Bretylium (Systemic)



INN:

Bretylium tosilate

VA CLASSIFICATION
Primary: CV300

Commonly used brand name(s): Bretylate; Bretylol.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antiarrhythmic—

Indications

Accepted

Arrhythmias, ventricular (prophylaxis and treatment)—Bretylium is indicated in the prophylaxis and management of ventricular fibrillation {12} {15}.
—Bretylium is also indicated in the treatment of life-threatening ventricular arrhythmias (e.g., ventricular tachycardias) refractory to first-line treatment (lidocaine and cardioversion) {12} {15} {16} {17} {19}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Bretylium tosylate: 414.37 {03}

Mechanism of action/Effect:

The exact mechanism of antiarrhythmic effects has not been fully determined. Bretylium is a quaternary ammonium compound that possesses both adrenergic and direct myocardial effects {19} {22}. Bretylium is selectively taken up into peripheral adrenergic nerve terminals where it produces an initial release of norepinephrine resulting in a sympathomimetic effect {15} {19} {22}. After this initial release phase, bretylium inhibits norepinephrine release, producing adrenergic blockade {15} {19} {22}. Finally, bretylium blocks the uptake of norepinephrine and epinephrine into adrenergic nerve endings {23}. The importance of these effects in mediating bretylium's antiarrhythmic action is not clear {15} {23}.

Bretylium's direct myocardial effect includes prolongation of action potential duration and effective refractory period by inhibition of potassium conductance {15} {19} {22} {25}. However, it does not directly depress conduction velocity or automaticity {19} {22}. Bretylium elevates the ventricular fibrillation threshold {15} {19} {22}. In infarcted canine hearts, bretylium reduces the disparity in action potential duration and refractory period between normal and infarcted regions and transiently improves conduction velocity in infarcted areas {15} {19} {22}. In the Vaughan Williams classification of antiarrhythmics, bretylium is considered to be a class III agent {02} {24}.


Other actions/effects:

Bretylium produces a positive inotropic effect, which may or may not be related to the norepinephrine release {12} {15}.

Biotransformation:

Insignificant. No metabolites have been identified {15} {22}.

Half-life:

Mean, 10 hours (range 4 to 17 hours) {22}; this variability may result partially from differences in renal function or administration procedures; increased to 16 to 31.5 hours in renal function impairment.

Onset of action:



 
Onset of Effect after Administration

 
Ventricular Fibrillation
(min)
Ventricular Tachycardia
(min)
Intravenous
5–10
20–120
Intramuscular
20–60
20–120

Time to peak serum concentration

Intramuscular, l hour {15}.

Duration of action:

6 to 24 hours.

Elimination:
    Renal, 90% (unchanged) {12} {15}.
    In dialysis—Removable by hemodialysis.


Precautions to Consider

Carcinogenicity/Mutagenicity

No information is available on the carcinogenic or mutagenic potential of bretylium {12} {15}.

Pregnancy/Reproduction

Pregnancy—
Studies have not been done in humans {15}.

Studies have not been done in animals {15}.

FDA Pregnancy Category C {15}.

Breast-feeding

It is not known whether bretylium is distributed into breast milk.

Pediatrics

Appropriate studies on the relationship of age to the effects of bretylium have not been performed in the pediatric population. Safety and efficacy have not been established {15}.


Geriatrics


No information is available on the relationship of age to the effects of bretylium in the geriatric population. However, elderly patients are more likely to have age-related renal function impairment, which may require reduction of dosage or increase of dosage intervals in patients receiving bretylium. Patients over 65 years may be at increased risk of postural hypotension, especially if the recommended rate of infusion is exceeded{27}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

» Digitalis glycosides    (initial norepinephrine release caused by bretylium may aggravate digitalis toxicity; concurrent use is not recommended {12} {15} {22})


Procainamide or
Quinidine    (concurrent administration may counteract inotropic effect of bretylium and potentiate hypotension)


Sympathomimetics, such as dopamine or norepinephrine    (the pressor effects of these agents may be enhanced during concurrent administration with bretylium; blood pressure should be monitored closely during concurrent use and dilute solutions should be used {15})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
Conditions with fixed cardiac output, such as:
Aortic stenosis or
Pulmonary hypertension, severe    (severe hypotension may occur as a result of reduced peripheral resistance without a compensatory increase in cardiac output; bretylium may be used if necessary for survival, but vasoconstrictive catecholamines may be necessary if severe hypotension occurs {15})


Renal function impairment    (elimination reduced; dosage intervals should be increased {11} {15})


Sensitivity to bretylium

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Blood pressure determinations and
Electrocardiogram (ECG)    (should be monitored continuously during administration)




Side/Adverse Effects

Note: Hypotension (both postural and supine) occurs routinely, with an incidence of about 50% in supine patients, but is rarely symptomatic. Hypotension may occur at doses lower than those necessary to treat arrhythmias. The risk of postural hypotension is increased in patients over 65 years of age due to decreased renal, hepatic, or cardiac function, and the possibility of concomitant disease or drug therapy{12}{27} {15}.
An initial increase in frequency of arrhythmias and a transient hypertension may occur as a result of the initial release of norepinephrine {12} {15}, and may last a few minutes to an hour. This effect may be reduced by slowing the rate of administration of bretylium.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence rare (less than 0.1%)
    
Hyperthermia {15} {18}
    
renal function impairment
    
respiratory depression from possible neuromuscular block


Note: Hyperthermia has been reported in a small number of patients {15}. Temperatures in excess of 106 °F have been observed {15} {18}. Temperature rise may begin within 1 hour or later after bretylium administration and may reach a peak within 1 to 3 days {15}. If hyperthermia is suspected or diagnosed, bretylium should be discontinued and appropriate treatment instituted immediately {15}.



Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent (3%)
    
Nausea and vomiting —especially following rapid (less than 8 minutes) intravenous administration {12}

Incidence rare
    
Angina (chest pain)
    
bradycardia (slow heartbeat)
    
feeling of pressure in the chest
    
postural hypotension (dizziness or lightheadedness when getting up from a lying or sitting position; sudden fainting)





Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Hypertension
hypotension

Note: Marked hypertension may be followed by marked refractory hypotension {15}. This exaggerated hemodynamic response may be due to rapid injection of a very large dose of bretylium while some effective circulation is still present {15}.


Treatment of overdose
For hypertensive response—Administration of nitroprusside or other short-acting intravenous antihypertensive agent {15}.

For hypotensive response—Appropriate fluid therapy and pressor agents such as dopamine or norepinephrine {15}.


General Dosing Information
Dosage must be adjusted to meet the individual requirements of each patient, on the basis of clinical response.

Bretylium injection is always diluted before intravenous administration, except when used in life-threatening ventricular fibrillation when it is administered undiluted and as rapidly as possible {12} {15}. Consult package insert for dilution information.

When administering bretylium by continuous intravenous infusion, an infusion pump or other suitable metering device should be used to control the rate of infusion {15}.

Intramuscular administration should be limited to 5 mL, undiluted, at each injection site. The injection site should be rotated to avoid tissue destruction {12} {15}.

Bretylium is used clinically for short-term therapy only {15}. It should be discontinued after 3 to 5 days by gradual dosage reduction and replaced with oral antiarrhythmic therapy if necessary.

Tolerance to the hypotensive effect of bretylium usually occurs within several days {15}. Until that occurs, the patient should remain supine or be observed carefully for hypotension {15}. No treatment is needed as long as the supine systolic blood pressure remains above 75 mm Hg, unless there are associated symptoms {15}. If it falls to less than 75 mm Hg, treatment should consist of intravenous infusion of dobutamine, dopamine, or norepinephrine and volume replacement with blood or plasma and intravenous fluids if necessary {12}. Hemodynamic monitoring is recommended in these unstable situations to help guide medication therapy {26}.


Parenteral Dosage Forms

BRETYLIUM TOSYLATE INJECTION

Usual adult and adolescent dose
Ventricular fibrillation or
Ventricular tachycardia, hemodynamically unstable
Immediate suppression: Intravenous (rapid), 5 mg per kg of body weight administered undiluted {15}. If the arrhythmia persists, the dosage may be increased to 10 mg per kg of body weight and repeated as necessary {15}.

Continuous suppression: Intravenous infusion, 1 to 2 mg per minute of the diluted solution {15}. Alternatively, infuse the diluted solution at a dosage of 5 to 10 mg per kg of body weight over a period greater than eight minutes every six hours {15}.

Note: For specific dilution information, see Preparation of Dosage Form.
Rapid infusion may cause nausea and vomiting, and in patients older than 65 years, may increase the risk of developing orthostatic hypotension{27}.


Ventricular arrhythmias, other
Intravenous infusion, 5 to 10 mg per kg of body weight of the diluted solution infused over a period greater than eight minutes {15}. If the arrhythmia persists, additional doses may be given at one- to two-hour intervals {15}. This same dosage may be administered every six hours, or a constant infusion of 1 to 2 mg per minute may be used for maintenance therapy; or {15}

Intramuscular, 5 to 10 mg per kg of body weight administered undiluted. If the arrhythmia persists, subsequent doses may be given at one- to two-hour intervals and thereafter maintaining the same dosage every six to eight hours {15}.

Note: The site of intramuscular injection should be rotated {15}. No more than 5 mL should be injected intramuscularly into one site {15}.



Usual pediatric dose
Safety and efficacy have not been established.

Strength(s) usually available
U.S.—


50 mg per mL (Rx) [Bretylol (preservative-free)][Generic]


100 mg per mL (Rx)[Generic]

Canada—


50 mg per mL (Rx) [Bretylate]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing.

Preparation of dosage form:
For intravenous infusion—Using sterile environment and technique, dilute each 500 mg bretylium tosylate in at least 50 mL of 5% dextrose injection or 0.9% sodium chloride injection.


BRETYLIUM TOSYLATE IN 5% DEXTROSE INJECTION

Usual adult and adolescent dose
Ventricular fibrillation or
Ventricular tachycardia, hemodynamically unstable
Intravenous infusion, 1 to 2 mg per minute {20}; or 5 to 10 mg per kg of body weight infused over a period greater than eight minutes every six hours .


Note: More rapid infusion may cause nausea and vomiting, and in patients older than 65 years, may increase the risk of developing orthostatic hypotension{27}.


Usual pediatric dose
Safety and efficacy have not been established.

Strength(s) usually available
U.S.—


1 mg per mL (Rx)[Generic]


2 mg per mL (Rx)[Generic]


4 mg per mL (Rx)[Generic]

Canada—


2 mg per mL (Rx)[Generic]


4 mg per mL (Rx)[Generic]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing.



Revised: 10/27/1999



References

Note: All references used in the development and earlier revisions of this monograph have not yet been incorporated into the computer database and, therefore, are not listed below. Citations for information not yet referenced in the monograph will be provided upon request.

  1. Bretylol package insert (American Critical Care—US), Rec 10/87.
  1. Chest 1985 Sep; 88: 452-60.
  1. Fleeger CA, Editor. USP dictionary of USAN and international drug names 1995. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1994: .
  1. Bretylium tosylate injection package insert (Astra—US), Rec 5/87.
  1. Bretylium tosylate injection in 5% dextrose injection package insert (Abbott—US), Rec 3/86.
  1. Bretylium tosylate injection in 5% dextrose injection package insert (Kendall-McGaw—US), Rec 1/86.
  1. Bretylium tosylate injection package insert (Abbott—US), Rec 5/86.
  1. Bretylium tosylate injection package insert (IMS—US), Rec 11/84.
  1. Bretylium tosylate injection package insert (LyphoMed—US), Rec 12/86.
  1. Bretylate product monograph (BW—Canada), Rec 12/13/84.
  1. Bretylol product information, PDR 1989.
  1. Bretylol package insert (DuPont—US), Rev 1/91, Rec 4/92.
  1. Bretylium tosylate in 5% dextrose injection package insert (Abbott—US), Rec 4/92.
  1. Bretylium tosylate and dextrose injection package insert (Abbott Labs—Canada), Rec 4/92.
  1. Bretylium tosylate package insert (IMS—US), Rev 6/94, Rec 1/95.
  1. Strang JM, Washington SE, Barnes SA, et al. Treatment of prehospital refractory ventricular fibrillation with bretylium tosylate. Ann Emerg Med 1984; 13: 234-6.
  1. Dronen SC. Antifibrillatory drugs: The case for bretylium tosylate. Ann Emerg Med 1984 (part 2); 13: 805-7.
  1. Thibault J. Hyperthermia associated with bretylium tosylate injection. Clin Pharm 1989; 9: 145-6.
  1. Cummins RO, editor. Textbook of advanced cardiac life support. Americal Heart Association 1994.
  1. Bretylium tosylate in 5% dextrose injection package insert (Abbott—US), Rev 3/94, Rec 9/95.
  1. Anderson JL. Bretylium tosylate: profile of the only available class III antiarrhythmic agent. Clin Ther 1985; 7(2): 205-24.
  1. Heissenbuttel RH, Bigger JT. Bretylium tosylate: a newly available antiarrhythmic drug for ventricular arrhythmias. Ann Intern Med 1979; 91: 229-38.
  1. Koch-Weser J. Bretylium. N Engl J Med 1989; 300(9): 473-7.
  1. Anderson JL. Antifibrillatory versus antiectopic therapy. Am J Cardiol 1984; 54: 7A-13A.
  1. Panel comment, 11/95.
  1. Panel comment, 11/95.
  1. Anon. Summary of safety-related drug labeling changes approved by FDA April 1999; Bretylium tosylate in 5% dextrose injection (April 16, 1999: Abbott). United States Food and Drug Administration, U.S. Department of Health and Human Services, Rockville, MD (cited 5/24/99). Available from: http://www.fda.gov/medwatch/safety/1999/apr99.
Hide
(web4)