Bretylate (Bretylium Tosylate)

BRETYLATE®

Glaxo Wellcome

Bretylium Tosylate

Antiarrhythmic

Action And Clinical Pharmacology: Bretylium is an adrenergic-neurone blocking agent. The mechanism by which it exerts its antiarrhythmic action is not fully understood. Although evidence has indicated that the benefit of bretylium in abating tachyarrhythmias may be due to its antiadrenergic properties, this has still not been firmly established. Some reports have even indicated that there is a clear-cut dissociation between the neuron-blocking and the antiarrhythmic actions of the drug.

I.V. injection of bretylium initially causes a release of norepinephrine from sympathetic nerve endings, followed by a prolonged antiadrenergic action which prevents further discharge of neurotransmitter from sympathetic nerve endings. Bretylium is preferentially taken up by the adrenergic nerve terminals. The initial release of norepinephrine accounts for the transient increased automaticity and the initial rise in the systemic and, usually more markedly, the pulmonary blood pressure. The blood pressure will revert later to control levels or fall below them during the adrenergic blocking phase.

Bretylium increases both the action potential duration in the heart and the functional refractory period. Bretylium does not depress automaticity in the Purkinje-fibers. The effectiveness of the drug is primarily in ventricular and not in supraventricular arrhythmias and the direct effect of bretylium in increasing refractoriness also accounts for its usefulness in abolishing re-entrant arrhythmias. Bretylium exerts a positive inotropic effect in the heart, probably due to catecholamine release, since this inotropic action can be blocked by propranolol. There is also an increase in myocardial oxygen consumption associated with bretylium administration. The heart rate following bretylium administration has been found to be variable, increasing in some patients and decreasing in others.

There is no conclusive evidence that bretylium has any direct effects on myocardial tissue. Bretylium does not have quinidine-like actions on the myocardium and in this respect, and in the increased contractility produced, differs from other antiarrhythmic agents.

Pharmacokinetics: Judging by therapeutic effectiveness bretylium is adequately absorbed after i.m. administration, but no pharmacokinetic comparison with the i.v. route has been reported. In one study elimination half-lives ranging from 4.2 to 16 hours (mean of 9.8 hours) were found. The concentration of bretylium in plasma has not been correlated with the intensity of its antiarrhythmic action and cannot be used to guide individualization of dosage.

Bretylium is eliminated intact by the kidneys. No metabolites have been identified following the administration of bretylium. Within 24 hours, 70 to 80% of i.m. dose is excreted in the urine with an additional 10% excreted over the next 3 days.

Bretylium causes an initial increase in urinary excretion of norepinephrine, but generally has no other effects on the renal system. Renal blood flow, glomerular filtration rate and potassium excretion are unchanged. Only slight increases in sodium, chloride or water excretion are found.

Indications And Clinical Uses: Bretylium may be of value as a last resort in life-threatening ventricular arrhythmias, principally ventricular tachycardia and fibrillation, which are resistant to conventional antiarrhythmic drug treatment.

Bretylium should be used only in intensive care units in hospitals where facilities for monitoring and treating patients with serious cardiac dysrhythmias are available.

Following administration of bretylium there may be a delay from 20 minutes to as long as 6 hours before the onset of antidysrhythmic activity. For this reason, quick-acting drugs such as lidocaine or procainamide remain the treatment of choice in patients with serious ventricular dysrhythmias. If these continue or recur despite treatment with lidocaine and other antiarrhythmic agents, bretylium may be of value in restoring sinus rhythm.

Contra-Indications: There is no evidence that prophylactic administration of bretylium confers clinical benefit in patients with recent but uncomplicated myocardial infarction. In such patients the use of bretylium may lead to unpredictable cardiovascular effects. Therefore, this drug should not be used to prevent the development of arrhythmias in patients with recent myocardial infarction.

Bretylium may potentially cause a severe hypertensive response in patients with pheochromocytoma and is therefore contraindicated in this condition.

Manufacturers’ Warnings In Clinical States: Hypotension: Administration of bretylium regularly results in postural hypotension, subjectively recognized by dizziness, lightheadedness, vertigo and faintness. Orthostatic hypotension may occur 20 to 30 minutes after acute administration of bretylium, and in patients with poor cardiac function clinically significant hypotension may occur even in the supine position. 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. Additionally, hypotension has been reported after cardiac surgery.

Patients should be kept in the supine position until tolerance to the hypotensive effect of bretylium develops. Tolerance occurs unpredictably but may be present after several days.

Hypotension with supine systolic pressure greater than 75 mm Hg need not be treated unless there are associated symptoms. Hypovolemia will augment the hypotensive response to bretylium. If the blood pressure does not respond to simple postural manoeuvers, i.v. fluid should be given. An infusion of dopamine or norepinephrine may also be required to raise blood pressure. When catecholamines are administered, a dilute solution should be employed and blood pressure monitored closely because the pressor effects of the catecholamines are enhanced by bretylium.

Transient Hypertension and Increased Frequency of Arrhythmias: Due to the initial release of norepinephrine from adrenergic postganglionic nerve terminals by bretylium, transient hypertension or increased frequency of premature ventricular contractions and other arrhythmias may occur in some patients. Such arrhythmias have been observed especially in persons receiving inotropic catecholamines.

Caution During Use With Digitalis Glycosides: The initial release of norepinephrine caused by bretylium may aggravate digitalis toxicity. When a life-threatening cardiac arrhythmia occurs in the digitalized patient, bretylium 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 glycoside and bretylium should be avoided.

Patients With Fixed Cardiac Output: In patients with fixed cardiac output (i.e., severe aortic stenosis or severe pulmonary hypotension), bretylium 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 may be used but vasoconstrictive catecholamines should be given promptly if severe hypotension occurs.

Pregnancy: Safety in human pregnancy has not been established. However, as the drug is intended for use only in life-threatening situations, it may be used in pregnant women when its benefits outweigh the potential risk to the fetus.

Lactation: It is not known if bretylium is excreted in breast milk.

Children: The safety and efficacy of this drug in children have not been established. Bretylium has been administered to a limited number of pediatric patients, but such use has been inadequate to define fully proper dosage and limitations for use.

Geriatrics: The use of bretylium in the elderly depends on the degree of reduction in cardiac and renal function. The decision to treat rests on whether the benefits of the antiarrhythmic effect outweigh the potential risks of inappropriate dosing.

Precautions: When used i.v., bretylium should be diluted and given slowly in all cases except when immediate life-threatening ventricular arrhythmia exists as in ventricular fibrillation (see Dosage). Rapid i.v. administration may cause severe nausea and vomiting.

Since bretylium is excreted principally via the kidney, dosage should be reduced in patients with impaired renal function (see Dosage).

Administration may aggravate sinus bradycardia and, therefore, should be used with caution in patients with this condition.

Drug Interactions: Patients should be carefully observed when bretylium is used in combination with drugs such as quinidine, procainamide and propranolol because the addition of bretylium to the above drugs may result in a significantly prolonged AV transmission time and could aggravate pre-existing AV block.

Hypersensitivity to infused catecholamines would be expected after bretylium administration because bretylium blocks the normal mechanism of cathecholamine metabolism, namely neuronal uptake and subsequent degradation by MAO. For this reason, when it is necessary to increase perfusion pressure to vital organs after bretylium-induced hypotension, norepinephrine or other sympathomimetics should only be given under expert supervision (see Warnings).

Adverse Reactions: Hypotension and postural hypotension have been the most frequently reported adverse reactions (see Warnings). Nausea and vomiting occurred in about 3% of patients, primarily when bretylium was administered rapidly by the i.v. route. Vertigo, dizziness, lightheadedness and syncope, which sometimes accompanied postural hypotension, were reported in about 7 patients in 1 000.

Bradycardia, increased frequency of premature ventricular contractions, transitory hypertension, initial increase in arrhythmias (see Warnings), precipitation of anginal attacks, and sensation of substernal pressure have also been reported in a small number of patients, i.e., approximately 1 to 2 patients in 1 000.

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 1 000. The relationship of bretylium administration to these reactions has not been clearly established.

Symptoms And Treatment Of Overdose: Symptoms: Bretylium overdose has been reported in a patient with recurrent ventricular fibrillation and tachycardia who was inadvertently given an i.v. bolus of 2 g (approximately 30 mg/kg body weight). The authors reported ultimately successful control of the ventricular tachyarrhythmias but the patient exhibited marked hypertension with peak blood pressure of 310/90 mm Hg, followed approximately an hour later by marked hypotension refractory to i.v. dobutamine and volume expansion therapy.

Symptoms of overdosage are blurred vision, headache, nausea, hypotension and circulatory failure.

Treatment: Should be symptomatic. Bretylium can be removed by hemodialysis.

Dosage And Administration: To be used clinically only for treatment of life-threatening ventricular arrhythmias under constant ECG monitoring. Since there is a delay in onset of its antiarrhythmic action, bretylium is not to be considered or used as a replacement for rapidly-acting antiarrhythmic agents currently in use. The clinical use is for short-term use only. Patients should either be kept supine during the course of therapy or be closely observed for postural hypotension. The optimal dose schedule for parenteral administration has not been determined. There is comparatively little experience with dosages greater than 30 mg/kg/day although such doses have been used without apparent adverse effects. The following dosage schedule is suggested:

Immediately Life-Threatening Ventricular Arrhythmia, as in Ventricular Fibrillation: Administer undiluted at a dosage of 5 mg/kg of body weight by rapid i.v. 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 10 mg/kg and repeated at 15- to 30-minute intervals until a total dose of not more than 30 mg/kg of body weight has been given.

Other Ventricular Arrhythmias: I.V.: Must be diluted as follows before i.v. administration: Using aseptic technique, dilute contents of 10 mL ampul containing 500 mg bretylium tosylate to a minimum of 50 mL with Dextrose Injection USP, or Sodium Chloride Injection USP. Diluted solutions must be used within 24 hours from the time of preparation.

Administer the diluted solution at a dosage of 5 to 10 mg/kg of body weight by i.v. infusion over a period greater than 8 minutes. More rapid infusion may cause nausea and vomiting. A second dose may be given in 1 to 2 hours if the arrhythmia persists.

I.M.: Do not dilute prior to i.m. injection. Inject 5 to 10 mg/kg of body weight. Dosage may be repeated in 1 to 2 hours if the arrhythmia persists. Thereafter, maintain with same dosage every 6 to 8 hours.

When injected i.m. not more than 5 mL should be given in one site and injection sites should be varied since repeated i.m. injection into the same site may cause atrophy and necrosis of muscle tissue, fibrosis, vascular degeneration and inflammatory changes. Care should be taken not to inject directly into or near a major nerve.

Maintenance Dosage: The diluted solution should be administered by intermittent bolus infusion or by constant infusion. The solution must be used within 24 hours.

Intermittent Infusion: Infuse the diluted solution at a dose of 5 to 10 mg/kg of body weight over a period greater than 8 minutes every 6 hours. More rapid infusion may cause nausea and vomiting.

Constant Infusion: Infuse the diluted solution at a dosage of 1 to 2 mg/minute.

Dosage should be reduced and discontinued in 3 to 5 days under ECG monitoring. Other appropriate antiarrhythmic agents should be substituted if indicated.

Method of Preparation of Bretylium for I.V. Administration: Using Dextrose Injection, USP or Sodium Chloride Injection, USP, bretylium may be diluted as follows before i.v. administration: dilute contents of 10 mL ampul (500 mg bretylium tosylate) to a minimum of 50 mL.

Diluted solution must be used within 24 hours from the time of preparation.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Should either be observed, the solution should be discarded and fresh solution prepared.

Bretylium causes an initial increase in urinary excretion of norepinephrine, but generally has no other effects on the renal system. Renal blood flow, glomerular filtration rate and potassium excretion are unchanged. Only slight increases in sodium, chloride or water excretion are found.

Availability And Storage: Each mL contains: bretylium tosylate 50 mg. Nonmedicinal ingredients: water for injection. Ampuls of 10 mL. Boxes of 5. Store at 15 to 25°C and protect from light.

BRETYLATE® Glaxo Wellcome Bretylium Tosylate Antiarrhythmic

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