LOPRESSOR

LOPRESSOR tablets contain metoprolol tartrate, a beta-adrenergic blocker. Metoprolol tartrate 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, practically odorless, crystalline powder with a molecular weight of 684.82 g/mol. It is very soluble in water; freely soluble in methylene chloride, in chloroform, and in alcohol; slightly soluble in acetone; and insoluble in ether. LOPRESSOR is available as 12.5 mg tablets for oral administration containing 12.5 mg metoprolol tartrate (equivalent to 9.76 mg of metoprolol). Inactive Ingredients : Tablets contain colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium starch glycolate. Film coating contains D&C Red 30, hypromellose, polyethylene glycol, talc, and titanium dioxide. Metoprolol tartrate Tablet Structure

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. ( 1.1 ) 1.1 Myocardial 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. ( 2.1 ) 2.1 Myocardial 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.

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. ( 4 ) Cardiogenic shock or decompensated heart failure. ( 4 ) Known hypersensitivity to product components. ( 4 )

The following adverse reactions are described elsewhere in labeling: Worsening Ischemia with Abrupt Discontinuation [see Warnings and Precautions (5) ] Worsening heart failure [see Warnings and Precautions (5) ]. Worsening atrioventricular (AV) block [see Contraindications (4) ]. Most common adverse reactions in the setting of treatment of myocardial infarction are hypotension and bradycardia. ( 6.1 ) 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 . 6.1 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. Myocardial Infarction In a randomized comparison of LOPRESSOR and placebo in the setting of acute MI [see Clinical studies 14.1 ] 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% 6.2 Post-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 [see Contraindications (4) ]. 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. ( 7.1 ) Patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction. ( 7.2 ) CYP2D6 Inhibitors are likely to increase metoprolol concentration. ( 7.3 ) Concomitant use of glycosides, clonidine, and diltiazem and verapamil with beta-blockers can increase the risk of bradycardia. ( 7.4 ) Beta-blockers including metoprolol, may exacerbate the rebound hypertension that can follow the withdrawal of clonidine. ( 7.4 ) 7.1 Catecholamine Depleting Drugs Observe patients treated with LOPRESSOR plus a catecholamine depletor for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension. Catecholamine depleting drugs (e.g., reserpine, monoamine oxidase (MAO) inhibitors) may have an additive effect when given with beta-blocking agents. 7.2 Epinephrine The cardiostimulating and bronchodilating effects of epinephrine are antagonized by beta-adrenergic blocking drugs, such as metoprolol. Higher doses of epinephrine might be necessary for patients taking metoprolol. 7.3 CYP2D6 Inhibitors Monitor patients closely when the combination use of CYP2D6 inhibitor and metoprolol cannot be avoided. 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 may also increase metoprolol concentration. Increases in plasma concentration decrease the beta 1 cardioselectivity of metoprolol [see Clinical Pharmacology (12.3) ] . 7.4 Negative Chronotropes If clonidine and metoprolol are coadministered, withdraw the beta-blocker several days before the gradual withdrawal of clonidine because metoprolol may exacerbate the rebound hypertension that can follow the withdrawal of clonidine. If replacing clonidine with metoprolol, delay the introduction of metoprolol for several days after clonidine discontinuation. Digitalis glycosides, clonidine, diltiazem, and verapamil slow atrioventricular conduction and decrease heart rate. Concomitant use with beta blockers can increase the risk of bradycardia.