AERRANE

A stable, non-explosive inhalation anesthetic, relatively free from significant side effects.

For induction and maintenance of general anesthesia.

Isoflurane is a general inhalation anesthetic used for induction and maintenance of general anesthesia.

It induces muscle relaxation and reduces pains sensitivity by altering tissue excitability.

It does so by decreasing the extent of gap junction mediated cell-cell coupling and altering the activity of the channels that underlie the action potential.

Gamma-aminobutyric acid receptor subunit alpha-1 Agonist Calcium-transporting ATPase type 2C member 1 Inhibitor Glycine receptor subunit alpha-1 Agonist + 3 more targets.

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The symptoms of overdosage of Isoflurane

USP can present as a deepening of anesthesia, cardiac and/or respiratory depression in spontaneously breathing patients, and cardiac depression in ventilated patients in whom hypercapnia and hypoxia may occur only at a late stage.

In the event of overdosage, or what may appear to be overdosage, the following action should be taken, as appropriate: Stop drug administration, establish a clear airway, and initiate assisted or controlled ventilation with pure oxygen.

Monitor cardiovascular function and manage signs of poor end-organ perfusion as clinically indicated.

• in whom general anesthesia is contraindicated.

• with known sensitivity to Isoflurane USP or to other halogenated agents.

• with known or suspected genetic susceptibility to malignant hyperthermia.

• with a history of confirmed hepatitis due to a halogenated inhalational anesthetic or a history of unexplained moderate to severe hepatic dysfunction (e.g., jaundice associated with fever and/or eosinophilia) after anesthesia with isoflurane or other halogenated inhalational anesthetics.

• Patients in whom general anesthesia is contraindicated.

• Patients with known sensitivity to Isoflurane USP or other halogenated agents.

• Patients with known or suspected genetic susceptibility to malignant hyperthermia.

• Patients with a history of confirmed hepatitis due to a halogenated inhalational anesthetic or a history of unexplained moderate to severe hepatic dysfunction (e.g., jaundice associated with fever and/or eosinophilia) after anesthesia with Isoflurane USP or other halogenated inhalational anesthetics.

• Isoflurane USP should be administered only by persons trained in the administration of general anesthesia.

USP should only be delivered using a vaporizer specifically designed and designated for use with isoflurane.

• The administration of general anesthesia must be individualized and titrated based on the patient’s age and clinical status. 2.1 Important Dosage and Administration Information Isoflurane 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.

Isoflurane is administered by inhalation.

Isoflurane should be delivered from a vaporizer specifically designed for use with isoflurane.

Dosage for induction and maintenance must be individualized and titrated to the desired effect according to the patient’s age and clinical status.

With the exception of neonates, the minimum alveolar concentration (MAC) of isoflurane decreases with increasing patient age.

Nitrous oxide decreases the

MAC of isoflurane.

Opioids decrease the

Isoflurane potentiates the muscle relaxant effect of all neuromuscular blockers and decreases the required doses of neuromuscular blocking agents.

The dose should be adjusted accordingly.

All patients anesthetized with isoflurane should be continually monitored (e.g., monitoring of the electrocardiogram, blood pressure, oxygen saturation, and end tidal CO 2 ).

Isoflurane is a profound respiratory depressant.

Excessive respiratory depression may be related to depth of anesthesia and respond to decreasing the inspired concentration of isoflurane.

The depressant effect is accentuated by concurrent use of opioids and other respiratory depressants.

Respiration should be closely monitored and assisted or controlled ventilation employed when necessary. 2.2 Premedication Premedication should be selected according to the need of the individual patient, taking into account that secretions are weakly stimulated by Isoflurane USP, and the heart rate tends to be increased. 2.3 Induction Induction with isoflurane in oxygen or in combination with oxygen-nitrous oxide mixtures may produce coughing, breath holding, laryngospasm and bronchospasm, which increases with the concentration of isoflurane.

These difficulties may be avoided by the use of a hypnotic dose of an ultra-short-acting barbiturate.

Inspired concentrations of 1.5 to 3% isoflurane usually produce surgical anesthesia in to 10 minutes. 2.4 Maintenance Isoflurane MAC values according to age are shown below: Table 1: Effect of Age on Minimum Alveolar Concentration of Isoflurane Age Average MAC Value In 100% Oxygen Average MAC Value In 30% Oxygen and 70% N 2 O Preterm neonates less than 32 weeks gestational age 1.28% Preterm neonates 32-37 weeks gestational age 1.41% 0-1 month 1.60% 1-6 months 1.87% 6-12 months 1.80% 1-5 years 1.60% 6-10 years 1.45% 11-18 years 1.38% 19-30 years 1.28% 0.56% 31-55 years 1.15% 0.50% 55-83 years 1.05% 0.37% Dosage for induction and maintenance must be individualized and titrated to the desired effect according to the patient’s age and clinical status.

Surgical levels of anesthesia may be sustained with a to 2.5% concentration when nitrous oxide is used concomitantly.

An additional 0.5 to 1% may be required when isoflurane is given using oxygen alone.

If added relaxation is required, supplemental doses of neuromuscular blocking agents may be used.

The level of blood pressure during maintenance is an inverse function of isoflurane concentration in the absence of other complicating problems.

Excessive decreases may be due to depth of anesthesia and in such instances may be corrected by lightening anesthesia.

Isoflurane causes a dose-dependent reduction in systemic vascular resistance and blood pressure.

Particular care must be taken when selecting the dosage for patients who are hypovolemic, hypotensive, or otherwise hemodynamically compromised, e.g., due to concomitant medications.

USP markedly increases cerebral blood flow at deeper levels of anesthesia to produce a transient increase in intracranial pressure.

In patients with or at risk for elevations of intracranial pressure (ICP), administer isoflurane in conjunction with ICP.

• reducing strategies, as clinically appropriate. 2.5 Use in Patients with Coronary Artery Disease Regardless of the anesthetics employed, maintenance of normal hemodynamics is important to the avoidance of myocardial ischemia in patients with coronary artery disease.

Isoflurane can cause dose-dependent coronary vasodilation and has been shown to divert blood from collateral-dependent myocardium to normally perfused areas in an animal model (“coronary steal”).

The extent to which coronary steal occurs in patients with steal-prone coronary anatomy is unclear.

Monitor for signs of inadequate myocardial perfusion via hemodynamic monitors (e.g., ECG, blood pressure) during isoflurane administration.

Consider additional cardiac monitoring in patients with known coronary artery disease, as clinically necessary.

USP, is available in the following presentations: FILL CONTAINER NDC 100 mL Amber-colored Bottle 66794-020-10 250 mL Amber-colored Bottle 66794-020-25 Replace the cap securely after each use. 16.1 Safety and Handling Occupational Caution The following reactions have been reported following occupational exposure to isoflurane: dyspnea, bronchospasm, stridor, cough, dizziness, paresthesia, hepatic reactions, flushing rash, contact dermatitis, erythema, periorbital edema, eye irritation, conjunctival hyperemia, and headache.

There is no specific work exposure limit established for Isoflurane USP.

However, the National Institute for Occupational Safety and Health Administration (NIOSH) recommends that no worker should be exposed at ceiling concentrations greater than 2 ppm of any halogenated anesthetic agent over a sampling period not to exceed one hour.

The predicted effects of acute overexposure by inhalation of Isoflurane USP include headache, dizziness or (in extreme cases) unconsciousness.

There are no documented adverse effects of chronic exposure to halogenated anesthetic vapors ( W aste A nesthetic G ases or WAGs) in the workplace.

Although results of some epidemiological studies suggest a link between exposure to halogenated anesthetics and increased health problems (particularly spontaneous abortion), the relationship is not conclusive.

Since exposure to

WAGs is one possible factor in the findings for these studies, operating room personnel, and pregnant women in particular, should minimize exposure.

Precautions include adequate general ventilation in the operating room, the use of a well-designed and well-maintained scavenging system, work practices to minimize leaks and spills while the anesthetic agent is in use, and routine equipment maintenance to minimize leaks. 16.2 Storage Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F) .

Preserve in tight containers.

Isoflurane contains no additives and has been demonstrated to be stable at room temperature for periods in excess of five years.

The following reactions have been reported following occupational exposure to isoflurane: dyspnea, bronchospasm, stridor, cough, dizziness, paresthesia, hepatic reactions, flushing rash, contact dermatitis, erythema, periorbital edema, eye irritation, conjunctival hyperemia, and headache.

There is no specific work exposure limit established for Isoflurane USP.

However, the National Institute for Occupational Safety and Health Administration (NIOSH) recommends that no worker should be exposed at ceiling concentrations greater than 2 ppm of any halogenated anesthetic agent over a sampling period not to exceed one hour.

The predicted effects of acute overexposure by inhalation of Isoflurane USP include headache, dizziness or (in extreme cases) unconsciousness.

There are no documented adverse effects of chronic exposure to halogenated anesthetic vapors ( W aste A nesthetic G ases or WAGs) in the workplace.

Although results of some epidemiological studies suggest a link between exposure to halogenated anesthetics and increased health problems (particularly spontaneous abortion), the relationship is not conclusive.

Since exposure to

WAGs is one possible factor in the findings for these studies, operating room personnel, and pregnant women in particular, should minimize exposure.

Precautions include adequate general ventilation in the operating room, the use of a well-designed and well-maintained scavenging system, work practices to minimize leaks and spills while the anesthetic agent is in use, and routine equipment maintenance to minimize leaks.

There are no adequate and well-controlled studies in pregnant women.

In animal reproduction studies, embryofetal toxicity was noted in pregnant mice exposed to 0.075% (increased post implantation losses) and 0.3% isoflurane (increased post implantation losses and decreased livebirth index) during organogenesis.

Published studies in pregnant primates demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of peak brain development increases neuronal apoptosis in the developing brain of the offspring when used for longer than 3 hours.

There are no data on pregnancy exposures in primates corresponding to periods prior to the third trimester in humans.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15.

Pregnant rats were exposed to isoflurane at concentrations of 0%, 0.1%, or 0.4% for two hours per day during organogenesis (Gestational Days 6-15).

Isoflurane did not cause malformations or clear maternal toxicity under these conditions.

Pregnant mice exposed to isoflurane at concentrations of 0%, 0.075%, or 0.30% for 2 hours per day during organogenesis (Gestational Days 6-15).

Isoflurane increased fetal toxicity (higher post implantation losses at 0.075 and 0.3% groups and significantly lower live-birth index in the 0.3% isoflurane treatment group).

Pregnant rats were exposed to concentrations of isoflurane at 0%, 0.1%, or 0.4% for 2 hours per day during late gestation (GD 15-20).

Animals appeared slightly sedated during exposure.

No adverse effects on the offspring or evidence of maternal toxicity were reported.

This study did not evaluate neurobehavioral function including learning and memory in the first generation (F1) of pups.

In a published study in primates, administration of an anesthetic dose of ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing brain of the fetus.

In other published studies, administration of either isoflurane or propofol for 5 hours on Gestation Day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing brain of the offspring.

With respect to brain development, this time period corresponds to the third trimester of gestation in the human.

The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits.

During the induction of anesthesia, saliva flow and tracheobronchial secretion can increase and can be the cause of larynogospasm, particularly in children.

Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as Isoflurane USP, that either block NMDA receptors or potentiate the activity of GABA 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 of gestation 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 ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss.

Data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with 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 pregnant women, neonates, and young children who require procedures with the potential risks suggested by the nonclinical data.

The minimum alveolar concentration (MAC) of isoflurane decreases with increasing patient age.

The dose should be adjusted accordingly.