Prescription Information

• Composition and Description
• Indications
• Precautions and Warnings
• Interactions
• Dosage and Administration
• Side Effects and Adverse Reactions
• Overdose
• Pharmaceutical Precaution

Composition and Description

Enflurane, USP, a nonflammable liquid administered by vaporizing, is a general inhalation Anaesthetic drug. It is 2-chloro-1,1,2-trifluoroethyl difluoromethyl ether, (CHF2OCF2CHFCI). The boiling point is 56.5°C at 760 mm Hg, and the vapor pressure (in mm Hg) is 175 at 20°C, 218 at 25°C, and 345 at 36°C. Vapor pressures can be calculated using the equation:

log₁₀P _vap = A +

where: A = 7.967, B = -1678.4, T = °C + 279.16 (Kelvin)

The specific gravity (25°/25°C) is 1.517. The refractive index at 20°C is 1.3026-1.3030. The blood/gas coefficient is 1.91 at 37°C and the oil/gas coefficient is 98.5 at 37°C.

Enflurane is a clear, colorless, stable liquid whose purity exceeds 99.9% (area percent by gas chromatography). No stabilizers are added as these have been found, through controlled laboratory tests, to be unnecessary even in the presence of ultraviolet light.Enflurane is stable to strong base, does not decompose in contact with soda lime (at normal operating temperatures) and does not react with aluminum, tin, brass, iron or copper. The partition coefficients of enflurane at 25°C are 74 in conductive rubber and 120 in polyvinyl chloride.

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Indications

Enflurane may be used for induction and maintenance of general anesthesia. Enflurane may be used to provide analgesia for vaginal delivery. Low concentrations of enflurane (see DOSAGE AND ADMINISTRATION) may also be used to supplement other general Anaesthetic agents during delivery by Cesarean section. Higher concentrations of enflurane may produce uterine relaxation and an increase in uterine bleeding.

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Precautions and Warnings

Use of inhaled Anaesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in pediatric patients during the postoperative period. Patients with latent as well as overt neuromuscular disease, particularly Duchenne muscular dystrophy, appear to be most vulnerable. Concomitant use of succinylcholine has been associated with most, but not all, of these cases. These patients also experienced significant elevations in serum creatinine kinase levels and, in some cases, changes in urine consistent with myoglobinuria. Despite the similarity in presentation to malignant hyperthermia, none of these patients exhibited signs or symptoms of muscle rigidity or hypermetabolic state. Early and aggressive intervention to treat the hyperkalemia and resistant arrhythmias is recommended, as is subsequent evaluation for latent neuromuscular disease.

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Interactions

The action of nondepolarizing relaxants is augmented by enflurane. Less than the usual amounts of these drugs should be used. If the usual amounts of nondepolarizing relaxants are given, the time for recovery from neuromuscular blockade will be longer in the presence of enflurane than when halothane or nitrous oxide with a balanced technique are used.

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Dosage and Administration

The concentration of enflurane being delivered from a vaporizer during anesthesia should be known. This may be accomplished by using:

1. vaporizers calibrated specifically for enflurane;
2. vaporizers from which delivered flows can be calculated.

PreAnaesthetic Medication
PreAnaesthetic medication should be selected according to the need of the individual patient, taking into account that secretions are weakly stimulated by enflurane and that enflurane does not alter heart rate. The use of anticholinergic drugs is a matter of choice.

Surgical Anesthesia
Induction may be achieved using enflurane alone with oxygen or in combination with oxygen-nitrous oxide mixtures. Under these conditions some excitement may be encountered. If excitement is to be avoided, a hypnotic dose of a short-acting barbiturate should be used to induce unconsciousness, followed by the enflurane mixture. In general, inspired concentrations of 2.0 to 4.5% enflurane produced surgical anesthesia in 7 to 10 minutes.

Maintenance
Surgical levels of anesthesia may be maintained with 0.5 to 3% enflurane. Maintenance concentrations should not exceed 3%. If added relaxation is required, supplemental doses of muscle relaxants may be used. Ventilation to maintain the tension of carbon dioxide in arterial blood in the 35 to 45 mm Hg range is preferred. Hyperventilation should be avoided in order to minimize possible CNS excitation.

The level of blood pressure during maintenance is an inverse function of enflurane concentration in the absence of other complicating problems. Excessive decreases (unless related to hypovolemia) may be due to depth of anesthesia and in such instances should be corrected by lightening the level of anesthesia.

Analgesia
Enflurane 0.25 to 1% provides analgesia for vaginal delivery equal to that produced by 30 to 60% nitrous oxide. These concentrations normally do not produce amnesia. See also the information on the effects of enflurane on uterine contraction contained in the CLINICAL PHARMACOLOGY section.

Cesarean Section
Enflurane should ordinarily be administered in the concentration range of 0.5 to 1% to supplement other general anesthetics. See also the information on the effects of enflurane on uterine contraction contained in the CLINICAL PHARMACOLOGY section.

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Side Effects and Adverse Reactions

1. Malignant hyperthermia (see WARNINGS).
2. Motor activity exemplified by movements of various muscle groups and/or seizures may be encountered with deep levels of enflurane anesthesia, or light levels with hypocapnia.
3. Hypotension, respiratory depression and hypoxia have been reported.
4. Arrhythmias, shivering, nausea and vomiting have been reported.
5. Elevation of the white blood count has been observed.
6. Mild, moderate and severe liver injury, including hepatic failure, may rarely follow anesthesia with enflurane.

Serum transaminases may be increased and histologic evidence of injury may be found.The histologic changes are neither unique nor consistent. In several of these cases, it has not been possible to exclude enflurane as the cause or as a contributing cause to liver injury. The incidence of unexplained hepatotoxicity following the administration of enflurane is unknown, but it appears to be rare and not dose related.

Enflurane has also been associated with perioperative hyperkalemia (see WARNINGS). There have been rare post-marketing reports of hepatic failure and hepatic necrosis associated with the use of potent volatile Anaesthetic agents, including Enflurane. Due to the spontaneous nature of these reports, the actual incidence and relationship of Enflurane to these events cannot be established with certainty.

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Overdose

In the event of overdosage, or what may appear to be overdosage, the following action should be taken:

Stop drug administration, establish a clear airway and initiate assisted or controlled ventilation with pure oxygen.

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Pharmaceutical Precaution

General
Enflurane should be used with caution in patients who by virtue of medical or drug history could be considered more susceptible to cortical stimulation produced by the drug. Enflurane, like some other inhalational anesthetics, can react with desiccated carbon dioxide (CO2) absorbents to produce carbon monoxide, which may result in elevated levels of carboxyhemoglobin in some patients. Case reports suggest that barium hydroxide lime and soda lime become desiccated when fresh gases are passed through the CO2 absorber canister at high flow rates over many hours or days. When a clinician suspects that CO2 absorbent may be desiccated, it should be replaced before the administration of enflurane.

Information to Patients
Enflurane, as well as other general anesthetics, may cause a slight decrease in intellectual function for 2 or 3 days following anesthesia. As with other anesthetics, small changes in moods and symptoms may persist for several days following administration.

Laboratory
Tests Bromsulfalein (BSP) retention is mildly elevated postoperatively in some cases. This may relate to the effect of surgery since prolonged anesthesia (5 to 7 hours) in human volunteers does not result in BSP elevation. There is some elevation of glucose and white blood count intraoperatively. Glucose elevation should be considered in diabetic patients.

Drug Interactions
The action of nondepolarizing relaxants is augmented by enflurane. Less than the usual amounts of these drugs should be used. If the usual amounts of nondepolarizing relaxants are given, the time for recovery from neuromuscular blockade will be longer in the presence of enflurane than when halothane or nitrous oxide with a balanced technique are used.

Carcinogenesis/Mutagenesis
Swiss ICR mice were given enflurane to determine whether such exposure might induce neoplasia. Enflurane was given at 1/2, 1/8, and 1/32 MAC for four in-utero exposures and for 24 exposures to the pups during the first nine weeks of life.

The mice were killed at 15 months of age. The incidence of tumors in these mice was the same as in untreated control mice which were given the same background gases, but not the Anaesthetic. Exposure of mice to 20 hours of 1.2% enflurane causes a small (about 1/2 of 1.0%) but statistically significant increase in sperm abnormalities. In contrast to these results, in vitro approaches to the study of mutagenesis (Ames test, sister chromatid exchange test, and the 8-azaguanine system) have not shown a mutagenic effect of enflurane.

Pregnancy Category B
Reproduction studies have been performed in rats and rabbits at doses up to four times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to enflurane. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

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 enflurane is administered to a nursing woman.

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