warnings and cautions
5 WARNINGS AND PRECAUTIONS • Malignant Hyperthermia : Malignant hyperthermia may occur, especially in individuals with known or suspected susceptibility based on genetic factors or family history. Discontinue triggering agents, administer intravenous dantrolene sodium, and apply supportive therapies. ( 5.1 ) • Perioperative Hyperkalemia : Perioperative hyperkalemia may occur. Patients with latent or overt neuromuscular disease, particularly with Duchenne muscular dystrophy, appear to be most vulnerable. Early, aggressive intervention is recommended. ( 5.2 ) • Hepatic Reactions : May cause sensitivity hepatitis in patients sensitized by previous exposure to halogenated anesthetics. Approach repeated anesthesia with caution. ( 5.3 ) • Hypersensitivity Reactions : Allergic-type hypersensitivity reactions, including anaphylaxis, have been reported with FORANE. ( 5.4 ) • Abortions : Increased blood loss comparable to that seen with halothane has been observed in patients undergoing abortions. ( 5.5 ) • QT Prolongation : Carefully monitor cardiac rhythm when administering FORANE to susceptible patients. ( 5.6 ) • Interactions with Desiccated Carbon Dioxide (CO 2 ) Absorbents : May react with desiccated CO 2 absorbents to produce carbon monoxide. Replace desiccated CO 2 absorbent before administration of FORANE. ( 5.7 ) • Pediatric Neurotoxicity : In developing animals, exposures greater than 3 hours cause neurotoxicity. Weigh benefits against potential risks when considering elective procedures in children under 3 years old. ( 5.8 ) 5.1 Malignant Hyperthermia In susceptible individuals, volatile anesthetic agents, including FORANE, may trigger malignant hyperthermia, a skeletal muscle hypermetabolic state leading to high oxygen demand. Fatal outcomes of malignant hyperthermia have been reported. The risk of developing malignant hyperthermia increases with the concomitant administration of succinylcholine and volatile anesthetic agents. FORANE can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history, including those with certain inherited ryanodine receptor ( RYR1 ) or dihydropyridine receptor ( CACNA1S ) variants [see Contraindications (4) , Clinical Pharmacology (12.5) ] . Signs consistent with malignant hyperthermia may include hyperthermia, hypoxia, hypercapnia, muscle rigidity (e.g., jaw muscle spasm), tachycardia (e.g., particularly that unresponsive to deepening anesthesia or analgesic medication administration), tachypnea, cyanosis, arrhythmias, hypovolemia, and hemodynamic instability. Skin mottling, coagulopathies, and renal failure may occur later in the course of the hypermetabolic process. Successful treatment of malignant hyperthermia depends on early recognition of the clinical signs. If malignant hyperthermia is suspected, discontinue all triggering agents (i.e., volatile anesthetic agents and succinylcholine), administer intravenous dantrolene sodium, and initiate supportive therapies. Consult prescribing information for intravenous dantrolene sodium for additional information on patient management. Supportive therapies include administration of supplemental oxygen and respiratory support based on clinical need, maintenance of hemodynamic stability and adequate urinary output, management of fluid and electrolyte balance, correction of acid base derangements, and institution of measures to control rising temperature. 5.2 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. 5.3 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 FORANE. Such reactions can represent hypersensitivity hepatitis, a known risk of exposure to halogenated anesthetics, including FORANE. As with other halogenated anesthetic agents, FORANE may cause sensitivity hepatitis in patients who have been sensitized by previous exposure to halogenated anesthetics [see Contraindications (4) ] . Clinical judgment should be exercised when FORANE is used in patients with underlying hepatic conditions or under treatment with drugs known to cause hepatic dysfunction [see Contraindications (4) ] . As with all halogenated anesthetics, repeated anesthetics within a short period of time may result in increased effects, particularly in patients with underlying hepatic conditions, or additive effects in patients treated with drugs known to cause hepatic dysfunction. Evaluate the need for repeated exposure in each individual patient and adjust the dose of FORANE based on signs and symptoms of adequate depth of anesthesia if repeated exposure in a short period of time is clinically indicated. 5.4 Hypersensitivity Reactions Allergic-type hypersensitivity reactions, including anaphylaxis, have been reported with FORANE. Manifestations of such reactions have included hypotension, rash, difficulty breathing and cardiovascular collapse 5.5 Abortions Increased blood loss comparable to that seen with halothane has been observed in patients undergoing abortions. 5.6 QT Prolongation QT prolongation, with rare instances of torsade de pointes, have been reported. Monitor QT interval when administering FORANE to susceptible patients (e.g., patients with congenital Long QT Syndrome or patients taking drugs that can prolong the QT interval). 5.7 Interactions with Desiccated Carbon Dioxide Absorbents FORANE, like some other inhalational anesthetics, can react with desiccated carbon dioxide (CO 2 ) absorbents to produce carbon monoxide, which may result in elevated levels of carboxyhemoglobin in some patients. Barium hydroxide lime and soda lime become desiccated when fresh gases are passed through the CO 2 absorber canister at high flow rates over many hours or days. When a clinician suspects that CO 2 absorbent may be desiccated, it should be replaced before the administration of FORANE. The color indicator of most CO 2 absorbents does not necessarily change as a result of desiccation. Therefore, the lack of significant color change should not be taken as assurance of adequate hydration of the CO 2 absorbent material. CO 2 absorbents should be replaced routinely regardless of the state of color indicator following current manufacturer’s guidelines for use of anesthesiology equipment. 5.8 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 Use in Specific Populations (8.1 , 8.4) , Nonclinical Toxicology (13.2) ] . 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 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. 5.9 Laboratory Tests Transient increases in BSP retention, blood glucose and serum creatinine with decrease in BUN, serum cholesterol and alkaline phosphatase have been observed.