Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3621
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Bisoprolol Fumarate and Hydrochlorothiazide (Tablet, Film Coated)
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Bisoprolol is an effective treatment of hypertension in once-daily doses of 2.5 to 40 mg, while hydrochlorothiazide is effective in doses of 12.5 to 50 mg. In clinical trials of bisoprolol/hydrochlorothiazide combination therapy using bisoprolol doses of 2.5 to 20 mg and hydrochlorothiazide doses of 6.25 to 25 mg, the antihypertensive effects increased with increasing doses of either component. The adverse effects of bisoprolol are a mixture of dose-dependent phenomena (primarily bradycardia, diarrhea, asthenia and fatigue) and dose-independent phenomena (e.g., occasional rash); those of hydrochlorothiazide are a mixture of dose-dependent phenomena (primarily hypokalemia) and dose-independent phenomena (e.g., possibly pancreatitis); the dose-dependent phenomena for each being much more common than the dose-independent phenomena. The latter consist of those few that are truly idiosyncratic in nature or those that occur with such low frequency that a dose relationship may be difficult to discern. Therapy with a combination of bisoprolol and hydrochlorothiazide will be associated with both sets of dose-independent adverse effects, and to minimize these, it may be appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy. On the other hand, regimens that combine low doses of bisoprolol and hydrochlorothiazide should produce minimal dose-dependent adverse effects, e.g., bradycardia, diarrhea, asthenia and fatigue, and minimal dose-dependent adverse metabolic effects, i.e., decreases in serum potassium .<br/>Therapy Guided by Clinical Effect: A patient whose blood pressure is not adequately controlled with 2.5 to 20 mg bisoprolol daily may instead be given bisoprolol and hydrochlorothiazide. Patients whose blood pressures are adequately controlled with 50 mg of hydrochlorothiazide daily, but who experience significant potassium loss with this regimen, may achieve similar blood pressure control without electrolyte disturbance if they are switched to bisoprolol and hydrochlorothiazide.<br/>Initial Therapy: Antihypertensive therapy may be initiated with the lowest dose of bisoprolol fumarate and hydrochlorothiazide, one 2.5/6.25 mg tablet once daily. Subsequent titration (14 day intervals) may be carried out with bisoprolol fumarate and hydrochlorothiazide tablets up to the maximum recommended dose 20/12.5 mg (two 10/6.25 mg tablets) once daily, as appropriate.<br/>Replacement Therapy: The combination may be substituted for the titrated individual components.<br/>Cessation of Therapy: If withdrawal of bisoprolol and hydrochlorothiazide therapy is planned, it should be achieved gradually over a period of about 2 weeks. Patients should be carefully observed.<br/>Patients with Renal or Hepatic Impairment: As noted in the WARNINGS section, caution must be used in dosing/titrating patients with hepatic impairment or renal dysfunction. Since there is no indication that hydrochlorothiazide is dialyzable, and limited data suggest that bisoprolol is not dialyzable, drug replacement is not necessary in patients undergoing dialysis.<br/>Geriatric Patients: Dosage adjustment on the basis of age is not usually necessary, unless there is also significant renal or hepatic dysfunction (see above and WARNINGS section).<br/>Pediatric Patients: There is no pediatric experience with bisoprolol and hydrochlorothiazide.
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Bisoprolol fumarate and hydrochlorothiazide is indicated for the treatment of hypertension. It combines two antihypertensive agents in a once-daily dosage: a synthetic beta-selective (cardioselective) adrenoceptor blocking agent (bisoprolol fumarate) and a benzothiadiazine diuretic (hydrochlorothiazide). Bisoprolol fumarate is chemically described as (��)-1-[4-[[2-(1-methylethoxy)ethoxy]methyl]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. The S(-) enantiomer is responsible for most of the beta-blocking activity. Its molecular formula is (CHNO)���CHOand it has a molecular weight of 766.97. Its structural formula is: Bisoprolol fumarate is a white crystalline powder, approximately equally hydrophilic and lipophilic, and readily soluble in water, methanol, ethanol, and chloroform. Hydrochlorothiazide (HCTZ) is 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. It 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 molecularformula is CHClNOSand it has a molecular weight of 297.73. Its structural formula is: Each bisoprolol fumarate and hydrochlorothiazide tablet, for oral administration, contains one of the following combinations of bisoprolol fumarate/hydrochlorothiazide: 2.5 mg/6.25 mg, 5 mg/6.25 mg or 10 mg/6.25 mg. Each tablet also contains the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, pregelatinized (corn) starch, sodium lauryl sulfate and titanium dioxide. In addition, the 2.5 mg/6.25 mg tablet contains FD&C yellow no. 6 aluminum lake and the 5 mg/6.25 mg tablet contains FD&C blue no. 2 aluminum lake and FD&C yellow no. 6 aluminum lake.
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Bisoprolol and HCTZ have been used individually and in combination for the treatment of hypertension. The antihypertensive effects of these agents are additive; HCTZ 6.25 mg significantly increases the antihypertensive effect of bisoprolol. The incidence of hypokalemia with the bisoprolol fumarate and HCTZ 6.25 mg combination (B/H) is significantly lower than with HCTZ 25 mg. In clinical trials of bisoprolol and hydrochlorothiazide, meanchanges in serum potassium for patients treated with bisoprolol fumarate and hydrochlorothiazide 2.5/6.25 mg, 5/6.25 mg or 10/6.25 mg or placebo were less than��0.1 mEq/L. Mean changes in serum potassium for patients treated with any dose of bisoprolol in combination with HCTZ 25 mg ranged from -0.1 to -0.3 mEq/L. Bisoprolol is a beta-selective (cardioselective) adrenoceptor blocking agent without significant membrane stabilizing or intrinsic sympathomimetic activities in its therapeutic dose range. At higher doses (���20 mg) bisoprolol fumarate also inhibits beta-adrenoreceptors located in bronchial and vascular musculature. To retain relative selectivity, it is important to use the lowest effective dose. Hydrochlorothiazide is a benzothiadiazine diuretic. Thiazides affect renal tubular mechanisms of electrolyte reabsorption and increase excretion of sodium and chloride in approximately equivalent amounts. Natriuresis causes a secondary loss of potassium.<br/>Pharmacokinetics and Metabolism:<br/>Bisoprolol and Hydrochlorothiazide: In healthy volunteers, both bisoprolol and hydrochlorothiazide are well absorbed following oral administration of bisoprolol and hydrochlorothiazide. No change is observed in the bioavailability of either agent when given together in a single tablet. Absorption is not affected whether bisoprolol and hydrochlorothiazide is taken with or without food. Mean peak bisoprolol plasma concentrationsof about 9.0 ng/mL, 19 ng/mL and 36 ng/mL occur approximately 3 hours after the administration of the 2.5 mg/6.25 mg, 5 mg/6.25 mg and 10 mg/6.25 mg combination tablets, respectively. Mean peak plasma hydrochlorothiazide concentrations of 30 ng/mL occur approximately 2.5 hours following the administration of the combination. Dose proportional increases in plasma bisoprolol concentrations are observed between the 2.5 and 5, as well as between the 5 and 10 mg doses. The elimination Tof bisoprolol ranges from 7 to 15 hours and that of hydrochlorothiazide ranges from 4 to 10 hours. The percent of dose excreted unchanged in urine is about 55% for bisoprolol and about 60% for hydrochlorothiazide.<br/>Bisoprolol: The absolute bioavailability after a 10 mg oral dose of bisoprolol fumarate is about 80%. The first pass metabolism of bisoprolol is about 20%. The pharmacokinetic profile of bisoprolol has been examined following single doses and at steady state. Binding to serum proteins is approximately 30%. Peak plasma concentrations occur within 2 to 4 hours of dosing with 2.5 to 20 mg, and mean peak values range from 9.0 ng/mL at 2.5 mg to 70 ng/mL at 20 mg. Once-daily dosing with bisoprolol results in less than twofold intersubject variation in peak plasma concentrations. Plasma concentrations are proportional to the administered dose in the range of 2.5 to 20 mg. The plasma elimination half-life is 9 to 12 hours and is slightly longer in elderly patients, in part because of decreased renal function. Steady state is attained within 5 days with once-daily dosing. In both young and elderly populations, plasma accumulation is low; the accumulation factor ranges from 1.1 to 1.3, and is what would be expected from the half-life and once-daily dosing. Bisoprolol is eliminated equally by renal and nonrenal pathways with about 50% of the dose appearing unchanged in the urine and the remainder in the form of inactive metabolites. In humans, the known metabolites are labile or have no known pharmacologic activity. Less than 2% of the dose is excreted in the feces. The pharmacokinetic characteristics of the two enantiomers are similar. Bisoprolol is not metabolized by cytochrome P450 II D6 (debrisoquin hydroxylase). In subjects with creatinine clearance less than 40 mL/min, the plasma half-life is increased approximately threefold compared to healthy subjects. In patients with liver cirrhosis, the rate of elimination of bisoprolol is more variable and significantly slower than that in healthy subjects, with a plasma half-life ranging from 8 to 22 hours. In elderly subjects, mean plasma concentrations at steady state are increased, in part attributed to lower creatinine clearance. However, no significant differences in the degree of bisoprolol accumulation is found between young and elderly populations.<br/>Hydrochlorothiazide: Hydrochlorothiazide is well absorbed (65% to 75%) following oral administration. Absorption of hydrochlorothiazide is reduced in patients with congestive heart failure. Peak plasma concentrations are observed within 1 to 5 hours of dosing, and range from 70 to 490 ng/mL following oral doses of 12.5 to 100 mg. Plasma concentrations are linearly related to the administered dose. Concentrations of hydrochlorothiazide are 1.6 to 1.8 times higher in whole blood than in plasma. Binding to serum proteins has been reported to be approximately 40% to 68%. The plasma elimination half-life has been reported to be 6 to 15 hours. Hydrochlorothiazide is eliminated primarily by renal pathways. Following oral doses of 12.5 to 100 mg, 55% to 77% of the administered dose appears in urine and greater than 95% of the absorbed dose is excreted in urine as unchanged drug. Plasma concentrations of hydrochlorothiazide are increased and the elimination half-life is prolonged in patients with renal disease.<br/>Pharmacodynamics:<br/>Bisoprolol: Findings in clinical hemodynamics studies with bisoprolol are similar to those observed with other beta-blockers. The most prominent effect is the negative chronotropic effect, giving a reduction in resting and exercise heart rate. There is a fall in resting and exercise cardiac output with little observed change in stroke volume, and only a small increase in right atrial pressure, or pulmonary capillary wedge pressure at rest or during exercise. In normal volunteers, bisoprolol therapy resulted in a reduction of exercise-and isoproterenol-induced tachycardia. The maximal effect occurred within 1 to 4 hours post-dosing. Effects generally persisted for 24 hours at doses of 5 mg or greater. In controlled clinical trials, bisoprolol given as a single daily dose has been shown to be an effective antihypertensive agent when used alone or concomitantly with thiazide diuretics . The mechanism of bisoprolol's antihypertensive effect has not been completely established. Factors that may be involved include: Beta-selectivity of bisoprolol has been demonstrated in both animal and human studies. No effects at therapeutic doses on beta-adrenoreceptor density have been observed. Pulmonary function studies have been conducted in healthy volunteers, asthmatics, and patients with chronic obstructive pulmonary disease (COPD). Doses of bisoprolol fumarate ranged from 5 to 60 mg, atenolol from 50 to 200 mg, metoprolol from 100 to 200 mg, and propranolol from 40 to 80 mg. In some studies, slight, asymptomatic increases in airway resistance (AWR) and decreases in forced expiratory volume (FEV) were observed with doses of bisoprolol fumarate 20 mg and higher, similar to the small increases in AWR noted with other cardioselective beta-blocking agents. The changes induced by beta-blockade with all agents were reversed by bronchodilator therapy. Electrophysiology studies in man have demonstrated that bisoprolol significantly decreases heart rate, increases sinus node recovery time, prolongs AV node refractory periods, and, with rapid atrial stimulation, prolongs AV nodal conduction.<br/>Hydrochlorothiazide: Acute effects of thiazides are thought to result from a reduction in blood volume and cardiac output, secondary to a natriuretic effect, although a direct vasodilatory mechanism has also been proposed. With chronic administration, plasma volume returns toward normal, but peripheral vascular resistance is decreased. Thiazides do not affect normal blood pressure. Onset of action occurs within 2 hours of dosing, peak effect is observed at about 4 hours, and activity persists for up to 24 hours.
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Bisoprolol and hydrochlorothiazide tablets are contraindicated in patients in 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.
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Bisoprolol fumarate and hydrochlorothiazide tablets are available in the following strengths: 2.5 mg/6.25 mg, 5 mg/6.25 mg or 10 mg/6.25 mg. The 2.5 mg/6.25 mg tablets are orange, film-coated, round, biconvex, beveled edge tablets debossed with 501 on one side of the tablet and M on the other side. They are available as follows: NDC 0378-0501-01bottles of 100 tablets NDC 0378-0501-05bottles of 500 tablets NDC 0378-0501-10bottles of 1000 tablets The 5 mg/6.25 mg tablets are blue, film-coated, round, biconvex, beveled edge tablets debossed with 503 on one side of the tablet and M on the other side. They are available as follows: NDC 0378-0503-01bottles of 100 tablets NDC 0378-0503-05bottles of 500 tablets NDC 0378-0503-10bottles of 1000 tablets The 10 mg/6.25 mg tablets are white, film-coated, round, biconvex, beveled edge tablets debossed with 505 on one side of the tablet and M on the other side. They are available as follows: NDC 0378-0505-01bottles of 100 tablets NDC 0378-0505-05bottles of 500 tablets Store at 20��to 25��C (68��to 77��F). [See USP for Controlled Room Temperature.] Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
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dailymed-ingredient:FD&C_yellow_no._6_aluminum_lake,
dailymed-ingredient:anhydrous_lactose,
dailymed-ingredient:colloidal_silicon_dioxide,
dailymed-ingredient:croscarmellose_sodium,
dailymed-ingredient:hypromellose,
dailymed-ingredient:magnesium_stearate,
dailymed-ingredient:microcrystalline_cellulose,
dailymed-ingredient:polydextrose,
dailymed-ingredient:polyethylene_glycol,
dailymed-ingredient:pregelatinized_(corn)_starch,
dailymed-ingredient:sodium_lauryl_sulfate,
dailymed-ingredient:titanium_dioxide
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Bisoprolol Fumarate and Hydrochlorothiazide
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Bisoprolol Fumarate and Hydrochlorothiazide (Tablet, Film Coated)
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Bisoprolol and Hydrochlorothiazide: Bisoprolol fumarate/H6.25 mg is well tolerated in most patients. Most adverse effects (AEs) have been mild and transient. In more than 65,000 patients treated worldwide with bisoprolol, occurrences of bronchospasm have been rare. Discontinuation rates for AEs were similar for B/H6.25 mg and placebo-treated patients. In the United States, 252 patients received bisoprolol fumarate (2.5, 5, 10, or 40 mg)/H6.25 mg and 144 patients received placebo in two controlled trials. In Study 1, bisoprolol fumarate 5/H6.25 mg was administered for 4 weeks. In Study 2, bisoprolol fumarate 2.5, 10 or 40/H6.25 mg was administered for 12 weeks. All adverse experiences, whether drug related or not, and drug related adverse experiences in patients treated with B2.5���10/H6.25 mg, reported during comparable, 4 week treatment periods by at least 2% of bisoprolol fumarate/H6.25 mg-treated patients (plus additional selected adverse experiences) are presented in the following table: Other adverse experiences that have been reported with the individual components are listed below.<br/>Bisoprolol: In clinical trials worldwide, or in postmarketing experience, a variety of other AEs, in addition to those listed above, have been reported. While in many cases it is not known whether a causal relationship exists between bisoprolol and these AEs, they are listed to alert the physician to a possible relationship. Central Nervous System: Unsteadiness, dizziness, vertigo, headache, syncope, paresthesia, hypoesthesia, hyperesthesia, sleep disturbance/vivid dreams, insomnia, somnolence, depression, anxiety/restlessness, decreased concentration/memory. Cardiovascular: Bradycardia, palpitations and other rhythm disturbances, cold extremities, claudication, hypotension, orthostatic hypotension, chest pain, congestive heart failure, dyspnea on exertion. Gastrointestinal: Gastric/epigastric/abdominal pain, peptic ulcer, gastritis, dyspepsia, nausea, vomiting, diarrhea, constipation, dry mouth. Musculoskeletal: Arthralgia, muscle/joint pain, back/neck pain, muscle cramps, twitching/tremor. Skin: Rash, acne, eczema, psoriasis, skin irritation, pruritus, purpura, flushing, sweating, alopecia, dermatitis, exfoliative dermatitis (very rarely), cutaneous vasculitis. Special Senses: Visual disturbances, ocular pain/pressure, abnormal lacrimation, tinnitus, decreased hearing, earache, taste abnormalities. Metabolic: Gout. Respiratory: Asthma, bronchospasm, bronchitis, dyspnea, pharyngitis, rhinitis, sinusitis, URI (upper respiratory infection). Genitourinary: Decreased libido/impotence, Peyronie's disease (very rarely), cystitis, renal colic, polyuria. General: Fatigue, asthenia, chest pain, malaise, edema, weight gain, angioedema. In addition, a variety of adverse effects have been reported with other beta-adrenergic blocking agents and should be considered potential adverse effects: Central Nervous System: Reversible mental depression progressing to catatonia, hallucinations, an acute reversible syndrome characterized by disorientation to time and place, emotional lability, slightly clouded sensorium. Allergic: Fever, combined with aching and sore throat, laryngospasm, and respiratory distress. Hematologic: Agranulocytosis, thrombocytopenia. Gastrointestinal: Mesenteric arterial thrombosis and ischemic colitis. Miscellaneous: The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with bisoprolol during investigational use or extensive foreign marketing experience.<br/>Hydrochlorothiazide: The following adverse experiences, in addition to those listed in the above table, have been reported with hydrochlorothiazide (generally with doses of 25 mg or greater). General: Weakness. Central Nervous System: Vertigo, paresthesia, restlessness. Cardiovascular: Orthostatic hypotension (may be potentiated by alcohol, barbiturates, or narcotics). Gastrointestinal: Anorexia, gastric irritation, cramping, constipation, jaundice (intrahepatic cholestatic jaundice), pancreatitis, cholecystitis, sialadenitis, dry mouth. Musculoskeletal: Muscle spasm. Hypersensitive Reactions: Purpura, photosensitivity, rash, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), fever, respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions. Special Senses: Transient blurred vision, xanthopsia. Metabolic: Gout. Genitourinary: Sexual dysfunction, renal failure, renal dysfunction, interstitial nephritis.
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Bisoprolol and hydrochlorothiazide tablets are indicated in the management of hypertension.
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Bisoprolol Fumarate and Hydrochlorothiazide
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