METOPROLOL TARTRATE AND HYDROCHLOROTHIAZIDE

Metoprolol tartrate and hydrochlorothiazide tablethas the antihypertensive effect of metoprolol tartrate, a selective beta 1 -adrenoreceptor blocking agent, and the antihypertensive and diuretic actions of hydrochlorothiazide. It is available as tablets for oral administration. The 50/25 tablets contain 50 mg of metoprolol tartrate USP and 25 mg of hydrochlorothiazide USP; the 100/25 tablets contain 100 mg of metoprolol tartrate USP and 25 mg of hydrochlorothiazide USP; and the 100/50 tablets contain 100 mg of metoprolol tartrate USP and 50 mg of hydrochlorothiazide USP. Metoprolol tartrate USP is (±)-1-(Isopropylamino)-3-[ p -(2-methoxyethyl)phenoxy]-2-propanol L-(+)-tartrate (2:1) salt, and its structural formula is Metoprolol tartrate USP is a white, crystalline powder. It is very soluble in water; freely soluble in methylene chloride, in chloroform, and in alcohol; slightly soluble in acetone; and insoluble in ether. Its molecular weight is 684.82. Hydrochlorothiazide is 6-chloro-3,4-dihydro-2 H -1,2,4-benzothiadiazine-7-sulfonamide 1,1- dioxide, and its structural formula is Hydrochlorothiazide USP is a white, or practically white, practically odorless, crystalline powder. It is freely soluble in sodium hydroxide solution, in n -butylamine, and in dimethylformamide; sparingly soluble in methanol; slightly soluble in water; and insoluble in ether, in chloroform, and in dilute mineral acids. Its molecular weight is 297.73. Inactive Ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, povidone, lactose, pregelatinized starch. Structure Metoprolol Tartrate Structure Hydrochlorothiazide

Metoprolol tartrate and hydrochlorothiazide tablets are indicated for the management of hypertension This fixed-combination drug is not indicated for initial therapy of hypertension. If the fixed combination represents the dose titrated to the individual patient’s needs, therapy with the fixed combination may be more convenient than with the separate components.

Dosage should be determined by individual titration (see INDICATIONS AND USAGE). Hydrochlorothiazide is usually given at a dosage of 12.5 to 50 mg per day. The usual initial dosage of metoprolol tartrate tablets is 100 mg daily in single or divided doses. Dosage may be increased gradually until optimum blood pressure control is achieved. The effective dosage range is 100 to 450 mg per day. While once-daily dosing is effective and can maintain a reduction in blood pressure throughout the day, lower doses (especially 100 mg) may not maintain a full effect at the end of the 24-hour period, and larger or more frequent daily doses may be required. This can be evaluated by measuring blood pressure near the end of the dosing interval to determine whether satisfactory control is being maintained throughout the day. Beta 1 selectivity diminishes as dosage of metoprolol tartrate tablets is increased. The following dosage schedule may be used to administer from 100 to 200 mg of metoprolol tartrate per day and from 25 to 50 mg of hydrochlorothiazide per day: Metoprolol Tartrate and Hydrochlorothiazide Dosage Tablets of 50/25 2 tablets per day in single or divided doses Tablets of 100/25 1 to 2 tablets per day in single or divided doses Tablets of 100/50 1 tablet per day in single or divided doses Dosing regimens that exceed 50 mg of hydrochlorothiazide per day are not recommended. When necessary, another antihypertensive agent may be added gradually, beginning with 50% of the usual recommended starting dose to avoid an excessive fall in blood pressure.

Metoprolol Metoprolol tartrate tablets are contraindicated in sinus bradycardia, heart block greater than first degree, cardiogenic shock, and overt cardiac failure (see WARNINGS). Hypersensitivity to metoprolol tartrate and related derivatives, or to any of the excipients; hypersensitivity to other beta blockers (cross sensitivity between beta blockers can occur). Sick-sinus syndrome. Severe peripheral arterial circulatory disorders. Hydrochlorothiazide Hydrochlorothiazide is contraindicated in patients with anuria or hypersensitivity to this or other sulfonamide-derived drugs (see WARNINGS).

Metoprolol Tartrate and Hydrochlorothiazide The following adverse reactions were reported in controlled clinical studies of the combination of metoprolol tartrate and hydrochlorothiazide. Body as a Whole: Fatigue or lethargy and flu syndrome have each been reported in about 10 in 100 patients. Nervous System: Dizziness or vertigo, drowsiness or somnolence, and headache have each occurred in about 10 in 100 patients. Nightmare has occurred in 1 in 100 patients. Cardiovascular: Bradycardia has occurred in about 6 in 100 patients. Decreased exercise tolerance and dyspnea have each occurred in about 1 of 100 patients. Digestive: Diarrhea, digestive disorder, dry mouth, nausea or vomiting, and constipation have each occurred in about 1 in 100 patients. Metabolic and Nutritional: Hypokalemia has occurred in fewer than 10 in 100 patients. Edema, gout, and anorexia have each occurred in 1 in 100 patients. Special Senses: Blurred vision, tinnitus, and earache have each been reported in 1 in 100 patients. Skin: Sweating and purpura have each occurred in 1 in 100 patients. Urogenital: Impotence has occurred in 1 in 100 patients. Musculoskeletal: Muscle pain has occurred in 1 in 100 patients. Metoprolol Most adverse effects have been mild and transient. Central Nervous System: Tiredness and dizziness have occurred in about 10 of 100 patients. Depression has been reported in about 5 of 100 patients. Mental confusion and short-term memory loss have been reported. Headache, nightmares, and insomnia have also been reported, but a drug relationship is not clear. Cardiovascular: Shortness of breath and bradycardia have occurred in approximately 3 of 100 patients. Cold extremities; arterial insufficiency, usually of the Raynaud type; palpitations; and congestive heart failure have been reported. Gangrene in patients with pre-existing severe peripheral circulatory disorders has also been reported very rarely (see CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS). Respiratory: Wheezing (bronchospasm) has been reported in fewer than 1 of 100 patients (see WARNINGS). Rhinitis has also been reported. Gastrointestinal: Diarrhea has occurred in about 5 of 100 patients. Nausea, gastric pain, constipation, flatulence, and heartburn have been reported in 1 of 100, or fewer, patients. Vomiting was a common occurrence. Postmarketing experience reveals very rare reports of hepatitis, jaundice and non-specific hepatic dysfunction. Isolated cases of transaminase, alkaline phosphatase, and lactic dehydrogenase elevations have also been reported. Hypersensitive Reactions: Pruritus has occurred in fewer than 1 of 100 patients. Rash has been reported. Very rarely, photosensitivity and worsening of psoriasis has been reported. Miscellaneous: Peyronie’s disease has been reported in fewer than 1 of 100,000 patients. Alopecia has been reported. There have been very rare reports of weight gain, arthritis, and retroperitoneal fibrosis (relationship to metoprolol has not been definitely established). The oculomucocutaneous syndrome associated with the beta blocker practolol has not been reported with metoprolol. Potential Adverse Reactions A variety of adverse reactions not listed above have been reported with other beta-adrenergic blocking agents and should be considered potential adverse reactions to metoprolol. Central Nervous System: Reversible mental depression progressing to catatonia; visual disturbances; hallucinations; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance on neuropsychometrics. Cardiovascular: Intensification of AV block (see CONTRAINDICATIONS). Hematologic: Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura. Hypersensitive Reactions: Fever combined with aching and sore throat, laryngospasm, and respiratory distress. Postmarketing Experience The following adverse reactions have been reported during postapproval use of metoprolol: confusional state, an increase in blood triglycerides and a decrease in High Density Lipoprotein (HDL). Because these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency. Hydrochlorothiazide The following adverse reactions have been observed, but there has not been enough systematic collection of data to support an estimate of their frequency. Consequently the reactions are categorized by organ systems and are listed in decreasing order of severity and not frequency. Digestive: Pancreatitis, jaundice (intrahepatic cholestatic), sialadenitis, vomiting, diarrhea, cramping, nausea, gastric irritation, constipation, anorexia. Cardiovascular: Orthostatic hypotension (may be potentiated by alcohol, barbiturates, or narcotics). Neurologic: Vertigo, dizziness, transient blurred vision, headache, paresthesia, xanthopsia, weakness, restlessness. Musculoskeletal: Muscle spasm. Hematologic: Aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia. Metabolic: Hyperglycemia, glycosuria, hyperuricemia. Hypersensitive Reactions: Necrotizing angiitis, Stevens-Johnson syndrome, respiratory distress including pneumonitis and pulmonary edema, purpura, urticaria, rash, photosensitivity.

Drug/Drug Interactions Metoprolol: Catecholamine-depleting drugs (e.g., reserpine) may have an additive effect when given with beta-blocking agents. Patients treated with metoprolol plus a catecholamine depletor should therefore be closely observed for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension. Both digitalis glycosides and beta blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Risk of Anaphylactic Reaction: While taking beta blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction. General Anesthetics Some inhalation anesthetics may enhance the cardiodepressant effect of beta blockers (see WARNINGS; Metoprolol; Major Surgery). CYP2D6 Inhibitors Potent inhibitors of the CYP2D6 enzyme may increase the plasma concentration of metoprolol. Strong inhibition of CYP2D6 would mimic the pharmacokinetics of CYP2D6 poor metabolizer. Caution should therefore be exercised when administering potent CYP2D6 inhibitors with metoprolol. Known clinically significant potent inhibitors of CYP2D6 are antidepressants such as fluoxetine, paroxetine or bupropion, antipsychotics such as thioridazine, antiarrhythmics such as quinidine or propafenone, antiretrovirals such as ritonavir, antihistamines such as diphenhydramine, antimalarials such as hydroxychloroquine or quinidine, antifungals such as terbinafine and medications for stomach ulcers such as cimetidine. Clonidine If a patient is treated with clonidine and metoprolol concurrently, and clonidine treatment is to be discontinued, metoprolol should be stopped several days before clonidine is withdrawn. Rebound hypertension that can follow withdrawal of clonidine may be increased in patients receiving concurrent beta blocker treatment. Hydrochlorothiazide: Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability). Hypokalemia may develop during concomitant use of steroids or ACTH. Insulin requirements in diabetic patients may be increased, decreased, or unchanged. Thiazides may decrease arterial responsiveness to norepinephrine, but not enough to preclude effectiveness of the pressor agent for therapeutic use. Thiazides may increase the responsiveness to tubocurarine. Lithium renal clearance is reduced by thiazides, increasing the risk of lithium toxicity. There have been rare reports in the literature of hemolytic anemia occurring with the concomitant use of hydrochlorothiazide and methyldopa. Concurrent administration of some nonsteroidal anti-inflammatory agents may reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics. Cholestyramine and colestipol resins: Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively.