FORANE (isoflurane, USP) liquid for inhalation

FORANE (isoflurane, USP) liquid for inhalation

FORANE (isoflurane, USP), a nonflammable liquid administered by vaporizing, is a general inhalation anesthetic drug. It is 1-chloro-2,2,2-trifluoroethyl difluoromethyl ether.

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.

CLINICAL PHARMACOLOGY

Induction of and recovery from isoflurane anesthesia are rapid. Isoflurane has a mild pungency which limits the rate of induction, although excessive salivation or tracheobronchial secretions do not appear to be stimulated. Pharyngeal and laryngeal reflexes are readily obtunded. The level of anesthesia may be changed rapidly with isoflurane. Isoflurane is a profound respiratory depressant. As anesthetic dose is increased, tidal volume decreases and respiratory rate is unchanged. This depression is partially reversed by surgical stimulation, even at deeper levels of anesthesia. Isoflurane evokes a sigh response reminiscent of that seen with diethyl ether and enflurane, although the frequency is less than with enflurane.

Blood pressure decreases with induction of anesthesia but returns toward normal with surgical stimulation. Progressive increases in depth of anesthesia produce corresponding decreases in blood pressure. Nitrous oxide diminishes the inspiratory concentration of isoflurane required to reach a desired level of anesthesia and may reduce the arterial hypotension seen with isoflurane alone. Heart rhythm is remarkably stable. With controlled ventilation and normal PaCO2, cardiac output is maintained despite increasing depth of anesthesia, primarily through an increase in heart rate which compensates for a reduction in stroke volume. The hypercapnia which attends spontaneous ventilation during isoflurane anesthesia further increases heart rate and raises cardiac output above awake levels.

Muscle relaxation is often adequate for intra-abdominal operations at normal levels of anesthesia. Complete muscle paralysis can be attained with small doses of muscle relaxants. ALL COMMONLY USED MUSCLE RELAXANTS ARE MARKEDLY POTENTIATED WITH ISOFLURANE, THE EFFECT BEING MOST PROFOUND WITH THE NONDEPOLARIZING TYPE. Neostigmine reverses the effect of nondepolarizing muscle relaxants in the presence of isoflurane. All commonly used muscle relaxants are compatible with isoflurane.

Isoflurane can produce coronary vasodilation at the arteriolar level in selected animal models; the drug is probably also a coronary dilator in humans. Isoflurane, like some other coronary arteriolar dilators, has been shown to divert blood from collateral dependent myocardium to normally perfused areas in an animal model (“coronary steal”). Clinical studies to date evaluating myocardial ischemia, infarction and death as outcome parameters have not established that the coronary arteriolar dilation property of isoflurane is associated with coronary steal or myocardial ischemia in patients with coronary artery disease.

INDICATIONS AND USAGE

FORANE may be used for induction and maintenance of general anesthesia. Adequate data have not been developed to establish its application in obstetrical anesthesia.

CONTRAINDICATIONS

Isoflurane is contraindicated in patients:

  • in whom general anesthesia is contraindicated.
  • with known sensitivity to FORANE 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.

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.

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 CO2 absorption system (hot canister). PaO2 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.

Hepatic Reactions

Cases of mild, moderate and severe postoperative hepatic dysfunction or hepatitis with or without jaundice, including fatal hepatic necrosis and hepatic failure, have been reported with isoflurane.

Such reactions can represent hypersensitivity hepatitis, a known risk of exposure to halogenated anesthetics, including isoflurane. As with other halogenated anesthetic agents, FORANE may cause sensitivity hepatitis in patients who have been sensitized by previous exposure to halogenated anesthetics

Hypersensitivity Reactions

Allergic-type hypersensitivity reactions, including anaphylaxis, have been reported with isoflurane. Manifestations of such reactions have included hypotension, rash, difficulty breathing and cardiovascular collapse

Abortions

Increased blood loss comparable to that seen with halothane has been observed in patients undergoing abortions.

QTc Prolongation

QTc prolongation, with rare instances of torsade de pointes, have been reported. Monitor QT interval when administering isoflurane to susceptible patients.

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.

PRECAUTIONS

As with any potent general anesthetic, FORANE should only be administered in an adequately equipped anesthetizing environment by those who are familiar with the pharmacology of the drug and qualified by training and experience to manage the anesthetized patient.

All patients anesthetized with isoflurane should be continually monitored (e.g., monitoring of the electrocardiogram, blood pressure, oxygen saturation, and end tidal CO2). 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.

With the exception of neonates, isoflurane MAC decreases with increasing age.

Regardless of the anesthetics employed, maintenance of normal hemodynamics is important to the avoidance of myocardial ischemia in patients with coronary artery disease.

Effect of anesthetic and sedation drugs on early brain development: Studies conducted in young animals and children suggest repeated or prolonged use of general anesthetic or sedation drugs in children younger than 3 years may have negative effects on their developing brains. Discuss with parents and caregivers the benefits, risks, and timing and duration of surgery or procedures requiring anesthetic and sedation drugs.

Laboratory Tests: Transient increases in BSP retention, blood glucose and serum creatinine with decrease in BUN, serum cholesterol and alkaline phosphatase have been observed.

Drug Interactions:

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.

Nitrous oxide decreases the MAC of isoflurane

Isoflurane potentiates the muscle relaxant effect of all muscle relaxants and decreases the required doses of neuromuscular blocking agents. In general, anesthetic concentrations of isoflurane at equilibrium reduce the ED95 of succinylcholine, atracurium, pancuronium, rocuronium and vecuronium by approximately 25 to 40% or more compared to N2O/opioid anesthesia. If added relaxation is required, supplemental doses of muscle relaxants may be used.

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. Isoflurane may lead to marked hypotension in patients treated with calcium antagonists.

Concomitant use of beta blockers may exaggerate the cardiovascular effects of inhalational anesthetics, including hypotension and negative inotropic effects.

Concomitant use of MAO inhibitors and inhalational anesthetics may increase the risk of hemodynamic instability during surgery or medical procedures.

Use in specific populations

Pregnancy

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.

Nursing Mothers

Due to insufficient information regarding the excretion of isoflurane in human milk, the potential risks and benefits for each specific patient should be carefully considered before isoflurane is administered to nursing women.

Pediatric Use

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

Effects on Ability to Drive and Use Machines

Patients should be advised that performance of activities requiring mental alertness, such as driving a vehicle or operating machinery, may be impaired for some time after general anesthesia. Therefore, patients should not undertake hazardous tasks, such as driving, for at least 24 hours following administration of a general anesthetic.

ADVERSE REACTIONS

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, Gamma­glutamyltransferase 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.

OVERDOSAGE

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.

DOSAGE AND ADMINISTRATION

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.

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

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

Maintenance:

Isoflurane MAC values according to age are shown below:

AgeAverage MAC Value
In 100% Oxygen
Average MAC Value
In 30% Oxygen and 70% N2 O
Preterm neonates ˂32 weeks gestational age1.28% 
Preterm neonates 32-37 weeks gestational age1.41% 
0-1 month1.60% 
1-6 months1.87% 
6-12 months1.80% 
1-5 years1.60%
6-10 years1.45%
11-18 years1.38%
19-30 years1.28%0.56%
31-55 years1.15%0.50%
55-83 years1.05%0.37%

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