochlorothiazide are not dialyzable.

General measures for management may include:

• Induction of Emesis and Gastric Lavage: These procedures may be considered to reduce absorption.

• Activated Charcoal: Administering activated charcoal can help mitigate the effects of the overdose.

• Respiratory Support: Ensure adequate respiratory function, particularly in cases of respiratory distress.

• Fluid and Electrolyte Correction: Address any imbalances promptly.

Specific Interventions

• Bradycardia: Administer intravenous atropine. If the response is inadequate, isoproterenol or another positive chronotropic agent may be cautiously used. In some cases, transvenous pacemaker insertion may be necessary.

• Hypotension and Shock: Elevate the patient's legs, administer intravenous fluids, and replace lost electrolytes (potassium, sodium). Intravenous glucagon may be beneficial, and vasopressors should be considered if necessary.

• Heart Block (Second or Third Degree): Patients should be monitored closely and treated with isoproterenol infusion or transvenous cardiac pacemaker insertion as appropriate.

• Congestive Heart Failure: Initiate conventional therapy, which may include digitalis, diuretics, vasodilators, and inotropic agents.

• Bronchospasm: Administer bronchodilators such as isoproterenol and/or aminophylline.

• Hypoglycemia: Provide intravenous glucose as needed.

Monitoring

Continuous surveillance of fluid and electrolyte balance, particularly serum potassium levels, as well as renal function, is crucial until normalization is achieved. This comprehensive approach will help ensure patient safety and recovery following an overdose incident.

Nonclinical Toxicology

No teratogenic effects were observed in the studies conducted. Reproduction studies in rats demonstrated that the bisoprolol fumarate/hydrochlorothiazide combination, at doses of up to 30 mg/kg/day of bisoprolol fumarate in conjunction with 75 mg/kg/day of hydrochlorothiazide, did not impair fertility. Additionally, no impairment of fertility was noted 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 have not been conducted with the bisoprolol fumarate/hydrochlorothiazide combination. However, long-term studies involving 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 identified 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 found 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

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

Patient Counseling

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

Patients should be advised to seek medical attention if they experience any difficulty in breathing or develop other signs or symptoms indicative of congestive heart failure or excessive bradycardia. This awareness is vital for their safety and well-being.

It is important to inform patients or their caregivers about the risk of hypoglycemia associated with bisoprolol fumarate and hydrochlorothiazide tablets, especially in situations where patients are fasting or experiencing vomiting. Patients should be encouraged to monitor for symptoms of hypoglycemia and report any concerns to their healthcare provider.

Patients should also be made aware of how this medication may affect their alertness. They should be advised to assess their individual response to the medication before engaging in activities that require mental alertness, such as operating automobiles or machinery.

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

Finally, patients taking hydrochlorothiazide should be advised to immediately consult their healthcare provider if they experience any visual field defects, decreased visual acuity, or ocular pain, as these may indicate serious side effects that require prompt medical evaluation.

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 taking bisoprolol fumarate and hydrochlorothiazide tablets, with careful observation for signs of fluid or electrolyte disturbances such as hyponatremia, hypochloremic alkalosis, hypokalemia, and hypomagnesemia. These tablets may reduce serum levels of protein-bound iodine without causing thyroid disturbances, and they should be discontinued prior to parathyroid function tests.

Clinicians should counsel patients, particularly those with coronary artery disease, against discontinuing the medication without medical supervision. Patients should be advised to seek medical attention for any breathing difficulties or symptoms indicative of congestive heart failure or excessive bradycardia. There is a risk of hypoglycemia, especially in fasting or vomiting patients, necessitating monitoring for symptoms. Patients should be aware of their response to the medication before engaging in activities requiring alertness. Additionally, 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 if they experience visual field defects, decreased visual acuity, or ocular pain. Postmarketing data indicate that hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma, especially in white patients receiving high cumulative doses.

FDA Insert (PDF)

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

View full prescribing information (PDF)