Metoroprolol Tartrate

1 INDICATIONS AND USAGE Metoprolol Tartrate Injection, USP is indicated in the treatment of definite or suspected acute myocardial infarction in hemodynamically stable patients to reduce cardiovascular mortality when used in conjunction with oral metoprolol maintenance therapy. Metoprolol Tartrate Injection is a beta-adrenergic receptor inhibitor indicated for the treatment of definite or suspected acute myocardial infarction in hemodynamically stable patients to reduce cardiovascular mortality when used in conjunction with oral metoprolol maintenance therapy. ( 1 )

2 DOSAGE AND ADMINISTRATION Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Initiate treatment in a coronary care or similar unit immediately after the patient’s hemodynamic condition has stabilized. Begin treatment in this early phase with the intravenous administration of three bolus injections of 5 mg of Metoprolol Tartrate Injection each; give the injections at approximately 2-minute intervals. During the intravenous administration of Metoprolol Tartrate Injection, monitor blood pressure, heart rate, and electrocardiogram. Transition to Oral Metoprolol: Following administration of Metoprolol Tartrate Injection, transition patients to an oral formulation of metoprolol. See prescribing information for oral metoprolol for dose selection. Initiate therapy in a coronary care or similar unit immediately after the patients hemodynamic condition has stabilized. ( 2 ) Begin treatment with an intravenous administration of three bolus injections of 5 mg each, at approximately 2-minute intervals. Monitor blood pressure, heart rate and electrocardiogram. ( 2 ) Following administration of Metoprolol Tartrate Injection, transition the patient to an oral formulation of metoprolol. ( 2 )

6 ADVERSE REACTIONS The following adverse reactions are described elsewhere in labeling: Worsening angina or myocardial infarction [see Warnings and Precautions (5) ] Worsening heart failure [see Warnings and Precautions (5) ] Worsening AV block [see Contraindications (4) ] • Most common adverse reactions: tiredness, dizziness, shortness of breath, bradycardia, hypotension, pruritus. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689 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. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Myocardial Infarction These adverse reactions were reported from treatment regimens where intravenous Metoprolol Tartrate Injection was administered, when tolerated. Central Nervous System: Tiredness has been reported in about 1 of 100 patients. Vertigo, sleep disturbances, hallucinations, headache, dizziness, visual disturbances, confusion, and reduced libido have also been reported, but a drug relationship is not clear. Cardiovascular: In a randomized comparison of Metoprolol Tartrate Injection and placebo, the following adverse reactions were reported: Metoprolol Tartrate Injection Placebo Hypotension (systolic BP <90 mmHg) 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% Respiratory: Dyspnea of pulmonary origin has been reported in fewer than 1 of 100 patients. Gastrointestinal: Nausea and abdominal pain have been reported in fewer than 1 of 100 patients. Miscellaneous: Unstable diabetes and claudication have been reported. 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of metoprolol. 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. Cardiovascular: Cold extremities, arterial insufficiency (usually of the Raynaud type), palpitations, peripheral edema, syncope, and hypotension. Respiratory: Wheezing (bronchospasm), dyspnea. Central Nervous System: Confusion, short-term memory loss, headache, nightmares, insomnia, nervousness, hallucinations. Gastrointestinal: Nausea, dry mouth, constipation, flatulence, heartburn, hepatitis, vomiting. Hypersensitive Reactions: Pruritus. Miscellaneous: Musculoskeletal pain, arthritis, blurred vision, decreased libido, tinnitus, reversible alopecia, agranulocytosis, dry eyes, worsening of psoriasis, Peyronie’s disease, photosensitivity.

12.3 Pharmacokinetics Distribution About 12% of the drug is bound to human serum albumin. Metoprolol crosses the blood-brain barrier and has been reported in the CSF in a concentration 78% of the simultaneous plasma concentration. Elimination Elimination is mainly by biotransformation in the liver, and the plasma half-life ranges from approximately 3 to 7 hours. Metabolism Metoprolol is a racemic mixture of R- and S-enantiomers and is primarily metabolized by CYP2D6. When administered orally, it exhibits stereoselective metabolism that is dependent on oxidation phenotype. Excretion Less than 5% of an oral dose of metoprolol is recovered unchanged in the urine; the rest is excreted by the kidneys as metabolites that appear to have no beta-blocking activity. Following intravenous administration of metoprolol, the urinary recovery of unchanged drug is approximately 10%. Mean dialytic clearance of metoprolol following oral administration in patients receiving high-flux hemodialysis is 87 mL/min. Mean total systemic clearance of metoprolol following intravenous administration in patients with chronic renal failure is 1 L/min. Drug Interactions CYP2D6 Metoprolol is metabolized predominantly by CYP2D6. In healthy subjects with CYP2D6 extensive metabolizer phenotype, coadministration of quinidine 100 mg, a potent CYP2D6 inhibitor, and immediate-release metoprolol 200 mg tripled the concentration of S-metoprolol and doubled the metoprolol elimination half-life. In four patients with cardiovascular disease, coadministration of propafenone 150 mg t.i.d. with immediate-release metoprolol 50 mg t.i.d. resulted in steady-state concentration of metoprolol 2-to 5-fold what is seen with metoprolol alone. Extensive metabolizers who concomitantly use CYP2D6 inhibiting drugs will have increased (several-fold) metoprolol blood levels, decreasing metoprolol's cardioselectivity [see Drug Interactions (7.2) ] .