CIV

For Intravenous Use in Adults

For Rectal and Intramuscular Use Only in Pediatric Patients

BREVITAL®  (methohexital sodium, USP) for injection, is 2,4,6 (1H, 3H, 5H)-Pyrimidinetrione, 1-methyl-5-(1-methyl-2-pentynyl)-5-(2-propenyl)-, (±)-, monosodium salt and has the empirical formula C14H17N2NaO3. Its molecular weight is 284.29.

The structural formula is as follows:

Methohexital sodium is a rapid, ultrashort-acting barbiturate anesthetic. Methohexital sodium for injection is a freeze-dried, sterile, nonpyrogenic mixture of methohexital sodium with 6% anhydrous sodium carbonate added as a buffer. It contains not less than 90% and not more than 110% of the labeled amount of methohexital sodium. It occurs as a white, freeze-dried plug that is freely soluble in water.

This product is oxygen sensitive. The pH of the 1% solution is between 10 and 11; the pH of the 0.2% solution in 5% dextrose is between 9.5 and 10.5.

Methohexital sodium may be administered by direct intravenous injection or continuous intravenous drip, intramuscular or rectal routes (see PRECAUTIONS/Pediatric Use). Reconstituting instructions vary depending on the route of administration (see DOSAGE AND ADMINISTRATION).

Compared with thiamylal and thiopental, methohexital is at least twice as potent on a weight basis, and its duration of action is only about half as long. Although the metabolic fate of methohexital in the body is not clear, the drug does not appear to concentrate in fat depots to the extent that other barbiturate anesthetics do. Thus, cumulative effects are fewer and recovery is more rapid with methohexital than with thiobarbiturates. In experimental animals, the drug cannot be detected in the blood 24 hours after administration.

Methohexital differs chemically from the established barbiturate anesthetics in that it contains no sulfur. Little analgesia is conferred by barbiturates; their use in the presence of pain may result in excitation.

Intravenous administration of methohexital results in rapid uptake by the brain (within 30 seconds) and rapid induction of sleep.

Following intramuscular administration to pediatric patients, the onset of sleep occurs in 2 to 10 minutes. A plasma concentration of 3 mcg/mL was achieved in pediatric patients 15 minutes after an intramuscular dose (10 mg/kg) of a 5% solution. Following rectal administration to pediatric patients, the onset of sleep occurs in 5 to 15 minutes. Plasma methohexital concentrations achieved following rectal administration tend to increase both with dose and with the use of more dilute solution concentrations when using the same dose. A 25 mg/kg dose of a 1% methohexital solution yielded plasma concentrations of 6.9 to 7.9 mcg/mL 15 minutes after dosing. The absolute bioavailability of rectal methohexital sodium is 17%.

With single doses, the rate of redistribution determines duration of pharmacologic effect. Metabolism occurs in the liver through demethylation and oxidation. Side-chain oxidation is the most important biotransformation involved in termination of biologic activity. Excretion occurs via the kidneys through glomerular filtration.

BREVITAL can be used in adults as follows:

• 1.For intravenous induction of anesthesia prior to the use of other general anesthetic agents.
• 2.For intravenous induction of anesthesia and as an adjunct to subpotent inhalational anesthetic agents (such as nitrous oxide in oxygen) for short surgical procedures; BREVITAL may be given by infusion or intermittent injection.
• 3.For use along with other parenteral agents, usually narcotic analgesics, to supplement subpotent inhalational anesthetic agents (such as nitrous oxide in oxygen) for longer surgical procedures.
• 4.As intravenous anesthesia for short surgical, diagnostic, or therapeutic procedures associated with minimal painful stimuli (see WARNINGS).
• 5.As an agent for inducing a hypnotic state.

BREVITAL can be used in pediatric patients older than 1 month as follows:

• 1.For rectal or intramuscular induction of anesthesia prior to the use of other general anesthetic agents.
• 2.For rectal or intramuscular induction of anesthesia and as an adjunct to subpotent inhalational anesthetic agents for short surgical procedures.
• 3.As rectal or intramuscular anesthesia for short surgical, diagnostic, or therapeutic procedures associated with minimal painful stimuli.

BREVITAL is contraindicated in patients in whom general anesthesia is contraindicated, in those with latent or manifest porphyria, or in patients with a known hypersensitivity to barbiturates.

As with all potent anesthetic agents and adjuncts, BREVITAL should be used only in hospital or ambulatory care settings that provide for continuous monitoring of respiratory (e.g. pulse oximetry) and cardiac function. Immediate availability of resuscitative drugs and age- and size-appropriate equipment for bag/valve/mask ventilation and intubation and personnel trained in their use and skilled in airway management should be assured. For deeply sedated patients, a designated individual other than the practitioner performing the procedure should be present to continuously monitor the patient.

Maintenance of a patent airway and adequacy of ventilation must be ensured during induction and maintenance of anesthesia with methohexital sodium solution. Laryngospasm is common during induction with all barbiturates and may be due to a combination of secretions and accentuated reflexes following induction or may result from painful stimuli during light anesthesia. Apnea/hypoventilation may be noted during induction, which may impair pulmonary ventilation; the duration of apnea may be longer than that produced by other barbiturate anesthetics. Cardiorespiratory arrest may occur.

This prescribing information describes intravenous use of methohexital sodium in adults. It also discusses intramuscular and rectal administration in pediatric patients older than one month. Although the published literature discusses intravenous administration in pediatric patients, the safety and effectiveness of intravenous administration of methohexital sodium in pediatric patients have not been established in well-controlled, prospective studies. (See PRECAUTIONS/Pediatric Use.)

Seizures may be elicited in subjects with a previous history of convulsive activity, especially partial seizure disorders.

Because the liver is involved in demethylation and oxidation of methohexital and because barbiturates may enhance preexisting circulatory depression, severe hepatic dysfunction, severe cardiovascular instability, or a shock-like condition may be reason for selecting another induction agent.

Prolonged administration may result in cumulative effects, including extended somnolence, protracted unconsciousness, and respiratory and cardiovascular depression. Respiratory depression in the presence of an impaired airway may lead to hypoxia, cardiac arrest, and death.

The CNS-depressant effect of BREVITAL may be additive with that of other CNS depressants, including ethyl alcohol and propylene glycol.

DANGER OF INTRA-ARTERIAL INJECTION—Unintended intra-arterial injection of barbiturate solutions may be followed by the production of platelet aggregates and thrombosis, starting in arterioles distal to the site of injection. The resulting necrosis may lead to gangrene, which may require amputation. The first sign in conscious patients may be a complaint of fiery burning that roughly follows the distribution path of the injected artery; if noted, the injection should be stopped immediately and the situation reevaluated. Transient blanching may or may not be noted very early; blotchy cyanosis and dark discoloration may then be the first sign in anesthetized patients. There is no established treatment other than prevention. The following should be considered prior to injection:

1. The extent of injury is related to concentration. Concentrations of 1% methohexital will usually suffice; higher concentrations should ordinarily be avoided.

2. Check the infusion to ensure that the catheter is in the lumen of a vein before injection.

Injection  through  a  running  intravenous  infusion  may  enhance  the  possibility  of detecting arterial placement; however, it should be remembered that the characteristic bright-red color of arterial blood is often altered by contact with drugs. The possibility of aberrant arteries should always be considered.

Post injury arterial injection of vasodilators and/or arterial infusion of parenteral fluids are generally regarded to be of no value in altering outcome. Animal experiments and published individual case reports concerned with a variety of arteriolar irritants, including barbiturates, suggest that 1 or more of the following may be of benefit in reducing the area of necrosis:

1. Arterial injection of heparin at the site of injury, followed by systemic anticoagulation.

2. Sympathetic blockade (or brachial plexus blockade in the arm).

3. Intra-arterial glucocorticoid injection at the site of injury, followed by systemic steroids.

4. A case report (nonbarbiturate injury) suggests that intra-arterial urokinase may promote fibrinolysis, even if administered late in treatment.

If extravasation is noted during injection of methohexital, the injection should be discontinued until the situation is remedied. Local irritation may result from extravasation; subcutaneous swelling may also serve as a sign of arterial or periarterial placement of the catheter.

Side effects associated with BREVITAL are extensions of pharmacologic effects and include:

Cardiovascular

Circulatory depression, thrombophlebitis, hypotension, tachycardia, peripheral vascular collapse, and convulsions in association with cardiorespiratory arrest

Respiratory

Respiratory depression (including apnea), cardiorespiratory arrest, laryngospasm, bronchospasm, hiccups, and dyspnea

Neurologic

Skeletal muscle hyperactivity (twitching), injury to nerves adjacent to injection site, and seizures

Psychiatric

Emergence delirium, restlessness, and anxiety may occur, especially in the presence of postoperative pain

Gastrointestinal

Nausea, emesis, abdominal pain, and liver function tests abnormal

Allergic

Erythema, pruritus, urticaria, and cases of anaphylaxis have been reported rarely

Other

Other adverse reactions include pain at injection site, salivation, headache, and rhinitis

For medical advice about adverse reactions contact your medical professional. To report SUSPECTED ADVERSE REACTIONS, contact Par Pharmaceutical at 1-800-828-9393 or FDA at 1-800-FDA-1088 (1-800-332-1088) or www.fda.gov/medwatch/.

Controlled Substance—BREVITAL is a Schedule IV drug.

BREVITAL may be habit-forming.

Facilities for assisting ventilation and administering oxygen are necessary adjuncts for all routes of administration of anesthesia. Since cardiorespiratory arrest may occur, patients should be observed carefully during and after use of BREVITAL. Age- and size- appropriate resuscitative equipment (i.e., intubation and cardioversion equipment, oxygen, suction, and a secure intravenous line) and personnel qualified in its use must be immediately available.

Preanesthetic medication is generally advisable. BREVITAL may be used with any of the recognized preanesthetic medications.

Store between 20° to 25°C (68° to 77°F). (See USP Controlled Room Temperature.)

BREVITAL® Vials*:

The 500 mg vials (with 30 mg anhydrous sodium carbonate) are available as follows:

•  NDC 42023-105-01 – Multi-Dose Vial – Pack of 1

*In crystalline form.

Published studies in animals demonstrate that the use of anesthetic agents during the period of rapid brain growth or synaptogenesis results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester through the first several months of life, but may extend out to approximately 3 years of age in humans.

In primates, exposure to 3 hours of an anesthetic regimen that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer increased neuronal cell loss. Data in rodents and in primates suggest that the neuronal and oligodendrocyte cell losses are associated with subtle but prolonged cognitive deficits in learning and memory. The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in neonates and young children who require procedures against the potential risks suggested by the nonclinical data. (See WARNINGS/Pediatric Neurotoxicity, PRECAUTIONS/Pregnancy, Pediatric Use.)

Rx only

Distributed by:

Par Pharmaceutical

Chestnut Ridge, NY 10977

R08/2020

3003014J

OS106J-01-90-03

NDC 42023-105-01

CIV

BREVITAL®

SODIUM

Methohexital Sodium

For Injection, USP

500 mg

ANESTHETIC BARBITURATE

Multiple Dose Vial

Preservative Free –

Discard Unused Portion After 24 hours

Rx only