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Caution: Federal law prohibits dispensing without prescription.
Fluothane (halothane, USP) is supplied as a liquid and is vaporized for use as an inhalation anesthetic. It is 2-bromo-2-chloro-1, 1, 1-trifluoro-ethane and has the following structural formula:
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C 2 HBrClF 3
The molecular weight is 197.38. The drug substance halothane molecule has an asymmetric carbon atom; the commercial product is a racemic mixture. Resolution of the mixture has not been reported. *
Halothane is miscible with alcohol, chloroform, ether, and other fat solvents.
The specific gravity is 1.872-1.877 at 20°C, and the boiling point (range) is 49°C-51°C at 760 mm Hg. The vapor pressure is 243 mm Hg at 20°C. The blood/gas coefficient is 2.5 at 37°C, and the olive oil/water coefficient is 220 at 37°C. Vapor concentrations within anesthetic range are nonirritating and have a pleasant odor.
Fluothane is nonflammable, and its vapors mixed with oxygen in proportions from 0.5 to 50% (v/v) are not explosive.
Fluothane does not decompose in contact with warm soda lime. When moisture is present, the vapor attacks aluminum, brass, and lead, but not copper. Rubber, some plastics, and similar materials are soluble in Fluothane; such materials will deteriorate rapidly in contact with Fluothane vapor or liquid. Stability of Fluothane is maintained by the addition of 0.01% thymol (w/w), up to 0.00025% ammonia (w/w).
Fluothane is an inhalation anesthetic.
Induction and recovery are rapid, and depth of anesthesia can be rapidly altered.
Fluothane progressively depresses respiration. There may be tachypnea with reduced tidal volume and alveolar ventilation. Fluothane is not an irritant to the respiratory tract, and no increase in salivary or bronchial secretions ordinarily occurs. Pharyngeal and laryngeal reflexes are rapidly obtunded. It causes bronchodilation. Hypoxia, acidosis, or apnea may develop during deep anesthesia.
Fluothane reduces the blood pressure and frequently decreases the pulse rate. The greater the concentration of the drug, the more evident these changes become. Atropine may reverse the bradycardia.
Fluothane does not cause the release of catecholamines from adrenergic stores. Fluothane also causes dilation of the vessels of the skin and skeletal muscles.
Cardiac arrhythmias may occur during Fluothane anesthesia. These include nodal rhythm, AV dissociation, ventricular extrasystoles, and asystole. Fluothane sensitizes the myocardial conduction system to the action of catecholamines, and the combination may cause serious cardiac arrhythmias.
Fluothane increases cerebrospinal-fluid pressure. Fluothane produces moderate muscular relaxation. Muscle relaxants are used as adjuncts in order to maintain lighter levels of anesthesia. Fluothane augments the action of nondepolarizing relaxants and ganglionic-blocking agents.
Fluothane is a potent uterine relaxant.
The mechanism(s) whereby Fluothane and other substances induce general anesthesia is unknown. Fluothane is a very potent anesthetic in humans, with a minimum alveolar concentration (MAG) determined to be 0.64%. The MAC has been found to decrease with age (see MAC table in " Dosage and Administration ").
Fluothane (halothane, USP) is indicated for the induction and maintenance of general anesthesia.
Fluothane should not be used:
in patients with known sensitivity to halothane or other halogenated anesthetics; in patients with known or suspected susceptibility to malignant hyperthermia; in obstetrical anesthesia except when uterine relaxation is required (see " Precautions , LABOR AND DELIVERY "); in patients who have developed jaundice or acute hepatic damage from previous exposure to halothane unless other causes of liver damage were demonstrated (see " Warnings , HEPATOTOXICITY ").
Fluothane should be administered only by persons trained in the administration of general anesthesia. Facilities for maintenance of a patent airway, artificial ventilation, oxygen enrichment, and circulatory resuscitation must be immediately available. Unless all recognized standards for anesthesia care are adhered to and qualified personnel and equipment and drugs are on hand to manage emergencies, Fluothane should not be administered.
The decision to administer Fluothane should include an assessment of the individual patient status and the safety profile of Fluothane which includes proarrhythmic properties, hepatotoxicity, and malignant hyperthermia.
ARRHYTHMIAS
Halothane administration is commonly associated with arrhythmias, some of which may be fatal. The risk of arrhythmias during halothane anesthesia may be increased in certain procedures (e.g., dental surgery), clinical states (e.g. metabolic abnormalities, hypoxia and/or hypercapnia, preexisting Q-T prolongation or history of arrhythmias), and populations (e.g. children).
In susceptible individuals, potent inhalation anesthetic agents, including halothane, may trigger a skeletal-muscle hypermetabolic state leading to a high oxygen demand and the clinical syndrome known as malignant hyperthermia. Frequently, the syndrome is heralded by muscle rigidity and/or increasing end-tidal CO 2 (ET CO 2 ). Other symptoms may include acidosis, tachycardia, tachypnea, cyanosis, arrhythmias and/or unstable blood pressure. These non-specific symptoms require immediate evaluation to rule out malignant hyperthermia. Hyperthermia can be a late finding. Core temperature should be monitored in all patients given general anesthesia with Fluothane. Treatment of malignant hyperthermia includes discontinuance of triggering agents, administration of intravenous dantrolene sodium (consult prescribing information for dantrolene sodium intravenous for additional information on patient management) and institution of supportive therapy. Such therapy includes vigorous efforts to restore body temperature to normal, respiratory and circulatory support as indicated, and management of electrolyte-fluid-acid-base derangements. Renal failure may appear later, and urine flow should be sustained if possible.
Cases of halothane-associated liver toxicity ("halothane hepatitis"), in some instances leading to liver failure and death, have been described in the literature and in spontaneous reports. Clinical symptoms of halothane hepatitis are similar to those resulting from other causes of hepatitis and may include fever, jaundice, and, in some cases, rash and eosinophilia. Histologic findings include centrilobular necrosis (see " Contraindications ").
Repeat exposure to Fluothane within a short period of time is not recommended.
GENERAL
The patient should be closely observed for signs of overdosage, i.e., depression of blood pressure, pulse rate, and ventilation, particularly during assisted or controlled ventilation.
Fluothane increases cerebrospinal-fluid pressure. Therefore, in patients with markedly raised intracranial pressure, if Fluothane is indicated, administration should be preceded by measures ordinarily used to reduce cerebrospinal-fluid pressure. Ventilation should be carefully assessed, and it may be necessary to assist, or control ventilation to ensure adequate oxygenation and carbon dioxide removal (see " Clinical Pharmacology ").
The recovery from general anesthesia should be assessed carefully before a patient is discharged from the post-anesthesia care unit.
Regardless of the anesthetics employed, maintenance of normal hemodynamics is important to avoid myocardial ischemia in patients with coronary artery disease.
Halothane should be used cautiously in patients with a history of arrhythmias (see " Clinical Pharmacology "). Halothane has been reported to cause prolongation of the Q-T interval, which constitutes a risk of ventricular tachycardia, including torsade de points. This should be taken into consideration when contemplating use of halothane in patients with existing Q-T prolongation or in patients receiving other drugs known to prolong the Q-T interval (see " DRUG INTERACTIONS ").
In pheochromocytoma, there may be an increased risk of cardiac arrhythmias because the patient has high endogenous catecholamine concentrations.
In myasthenia gravis, muscle weakness may be increased because of neuromuscular blocking effects of anesthetics.
INFORMATION FOR PATIENTS
When appropriate, as in some cases where discharge is anticipated soon after general anesthesia, patients should be cautioned not to drive automobiles, operate hazardous machinery, or engage in hazardous sports for 24 hours or more (depending on the total dose of Fluothane, condition of the patient, and consideration given to other drugs administered after anesthesia).
Patients also should avoid the use of alcohol or any other CNS depressants within 24 hours following anesthesia unless authorized or prescribed by a health care professional.
LABORATORY TESTS
Transient increases in serum transaminases or lactate dehydrogenase activity may occur in the absence of clinical hepatotoxicity.
Drugs that prolong the Q-T interval: As halothane has been reported to prolong the Q-T interval, caution should be exercised in concurrent use with other drugs known to prolong the Q-T interval.
Catecholamines: Epinephrine, norepinephrine, isoproterenol, or other sympathomimetics should be employed cautiously, if at all, during Fluothane anesthesia, since their simultaneous use may induce ventricular tachycardia or fibrillation.
Neuromuscular Blocking Agents: Nondepolarizing relaxants and ganglionic-blocking agents should be administered cautiously, since their actions are augmented by halothane.
Pancuronium: Clinical experience and animal experiments suggest that pancuronium should be given with caution to patients receiving chronic tricyclic antidepressant therapy who are anesthetized with Fluothane, because severe ventricular arrhythmias may result from such usage.
Phenytoin Concurrent use of phenytoin may increase the risk of halothane hepatotoxicity: also, halothane-induced hepatic function impairment may increase the risk of phenytoin toxicity.
Theophylline: The concurrent use of theophylline and halothane may increase the risk of ventricular arrhythmias and cardiac arrest.
Drugs that are affected by the cytochrome P 450 system Halothane undergoes metabolism in the liver by cytochrome P 450 . Drugs such as isoniazid and ethanol are known to elevate hepatic levels of this enzyme and enhance the metabolism of volatile anesthetics. Chronic exposure to trace concentrations of halothane also have been reported to increase hepatic microsomal enzyme activity. On the other hand, halothane can inhibit the metabolism of a variety of drugs eliminated by the liver microsomal enzyme system such as propranolol, lidocaine, verapamil, fentanyl, meperidine, and ketamine. The clinician should anticipate potential alterations in metabolism of other drugs cleared by the liver when administered in conjunction with Fluothane.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
An 18-month inhalational carcinogenicity study of halothane at 0.05% in the mouse revealed no evidence of anesthetic-related carcinogenicity. This concentration is equivalent to 24 hours of 1% halothane.
Mutagenesis testing of halothane revealed both positive and negative results. In the rat, one-year exposure to trace concentrations of halothane (1 and 10 ppm) and nitrous oxide produced chromosomal damage to spermatogonia cells and bone marrow cells. Negative mutagenesis tests included: Ames bacterial assay, Chinese hamster lung fibroblast assay, sister chromatid exchange in Chinese hamster ovary cells, and human leukocyte culture assay.
Reproduction studies of halothane (10 ppm) and nitrous oxide in the rat caused decreased fertility. This trace concentration corresponds to 1/1000 the human maintenance dose.
PREGNANCY
Teratogenic Effects: Pregnancy Category C. Some studies have shown Fluothane to be teratogenic, embryotoxic, and fetotoxic in the mouse, rat, hamster, and rabbit at subanesthetic and/or anesthetic concentrations. There are no adequate and well-controlled studies in pregnant women. Fluothane should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Halothane produces dose-dependent uterine relaxation. Inhibition of natural or induced uterine contractions by halothane during parturition may prolong the process of delivery, as well as increase blood loss. However, when used as supplementation to nitrous oxide/oxygen to reduce maternal awareness in cesarean section, low concentrations (0.5%) have been effective, without increasing blood loss or producing adverse neonatal effects.
The uterine relaxation obtained with Fluothane, unless carefully controlled, may fail to respond to ergot derivatives and oxytocic posterior pituitary extract. Use of Fluothane during vaginal delivery is not recommended unless uterine relaxation is required (see " Contraindications ").
NURSING MOTHERS
Halothane is excreted in breast milk. Because of the potential for serious adverse reactions in nursing infants exposed to halothane, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
GERIATRIC USE
The MAC of an anesthetic is decreased in geriatric patients. The average concentration of Fluothane to achieve MAC in an 81 year old is approximately 25% of that required in a 24 year old (see " Dosage and Administration "). Also, geriatric patients may be more susceptible to anesthetic-induced hypotension and circulatory depression; therefore, careful attention to dosage is recommended.
PEDIATRIC USE
Halothane has a low propensity to induce airway irritation; therefore, a rapid increase in inspired gas concentration can be tolerated. Due to its low tendency of irritation to the airways, halothane is a suitable inhalation agent in pediatric patients.
In a prospective randomized clinical trial in children undergoing general anesthesia for dental procedures, there was a strong association between halothane and ventricular arrhythmias, especially ventricular tachycardia.
Induction
In pediatric patients from 1 to 12 years of age, induction has been observed in approximately 3 to 5 minutes with halothane in concentrations of up to 2% in nitrous oxide/oxygen.
Maintenance and Recovery
The concentration of halothane for maintenance of general anesthesia is age-dependent (see MAC table in " Dosage and Administration "). The incidence of arrhythmias during maintenance is usually higher and the heart rate is slower when compared to other anesthetic agents. Emergence times after halothane anesthesia in pediatric patients 1 to 7 years of age have ranged from 4 to 16 minutes. In one study involving 40 pediatric patients (from 5 to 12 years of age), time to return of the eyelash reflex was 4.6 minutes; time to recovery (ability to walk) was 29 minutes.
Extensive clinical experience reveals that maintenance concentrations of halothane are generally higher in infants and children, and that maintenance requirements decrease with age. However, the MAC of halothane for neonates has been shown to be 25% less than the MAC for infants between the ages of 1 to 6 months. (See MAC table in " Dosage and Administration ").
The major clinical considerations when using Fluothane in the pediatric population are hepatotoxicity (see " Contraindications " and " Warnings , HEPATOTOXICITY "), malignant hyperthermia (see " Contraindications " and " Warnings , MALIGNANT HYPERTHERMIA ") and cardiovascular effects (see " Warnings ").
Although the incidence of hepatitis in pediatric patients is considered to be low, repeated exposures to Fluothane within a short period of time are not recommended (see " Warnings "). Caution is recommended in pediatric patients who have a deficiency in (alpha) 1 -antitrypsin. There have been reports of liver failure in pediatric patients with this deficiency following surgery performed under halothane anesthesia.
Malignant hyperthermia, a rare but sometimes fatal complication of inhalation anesthetics, has been reported during halothane anesthesia in susceptible pediatric patients (see " Warnings , MALIGNANT HYPERTHERMIA ").
Several published clinical reports suggest that acute rhabdomyolysis can be precipitated in pediatric patients with certain muscle diseases, such as Duchennne's muscular dystrophy and Becker' muscular dystrophy. In some of these reports, succinylcholine, an agent also known to trigger rhabdomyolysis, was used to facilitate intubation.
In pediatric patients, halothane decreases the systolic arterial pressure in a dose-dependent manner, the heart rate and the cardiac output. It also depresses the baroreflex response in a dose-dependent manner and the myocardial contractility. Neonates and infants with preexisting anemias subjected to lengthy fasts appear to be more susceptible to the cardiovascular depressant effects of halothane. Respiratory distress syndrome survivors with chronic oxygenation deficits (bronchopulmonary dysplasia) or disorders of ventilatory control (periodic apnea-bradycardia syndrome) and premature neonates may be at greater risk of cardiorespiratory depression during halothane anesthesia.
Adverse reactions reported coincident with the administration of Fluothane include:
Body as a whole: Fever; shivering; nausea and vomiting; rarely headache.
Cardiovascular: Cardiac arrest; Q-T interval prolongation; cardiac arrhythmias (including bradycardia, tachycardia, nodal rhythm, AV dissociation, ventricular extrasystoles, and asystole); hypotension; rarely hypertension.
Hepatic Function: Mild, moderate and severe (some fatal) hepatic dysfunction (including abnormal liver function tests, jaundice, hepatitis, hepatic necrosis, liver failure, and hepatorenal syndrome) (see " Contraindications " and " Warnings , HEPATOTOXICITY ").
Musculoskeletal System: Malignant hyperthermia (see " Warnings , MALIGNANT HYPERTHERMIA "); myoglobinuria and rhabdomyolysis (see " Precautions , PEDIATRIC USE ").
Renal System: Acute renal failure (sometimes associated with rhabdomyolysis).
Respiratory System: Dose-dependent respiratory depression; respiratory arrest. Also, there have been spontaneous reports of pneumonitis and pulmonary edema.
Skin and Special Senses: Rarely rash.
In the event of overdosage, or what may appear to be overdosage, the following action should be taken: discontinue administration of Fluothane, maintain a patent airway, initiate assisted or controlled ventilation with oxygen, and maintain adequate cardiovascular function.
The concentration of Fluothane being delivered from a vaporizer during anesthesia should be known. This can be accomplished by administering Fluothane through a vaporizer specifically designed, calibrated and designated for its use. Since Fluothane contains thymol, which does not volatilize, the vaporizer should be drained periodically to prevent build up. Fluothane can be delivered through any anesthesia circuit (see " Precautions ").
The administration of general anesthesia must be individualized based on the patient' response. The induction dose varies from patient to patient but is usually within the range of 0.5% to 3% in oxygen or nitrous oxide/oxygen. During maintenance of anesthesia, the concentrations of inhaled anesthetic may be progressively decreased as necessary to prevent further increases in depth of anesthesia and/or hypotension.
The maintenance dose varies from 0.5% to 1.5%.
Because of the more rapid uptake of Fluothane and the increased blood concentration required for anesthesia in younger patients, the minimum alveolar concentration (MAC) values are as follows:
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Fluothane® (halothane, USP) is available in unit packages of 125 mL (NDC 0046-3125-81) and 250 mL (NDC 0046-3125-82) of halothane, USP, stabilized with 0.01% thymol (w/w) and up to 0.00025% ammonia (w/w).
Store at room temperature (approximately 25°C) in a tight, closed container.
Protect from light.
Use carton to protect contents from light.
Manufactured for
Ayerst Laboratories Inc.
A Wyeth-Ayerst Company
Philadelphia, PA 19101
By ICI Chemicals and Polymers Ltd.
Runcorn, Cheshire, U.K.
CI 6145-1 Issued February 28, 2000