Prescription Drugs

CLINICAL PHARMACOLOGY Bretylium (bretylium tosylate injection ) tosylate is abromobenzyl quaternary ammonium compound which selectively accumulates in sympathetic ganglia and their postganglionic adrenergic neurons where it inhibits norepinephrine release by depressing adrenergic nerve terminal excitability. Bretylium (bretylium tosylate injection ) also suppresses ventricular fibrillation and ventricular arrhythmias. The mechanisms of the antifibrillatory and antiarrhythmic actions of bretylium (bretylium tosylate injection ) are not established. In efforts to define these mechanisms, the following electrophysiologic actions of bretylium (bretylium tosylate injection ) have been demonstrated in animal experiments: Increase in ventricular fibrillation threshold. Increase in action potential duration and effective refractory period without changes in heart rate. Little effect on the rate of rise or amplitude of the cardiac action potential (Phase 0) or in resting membrane potential (Phase 4) in normal myocardium. However, when cell injury slows the rate of rise, decreases amplitude, and lowers resting membrane potential, bretylium (bretylium tosylate injection ) transiently restores these parameters toward normal. In canine hearts with infarcted areas bretylium (bretylium tosylate injection ) decreases the disparity in action potential duration between normal and infarcted regions. Increase in impulse formation and spontaneous firing rate of pacemaker tissue as well as increase ventricular conduction velocity. The restoration of injured myocardial cell electrophysiology toward normal, as well as the increase of the action potential duration and effective refractory period without changing their ratio to each other, may be important factors in suppressing re-entry of aberrant impulses and decreasing induced dispersion of local excitable states. Bretylium (bretylium tosylate injection ) induces a chemical sympathectomy-like state which resembles a surgical sympathectomy. Catecholamine stores are not depleted by bretylium (bretylium tosylate injection ) tosylate, but catecholamine effects on the myocardium and on peripheral vascular resistance are often seen shortly after administration because bretylium (bretylium tosylate injection ) causes an early release of norepinephrine from the adrenergic postganglionic nerve terminals. Subsequently, bretylium (bretylium tosylate injection ) tosylate blocks the release of norepinephrine in response to neuron stimulation. Peripheral adrenergic blockade regularly causes orthostatic hypotension but has less effect on supine blood pressure. The relationship of adrenergic blockade to the antifibrillatory and antiarrhythmic actions of bretylium (bretylium tosylate injection ) is not clear. In a study in patients with bretylium (bretylium tosylate injection ) , peak hypotensive effects were seen within one hour of intramuscular administration, presumably reflecting adrenergic neuronal blockade. However, suppression of premature ventricular beats was not maximal until 6-9 hours after dosing, when mean plasma concentration had declined to less than one-half of peak level. This suggests a slower mechanism, other than neuronal blockade, was involved in suppression of the arrhythmia. On the other hand, antifibrillatory effects can be seen wfthin minutes of an intravenous injection, suggesting that the effect on the myocardium may occur quite rapidly. Bretylium (bretylium tosylate injection ) has a positive inotropic effect on the myocardium, but it is not yet certain whether this effect is direct or is mediated by catecholamine release. Bretylium (bretylium tosylate injection ) is eliminated intact by the kidneys. No metabolites have been identified following administration of BRETYLIUM (bretylium tosylate injection ) TOSYLATE INJECTION in man and laboratory animals. In man, approximately 70%-80% of a 14C-labelled intramuscular dose is excreted in the urine during the first 24 hours, with an additional 10% excreted over the next three days. The terminal half-life in four normal volunteers averaged 7.8±0.6 hours (range 6.9-8.1). In one patient with a creatinine clearance of 21.0 mL/min. x 1.73m2 the half-life was 16 hours. In one patient with a creatinine clearance of 1.0 mL/min. x 1.73m2 the half-life was 31.5 hours. During hemodialysis, this patient†s arterial and venous bretylium (bretylium tosylate injection ) concentrations declined rapidly, resulting in a half-life of 13 hours. During dialysis there was two-fold increase in total bretylium (bretylium tosylate injection ) clearance. Effect on heart rate: There is sometimes an initial small increase in heart rate when bretylium (bretylium tosylate injection ) tosylate is administered, but this is an inconsistent and transient occurrence. Hemodynamic effects: Following intravenous administration of 5mg/kg of BRETYLIUM (bretylium tosylate injection ) TOSYLATE INJECTION to patients with acute myocardial infarction, there was a mild increase in arterial pressure, followed by a modest decrease, remaining within normal limits throughout. Pulmonary artery pressures, pulmonary capillary wedge pressure, right atrial pressure, cardiac index, stroke volume index, and stroke work index were not significantly changed. These hemodynamic effects were not correlated with antiarrhythmic activity. Onset of action: Suppression of ventricular fibrillation is rapid, usually occurring within minutes following intravenous administration. Suppression of ventricular tachycardia and other ventricular arrhythmias develops more slowly, usually 20 minutes to 2 hours after parenteral administration.

DESCRIPTION BRETYLIUM (bretylium tosylate injection ) TOSYLATE INJECTION For Intravenous or Intramuscular Use Bretylium (bretylium tosylate injection ) tosylate injection is an antifibrillatory and antiarrhythmic agent; intended for intravenous or intramuscular use. It has a molecular formular: C18H24BrNO3S. Bretylium (bretylium tosylate injection ) tosylate is a white, crystalline powder with an extremely bitter taste. It is freely soluble in water and alcohol. Each mL of sterile, nonpyrogenic solution contains 50mg bretylium (bretylium tosylate injection ) tosylate in Water for Injection, USP. The pH is adjusted, when necessary, with dilute hydrochloric acid and/or sodium hydroxide. Bretylium (bretylium tosylate injection ) tosylate injection contains no preservative.

INDICATIONS Bretylium (bretylium tosylate injection ) Tosylate is indicated in the prophylaxis and therapy of ventricular fibrillation. Bretylium (bretylium tosylate injection ) tosylate is also indicated in the treatment of life-threatening ventricular arrhythmias, such as ventricular tachycardia, that have failed to respond to adequate doses of a first-line antiarrhythmic agent, such as lidocaine. Use of BRETYLIUM (bretylium tosylate injection ) TOSYLATE INJECTION should be limited to intensive care units, coronary care units or other facilities where equipment and personnel for constant monitoring of cardiac arrhythmias and blood pressure are available. Following injection of BRETYLIUM (bretylium tosylate injection ) TOSYLATE INJECTION there may be a delay of 20 minutes to 2 hours in the onset of antiarrhythmic action, although it appears to act within minutes in ventricular fibrillation. The delay in effect appears to be longer after intramuscular than after intravenous injection. DOSAGE AND ADMINISTRATION BRETYLIUM (bretylium tosylate injection ) TOSYLATE INJECTION is to be used clinically only for treatment of life-threatening ventricular arrhythmias under constant electrocardiographic monitoring. The clinical use of BRETYLIUM (bretylium tosylate injection ) TOSYLATE INJECTION is for short-term use only. Patients should either be kept supine during the course of bretylium (bretylium tosylate injection ) therapy or be closely observed for postural hypotension. The optimal dose schedule for parenteral administration of the drug has not been determined. There is comparatively little experience with dosages greater than 40mg/kg/day, although such doses have been used without apparent adverse effects. The following schedules are suggested: A. For immediately Life-threatening Ventricular Arrhythmias such as Ventricular Fibrillation or Hemodynamically Unstable Ventricular Tachycardia: Administer undiluted BRETYLIUM (bretylium tosylate injection ) TOSYLATE INJECTION at a dosage of 5mg/kg of body weight by rapid intravenous injection. Other usual cardiopulmonary resuscitative procedures, including electrical cardioversion, should be employed prior to and following the injection in accordance with good medical practice. If ventricular fibrillation persists, the dosage may be increased to 10mg/kg and repeated as necessary. For continuous suppression, dilute Bretylium (bretylium tosylate injection ) Tosylate Injection with Dextrose Injection, USP or Sodium Chloride Injection, USP using the table below and administer the diluted solution as a constant infusion of 1 to 2mg Bretylium (bretylium tosylate injection ) Tosylate Injection per minute, (see Table below). When administering Bretylium (bretylium tosylate injection ) Tosylate Injection (or any potent medication) by continuous intravenous infusion, it is advisable to use a precision volume control device. An alternative maintenance schedule is to infuse the diluted solution at a dosage of 5 to 10mg Bretylium (bretylium tosylate injection ) Tosylate per kg body weight, over a period greater than 8 minutes, every 6 hours. More rapid infusion may cause nausea and vomiting, and in patients older than 65 years, may increase the risk of developing orthostatic hypotension. B. Other ventricular arrhythmias: 1) Intravenous Use: Bretylium (bretylium tosylate injection ) tosylate injection must be diluted as described above before intravenous use. Administer the diluted solution at a dosage of 5 to 10mg bretylium (bretylium tosylate injection ) tosylate per kg of body weight by intravenous infusion over a period greater than 8 minutes. More rapid infusion may cause nausea and vomiting, and in patients older than 65 years, may increase the risk of developing orthostatic hypotension. Subsequent doses may be given at 1 to 2 hour intervals if the arrhythmia persists. For maintenance therapy, the same dosage may be administered every 6 hours, or a constant infusion of 1 to 2mg bretylium (bretylium tosylate injection ) tosylate per minute may be given, (See following table). Suggested Bretylium (bretylium tosylate injection ) Tosylate Injection Admixture Dilution and Administration rates for Continuous Infusion Maintenance Therapy Arranged in Descending Order of Concentration. PREPARATION /ADMINISTRATION Amount of Bretylium (bretylium tosylate injection ) Tosylate Injection Volume of IV Fluid* Final Volume Final Conc. (mg/ mL) Dose mg/ min Microdrops per mm. mL/ hour FOR FLUID RESTRICTED PATIENTS: 1.0 7 7 500mg (10mL) 50mL 60mL 8.3 1.5 2.0 11 14 11 14 2g (40mL) 1g (20mL) 500mL 250mL 540mL 270mL 3.7 3.7 1.0 1.5 16 24 16 24 2.0 32 32 1g (20mL) 500mg (10mL) 500mL 250mL 520mL 260mL 1 .9 1 .9 1.0 1.5 2.0 32 47 63 32 47 63 *lV fluid may be either Dextrose Injection, USP or Sodium Chloride Injection, USP. This table does not consider the overfill volume present in the IV fluids. 2) For Intramuscular Injection: DO NOT DILUTE BRETYLIUM (bretylium tosylate injection ) TOSYLATE INJECTION PRIOR TO INTRAMUSCULAR INJECTION. Inject 5 to 10mg bretylium (bretylium tosylate injection ) tosylate per kg of body weight. Subsequent doses may be given at 1 to 2 hour intervals if the arrhythmia persists. Thereafter, maintain the same dosage every 6 to 8 hours. Intramuscular injection should not be made directly into or near a major nerve, and the site of injection should be varied on repeated injection. Not more than 5mL should be injected intramuscularly in one site. (See PRECAUTONS) As soon as possible, and when indicated, patients should be changed to an oral antiarrhythmic agent for maintenance therapy. Note: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. HOW SUPPLIED Bretylium (bretylium tosylate injection ) Tosylate Injection, 50mg/mL 0517-8810-01 10mL Single Dose Vial Packaged individually Store at controlled room temperature 15°-30°C(59°-86°F). CAUTION: Federal (USA) law prohibits dispensing without prescription.

PATIENT INFORMATION See WARNINGS, CONTRAINDICATIONS and PRECAUTIONS.

OVERDOSE In the presence of life-threatening arrhythmias, underdosing with bretylium (bretylium tosylate injection ) probably presents a greater risk to the patient than potential overdosage. However, one case of accidental overdose has been reported in which a rapidly injected intravenous bolus of 30 mg/kg was given instead of an intended 10 mg/kg dose during an episode of ventricular tachycardia. Marked hypertension resulted, followed by protracted refractory hypotension. The patient expired 18 hours later in asystole, complicated by renal failure and aspiration pneumonitis. Bretylium (bretylium tosylate injection ) serum levels were 8000 ng/mL. The exaggerated hemodynamic response was attributed to the rapid injection of a very large dose while some effective circulation was still present. Neither the total dose nor the serum levels observed in this patient are in themselves associated with toxicity. Total doses of 30 mg/kg are not unusual and do not cause toxicity when given incrementally during cardiopulmonary resuscitation procedures. Similarly, patients maintained on chronic Bretylium (bretylium tosylate injection ) Tosylate Injection therapy have had documented serum levels of 12,000 ng/mL. These levels were achieved after sequential dosage increases over time with no apparent ill effects. If Bretylium (bretylium tosylate injection ) Tosylate Injection is overdosed and symptoms of toxicity develop, administration of nitroprusside or another short acting intravenous antihypertensive agent should be considered for the treatment of the hypertensive response. Long acting drugs that might potentiate the subsequent hypotensive effects of Bretylium (bretylium tosylate injection ) Tosylate Injection should not be used. Hypotension should be treated with appropriate fluid therapy and pressor agents such as dopamine or norepinephrine. Dialysis is probably not useful in the treatment of Bretylium (bretylium tosylate injection ) Tosylate Injection overdose. CONTRAINDICATIONS There are no contraindications to use in treatment of ventricular fibrillation or life-threatening refractory ventricular arrhythmias.

SIDE EFFECTS Hypotension and postural hypotension have been the most frequently reported adverse reactions (See WARNINGS section). Nausea and vomiting occurred in about three percent of patients, primarily when bretylium (bretylium tosylate injection ) tosylate was administered rapidly by the intravenous route (See PRECAUTIONS section). Vertigo, dizziness, light-headedness and syncope, which sometimes accompanied postural hypotension, were reported in about 7 patients in 1000. Bradycardia, increased frequency of premature ventricular contractions, transitory hypertension, initial increase in arrhythmias (See WARNINGS section), precipitation of anginal attacks, and sensation of substernal pressure have also been reported in a small number of patients, i.e., approximately 1-2 patients in 1000. Renal dysfunction, diarrhea, abdominal pain, hiccups, erythematous macular rash, flushing, hyperthermia, confusion, paranoid psychosis, emotional lability, lethargy, generalized tenderness, anxiety, shortness of breath, diaphoresis, nasal stuffiness and mild conjunctivitis, have been reported in about 1 patient in 1000. Hyperthermia has also been reported (see WARNINGS). The relationship of bretylium (bretylium tosylate injection ) tosylate administration to these reactions has not been clearly established. DRUG INTERACTIONS Digitalis toxicity may be aggravated by the initial release of norepinephrine caused by Bretylium (bretylium tosylate injection ) Tosylate Injection. The pressor effects of catecholamines such as dopamine or norepinephrine are enhanced by Bretylium (bretylium tosylate injection ) Tosylate. When catecholamines are administered, dilute solutions should be used and blood pressure should be monitored closely. (See WARNINGS) Although there is little published information on concomitant administration of lidocaine and Bretylium (bretylium tosylate injection ) Tosylate, these drugs are often administered concurrently without any evidence of interactions resulting in adverse effects or diminished efficacy.

WARNINGS Hypotension: Administration of bretylium (bretylium tosylate injection ) tosylate regularly results in postural hypotension, subjectively recognized by dizziness, light-headedness, vertigo or faintness. Some degree of hypotension is present in about 50% of patients while they are supine. Hypotension may occur at doses lower than those needed to suppress arrhythmias. Patients should be kept in the supine position until tolerance to the hypotensive effect of bretylium (bretylium tosylate injection ) develops. Tolerance occurs unpredictably but may be present after several days. Patients over 65 years may be at increased risk of developing orthostatic hypotension, especially when the recommended rate of intravenous infusion is exceeded. See DOSAGE AND ADMINISTRATION Hypotension with supine systolic pressure greater than 75 mm Hg need not be treated unless there are associated symptoms. If supine systolic pressure falls below 75 mm Hg, an infusion of dopamine or norepinephrine may be used to raise blood pressure. When catecholamines are administered, a dilute solution should be employed and blood pressure monitored dosely because the pressor effects of the catecholamines are enhanced by bretylium (bretylium tosylate injection ) . Volume expansion with blood or plasma and correction of dehydration should be carried out where appropriate. Transient hypertension and increased frequency of arrhythmias: Due to the initial release of norepinephrine from adrenergic postganglionic nerve terminals by bretylium (bretylium tosylate injection ) , transient hypertension or increased frequency of premature ventricular contractions and other arrhythmias may occur in some patients. Caution during use with digitalis glycosides: The initial release of norepinephrine caused by bretylium (bretylium tosylate injection ) may aggravate digitalis toxicity. When a life-threatening cardiac arrhythmia occurs in a digitalized patient, bretylium (bretylium tosylate injection ) should be used only if the etiology of the arrhythmia does not appear to be digitalis toxicity and other antiarrhythmic drugs are not effective. Simultaneous initiation of therapy with digitalis glycosides and bretylium (bretylium tosylate injection ) should be avoided. Patients with fixed cardiac output: In patients with fixed cardiac output (i.e., severe aortic stenosis or severe pulmonary hypertension) bretylium (bretylium tosylate injection ) should be avoided since severe hypotension may result from a fall in peripheral resistance without a compensatory increase in cardiac output. If survival is threatened by the arrhythmia, bretylium (bretylium tosylate injection ) tosylate may be used but vasoconstrictive catecholamines should be given promptly if severe hypotension occurs. Hyperthermia: In a small number of patients, hyperthermia, characterized by temperature in excess of 106°F, has been reported in association with bretylium (bretylium tosylate injection ) tosylate administration. Temperature rise can begin within one hour or later after administration of drug, and reach a peak within 1 to 3 days. If hyperthermia is suspected or diagnosed, bretylium (bretylium tosylate injection ) should be discontinued and appropriate treatment instituted immediately. PRECAUTIONS General Dilution for Intravenous use: One vial of BRETYLIUM (bretylium tosylate injection ) TOSYLATE INJECTION should be diluted with a minimum of 50 mL of Dextrose Injection 5%, USP, or Sodium Chloride Injection, USP, prior to intravenous use. Rapid intravenous administration may cause severe nausea and vomiting. Therefore, the diluted solution should be infused over a period greater than 8 minutes. In treating existing ventricular fibrillation bretylium (bretylium tosylate injection ) tosylate should be given as rapidly as possible and may be given without dilution. Use various sites for intramuscular injection: When injected intramuscularly, not more than 5mL should be given in a site, and injection sites should be varied since repeated intramuscular injection into the same site may cause atrophy and necrosis of muscle tissue, fibrosis, vascular degeneration and inflammatory changes. Reduce dosage in impaired renal function: Since bretylium (bretylium tosylate injection ) is excreted principally via the kidney, the dosage interval should be increased in patients with impaired renal function. See CLINICAL PHARMACOLOGY section for information of the effect of reduced renal function on half-life. Carcinogenesis, Mutagenesis, Impairment of Fertility No data are available on potential for carcinogenicity, mutagenicity or impairment of fertility in animals or humans. Studies with solutions in polypropylene syringes have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility. Pregnancy Category C: Animal reproduction studies have not been conducted with bretylium (bretylium tosylate injection ) tosylate. It is also not known whether bretylium (bretylium tosylate injection ) tosylate can cause harm when administered to a pregnant woman or can affect reproduction capacity. Bretylium (bretylium tosylate injection ) tosylate should be given to pregnant women only if clearly needed. Pediatric Use The safety and effectiveness of Bretylium (bretylium tosylate injection ) Tosylate have not been established. Its limited use in pediatric patients has been inadequate to fully define proper dosage and limitations for use. Geriatric Use Clinical studies of bretylium (bretylium tosylate injection ) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or drug therapy. Intravenous infusion, especially if administered at a rate beyond that recommended in the DOSAGE AND ADMNISTRATION section, may produce an increased risk of orthostatic hypotension in the elderly. See WARNINGS) This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function, See CLINICAL PHARMACOLOGY.