Suprane Drug Information

Induction of Anesthesia SUPRANE is indicated as an inhalation agent for induction of anesthesia for inpatient and outpatient surgery in adults. SUPRANE is contraindicated as an inhalation agent for the induction of anesthesia in pediatric patients because of a high incidence of moderate to severe upper airway adverse events.

After induction of anesthesia with agents other than SUPRANE, and tracheal intubation, SUPRANE is indicated for maintenance of anesthesia in infants and children. SUPRANE is not approved for maintenance of anesthesia in non-intubated children due to an increased incidence of respiratory adverse reactions, including coughing, laryngospasm, and secretions.

Preanesthetic Medication

Issues such as whether or not to premedicate and the choice of premedication(s) must be individualized. In clinical studies, patients scheduled to be anesthetized with SUPRANE frequently received IV preanesthetic medication, such as opioid and/or benzodiazepine.

Induction

In adults, some premedicated with opioid, a frequent starting concentration was 3% SUPRANE, increased in 0.5-1.0% increments every 2 to 3 breaths. When SUPRANE was tested as the primary anesthetic induction agent, the incidence of upper airway irritation (apnea, breathholding, laryngospasm, coughing and secretions) was high. During induction in adults, the overall incidence of oxyhemoglobin desaturation (SpO 2 < 90%) was 6%.

After induction in adults with an intravenous drug such as thiopental or propofol, SUPRANE can be started at approximately 0.5-1 MAC, whether the carrier gas is O 2 or N 2 O/O 2. Inspired concentrations of SUPRANE greater than 12% have been safely administered to patients, particularly during induction of anesthesia. Such concentrations will proportionately dilute the concentration of oxygen; therefore, maintenance of an adequate concentration of oxygen may require a reduction of nitrous oxide or air if these gases are used concurrently.

Maintenance

Surgical levels of anesthesia in adults may be maintained with concentrations of 2.5-8.5% SUPRANE with or without the concomitant use of nitrous oxide. During the maintenance of anesthesia with inflow rates of 2 L/min or more, the alveolar concentration of SUPRANE will usually be within 10% of the inspired concentration. During the maintenance of anesthesia, increasing concentrations of SUPRANE produce dose-dependent decreases in blood pressure.

Excessive decreases in blood pressure may be due to depth of anesthesia and in such instances may be corrected by decreasing the inspired concentration of SUPRANE. Concentrations of SUPRANE exceeding 1 MAC may increase heart rate. Thus with this drug, an increased heart rate may not serve reliably as a sign of inadequate anesthesia.

Maintenance of Anesthesia in Intubated Pediatric Patients SUPRANE is indicated for maintenance of anesthesia in infants and children after induction of anesthesia with agents other than SUPRANE, and tracheal intubation. The concentration of SUPRANE required for maintenance of general anesthesia is age-dependent. Heart rate during maintenance of anesthesia is approximately 10 beats per minute faster with SUPRANE than with halothane.

Patients were judged fit for discharge from post-anesthesia care units within one hour with both SUPRANE and halothane. There were no differences in the incidence of nausea and vomiting between patients receiving SUPRANE or halothane.

Recovery

The recovery from general anesthesia should be assessed carefully before patients are discharged from the post anesthesia care unit (PACU).

Use in Patients with Coronary Artery Disease

In patients with coronary artery disease, maintenance of normal hemodynamics is important to prevent myocardial ischemia. A rapid increase in desflurane concentration is associated with marked increase in pulse rate, mean arterial pressure and levels of epinephrine and norepinephrine. SUPRANE should not be used as the sole agent for anesthetic induction in patients with coronary artery disease or patients where increases in heart rate or blood pressure are undesirable.

It should be used with other medications, preferably intravenous opioids and hypnotics.

Neurosurgical Use SUPRANE may produce a dose-dependent increase in cerebrospinal fluid pressure (CSFP) when administered to patients with intracranial space occupying lesions. SUPRANE should be administered at 0.8 MAC or less, and in conjunction with a barbiturate induction and hyperventilation (hypocapnia) until cerebral decompression in patients with known or suspected increases in CSFP. Appropriate attention must be paid to maintain cerebral perfusion pressure.

Observations Related to Vaporizer Use

Yellow discoloration of SUPRANE sometimes accompanied by particulates, has been observed through the vaporizer sight glass or after draining the vaporizer. The presence of discoloration or particulates in these situations does not alter the quality or efficacy of SUPRANE. If observed, refer to the respective vaporizer Instructions For Use (IFU) for recommended actions or contact Baxter Product Surveillance.

Clinical Trials Experience

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. Adverse event information is derived from controlled clinical trials, the majority of which were conducted in the United States. The studies were conducted using a variety of premedications, other anesthetics, and surgical procedures of varying length.

Most adverse events reported were mild and transient, and may reflect the surgical procedures, patient characteristics (including disease) and/or medications administered. The frequencies given reflect the percent of patients with the event. Each patient was counted once for each type of adverse event.

They are presented in alphabetical order according to body system. Table 2

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of SUPRANE. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: Coagulopathy Metabolism and Nutrition Disorders: Hyperkalemia, Hypokalemia, metabolic acidosis Psychiatric Disorders: Delirium Nervous System Disorders: Convulsion, Post-operative agitation in children Eye Disorders: Ocular icterus Cardiac Disorders: Cardiac arrest, electrocardiogram QT prolonged, torsade de pointes, ventricular failure, ventricular hypokinesia, atrial fibrillation Vascular Disorders: Malignant hypertension, hemorrhage, hypotension, shock Respiratory, Thoracic and Mediastinal Disorders: Respiratory arrest, respiratory failure, respiratory distress, bronchospasm, hemoptysis Gastrointestinal Disorders: Pancreatitis acute, abdominal pain Hepatobiliary Disorders: Hepatic failure, hepatic necrosis, hepatitis, cytolytic hepatitis, cholestasis, jaundice, hepatic function abnormal, liver disorder Skin and Subcutaneous Tissue Disorder: Urticaria, erythema Musculoskeletal, Connective Tissue and Bone Disorders: Rhabdomyolysis General Disorders and Administration Site Conditions: Hyperthermia malignant, asthenia, malaise Investigations: Electrocardiogram ST-T change, electrocardiogram T-wave inversion, tranaminases increased, alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, coagulation test abnormal, ammonia increased Injury, Poisoning, and Procedural Complications*: Tachyarrhythmia, palpitations, eye burns, blindness transient, encephalopathy, ulcerative keratitis, ocular hyperemia, visual acuity reduced, eye irritation, eye pain, dizziness, migraine, fatigue, accidental exposure, skin burning sensation, drug administration error *Reactions categorized within this System Organ Class (SOC) were accidental exposures to non-patients.

Benzodiazepines and Opioids (MAC Reduction) Benzodiazepines and opioids decrease the amount of desflurane (MAC) needed to produce anesthesia. This effect is shown in Table 3 for intravenous midazolam (25-50 µg/kg) and intravenous fentanyl (3-6 µg/kg) in patients of two different age groups. The effect of desflurane on duration of nondepolarizing neuromuscular blockade has not been studied.

Table 4 Dosage reduction of neuromuscular blocking agents during induction of anesthesia may result in delayed onset of conditions suitable for endotracheal intubation or inadequate muscle relaxation, because potentiation of neuromuscular blocking agents requires equilibration of muscle with the delivered partial pressure of SUPRANE. Among nondepolarizing drugs, pancuronium, atracurium, and vecuronium interactions have been studied. In the absence of specific guidelines: 1.

For endotracheal intubation, do not reduce the dose of nondepolarizing muscle relaxants or succinylcholine. 2. During maintenance of anesthesia, the dose of nondepolarizing muscle relaxants is likely to be reduced compared to that during N 2 O/opioid anesthesia. Administration of supplemental doses of muscle relaxants should be guided by the response to nerve stimulation.

Concomitant use with N 2 O

Concomitant administration of N 2 O reduces the MAC of SUPRANE.

Pregnancy Risk Summary There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, embryo-fetal toxicity (reduced viable fetuses and/or increased post-implantation loss) was noted in pregnant rats and rabbits administered 1 MAC desflurane for 4 hours a day (4 MAC-hours/day) during organogenesis. Published studies in pregnant primates demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of peak brain development increases neuronal apoptosis in the developing brain of the offspring when used for longer than 3 hours.

There are no data on pregnancy exposures in primates corresponding to periods prior to the third trimester in humans. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15- 20%, respectively. Clinical Considerations Labor or Delivery The safety of SUPRANE during labor or delivery has not been demonstrated. SUPRANE is a uterine-relaxant.

Embryo-fetal toxicity (increased post-implantation loss and reduced viable fetuses) was noted in the 4 hour treatment group in the presence of maternal toxicity (reduced body weight gain). There was no evidence of malformations in any group. Pup body weights were reduced in the 4 hours per day group in the presence of maternal toxicity (increased mortality and reduced body weight gain).

This study did not evaluate neurobehavioral function including learning and memory or reproductive behavior in the first generation (F1) pups. In a published study in primates, administration of an anesthetic dose of ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing brain of the fetus. In other published studies, administration of either isoflurane or propofol for 5 hours on Gestation Day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing brain of the offspring.

With respect to brain development, this time period corresponds to the third trimester of gestation in the human. The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits.

Pediatric Use Respiratory Adverse Reactions in Pediatric Patients SUPRANE is indicated for maintenance of anesthesia in infants and children after induction of anesthesia with agents other than SUPRANE, and tracheal intubation. Is not approved for maintenance of anesthesia in non-intubated children due to an increased incidence of respiratory adverse reactions, including coughing (26%), laryngospasm (13%) and secretions (12%). Children, particularly if 6 years old or younger, who are under an anesthetic maintenance of SUPRANE delivered via laryngeal mask airway (LMA™ mask) are at increased risk for adverse respiratory reactions, e.g., coughing and laryngospasm, especially with removal of the laryngeal mask airway under deep anesthesia.

Therefore, closely monitor these patients for signs and symptoms associated with laryngospasm and treat accordingly. When SUPRANE is used for maintenance of anesthesia in children with asthma or a history of recent upper airway infection, there is an increased risk for airway narrowing and increases in airway resistance. Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as SUPRANE, that either block NMDA receptors or potentiate the activity of GABA during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis.

Based on comparisons across species, 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 3 years of age in humans. In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss. Data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory.

The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in pregnant women, neonates, and young children who require procedures with the potential risks suggested by the nonclinical data.

• The use of SUPRANE is contraindicated in the following conditions:
• Known or suspected genetic susceptibility to malignant hyperthermia.
• Patients in whom general anesthesia is contraindicated.
• Induction of anesthesia in pediatric patients.
• Patients with known sensitivity to SUPRANE or to other halogenated agents.
• Patients with a history of moderate to severe hepatic dysfunction following anesthesia with SUPRANE or other halogenated agents and not otherwise explained.
• Patients with known or suspected genetic susceptibility to malignant hyperthermia
• Patients with known sensitivity to halogenated agents

The symptoms of overdosage of SUPRANE 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 suspected overdosage, take the following actions: discontinue administration of SUPRANE, maintain a patent airway, initiate assisted or controlled ventilation with oxygen, and maintain adequate cardiovascular function.