Drug Facts
Composition & Profile
Identifiers & Packaging
HOW SUPPLIED Isoflurane, USP is available in unit packages of 100 mL (NDC 12164-012-10) and 250 mL (NDC 12164-012-25) amber colored bottles. Safety and Handling Occupational Caution 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 (Waste Anesthetic Gases 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. Storage Store at controlled room temperature 15° - 30°C (59° - 86°F) (see USP). Isoflurane contains no additives and has been demonstrated to be stable at room temperature for a period in excess of five years.; PRINCIPAL DISPLAY PANEL - 250 mL Bottle Label NDC 12164-012-25 250 mL Isoflurane, USP LIQUID FOR INHALATION A NONFLAMMABLE, NONEXPLOSIVE, INHALATION ANESTHETIC Rx ONLY Halocarbon LIFE SCIENCES, LLC 1100 Dittman Ct. North Augusta, SC 29841 www.halocarbon.com PRINCIPAL DISPLAY PANEL - 250 mL Bottle Label
- HOW SUPPLIED Isoflurane, USP is available in unit packages of 100 mL (NDC 12164-012-10) and 250 mL (NDC 12164-012-25) amber colored bottles. Safety and Handling Occupational Caution 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 (Waste Anesthetic Gases 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. Storage Store at controlled room temperature 15° - 30°C (59° - 86°F) (see USP). Isoflurane contains no additives and has been demonstrated to be stable at room temperature for a period in excess of five years.
- PRINCIPAL DISPLAY PANEL - 250 mL Bottle Label NDC 12164-012-25 250 mL Isoflurane, USP LIQUID FOR INHALATION A NONFLAMMABLE, NONEXPLOSIVE, INHALATION ANESTHETIC Rx ONLY Halocarbon LIFE SCIENCES, LLC 1100 Dittman Ct. North Augusta, SC 29841 www.halocarbon.com PRINCIPAL DISPLAY PANEL - 250 mL Bottle Label
Overview
Isoflurane, USP, 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 (uncorr.) Refractive index n 20 D 1.2990-1.3005 Specific gravity 25° / 25°C 1.496 Vapor pressure in mm Hg Equation for vapor pressure calculation: 20°C 238 25ºC 295 30°C 367 35°C 450 Log 10 P vap = A + B T 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 23ºC None Lower limit of flammability in oxygen or nitrous oxide at 900 joules/sec. and 23ºC 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. Chemical Structure
Indications & Usage
Isoflurane may be used for induction and maintenance of general anesthesia. Adequate data have not been developed to establish its application in obstetrical anesthesia.
Dosage & Administration
Premedication Premedication should be selected according to the need of the individual patient, taking into account that secretions are weakly stimulated by isoflurane and the heart rate tends to be increased. The use of anticholinergic drugs is a matter of choice. Inspired Concentration The concentration of isoflurane being delivered from a vaporizer during anesthesia should be known. This may be accomplished by using: a) vaporizers calibrated specifically for isoflurane; b) vaporizers from which delivered flows can be calculated, such as vaporizers delivering a saturated vapor which is then diluted. The delivered concentration from such a vaporizer may be calculated using the formula: % isoflurane = 100 P V F V ––––––––– F T (P A -P V ) Where: P A = Pressure of atmosphere P V = Vapor pressure of isoflurane F V = Flow of gas through vaporizer (mL/min) F T = Total gas flow (mL/min) Isoflurane contains no stabilizer. Nothing in the agent alters calibration or operation of these vaporizers. Induction Induction with isoflurane in oxygen or in combination with oxygen-nitrous oxide mixtures may produce coughing, breath holding, or laryngospasm. These difficulties may be avoided by the use of a hypnotic dose of an ultra-short-acting barbiturate. Inspired concentrations of 1.5 to 3.0% isoflurane usually produce surgical anesthesia in 7 to 10 minutes. Maintenance Surgical levels of anesthesia may be sustained with a 1.0 to 2.5% concentration when nitrous oxide is used concomitantly. An additional 0.5 to 1.0% may be required when isoflurane is given using oxygen alone. If added relaxation is required, supplemental doses of muscle relaxants 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.
Warnings & Precautions
WARNINGS Perioperative Hyperkalemia Use of inhaled anesthetic 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. Malignant Hyperthermia In susceptible individuals, isoflurane anesthesia may trigger a skeletal muscle hypermetabolic state leading to 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 cannister). PaO 2 and pH may decrease, and hyperkalemia and a base deficit may appear. Treatment includes discontinuance of triggering agents (e.g., isoflurane), administration of intravenous dantrolene sodium, 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. (Consult prescribing information for dantrolene sodium intravenous for additional information on patient management). Renal failure may appear later, and urine flow should be sustained if possible. Since levels of anesthesia may be altered easily and rapidly, only vaporizers producing predictable concentrations should be used Hypotension and respiratory depression increase as anesthesia is deepened. Increased blood loss comparable to that seen with halothane has been observed in patients undergoing abortions. Isoflurane markedly increases cerebral blood flow at deeper levels of anesthesia. There may be a transient rise in cerebral spinal fluid pressure which is fully reversible with hyperventilation. Pediatric Neurotoxicity Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours. The clinical significance of these findings is not clear. However, based on the available data, 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 three years of age in humans (See PRECAUTIONS/ Pregnancy , Pediatric Use , and ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY ). Some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects. These studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness. Anesthetic and sedation drugs are a necessary part of the care of children and pregnant women needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other. Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks.
Contraindications
Known sensitivity to isoflurane, or to other halogenated agents. Known or suspected genetic susceptibility to malignant hyperthermia.
Adverse Reactions
Adverse reactions encountered in the administration of isoflurane are in general dose dependent extensions of pharmacophysiologic effects and include respiratory depression, hypotension and arrhythmias. Shivering, nausea, vomiting and ileus have been observed in the postoperative period. As with all other general anesthetics, transient elevations in white blood count have been observed even in the absence of surgical stress. See WARNINGS for information regarding malignant hyperthermia and elevated carboxyhemoglobin levels. During marketing, there have been rare reports of mild, moderate and severe (some fatal) post-operative hepatic dysfunction and hepatitis. Isoflurane has also been associated with perioperative hyperkalemia (see WARNINGS ). Post-Marketing Events The following adverse events have been identified during post-approval use of isoflurane, USP. Due to the spontaneous nature of these reports, the actual incidence and relationship of isoflurane, USP to these events cannot be established with certainty. Cardiac Disorders : Cardiac arrest Hepatobiliary Disorders : Hepatic necrosis, Hepatic failure.
Drug Interactions
Isoflurane potentiates the muscle relaxant effect of all muscle relaxants, most notably nondepolarizing muscle relaxants, and MAC (minimum alveolar concentration) is reduced by concomitant administration of N 2 O. See CLINICAL PHARMACOLOGY .
Storage & Handling
Storage Store at controlled room temperature 15° - 30°C (59° - 86°F) (see USP). Isoflurane contains no additives and has been demonstrated to be stable at room temperature for a period in excess of five years.
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