Kenyan Health Patient Information Leaflet
General Anesthetic [EPC]
1 INDICATIONS AND USAGE Isoflurane USP 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, a general anesthetic, is an inhalation agent indicated for induction and maintenance of general anesthesia. ( 1 )
• Isoflurane USP should be administered only by persons trained in the administration of general anesthesia. Isoflurane USP 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, 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 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 1 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. Isoflurane 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.
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 Piramal Critical Care, Inc. at 1-888-822-8431 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. 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 ³ 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 observed, but due to limited data, frequency could not be determined. Table 5: Adverse Reactions with Unknown Frequency BLOOD AND LYMPHATIC SYSTEM DISORDERS: White blood cell count increased METABOLISM AND NUTRITION DISORDERS: Blood glucose increased PSYCHIATRIC DISORDERS: Confused state, Nervousness NERVOUS SYSTEM DISORDERS: Ataxia; Dizziness; Drowsiness; Intellectual function decrease VASCULAR DISORDERS: Hypotension (Intraoperative); Hypertension (Intraoperative) HEPATOBILIARY DISORDERS: Blood bilirubin increased; Bromsulphthalein clearance decreased; Alanine aminotransferase increased; Aspartate aminotransferase increased; Blood alkaline phosphatase increased; Blood lactate dehydrogenase increased MUSCULOSKELETAL, CONNECTIVE TISSUE AND BONE DISORDERS: Myalgia GENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONS: Asthenia; Fatigue 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of Isoflurane USP. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Post-marketing adverse reactions are listed by MedDRA System Organ Class (SOC), then by preferred term in order of decreasing severity. BLOOD AND LYMPHATIC SYSTEM DISORDERS: Carboxyhemoglobin increased IMMUNE SYSTEM DISORDERS: Anaphylactic reaction METABOLISM AND NUTRITION DISORDERS: Hyperkalemia in patients with underlying myopathies PSYCHIATRIC DISORDERS: Withdrawal syndrome (following multi-day exposure; symptoms include seizure, hallucination, ataxia, agitation, confusion) NERVOUS SYSTEM DISORDERS: Brain edema, Intracranial pressure increased, Migraine, Myoclonus, Nystagmus, Pupils unequal, Headache CARDIAC DISORDERS: Cardiac arrest, Ventricular fibrillation, Torsade de pointes, Myocardial infarction, Myocardial ischemia, Atrioventricular block complete, Atrioventricular block second degree, Atrial fibrillation, Electrocardiogram QT prolonged, Atrioventricular block first degree, Ventricular tachycardia, Ventricular extrasystoles, Tachycardia, Bradycardia, Cardiac output decreased VASCULAR DISORDERS: Flushing RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS: Apnea, Hypoxia, Bronchospasm, Airway obstruction, Respiratory depression, Hypercapnia, Stridor, Hiccough GASTROINTESTINAL DISORDERS: Pancreatitis HEPATOBILIARY DISORDERS: Hepatic necrosis, Hepatic failure, Hepatitis fulminant, Cholestatic hepatitis, Hepatitis, Hepatic steatosis, Jaundice, Gamma- glutamyltransferase increased SKIN AND SUBCUTANEOUS TISSUE DISORDERS: Rash MUSCULOSKELETAL, CONNECTIVE TISSUE AND BONE DISORDERS: Rhabdomyolysis RENAL AND URINARY DISORDERS: Acute renal failure**, Oliguria** GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: Malignant hyperthermia, hypothermia INJURY, POISONING, AND PROCEDURAL COMPLICATIONS*: Unwanted awareness during anesthesia; Dyspnea, Bronchospasm, Stridor, Cough, Dizziness, Paresthesia, Hepatic reactions, Flushing, Rash, Contact dermatitis, Erythema, Periorbital edema, Eye irritation, Conjunctival hyperemia, Headache *All reactions categorized within this SOC, with the exception of, Unwanted awareness during anesthesia, were from occupational exposure in non-patients. **Cases of acute renal failure and oliguria have been reported after isoflurane anesthesia. These events may be secondary to hypotension or other effects of isoflurane.
16 HOW SUPPLIED/STORAGE AND HANDLING Isoflurane 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 [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 Storage Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. 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.