Metoprolol Tartrate and Hydrochlorothiazide

Metoprolol tartrate and hydrochlorothiazide tablets is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure lowers the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including metoprolol. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program's Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (eg, on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. Metoprolol tartrate and hydrochlorothiazide tablets may be administered with other antihypertensive agents. Limitation of Use Metoprolol tartrate and hydrochlorothiazide tablets 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. Metoprolol tartrate and hydrochlorothiazide tablet is the combination tablet of metoprolol tartrate, a beta adrenoceptor blocker and hydrochlorothiazide (HCTZ), a thiazide diuretic, indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. ( 1 )

Metoprolol tartrate and hydrochlorothiazide tablets, USP are supplied in the following strengths: 50 mg/25 mg: Tablets are white to off white, round shaped, biconvex, bevel edged scored uncoated tablets de bossed with "A" on one side of score line and "47" on another side of score line and plain on other side. 100 mg/25 mg: Tablets are white to off white, oval shaped, biconvex, bevel edged scored uncoated tablets debossed with "A" on one side of score line and "48" on another side of score line and plain on other side. Tablets (metoprolol tartrate/hydrochlorothiazide: 50/25mg; 100/25mg ( 3 )

Metoprolol tartrate and hydrochlorothiazide tablets is contraindicated in patients with: Cardiogenic shock or decompensated heart failure . Sinus bradycardia, sick sinus syndrome, and greater than first-degree block unless a permanent pacemaker is in place . Anuria Hypersensitivity to metoprolol tartrate or hydrochlorothiazide or to other sulfonamide- derived drugs. Hypersensitivity to metoprolol tartrate or hydrochlorothiazide or other sulfonamide-derived drugs. ( 4 ) Cardiogenic shock or decompensated heart failure. ( 4 ) Sinus bradycardia, sick sinus syndrome, and greater than first-degree block unless a permanent pacemaker is in place. ( 4 ) Anuria. ( 4 )

Abrupt cessation may exacerbate myocardial ischemia. ( 5.1 ) May worsen congestive heart failure. ( 5.2 ) Bronchospasm: Avoid beta-blockers. ( 5.3 ) Bradycardia. ( 5.4 ) Avoid discontinuing therapy prior to major surgery. ( 5.5 ) Diabetes: May mask symptoms of hypoglycemia and alter glucose levels; monitor. ( 5.6 ) Monitor serum electrolytes and creatinine periodically. ( 5.7 ) Peripheral vascular disease: Can aggravate symptoms of arterial insufficiency. ( 5.9 ) Pheochromocytoma: First initiate therapy with an alpha blocker. ( 5.10 ) Abrupt withdrawal in thyrotoxicosis might precipitate a thyroid storm. ( 5.11 ) Patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction. ( 5.12 )

5.1 Abrupt Cessation of Therapy Following abrupt cessation of therapy with beta adrenergic blockers, exacerbations of angina pectoris and myocardial infarction may occur. When discontinuing chronically administered metoprolol tartrate and hydrochlorothiazide tablets, particularly in patients with ischemic heart disease, gradually reduce the dosage over a period of 1 to 2 weeks and monitor the patient. If angina markedly worsens or acute coronary ischemia develops, promptly resume therapy and take measures appropriate for the management of unstable angina. Warn patients not to interrupt therapy without their physician's advice. Because coronary artery disease is common and may be unrecognized, avoid abruptly discontinuing metoprolol tartrate in patients treated only for hypertension.

5.2 Heart Failure Worsening cardiac failure may occur during up-titration of beta-blockers. If such symptoms occur, increase diuretics and restore clinical stability before advancing the dose of metoprolol. It may be necessary to lower the dose of metoprolol tartrate or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of metoprolol tartrate.

5.3 Bronchospastic Disease Beta adrenergic blockers can cause bronchospasm. Patients with bronchospastic diseases should, in general, not receive beta-blockers. Because of its relative beta 1 cardio-selectivity, however, metoprolol tartrate may be used in patients with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive treatment. Because beta1-selectivity is not absolute, use the lowest possible dose of metoprolol tartrate and have bronchodilators (e.g., beta 2 -agonists) readily available or administered concomitantly .

5.4 Bradycardia Bradycardia, including sinus pause, heart block, and cardiac arrest have occurred with the use of metoprolol tartrate and hydrochlorothiazide tablets. Patients with first-degree atrioventricular block, sinus node dysfunction, conduction disorders (including Wolff-Parkinson-White) or on concomitant drugs [see Drug Interactions ( 7 )] that cause bradycardia may be at increased risk. Monitor heart rate in patients receiving metoprolol tartrate and hydrochlorothiazide tablets. If severe bradycardia develops, reduce or stop metoprolol tartrate and hydrochlorothiazide tablets.

5.5 Major Surgery Avoid initiation of high-dose regimen of metoprolol tartrate and hydrochlorothiazide tablets in patients with cardiovascular risk factors undergoing non-cardiac surgery, since use in such patients has been associated with bradycardia, hypotension, stroke and death. Chronically administered beta adrenergic blockers 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 [see Warnings and Precautions ( 5.1 )].

5.6 Masked Symptoms of Hypoglycemia Beta-blockers may prevent early warning signs of hypoglycemia, such as tachycardia, and increase the risk for severe or prolonged hypoglycemia at anytime during treatment, especially in patients with diabetes mellitus or children and patients who are fasting (i.e., surgery, not eating regularly, or are vomiting). If severe hypoglycemia occurs, patients should be instructed to seek emergency treatment.

5.7 Electrolyte and Metabolic Effects Metoprolol tartrate and hydrochlorothiazide tablets contains hydrochlorothiazide which can cause hypokalemia and hyponatremia. Hypomagnesemia can result in hypokalemia which may be difficult to treat despite potassium repletion. Monitor serum electrolytes periodically. Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides. Hydrochlorothiazide reduces clearance of uric acid and may cause or exacerbate hyperuricemia and precipitate gout in susceptible patients. Hydrochlorothiazide decreases urinary calcium excretion and may cause elevations of serum calcium. Monitor calcium levels.

5.8 Renal Impairment Patients with chronic kidney disease, severe heart failure, or volume depletion may be at increased risk for developing acute renal failure on drugs containing hydrochlorothiazide, including metoprolol tartrate and hydrochlorothiazide tablets.

5.9 Peripheral Vascular Disease Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease.

5.10 Pheochromocytoma If metoprolol tartrate and hydrochlorothiazide tablets 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.

5.11 Thyrotoxicosis Beta-adrenergic blockade may mask certain clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of beta-blockade may precipitate a thyroid storm.

5.12 Anaphylactic Reaction While taking beta-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenge and may be unresponsive to the usual doses of epinephrine used to treat an allergic reaction.

5.13 Acute Myopia and Second Angle-Closure Glaucoma Hydrochlorothiazide, a sulfonamide, can cause acute transient myopia and acute angle-closure glaucoma (idiosyncratic reactions). Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of hydrochlorothiazide initiation. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy. Untreated acute angle-closure glaucoma can lead to permanent vision loss. Given that metoprolol tartrate and hydrochlorothiazide tablets contains hydrochlorothiazide, if these symptoms occur, discontinue metoprolol tartrate and hydrochlorothiazide tablets. Consider prompt medical or surgical treatment if the intraocular pressure remains uncontrolled.

5.14 Exacerbation of Systemic Lupus Erythematosus Hydrochlorothiazide can exacerbate or activate systemic lupus erythematosus.

The following adverse reactions are described in more detail elsewhere in the label; Worsening angina or myocardial infarction [see Warnings and Precautions ( 5 )] Worsening heart failure [see Warnings and Precautions ( 5 )] Worsening AV block [see Contraindications ( 4 )] To report SUSPECTED ADVERSE REACTIONS, contact Ajanta Pharma USA Inc. at 1-855-664-7744 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.2 Post-Marketing Experience The following adverse reactions have been reported in postmarketing experience: adverse reactions have been identified during post approval use of metoprolol tartrate and hydrochlorothiazide tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Metoprolol Confusional state, an increase in blood triglycerides and a decrease in High Density Lipoprotein (HDL). 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. Hydrochlorothiazide 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. Other beta-adrenergic agent reactions A variety of adverse reactions have been reported with other beta-adrenergic blocking agents and should be considered potential adverse reactions to metoprolol tartrate. Central Nervous System: Reversible mental depression progressing to catatonia; visual disturbances; hallucinations; an acute reversible syndrome characterized by disorientation for time and place, emotional lability, clouded sensorium, and decreased performance on neuropsychometrics. Hematologic: Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura. Hypersensitive Reactions: Laryngospasm and respiratory distress.

Catecholamine-depleting drugs (e.g., MAO inhibitors): Hypotension, bradycardia. ( 7.1 ) CYP2D6 inhibitors: Increased metoprolol concentration. ( 12.3 ) Digitalis glycosides, clonidine, diltiazem and verapamil: Bradycardia. ( 5.4 , 7.1 ) Clonidine: Rebound hypertension following clonidine withdrawal. ( 7.1 ) Antidiabetic drugs: Dosage adjustment may be required. ( 7.2 ) Cholestyramine and colestipol: Reduced absorption of thiazides. ( 7.2 ) Lithium: Risk of lithium toxicity. ( 7.2 ) Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): Reduced diuretic, natriuretic, and antihypertensive effects of diuretics. ( 7.2 )

7.1 Drug Interactions with Metoprolol Catecholamine Depleting Drugs: The concomitant use of catecholamine-depleting drugs (e.g., reserpine, monoamine oxidase (MAO) inhibitors) with beta adrenergic blockers may have an additive affect and increase the risk of hypotension or bradycardia CYP2D6 Inhibitors: Drugs that are strong inhibitors of CYP2D6 such as quinidine, fluoxetine, paroxetine, and propafenone were shown to double metoprolol concentrations. While there is no information about moderate or weak inhibitors, these too are likely to increase metoprolol concentration. Increases in plasma concentration decrease the cardioselectivity of metoprolol [see Clinical Pharmacology ( 12.3 )] . Monitor patients closely when the combination cannot be avoided. Digitalis, Clonidine, and Calcium Channel Blockers: Digitalis glycosides, clonidine, diltiazem and verapamil slow atrioventricular conduction and decrease heart rate. Concomitant use with beta blockers can increase the risk of bradycardia. If clonidine and a beta blocker, such as metoprolol are coadministered, withdraw the beta- blocker several days before the gradual withdrawal of clonidine because beta-blockers may exacerbate the rebound hypertension that can follow the withdrawal of clonidine. If replacing clonidine by beta-blocker therapy, delay the introduction of beta-blockers for several days after clonidine administration has stopped.

7.2 Drug Interactions with Hydrochlorothiazide Antidiabetic drugs (oral agents and insulin) : Dosage adjustment of the antidiabetic drug may be required. Ion exchange 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. Stagger the dosage of hydrochlorothiazide and ion exchange resins ( e.g., cholestyramine and colestipol resins ) such that hydrochlorothiazide is administered at least 4 hours before or 4-6 hours after the administration of resins to minimize the interaction. Lithium : Diuretics reduce the renal clearance of lithium and increase the risk of lithium toxicity. Monitor serum lithium concentrations during concurrent use. Non-Steroidal Anti-Inflammatory Drugs : NSAIDs can reduce the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics.

8 SPECIFIC POPULATIONS Hepatic Impairment: Consider initiating metoprolol tartrate therapy at low doses and gradually increase dosage to optimize therapy, while monitoring closely for adverse events. (8.6)

8.1 Pregnancy Risk Summary Untreated hypertension during pregnancy can lead to adverse outcomes for the mother and the fetus ( see Clinical Considerations ). Available data from published observational studies have not demonstrated a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes with metoprolol use during pregnancy. However, there are inconsistent reports of intrauterine growth restriction, preterm birth, and perinatal mortality with maternal use of beta blockers, including metoprolol, during pregnancy ( see Data ). There have been rare reports of jaundice, thrombocytopenia, and electrolyte imbalances in infants exposed to thiazide medications during pregnancy. In animal reproduction studies, metoprolol has been shown to increase post-implantation loss and decrease neonatal survival in rats at oral dosages up to 24 times, on a mg/m 2 basis, the daily dose of 200 mg in a 60-kg patient. The combination of metoprolol tartrate/hydrochlorothiazide administered to rats from mid-late gestation through lactation also produced increased post-implantation loss and decreased neonatal survival ( see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical consideration Disease-associated maternal and/or embryo/fetal risk Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly. Fetal/Neonatal adverse reactions Metoprolol Metoprolol crosses the placenta. Neonates born to mothers who are receiving metoprolol during pregnancy, may be at risk for hypotension, hypoglycemia, bradycardia, and respiratory depression. Observe neonates for symptoms of hypotension, bradycardia, hypoglycemia and respiratory depression and manage accordingly. Data Human Data Data from published observational studies did not demonstrate an association of major congenital malformations and use of either metoprolol or hydrochlorothiazide in pregnancy. The published literature has reported inconsistent findings of intrauterine growth retardation, preterm birth and perinatal mortality with maternal use of metoprolol during pregnancy; however, these studies have methodological limitations hindering interpretation. Methodological limitations include retrospective design, concomitant use of other medications, and other unadjusted confounders that may account for the study findings including the underlying disease in the mother. These observational studies cannot definitely establish or exclude any drug-associated risk during pregnancy. Animal Data Oral administration of metoprolol tartrate/hydrochlorothiazide combinations to pregnant rats during organogenesis at doses up to 200/50 mg/kg/day (10 and 20 times the MRHD on a mg/m 2 basis for metoprolol and hydrochlorothiazide, respectively) or to pregnant rabbits at doses up to 25/6.25 mg/kg/day (about 2.5 and 5 times the MRHD on a mg/m 2 basis for metoprolol and hydrochlorothiazide, respectively) produced no teratogenic effects. A 200/50 mg/kg/day metoprolol tartrate/hydrochlorothiazide combination administered to rats from mid-late gestation through lactation produced increased post-implantation loss and decreased neonatal survival. Metoprolol Metoprolol has been shown to increase post-implantation loss and decrease neonatal survival in rats at doses up to 24 times, on a mg/m 2 basis, the daily dose of 200 mg in a 60-kg patient. Distribution studies in mice confirm exposure of the fetus when metoprolol tartrate is administered to the pregnant animal. These studies have revealed no evidence of impaired fertility or teratogenicity. Hydrochlorothiazide Hydrochlorothiazide administered to pregnant mice and rats during organogenesis at doses up to 3000 and 1000 mg/kg/day (600 and 400 times the MRHD on a mg/m 2 basis), respectively, produced no harm to the fetus. Thiazides cross the placental barrier and appear in the cord blood.

8.2 Lactation Risk Summary There are no data on the presence of metoprolol tartrate and hydrochlorothiazide tablets in human milk, the effects on the breastfed infant, or the effects on milk production. However, data are available on the individual components of metoprolol tartrate and hydrochlorothiazide tablets . Available data from published literature on metoprolol and hydrochlorothiazide report that each drug is present in human milk (see Data) . There are no reports of adverse effects on breastfed infants exposed to metoprolol or hydrochlorothiazide during lactation. Doses of hydrochlorothiazide associated with clinically significant diuresis have been associated with impaired milk production. There is no information regarding the effects of metoprolol on milk production. Monitor infants exposed to metoprolol tartrate and hydrochlorothiazide tablets though breastmilk for drowsiness or poor feeding (see Clinical Considerations). The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for metoprolol tartrate and hydrochlorothiazide tablets and any potential adverse effects on the breastfed child from metoprolol tartrate and hydrochlorothiazide tablets or from the underlying maternal condition. Clinical Considerations Monitor the breastfed infant for bradycardia or somnolence. Data Metoprolol Based on published case reports, the estimated daily infant dose of metoprolol received from breastmilk ranged from 0.05 mg to less than 1 mg. The estimated relative infant dosage was 0.5% to 2% of the mother's weight-adjusted dosage. In two women who were taking unspecified amount of metoprolol, milk samples were taken after one dose of metoprolol. The estimated amount of metoprolol and alpha-hydroxymetoprolol in breast milk is reported to be less than 2% of the mother's weight-adjusted dosage. In a small study, breast milk was collected every 2 to 3 hours over one dosage interval, in three mothers (at least 3 months postpartum) who took metoprolol of unspecified amount. The average amount of metoprolol present in breast milk was 71.5 mcg/day (range 17.0 to 158.7). The average relative infant dosage was 0.5% of the mother's weight-adjusted dosage. Hydrochlorothiazide A single study involving one woman and her infant showed a peak concentration of 275 mcg/L at 3 hours following 50 mg dose. No drug was detected (< 20 mcg/L) in the infant's plasma at 2 and 11 hours following mother's dose.

8.3 Females and Males of Reproductive Potential Infertility Males Based on the published literature, beta blockers (including metoprolol) may cause erectile dysfunction and inhibit sperm motility. No evidence of impaired fertility due to metoprolol or hydrochlorothiazide was observed in rats [see Nonclinical Toxicology ( 13.1 )].

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use Clinical studies of metoprolol tartrate and hydrochlorothiazide tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. […]

Metoprolol is a beta 1 -selective (cardioselective) adrenergic receptor blocker. This preferential effect is not absolute however, and at higher plasma concentrations, metoprolol also inhibits beta 2 -adrenoreceptors, chiefly located in the bronchial and vascular musculature. Metoprolol has no intrinsic sympathomimetic activity, and membrane-stabilizing activity is detectable only at plasma concentrations much greater than required for beta-blockade. Animal and human experiments indicate that metoprolol slows the sinus rate and decreases AV nodal conduction. The mechanism of the antihypertensive effects of beta-blocking agents has not been elucidated. However, several possible mechanisms have been proposed: (1) competitive antagonism of catecholamines at peripheral (especially cardiac) adrenergic neuron sites, leading to decreased cardiac output; (2) a central effect leading to reduced sympathetic outflow to the periphery; and (3) suppression of renin activity. The mechanism of antihypertensive effect of thiazide diuretics is unknown.