Methohexital

INDICATIONS AND USAGE Methohexital Sodium for Injection 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; Methohexital Sodium for Injection 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. Methohexital Sodium for Injection 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.

CLINICAL PHARMACOLOGY 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.

DOSAGE AND ADMINISTRATION 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 Methohexital Sodium for Injection. 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. Methohexital Sodium for Injection may be used with any of the recognized preanesthetic medications. Preparation of Solution FOLLOW DILUTION INSTRUCTIONS EXACTLY. Freshly prepare solutions of Methohexital Sodium for Injection and use promptly. Reconstituted solutions of Methohexital Sodium for Injection are chemically stable at room temperature for 24 hours. Diluents ONLY USE BACTERIOSTATIC-FREE DILUENT - Recommended diluents are based on route of administration (see Dilution Instructions ). Incompatible diluents: Lactated Ringer's Injection Dilution Instructions 1% solutions (10 mg/mL) should be prepared for intermittent intravenous and rectal administration; 0.2% solutions (2 mg/mL) should be prepared for continuous intravenous drug administration; 5% solutions (50 mg/mL) should be prepared for intramuscular administration. Contents of vials should be diluted as follows: FOR INTERMITTENT INTRAVENOUS and RECTAL ADMINISTRATION The preferred diluent for intermittent intravenous and rectal administration is Sterile Water for Injection. 5% Dextrose Injection, or 0.9% Sodium Chloride Injection are also acceptable diluents. Strength Amount of Diluent to Be Added to the Contents of the Methohexital Sodium for Injection Vial For 1% methohexital solution (10 mg/mL) 500 mg 50 mL no further dilution needed FOR CONTINUOUS INTRAVENOUS ADMINISTRATION For continuous drip anesthesia, prepare a 0.2% solution by adding 500 mg of Methohexital Sodium for Injection to 250 mL of diluent. For this dilution, either 5% glucose solution or isotonic (0.9%) sodium chloride solution ONLY is recommended as the diluent instead of sterile water for injection in order to avoid extreme hypotonicity. Strength Amount of Diluent to Be Added to the Contents of the Methohexital Sodium for Injection Vial For 0.2% methohexital solution (2 mg/mL) 500 mg 15 mL add to 235 mL diluent for 250 mL total volume FOR INTRAMUSCULAR ADMINISTRATION The preferred diluent for intramuscular administration is Sterile Water for Injection. 0.9% Sodium Chloride Injection is also an acceptable diluent. Strength Amount of Diluent to Be Added to the Contents of the Methohexital Sodium for Injection Vial For 5% methohexital solution (50 mg/mL) 500 mg 10 mL no further dilution needed Administration Dosage is highly individualized; the drug should be administered only by those completely familiar with its quantitative differences from other barbiturate anesthetics. Adults Methohexital Sodium for Injection is administered intravenously in a concentration of no higher than 1%. Higher concentrations markedly increase the incidence of muscular movements and irregularities in respiration and blood pressure. Induction of anesthesia For induction of anesthesia, a 1% solution is administered at a rate of about 1 mL/5 seconds. Gaseous anesthetics and/or skeletal muscle relaxants may be administered concomitantly. The dose required for induction may range from 50 to 120 mg or more but averages about 70 mg. The usual dosage in adults ranges from 1 to 1.5 mg/kg. The induction dose usually provides anesthesia for 5 to 7 minutes. Maintenance of anesthesia Maintenance of anesthesia may be accomplished by intermittent injections of the 1% solution or, more easily, by continuous intravenous drip of a 0.2% solution. Intermittent injections of about 20 to 40 mg (2 to 4 mL of a 1% solution) may be given as required, usually every 4 to 7 minutes. For continuous dri

ADVERSE REACTIONS Side effects associated with Methohexital Sodium for Injection 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 Onesource at 1-888-217-8103 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

WARNINGS As with all potent anesthetic agents and adjuncts, Methohexital Sodium for Injection 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 Methohexital Sodium for Injection 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 fluid

CONTRAINDICATIONS Methohexital Sodium for Injection 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.

OVERDOSAGE Signs and Symptoms The onset of toxicity following an overdose of intravenously administered methohexital will be within seconds of the infusion. If methohexital is administered rectally or is ingested, the onset of toxicity may be delayed. The manifestations of an ultrashort-acting barbiturate in overdose include central nervous system depression, respiratory depression, hypotension, loss of peripheral vascular resistance, and muscular hyperactivity ranging from twitching to convulsive-like movements. Other findings may include convulsions and allergic reactions. Following massive exposure to any barbiturate, pulmonary edema, circulatory collapse with loss of peripheral vascular tone, and cardiac arrest may occur. Treatment To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians’ Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient. Establish an airway and ensure oxygenation and ventilation. Resuscitative measures should be initiated promptly. For hypotension, intravenous fluids should be administered and the patient’s legs raised. If desirable increase in blood pressure is not obtained, vasopressor and/or inotropic drugs may be used as dictated by the clinical situation. For convulsions, diazepam intravenously and phenytoin may be required. If the seizures are refractory to diazepam and phenytoin, general anesthesia and paralysis with a neuromuscular blocking agent may be necessary. Protect the patient’s airway and support ventilation and perfusion. Meticulously monitor and maintain, within acceptable limits, the patient’s vital signs, blood gases, serum electrolytes, etc. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient’s airway when employing gastric emptying or charcoal.