Lopressor

1 INDICATIONS AND USAGE LOPRESSOR is a beta-adrenergic blocker indicated in the treatment of hemodynamically stable adult patients with myocardial infarction, to reduce the risk of cardiovascular mortality.

1.1Myocardial Infarction

LOPRESSOR is indicated in the treatment of hemodynamically stable adult patients with myocardial infarction (MI) to reduce cardiovascular mortality.

Myocardial Infarction: The recommended starting dosage is 50 mg orally every 6 hours. Maintenance dosage depends upon hemodynamic tolerance, see full prescribing information.

2.1Myocardial Infarction The

recommended starting dose in hemodynamically stable patients is 50 mg orally every 6 hours. In case of intolerance, reduce the starting dose to 25 mg orally every 6 hours and administer for 48 hours. Titrate dosage based on tolerability and hemodynamic parameters (i.e., heart rate, blood pressure).

LOPRESSOR should preferably be administered with or following meals. The maximum daily maintenance dosage is 100 mg orally twice daily.

Abrupt cessation may exacerbate myocardial ischemia. Heart Failure: Worsening cardiac failure may occur. Bronchospastic Disease: Avoid beta-blockers. Pheochromocytoma: Initiate therapy with an alpha blocker. Major Surgery: Avoid initiation of high-dose metoprolol in patients undergoing non- cardiac surgery. Do not routinely withdraw chronic beta-blocker therapy prior to surgery. ( 5.5 , 6.1 ) Diabetes: May mask symptoms of hypoglycemia. Thyrotoxicosis: Abrupt withdrawal in patients with thyrotoxicosis might precipitate a thyroid storm. Peripheral Vascular Disease: Can aggravate symptoms of arterial insufficiency.

5.1Abrupt Cessation of Therapy Following

abrupt cessation of therapy with certain beta-blocking agents, exacerbations of angina pectoris and, in some cases, myocardial infarction have occurred. When discontinuing chronically administered LOPRESSOR, gradually reduce the dosage over a period of 1 to 2 weeks and monitor the patient. Warn patients not to interrupt therapy without their physician’s advice.

5.2Heart Failure Worsening

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

5.3Bronchospastic Disease Patients with

bronchospastic disease, should in general, not receive beta-blockers, including LOPRESSOR. Because of its relative beta 1 cardio-selectivity, however, LOPRESSOR 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 LOPRESSOR. Bronchodilators, including beta 2 -agonists, should be readily available or administered concomitantly .

5.4Pheochromocytoma If

LOPRESSOR 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.

5.5Major Surgery Avoid

initiation of a high-dose regimen of beta blocker therapy in patients undergoing non-cardiac surgery, since such use in patients with cardiovascular risk factors has been associated with bradycardia, hypotension, stroke and death. 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.

5.6Hypoglycemia Beta-blockers

may prevent early warning signs of hypoglycemia, such as tachycardia, and increase the risk for severe or prolonged hypoglycemia at any time 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.

5.7Thyrotoxicosis Beta-adrenergic

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

5.8Risk of Anaphylactic Reactions 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.

5.9Peripheral Vascular Disease Beta-blockers

can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease.

4 CONTRAINDICATIONS LOPRESSOR is contraindicated in severe bradycardia, second or third degree heart block, cardiogenic shock, systolic blood pressure <100, decompensated heart failure, sick sinus syndrome (unless a permanent pacemaker is in place), and in patients who are hypersensitive to any component of this product. Severe bradycardia: Greater than first degree heart block, or sick sinus syndrome without a pacemaker. Cardiogenic shock or decompensated heart failure.

Known hypersensitivity to product components.

Hepatic Impairment: Consider initiating LOPRESSOR therapy at low doses and gradually increase dosage to optimize therapy, while monitoring closely for adverse events.

8.1Pregnancy Risk Summary Available

data from published observational studies have not demonstrated an association of adverse developmental outcomes with maternal use of metoprolol during pregnancy . Untreated myocardial infarction during pregnancy can lead to adverse outcomes for the mother and the fetus . 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 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 definitively 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.

8.2Lactation 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 . 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 mcg to 158.7 mcg). The average relative infant dosage was 0.5% of the mother's weight-adjusted dosage.

8.3Females 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/m 2 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 .

8.4Pediatric Use Safety and

effectiveness of LOPRESSOR have not been established in pediatric patients.

8.5Geriatric Use In

worldwide clinical trials of LOPRESSOR in myocardial infarction, where approximately 478 patients were over 65 years 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.

8.6Hepatic Impairment No

studies have been performed with LOPRESSOR in patients with hepatic impairment. LOPRESSOR 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; and increase doses gradually in patients with impaired hepatic function.

8.7Renal 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 renal failure .

The following adverse reactions are described elsewhere in labeling: Worsening Ischemia with Abrupt Discontinuation Worsening heart failure . Worsening atrioventricular (AV) block . Most common adverse reactions in the setting of treatment of myocardial infarction are hypotension and bradycardia. To report SUSPECTED ADVERSE REACTIONS, contact Validus Pharmaceuticals LLC at 1-866-982-5438 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical 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. Myocardial Infarction In a randomized comparison of LOPRESSOR and placebo in the setting of acute MI the following adverse reactions were reported: Adverse Reaction LOPRESSOR N=698 % Placebo N=697 % 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%

6.2Post-Marketing Experience The

following adverse reactions have been reported during post-approval use of LOPRESSOR. 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 cognitive performance. Cardiovascular: Worsening AV block . 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)