Metoprolol Tartrate and Hydrochlorothiazide 50 mg; 25 mg Tablet, 1,000-count

WARNINGS Metoprolol Cardiac Failure: Sympathetic stimulation is a vital component supporting circulatory function in congestive heart failure, and beta blockade carries the potential hazard of further depressing myocardial contractility and precipitating more severe failure. In hypertensive patients who have congestive heart failure controlled by digitalis and diuretics, metoprolol should be administered cautiously. In Patients Without a History of Cardiac Failure: Continued depression of the myocardium with beta-blocking agents over a period of time can, in some cases, lead to cardiac failure.

At the first sign or symptom of impending cardiac failure, patients should be fully digitalized and/or given a diuretic. The response should be observed closely. If cardiac failure continues, despite adequate digitalization and diuretic therapy, metoprolol should be withdrawn.

Ischemic Heart Disease: Following abrupt cessation of therapy with certain beta-blocking agents, exacerbations of angina pectoris and in some cases, myocardial infarction have been reported. Even in the absence of overt angina pectoris, when discontinuing therapy, metoprolol should not be withdrawn abruptly, and patients should be cautioned against interruption of therapy without the physician’s advice (see PRECAUTIONS: Information for Patients). Bronchospastic Diseases: PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD, IN GENERAL, NOT RECEIVE BETA BLOCKERS, including metoprolol tartrate and hydrochlorothiazide.

Because of its relative beta 1 selectivity, however, metoprolol may be used with caution in patients with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive treatment. Since beta 1 selectivity is not absolute, a beta 2 -stimulating agent should be administered concomitantly, and the lowest possible dose of metoprolol should be used. In these circumstances it would be prudent initially to administer metoprolol in smaller doses three times daily, instead of larger doses two times daily, to avoid the higher plasma levels associated with the longer dosing interval (see DOSAGE AND ADMINISTRATION).

Major Surgery: Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. Diabetes and Hypoglycemia: Metoprolol should be used with caution in diabetic patients if a beta-blocking agent is required. Beta blockers, including metoprolol tartrate and hydrochlorothiazide, may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected.

Selective beta blockers do not potentiate insulin-induced hypoglycemia and, unlike nonselective beta blockers, do not delay recovery of blood glucose to normal levels. Pheochromocytoma: If metoprolol tartrate is used in the setting of pheochromocytoma, it should be given in combination with an alpha blocker, and only after the alpha blocker has been initiated. Administration of beta blockers alone in the setting of pheochromocytoma has been associated with a paradoxical increase in blood pressure due to the attenuation of beta-mediated vasodilatation in skeletal muscle.

Thyrotoxicosis: Beta-adrenergic blockade may mask certain clinical signs (e.g., tachycardia) or hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta blockade, which might precipitate a thyroid storm. Hydrochlorothiazide Thiazides should be used with caution in patients with severe renal disease.

In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function. Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrol…

ADVERSE REACTIONS 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 report…

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.

Drug/Laboratory Test Interactions Hydrochlorothiazide: Thiazides may decrease serum levels of protein-bound iodine without signs of thyroid disturbance. Thiazides should be discontinued before tests for parathyroid function are made. (see General, Hydrochlorothiazide, Calcium excretion).