Prescription Drugs

CLINICAL PHARMACOLOGY Fluothane (halothane) is an inhalation anesthetic. Induction and recovery are rapid, and depth of anesthesia can be rapidly altered. Fluothane (halothane) progressively depresses respiration. There may be tachypnea with reduced tidal volume and alveolar ventilation. Fluothane (halothane) 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 (halothane) 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 (halothane) does not cause the release of catecholamines from adrenergic stores. Fluothane (halothane) also causes dilation of the vessels of the skin and skeletal muscles. Cardiac arrhythmias may occur during Fluothane (halothane) anesthesia. These include nodal rhythm, AV dissociation, ventricular extrasystoles, and asystole. Fluothane (halothane) sensitizes the myocardial conduction system to the action of epinephrine and norepinephrine, and the combination may cause serious cardiac arrhythmias. Fluothane (halothane) increases cerebrospinal-fluid pressure. Fluothane (halothane) produces moderate muscular relaxation. Muscle relaxants are used as adjuncts in order to maintain lighter levels of anesthesia. Fluothane (halothane) augments the action of nondepolarizing relaxants and ganglionic-blocking agents. Fluothane (halothane) is a potent uterine relaxant. The mechanism(s) whereby Fluothane (halothane) and other substances induce general anesthesia is unknown. Fluothane (halothane) is a very potent anesthetic in humans, with a minimum alveolar concentration (MAC) determined to be 0.64%. The MAC has been found to decrease with age (see MAC table in "Dosage and Administration").

DESCRIPTION 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. 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.* * Klaus Florey, editor, Analytical Profiles of Drug Substances, Vol. 1, page 127, (1972). 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 (halothane) is nonflammable, and its vapors mixed with oxygen in proportions from 0.5 to 50% (v/v) are not explosive. Fluothane (halothane) 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 (halothane) ; such materials will deteriorate rapidly in contact with Fluothane (halothane) vapor or liquid. Stability of Fluothane (halothane) is maintained by the addition of 0.01% thymol (w/w), up to 0.00025% ammonia (w/w).

PATIENT INFORMATION 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 (halothane) , condition of the patient, and consideration given to other drugs administered after anesthesia).

OVERDOSE In the event of overdosage, or what may appear to be overdosage, drug administration should be stopped, and assisted or controlled ventilation with pure oxygen initiated. There is no specific antidote. Treatment should be aimed at maintaining respiratory function (by moving the patient to fresh air or inserting an emergency airway with respiratory support) and cardiovascular function. Cases of internal ingestion must be treated symptomatically. CONTRAINDICATIONS Fluothane (halothane) is not recommended for obstetrical anesthesia except when uterine relaxation is required.

SIDE EFFECTS As with other agents of this type, halothane anaesthesia has been shown to trigger a skeletal muscle hypermetabolic state leading to high oxygen demand and the clinical syndrome known as malignant hyperthermia (MH). The syndrome includes non specific features such as hypercapnia, muscle rigidity, tachycardia, tachypnoea, cyanosis, arrhythmias and unstable blood pressure. An increase in overall metabolism may be reflected in an elevated temperature. Treatment includes discontinuation of triggering agents, administration of intravenous dantrolene sodium and application of supportive therapy. Cardiac arrhythmias, in particular ventricular arrthymias, have been reported as being very common during FLUOTHANE (halothane) use. Typically these are without clinical consequences. Bradycardia and/or hypotension may occur during FLUOTHANE (halothane) anaesthesia. Hypotension may occur particularly during induction. Shivering may be observed during recovery from anaesthesia, especially if the patient is in cool surroundings. Post-operative nausea and vomiting may occur after FLUOTHANE anaesthesia. Anaesthesia with halothane may be followed by abnormalities of liver function or more rarely liver damage (see Contraindications). DRUG INTERACTIONS FLUOTHANE (halothane) augments the action of non-depolarising muscle relaxants and the muscle relaxant effects of aminoglycosides. FLUOTHANE (halothane) may augment the hypotension caused by the ganglionic-blocking effect of tubocurarine. Caution should be exercised during the administration of adrenaline to patients anaesthetised with FLUOTHANE (halothane) as arrhythmias may be precipitated. For this reason the dose of adrenaline should be restricted and an antiarrhythmic agent administered as appropriate. Caution should also be applied for other sympathomimetics, and for aminophylline and theophylline and tricyclic antidepressants, which may also precipitate arrhythmias.

WARNINGS When previous exposure to Fluothane (halothane) was followed by unexplained hepatic dysfunction and/or jaundice, consideration should be given to the use of other agents. PRECAUTIONS GENERAL Fluothane (halothane) should be used in vaporizers that permit a reasonable approximation of output, and preferably of the calibrated type. The vaporizer should be placed out of circuit in closed-circuit rebreathing systems; otherwise, overdosage is difficult to avoid. 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 (halothane) increases cerebrospinal-fluid pressure. Therefore, in patients with markedly raised intracranial pressure, if Fluothane (halothane) 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. In susceptible individuals, halothane anesthesia may trigger a skeletal-muscle hypermetabolic state leading to a high oxygen demand and the clinical syndrome known as malignant hyperthermia. The syndrome includes nonspecific features such as muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmias, and unstable blood pressure. (It should also be noted that many of these nonspecific signs may appear with light anesthesia, acute hypoxia, etc.) An increase in overall metabolism may be reflected in an elevated temperature (which may rise rapidly, early or late in the case, but usually is not the first sign of augmented metabolism) and an increased usage of the CO 2 absorption system (hot canister). PaO 2 and pH may decrease, and hyperkalemia and a base deficit may appear. Treatment includes discontinuance of triggering agents (e.g., halothane), administration of intravenous dantrolene, and application 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. It should be noted that the syndrome of malignant hyperthermia secondary to halothane appears to be rare. 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 (halothane) , condition of the patient, and consideration given to other drugs administered after anesthesia). DRUG INTERACTIONS Epinephrine or norepinephrine should be employed cautiously, if at all, during Fluothane (halothane, USP) anesthesia, since their simultaneous use may induce ventricular tachycardia or fibrillation. Nondepolarizing relaxants and ganglionic-blocking agents should be administered cautiously, since their actions are augmented by Fluothane (halothane, USP). Clinical experience and animal experiments suggest that pancuronium should be given with caution to patients receiving chronic tricyclic antidepressant therapy who are anesthetized with halothane, because severe ventricular arrhythmias may result from such usage. 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 (halothane) 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 (halothane) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. LABOR AND DELIVERY The uterine relaxation obtained with Fluothane (halothane) , unless carefully controlled, may fail to respond to ergot derivatives and oxytocic posterior pituitary extract. NURSING MOTHERS It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Fluothane (halothane) is administered to a nursing woman. PEDIATRIC USE Extensive clinical experience reveals that maintenance concentrations of halothane are generally higher in infants and children, and that maintenance requirements decrease with age. See MAC table, based upon age, in "Dosage and Administration."