metoprolol tartrate

Metoprolol tartrate is a beta-adrenergic blocker indicated for the treatment of:

• Hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions.
• Angina Pectoris.
• Myocardial Infarction, to reduce the risk of cardiovascular mortality when used in conjunction with intravenous metoprolol therapy in patients with definite or suspected acute myocardial infarction in hemodynamically stable patients. 1.1 Hypertension Metoprolol tartrate is indicated for the treatment of hypertension in adult patients, 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 (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. Metoprolol tartrate may be administered with other antihypertensive agents. 1.2 Angina Pectoris Metoprolol tartrate is indicated in the long-term treatment of angina pectoris, to reduce angina attacks and to improve exercise tolerance. 1.3 Myocardial Infarction Metoprolol tartrate tablets are indicated in the treatment of hemodynamically stable patients with definite or suspected acute myocardial infarction to reduce cardiovascular mortality when used alone or in conjunction with intravenous metoprolol.

• Administer once daily with food or after a meal. Titrate at weekly or longer intervals as needed and tolerated.
• Hypertension: Recommended starting dosage is 100 mg daily, in single or divided doses.
• Angina Pectoris: Recommended starting dosage is 100 mg daily, given as two divided doses.
• Myocardial Infarction: The starting dosage depends upon tolerance of intravenous metoprolol, see full prescribing information.

Hypertension Individualize the dosage of Metoprolol tartrate tablets.

Metoprolol tartrate tablets should be taken with or immediately following meals. The usual initial dosage is 100 mg daily in single or divided doses. Adjust dosage at weekly (or longer) intervals until optimum blood pressure reduction is achieved. In general, the maximum effect of any given dosage level will be apparent after 1 week of therapy. The effective dosage range of Metoprolol tartrate tablets is 100 mg to 450 mg per day. Dosages above 450 mg per day have not been studied. While once-daily dosing 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. Larger or more frequent daily doses may be required. Measure blood pressure near the end of the dosing interval to determine whether satisfactory control is being maintained throughout the day. 2.2 Angina Pectoris The dosage of Metoprolol tartrate tablets should be individualized. Metoprolol tartrate tablets should be taken with or immediately following meals. The usual initial dosage is 100 mg daily, given in two divided doses. Gradually increase the dosage at weekly intervals until optimum clinical response has been obtained or there is a pronounced slowing of the heart rate. The effective dosage range of Metoprolol tartrate tablets is 100 to 400 mg per day. Dosages above 400 mg per day have not been studied. If treatment is to be discontinued, reduce the dosage gradually over a period of 1 - 2 weeks [see Warnings and Precautions ]. 2.3 Myocardial Infarction See prescribing information of intravenous metoprolol for dosage instructions for intravenous therapy. In patients who tolerate the full intravenous dose, initiate Metoprolol tartrate tablets, 50 mg every 6 hours, 15 minutes after the last intravenous dose of metoprolol and continue for 48 hours. In the case of intolerance, reduce dose to 25 mg and administer for 48 hours. Titrate, based on tolerability, to a maintenance dosage of 100 mg twice daily. Continue therapy for at least 3 months. Although the efficacy of Metoprolol tartrate beyond 3 months has not been conclusively established, data from studies with other beta-blockers suggest that treatment should be continued for 1 to 3 years.

The following adverse reactions are described elsewhere in labeling:

• Worsening angina or myocardial infarction [see Warnings and Precautions ]
• Worsening heart failure [see Warnings and Precautions ].
• Worsening AV block [see Contraindications ].
• Most common adverse reactions: tiredness, dizziness, depression, shortness of breath, bradycardia, hypotension, diarrhea, pruritus, rash. To report SUSPECTED ADVERSE REACTIONS, contact TruPharma, LLC at 541-5504 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Hypertension and Angina Most adverse effects have been mild and transient. Central Nervous System: Tiredness and dizziness have occurred in about 10% of 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. Cardiovascular: Shortness of breath and bradycardia have occurred in approximately 3% of patients. Cold extremities; arterial insufficiency, usually of the Raynaud type; palpitations; heart failure exacerbations; peripheral edema; and hypotension have been reported in about 1% of patients. Gangrene in patients with preexisting severe peripheral circulatory disorders has also been reported. [see Contraindications and Warnings and Precautions ]. Respiratory: Wheezing (bronchospasm) and dyspnea have been reported in about 1% of patients [see Warnings and Precautions ]. Rhinitis has also been reported. Gastrointestinal: Diarrhea has occurred in about 5% of patients. Nausea, dry mouth, gastric pain, constipation, flatulence, and heartburn have been reported in about 1% of patients. Vomiting was a common occurrence. Hypersensitive Reactions: Pruritus or rash have occurred in about 5% of patients. Photosensitivity and worsening of psoriasis has been reported. Miscellaneous: Peyronie’s disease, musculoskeletal pain, blurred vision, and tinnitus has been reported. Myocardial Infarction In general, the adverse reactions observed in trials with metoprolol in MI are consistent with the hypertension and angina experience. In the randomized comparison of Metoprolol tartrate and placebo in the setting of acute MI the following adverse reactions were reported: Metoprolol Tartrate Placebo Hypotension (systolic BP < 90 mm Hg) 27.4% 23.2% Bradycardia (heart rate < 40 beats/min) 15.9% 6.7% Second- or third-degree heart block 4.7% 4.7% First-degree heart block (P-R ≥ 0.26 sec) 5.3% 1.9% Heart failure 27.5% 29.6% 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of drug METOPROLOL TARTRATE. 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. Central Nervous System: Reversible mental depression progressing to catatonia; 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 and thrombocytopenic purpura. Hypersensitive Reactions: Fever combined with aching and sore throat, laryngospasm and respiratory distress. Laboratory Findings: Increase in blood triglycerides, elevated transaminase and decrease in High Density Lipoprotein (HDL)

• Catecholamine-depleting drugs may have an additive effect when given with beta-blocking agents.
• Patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.
• CYP2D6 Inhibitors are likely to increase metoprolol concentration.
• Concomitant use of glycosides, clonidine, and diltiazem and verapamil with beta-blockers can increase the risk of bradycardia.
• Beta-blockers including metoprolol, may exacerbate the rebound hypertension that can follow the withdrawal of clonidine. 7.1 Catecholamine Depleting Drugs Catecholamine depleting drugs (e.g., reserpine, monoamine oxidase (MAO) inhibitors) may have an additive effect when given with beta-blocking agents. Observe patients treated with Metoprolol tartrate plus a catecholamine depletor for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension. 7.2 Epinephrine 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. 7.3 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 ] . Monitor patients closely, when the combination cannot be avoided. 7.4 Negative Chronotropes 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.

• Hepatic Impairment: Consider initiating Metoprolol tartrate therapy at low doses and gradually increase dosage to optimize therapy, while monitoring closely for adverse events. 8.1 Pregnancy Risk Summary Available data from published observational studies have not demonstrated an association of adverse developmental outcomes with maternal use of metoprolol during pregnancy (see Data ) . Untreated hypertension and myocardial infarction during pregnancy can lead to adverse outcomes for the mother and the fetus (see Clinical Considerations ). In animal reproduction studies, metoprolol has been shown to increase post- implantation loss and decrease neonatal survival in rats at oral dosages of 500 mg/kg/day, approximately 11 times the daily dose of 450 mg in a 60-kg patient on a mg/m 2 basis. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 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 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 and manage accordingly. Data Human Data Data from published observational studies did not demonstrate an association of major congenital malformations and use of metoprolol 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 Metoprolol has been shown to increase post-implantation loss and decrease neonatal survival in rats at oral dosages of 500 mg/kg/day, i.e. 11 times, on a mg/m 2 basis, the daily dose of 450 mg in a 60-kg patient. No fetal abnormalities were observed when pregnant rats received metoprolol orally up to a dose of 200 mg/kg/day, i.e. 4 times, the daily dose of 400mg in a 60-kg patient. 8.2 Lactation Risk Summary Limited available data from published literature report that metoprolol is present in human milk. The estimated daily infant dose of metoprolol received from breastmilk ranges 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 (see Data ). No adverse reactions of metoprolol on the breastfed infant have been identified. There is no information regarding the effects of metoprolol on milk production. Clinical consideration Monitoring for adverse reactions For a lactating woman who is a slow metabolizer of metoprolol, monitor the breastfed infant for bradycardia and other symptoms of beta blockade such as dry mouth, skin or eyes, diarrhea or constipation. In a report of 6 mothers taking metoprolol, none reported adverse effects in her breastfed infant. Data Limited published cases estimate the infant daily dose of metoprolol received from breast milk range from 0.05 mg to less than 1 mg. In 2 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. 8.3 Females and Males of Reproductive Potential Risk Summary Based on the published literature, beta blockers (including metoprolol) may cause erectile dysfunction and inhibit sperm motility. In animal fertility studies, metoprolol has been associated with reversible adverse effects on spermatogenesis starting at oral dose level of 3.5 mg/kg in rats, which would correspond to a dose of 34 mg/day in humans in mg/m2 equivalent, although other studies have shown no effect of metoprolol on reproductive performance in male rats. No evidence of impaired fertility due to metoprolol was observed in rats [see Nonclinical Toxicology ]. 8.4 Pediatric Use Safety and effectiveness of Metoprolol tartrate have not been established in pediatric patients. 8.5 Geriatric Use Clinical studies of Metoprolol tartrate in hypertension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience in hypertensive patients has not identified differences in responses between elderly and younger patients. In worldwide clinical trials of Metoprolol tartrate in myocardial infarction, where approximately 478 patients were over 65years of age (0 over 75 years of age), no age-related differences in safety and effectiveness were found. Other reported clinical experience in myocardial infarction has not identified differences in response between the elderly and younger patients. In general, use a low initial starting dose in elderly patients given their greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Hepatic Impairment No studies have been performed with Metoprolol tartrate in patients with hepatic impairment. Because Metoprolol tartrate is metabolized by the liver, metoprolol blood levels are likely to increase substantially with poor hepatic function. Therefore, initiate therapy at doses lower than those recommended for a given indication; and increase doses gradually in patients with impaired hepatic function. 8.7 Renal Impairment The systemic availability and half-life of metoprolol in patients with renal failure do not differ to a clinically significant degree from those in normal subjects. No reduction in dosage is needed in patients with chronic renal failure [ see Clinical Pharmacology ].