Isoflurane

FDA Drug Information • Also known as: Forane, Isoflurane, Terrell

Brand Names: Forane, Isoflurane, Terrell
Drug Class: General Anesthetic [EPC]
Route: RESPIRATORY (INHALATION)
Dosage Form: LIQUID
Product Type: HUMAN PRESCRIPTION DRUG

Description

11. DESCRIPTION Isoflurane, USP liquid for inhalation, a nonflammable liquid administered by vaporizing, is a general inhalation anesthetic drug. It is 1-chloro-2,2,2-trifluoroethyl difluoromethyl ether, and its structural formula is: Some physical constants are: Molecular weight 184.5 Boiling point at 760 mm Hg 48.5°C Refractive index n 1.2990-1.3005 Specific gravity 25°/25°C 1.496 Vapor pressure in mm Hg** 20°C 238 25°C 295 30°C 367 35°C 450 **Equation for vapor pressure calculation: log 10 P vap =A+ where: A = 8.056 B = −1664.58 T = °C + 273.16 (Kelvin) Partition coefficients at 37°C Water/gas 0.61 Blood/gas 1.43 Oil/gas 90.8 Partition coefficients at 25°C -rubber and plastic Conductive rubber/gas 62.0 Butyl rubber/gas 75.0 Polyvinyl chloride/gas 110.0 Polyethylene/gas ~2.0 Polyurethane/gas ~1.4 Polyolefin/gas ~1.1 Butyl acetate/gas ~2.5 Purity by gas chromatography >99.9% Lower limit of flammability in oxygen or nitrous oxide at 9 joules/sec. and 23°C None Lower limit of flammability in oxygen or nitrous oxide at 900 joules/sec. and 23°C Greater than useful concentration in anesthesia. Isoflurane is a clear, colorless, stable liquid containing no additives or chemical stabilizers. Isoflurane has a mildly pungent, musty, ethereal odor. Samples stored in indirect sunlight in clear, colorless glass for five years, as well as samples directly exposed for 30 hours to a 2 amp, 115 volt, 60 cycle long wave U.V. light were unchanged in composition as determined by gas chromatography. Isoflurane in one normal sodium methoxide-methanol solution, a strong base, for over six months consumed essentially no alkali, indicative of strong base stability. Isoflurane does not decompose in the presence of soda lime (at normal operating temperatures), and does not attack aluminum, tin, brass, iron or copper. image description

What Is Isoflurane Used For?

1 INDICATIONS AND USAGE Isoflurane, USP liquid for inhalation may be used for induction and maintenance of general anesthesia. Adequate data have not been developed to establish its application in obstetrical anesthesia. Isoflurane, USP liquid for inhalation, a general anesthetic, is an inhalation agent indicated for induction and maintenance of general anesthesia. (1)

Dosage and Administration

2 DOSAGE AND ADMINISTRATION Isoflurane, USP liquid for inhalation should be administered only by persons trained in the administration of general anesthesia. Isoflurane, USP liquid for inhalation should only be delivered using a vaporizer specifically designed and designated for use with isoflurane. (2) The administration of general anesthesia must be individualized and titrated based on the patient’s age and clinical status. (2) 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 (see Table 1). Opioids decrease the MAC of isoflurane [see Drug Interactions (7)] . Isoflurane potentiates the muscle relaxant effect of all neuromuscular blockers and decreases the required doses of neuromuscular blocking agents [see Drug Interactions (7) . 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 liquid for inhalation, 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 7 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...

Side Effects (Adverse Reactions)

6. ADVERSE REACTIONS Most common adverse reactions (incidence ≥ 5%) are agitation, cough, breath holding, nausea, chills/shivering, vomiting, laryngospasm, delirium. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Emprise Pharma LLC. at (610) 933-1969 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience The following adverse reactions were identified from controlled clinical trials of adult and pediatric subjects exposed to isoflurane, USP liquid for inhalation. The trials were conducted using a variety of pre-medications, other anesthetics, and surgical procedures of varying lengths. The most serious reported adverse reactions in alphabetical order are agitation, arrhythmia, breath holding, elevated liver enzyme, hypotension and laryngospasm. The most frequent adverse reactions (incidence ≥ 5%) described in Table 1 are agitation, breath holding, chills/shivering, cough, delirium, laryngospasm, nausea, and vomiting. Adverse reactions with an incidence between 1% and 5% are provided in Table 2. Adverse reactions with an incidence less than 1% are provided in Table 3. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Table 2: Adverse Reactions ≥ 5% System Organ Class (SOC) Adverse Reaction Frequency PSYCHIATRIC DISORDERS Delirium 6.2% (N=2830) NERVOUS SYSTEM DISORDERS Agitation (Excitement) Induction 51.8% (N=515) 1 RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS Breath holding Induction 23.9% (N=515) 1 Cough Induction 28.2% (N=515) 1 Laryngospasm Induction 8.0% (N=515) 1 GASTROINTESTINAL DISORDERS Nausea Recovery 15.4 % (N=2830) Vomiting Recovery 9.5% (N=2830) GENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONS Chills/shivering 14.0% (N=1691) 2 1 Represents patients not receiving intravenous agents or neuromuscular blocking agents for intubation (i.e., patients receiving inhalation induction). 2 Reflects the number of patients with recorded body temperature measurements. Table 3: Adverse Reactions between 1% and 5% System Organ Class (SOC) Adverse Reaction Frequency NERVOUS SYSTEM DISORDERS Movement Maintenance 1.8% (N=2830) CARDIAC DISORDERS Ventricular arrhythmia (Intraoperative) Induction 2.1% (N=2161) Maintenance 2.7% (N=2253) Nodal arrhythmia (Intraoperative) Induction 4.0% (N=2161) Maintenance 1.7% (N=2253) Atrial arrhythmia (Intraoperative) Induction 1.6% (N=2161) Maintenance 2.2% (N=2253) Arrhythmia (Postoperative) 1.1% (N=2830) RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS Breath holding Maintenance 1.1% (N=359) 1 Cough Maintenance 4.2 % (N=359) 1 1 Represents patients not receiving intravenous agents or neuromuscular blocking agents for intubation (i.e., patients receiving inhalation induction). Table 4: Adverse Reactions less than 1% System Organ Class (SOC) Adverse Reaction Frequency PSYCHIATRIC DISORDERS Mood changes 0.3% (N=2830) Nightmare 0.4% (N=2175) 1 NERVOUS SYSTEM DISORDERS Convulsive pattern on electroencephalogram 0.5% (N=200) 2 Seizure 0.04% (N=2830) VASCULAR DISORDERS Hypotension Postoperative 0.3% (N=2830) Hypertension Postoperative 0.1% (N=2830) RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS Laryngospasm Maintenance 0.8% (N=359) 3 Secretions Induction 0.2% (N=515) 3 Maintenance 0.0% (N=359) 3 GASTROINTESTINAL DISORDERS Vomiting Induction 0.8% (N=515) 3 Retching Induction 1.0% (N=515) 3 Maintenance 0.8% (N=359) 3 SKIN AND SUBCUTANEOUS TISSUE DISORDERS Diaphoresis Induction 0.2% (N=515) 3 Maintenance 0.0% (N=359) 3 1 Reflects the number of patients interviewed by a physician in the recovery period. 2 Reflects the number of recorded electroencephalograms. 3 Represents patients not receiving intravenous agents or neuromuscular blocking agents for intubation (i.e., patients receiving inhalation induction). The following adverse reactions (see Table 5) were...

Drug Interactions

7. DRUG INTERACTIONS Concomitant use of N 2 O and/or opioids reduces the MAC of isoflurane, USP liquid for inhalation. Adjust dose accordingly. (7.1, 7.2) Isoflurane, USP liquid for inhalation decreases the doses of neuromuscular blocking agents required. Adjust dose accordingly. (7.3) 7.1 Opioids Opioids decrease the Minimum Alveolar Concentration (MAC) of isoflurane. Opioids such as fentanyl and its analogues, when combined with isoflurane, may lead to a synergistic fall in blood pressure and respiratory rate. 7.2 Nitrous Oxide Nitrous oxide decreases the MAC of isoflurane [see Dosage and Administration (2.1)] . 7.3 Neuromuscular Blocking Agents Isoflurane potentiates the muscle relaxant effect of all neuromuscular blocking agents and decreases the required doses of neuromuscular blocking agents. In general, anesthetic concentrations of isoflurane at equilibrium reduce the ED 95 of succinylcholine, atracurium, pancuronium, rocuronium and vecuronium by approximately 25 to 40% or more compared to N 2 O/opioid anesthesia. If added relaxation is required, supplemental doses of neuromuscular blocking agents may be used. 7.4 Adrenaline Isoflurane is similar to sevoflurane in the sensitization of the myocardium to arrhythmogenic effect of exogenously administered adrenaline. Doses of adrenaline greater than 5mcg/kg, when administered submucosally may produce multiple ventricular arrhythmias. 7.5 Calcium Antagonists Isoflurane may lead to marked hypotension in patients treated with calcium antagonists. 7.6 Concomitant Use with Beta Blockers Concomitant use of beta blockers may exaggerate the cardiovascular effects of inhalational anesthetics, including hypotension and negative inotropic effects. 7.7 Concomitant Use with MAO Inhibitors Concomitant use of MAO inhibitors and inhalational anesthetics may increase the risk of hemodynamic instability during surgery or medical procedures.

Contraindications

4. CONTRAINDICATIONS Isoflurane, USP liquid for inhalation is contraindicated in patients: in whom general anesthesia is contraindicated. with known sensitivity to isoflurane, USP liquid for inhalation or to other halogenated agents [see Warnings and Precautions (5.3)] . with known or suspected genetic susceptibility to malignant hyperthermia [see Warnings and Precautions (5.1), Clinical Pharmacology (12.5)]. 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 (4) Patients with known sensitivity to isoflurane, USP liquid for inhalation or other halogenated agents (4) Patients with known or suspected genetic susceptibility to malignant hyperthermia (4) 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 liquid for inhalation or other halogenated inhalational anesthetics (4)

Overdosage

10. OVERDOSAGE The symptoms of overdosage of isoflurane, USP liquid for inhalation 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.

How Supplied

16. HOW SUPPLIED/STORAGE AND HANDLING Isoflurane, USP liquid for inhalation, a clear, colorless, volatile liquid, having a slight odor, is available in the following presentations: FILL CONTAINER PACK SIZE NDC 100 mL Amber-colored Glass 1 Bottle 42677-326-01 250 mL Amber-colored Glass 1 Bottle 42677-327-01 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 liquid for inhalation. 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 liquid for inhalation include headache, dizziness or (in extreme cases) unconsciousness [see Overdosage (10)] . 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...

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.