BISOPROLOL FUMARATE AND HYDROCHLOROTHIAZIDE

Bisoprolol fumarate and hydrochlorothiazide tablets USP are indicated for the treatment of hypertension. It combines two antihypertensive agents in a once–daily dosage: a synthetic beta 1 -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 (C 18 H 31 NO 4 ) 2 •C 4 H 4 O 4 and 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 molecular formula is C 7 H 8 ClN 3 O 4 S 2 and it has a molecular weight of 297.73. Its structural formula is: Each Bisoprolol Fumarate and Hydrochlorothiazide tablet USP 2.5 mg/6.25 mg for oral administration contains: Bisoprolol fumarate USP….. 2.5 mg Hydrochlorothiazide USP…. 6.25 mg Each Bisoprolol Fumarate and Hydrochlorothiazide tablet USP 5 mg/6.25 mg for oral administration contains: Bisoprolol fumarate USP….. 5 mg Hydrochlorothiazide USP…. 6.25 mg Each Bisoprolol Fumarate and Hydrochlorothiazide tablet USP 10 mg/6.25 mg for oral administration contains: Bisoprolol fumarate USP….. 10 mg Hydrochlorothiazide USP…. 6.25 mg Inactive ingredients include pregelatinized starch, dibasic calcium phosphate anhydrous, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, colloidal silicon dioxide, copovidone and titanium dioxide. The 5 mg/6.25 mg tablet also contains red and yellow iron oxide. The 2.5 mg/6.25 mg tablet also contains yellow iron oxide.

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

Bisoprolol is an effective treatment of hypertension in once-daily doses of 2.5 mg 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 mg to 25 mg, the antihypertensive effects increased with increasing doses of either component. The adverse effects (see WARNINGS ) 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 (see CLINICAL PHARMACOLOGY ). 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 fumarate 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 fumarate and hydrochlorothiazide. 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. Replacement Therapy The combination may be substituted for the titrated individual components. Cessation of Therapy If withdrawal of bisoprolol fumarate and hydrochlorothiazide therapy is planned, it should be achieved gradually over a period of about 2 weeks. Patients should be carefully observed. 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. 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). Pediatric Patients: There is no pediatric experience with bisoprolol fumarate and hydrochlorothiazide.

Bisoprolol fumarate and hydrochlorothiazide tablets are contraindicated in patients in cardiogenic shock, overt cardiac failure (see WARNINGS ), second or third degree AV block, marked sinus bradycardia, anuria, and hypersensitivity to either component of this product or to other sulfonamide-derived drugs.

Bisoprolol fumarate and hydrochlorothiazide Bisoprolol fumarate/HCTZ 6.25 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 fumarate, occurrences of bronchospasm have been rare. Discontinuation rates for AEs were similar for bisoprolol fumarate/HCTZ 6.25 mg and placebo-treated patients. In the United States, 252 patients received bisoprolol fumarate (2.5, 5, 10, or 40 mg)/ HCTZ 6.25 mg and 144 patients received placebo in two controlled trials. In Study 1, bisoprolol fumarate 5/HCTZ 6.25 mg was administered for 4 weeks. In Study 2, bisoprolol fumarate 2.5, 10, or 40/HCTZ 6.25 mg was administered for 12 weeks. All adverse experiences, whether drug related or not, and drug related adverse experiences in patients treated with bisoprolol fumarate 2.5-10/ HCTZ 6.25 mg, reported during comparable, 4 week treatment periods by at least 2% of bisoprolol fumarate/ HCTZ 6.25 mg-treated patients (plus additional selected adverse experiences) are presented in the following table: % of Patients with Adverse Experiences a Body System/ Adverse Experience All Adverse Experiences Drug Related Adverse Experiences Placebo b B2.5-40/H 6.25 b Placebo b B2.5-10/H 6.25 b (n=144) (n=252) (n=144) (n=221) % % % % Cardiovascular bradycardia 0.7 1.1 0.7 0.9 arrhythmia 1.4 0.4 0.0 0.0 peripheral ischemia 0.9 0.7 0.9 0.4 chest pain 0.7 1.8 0.7 0.9 Respiratory bronchospasm 0.0 0.0 0.0 0.0 cough 1.0 2.2 0.7 1.5 rhinitis 2.0 0.7 0.7 0.9 URI 2.3 2.1 0.0 0.0 Body as a Whole asthenia 0.0 0.0 0.0 0.0 fatigue 2.7 4.6 1.7 3.0 peripheral edema 0.7 1.1 0.7 0.9 Central Nervous System dizziness 1.8 5.1 1.8 3.2 headache 4.7 4.5 2.7 0.4 Musculoskeletal muscle cramps 0.7 1.2 0.7 1.1 myalgia 1.4 2.4 0.0 0.0 Psychiatric insomnia 2.4 1.1 2.0 1.2 somnolence 0.7 1.1 0.7 0.9 loss of libido 1.2 0.4 1.2 0.4 impotence 0.7 1.1 0.7 1.1 Gastrointestinal diarrhea 1.4 4.3 1.2 1.1 nausea 0.9 1.1 0.9 0.9 dyspepsia 0.7 1.2 0.7 0.9 a Averages adjusted to combine across studies. b Combined across studies. Other adverse experiences that have been reported with the individual components are listed below. Bisoprolol Fumarate 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 fumarate during investigational use or extensive foreign marketing experience. 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, choroidal effusion, xanthopsia. Metabolic Gout. Genitourinary Sexual dysfunction, renal failure, renal dysfunction, interstitial nephritis. Skin Erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis. Postmarketing Experience Non-melanoma Skin Cancer Hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer. In a study conducted in the Sentinel System, increased risk was predominantly for squamous cell carcinoma (SCC) and in white patients taking large cumulative doses. The increased risk for SCC in the overall population was approximately 1 additional case per 16,000 patients per year, and for white patients taking a cumulative dose of ≥50,000 mg the risk increase was approximately 1 additional SCC case for every 6,700 patients per year. Laboratory Abnormalities Bisoprolol fumarate and hydrochlorothiazide Because of the low dose of hydrochlorothiazide in bisoprolol fumarate and hydrochlorothiazide, adverse metabolic effects with bisoprolol fumarate/HCTZ 6.25 mg are less frequent and of smaller magnitude than with HCTZ 25 mg. Laboratory data on serum potassium from the U.S. placebo-controlled trials are shown in the following table: Serum Potassium Data from U.S. Placebo Controlled Studies Placebo a B2.5/ H6.25 mg B5/ H6.25 mg B10/H 6.25 mg HCTZ 25 mg a (N=130 b ) (N=28 b ) (N=149 b ) (N=28 b ) (N=142 b ) Potassium Mean Change c (mEq/L) +0.04 +0.11 -0.08 0.00 -0.30% Hypokalemia d 0.0% 0.0% 0.7% 0.0% 5.5% a Combined across studies. b Patients with normal serum potassium at baseline. c Mean change from baseline at Week 4. d Percentage of patients with abnormality at Week 4. Treatment with both beta-blockers and thiazide diuretics is associated with increases in uric acid. However, the magnitude of the change in patients treated with B/H 6.25 mg was smaller than in patients treated with HCTZ 25 mg. Mean increases in serum triglycerides were observed in patients treated with bisoprolol fumarate and hydrochlorothiazide 6.25 mg. Total cholesterol was generally unaffected, but small decreases in HDL cholesterol were noted. Other laboratory abnormalities that have been reported with the individual components are listed below. Bisoprolol Fumarate In clinical trials, the most frequently reported laboratory change was an increase in serum triglycerides, but this was not a consistent finding. Sporadic liver test abnormalities have been reported. In the U.S. controlled trials experience with bisoprolol fumarate treatment for 4-12 weeks, the incidence of concomitant elevations in SGOT and SGPT from 1 to 2 times normal was 3.9%, compared to 2.5% for placebo. No patient had concomitant elevations greater than twice normal. In the long-term, uncontrolled experience with bisoprolol fumarate treatment for 6-18 months, the incidence of one or more concomitant elevations in SGOT and SGPT from 1 to 2 times normal was 6.2%. The incidence of multiple occurrences was 1.9%. For concomitant elevations in SGOT and SGPT of greater than twice normal, the incidence was 1.5%. The incidence of multiple occurrences was 0.3%. In many cases these elevations were attributed to underlying disorders, or resolved during continued treatment with bisoprolol fumarate. Other laboratory changes included small increases in uric acid, creatinine, BUN, serum potassium, glucose, and phosphorus and decreases in WBC and platelets. There have been occasional reports of eosinophilia. These were generally not of clinical importance and rarely resulted in discontinuation of bisoprolol fumarate. As with other beta-blockers, ANA conversions have also been reported on bisoprolol fumarate. About 15% of patients in long-term studies converted to a positive titer, although about one-third of these patients subsequently reconverted to a negative titer while on continued therapy. Hydrochlorothiazide Hyperglycemia, glycosuria, hyperuricemia, hypokalemia and other electrolyte imbalances (see PRECAUTIONS ), hyperlipidemia, hypercalcemia, leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia, and hemolytic anemia have been associated with HCTZ therapy.