General Anesthetic

Sojourn

Approved 2 May 2007InhalationLiquid

Indications

Sevoflurane, USP is indicated for induction and maintenance of general anesthesia in adult and pediatric patients for inpatient and outpatient surgery. Sevoflurane, USP 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. Since level of anesthesia may be altered rapidly, only vaporizers producing predictable concentrations of sevoflurane, USP should be used.

Contraindications

Known or suspected genetic susceptibility to malignant hyperthermia. (see WARNINGS - Malignant Hyperthermia , CLINICAL PHARMACOLOGY - Pharmacogenomics ).
Known or suspected sensitivity to sevoflurane or to other halogenated inhalational anesthetics.

Warnings and precautions

Risk of Renal Injury Although data from controlled clinical studies at low flow rates are limited, findings taken from patient and animal studies suggest that there is a potential for renal injury which is presumed due to Compound A. Animal and human studies demonstrate that sevoflurane administered for more than 2 MAC·hours and at fresh gas flow rates of < 2 L/min may be associated with proteinuria and glycosuria. While a level of Compound A exposure at which clinical nephrotoxicity might be expected to occur has not been established, it is prudent to consider all of the factors leading to Compound A exposure in humans, especially duration of exposure, fresh gas flow rate, and concentration of sevoflurane.

During sevoflurane anesthesia the clinician should adjust inspired concentration and fresh gas flow rate to minimize exposure to Compound A. To minimize exposure to Compound A, sevoflurane exposure should not exceed 2 MAC·hours at flow rates of 1 to < 2 L/min. Fresh gas flow rates < 1 L/min are not recommended. Because clinical experience in administering sevoflurane to patients with renal insufficiency (creatinine >1.5 mg/dL) is limited, its safety in these patients has not been established.

Sevoflurane may be associated with glycosuria and proteinuria when used for long procedures at low flow rates. The safety of low flow sevoflurane on renal function was evaluated in patients with normal preoperative renal function. One study compared sevoflurane (N = 98) to an active control (N = 90) administered for ≥ 2 hours at a fresh gas flow rate of ≤ 1 Liter/minute. Per study defined criteria, one patient in the sevoflurane group developed elevations of creatinine, in addition to glycosuria and proteinuria.

At a glance

Brand name: Sojourn
Active substance: sevoflurane
Pharmacologic class: General Anesthetic
Route: Inhalation
Dosage form: Liquid
Applicant: Piramal Critical
Status: Prescription
FDA approval: 2 May 2007
Application: ANDA077867-001

Indications

Warnings and precautions

Interactions

Drug Interactions In clinical studies, no significant adverse reactions occurred with other drugs commonly used in the perioperative period, including central nervous system depressants, autonomic drugs, skeletal muscle relaxants, anti-infective agents, hormones and synthetic substitutes, blood derivatives, and cardiovascular drugs. Epinephrine Epinephrine administered with sevoflurane may increase the risk of ventricular arrhythmias.

Monitor the electrocardiogram and blood pressure and ensure emergency medications to treat ventricular arrhythmias are readily available. Calcium antagonists Sevoflurane may lead to marked hypotension in patients treated with calcium antagonists. Blood pressure should be closely monitored and emergency medications to treat hypotension should be readily available when calcium antagonists are used concomitantly with sevoflurane.

In animals, impairment of atrioventricular conduction has been observed when verapamil and sevoflurane are administered concomitantly. Succinylcholine See WARNINGS - Perioperative Hyperkalemia . Non-selective MAO-inhibitors Concomitant use of MAO inhibitors and inhalational anesthetics may increase the risk of hemodynamic instability during surgery or medical procedures. Intravenous Anesthetics Sevoflurane administration is compatible with barbiturates, propofol, and other commonly used intravenous anesthetics.

Benzodiazepines and Opioids Benzodiazepines and opioids would be expected to decrease the MAC of sevoflurane in the same manner as with other inhalational anesthetics. Sevoflurane administration is compatible with benzodiazepines and opioids as commonly used in surgical practice. Nitrous Oxide As with other halogenated volatile anesthetics, the anesthetic requirement for sevoflurane is decreased when administered in combination with nitrous oxide.

Using 50% N 2 O, the MAC equivalent dose requirement is reduced approximately 50% in adults, and approximately 25% in pediatric patients (see DOSAGE AND ADMINISTRATION ). Neuromuscular Blocking Agents As is the case with other volatile anesthetics, sevoflurane increases both the intensity and duration of neuromuscular blockade induced by nondepolarizing muscle relaxants. When used to supplement alfentanil-N 2 O anesthesia, sevoflurane and isoflurane equally potentiate neuromuscular block induced with pancuronium, vecuronium or atracurium.

Therefore, during sevoflurane anesthesia, the dosage adjustments for these muscle relaxants are similar to those required with isoflurane. Potentiation of neuromuscular blocking agents requires equilibration of muscle with delivered partial pressure of sevoflurane. Reduced doses of neuromuscular blocking agents during induction of anesthesia may result in delayed onset of conditions suitable for endotracheal intubation or inadequate muscle relaxation.

Among available nondepolarizing agents, only vecuronium, pancuronium and atracurium interactions have been studied during sevoflurane anesthesia. In the absence of specific guidelines: 1. For endotracheal intubation, do not reduce the dose of nondepolarizing muscle relaxants. 2. During maintenance of anesthesia, the required 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. The effect of sevoflurane on the duration of depolarizing neuromuscular blockade induced by succinylcholine has not been studied.

Pregnancy and breastfeeding

Pregnancy Risk Summary There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, reduced fetal weights were noted following exposure to 1 MAC sevoflurane for three hours a day during organogenesis. Developmental and reproductive toxicity studies of sevoflurane in animals in the presence of strong alkalies (i.e., degradation of sevoflurane and production of Compound A) have not been conducted.

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. Data Animal Data Pregnant rats were treated with sevoflurane (0.22%, 0.66%, or 2.2% equals 0.1, 0.3, or

1.0MAC) without CO

2 absorbent for three hours per day during organogenesis (from Gestation Day 7 to 17). Fetuses obtained by Cesarean section were examined on Gestation Day 20 while some animals were maintained for littering and pups were examined for adverse effects. There were no adverse effects on fetuses at

0.3MAC.

Reduced fetal body weights and increased skeletal variations such as delayed ossifications in the presence of maternal toxicity (reduced food and water intake and body weight of the dams) were noted at 1 MAC. In dams allowed to litter, reduced pup bodyweight gain and evidence of developmental delays (slight delay in eyelid opening and increased incidence of nonreactive animals in the visual placing reflex test) were noted in the

1.0 MAC treatment group. Pregnant rabbits were treated with sevoflurane (0.1, 0.3, or

1.0MAC) without CO

2 absorbent for three hours per day during organogenesis (from Gestation Day 6 to 18). There were no adverse effects on the fetus at any dose; the mid- and high-dose produced a 5% and 6% decrease in maternal body weight, respectively. In another study, pregnant rats were administered sevoflurane (0.1, 0.3, or

1.0MAC) from Gestation Day 17 to Postnatal Day 21.

Pup body weights were reduced in the

1.0 MAC treatment group in the absence of maternal toxicity. There was no effect of sevoflurane on sensory function (visual, auditory, nociception, righting reflexes), motor (roto-rod), open field test, or learning tasks (shuttle box avoidance and water T-maze). 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 (see WARNINGS – Pediatric Neurotoxicity, PRECAUTIONS – Pediatric Use, ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY ).

Adverse reactions

Clinical Trials Experience Adverse events are derived from controlled clinical studies conducted in the United States, Canada, and Europe. The reference drugs were isoflurane, enflurane, and propofol in adults and halothane in pediatric patients. 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.

Of the 5182 patients enrolled in the clinical studies, 2906 were exposed to sevoflurane, including 118 adults and 507 pediatric patients who underwent mask induction. Each patient was counted once for each type of adverse event. Adverse events reported in patients in clinical studies and considered to be possibly or probably related to sevoflurane are presented within each body system in order of decreasing frequency in the following listings.

One case of malignant hyperthermia was reported in pre-registration clinical studies. Adverse Events During the Induction Period (from Onset of Anesthesia by Mask Induction to Surgical Incision) Incidence >1% Adult Patients (N = 118) Cardiovascular Bradycardia 5%, Hypotension 4%, Tachycardia 2% Nervous System Agitation 7% Respiratory System Laryngospasm 8%, Airway obstruction 8%, Breathholding 5%, Cough Increased 5% Pediatric Patients (N = 507) Cardiovascular Tachycardia 6%, Hypotension 4% Nervous System Agitation 15% Respiratory System Breathholding 5%, Cough Increased 5%, Laryngospasm 3%, Apnea 2% Digestive System Increased salivation 2% Adverse Events During Maintenance and Emergence Periods, Incidence > 1% (N = 2906) Body as a whole Fever 1%, Shivering 6%, Hypothermia 1%, Movement 1%, Headache 1% Cardiovascular Hypotension 11%, Hypertension 2%, Bradycardia 5%, Tachycardia 2% Nervous System Somnolence 9%, Agitation 9%, Dizziness 4%, Increased salivation 4% Digestive System Nausea 25%, Vomiting 18% Respiratory System Cough increased 11%, Breathholding 2%, Laryngospasm 2% Adverse Events, All Patients in Clinical Studies (N = 2906), All Anesthetic Periods, Incidence < 1% (Reported in 3 or More Patients) Body as a whole Asthenia, Pain Cardiovascular Arrhythmia, Ventricular Extrasystoles, Supraventricular Extrasystoles, Complete AV Block, Bigeminy, Hemorrhage, Inverted T Wave, Atrial Fibrillation, Atrial Arrhythmia, Second Degree AV Block, Syncope, S-T Depressed Nervous System Crying, Nervousness, Confusion, Hypertonia, Dry Mouth, Insomnia Respiratory System Sputum Increased, Apnea, Hypoxia, Wheezing, Bronchospasm, Hyperventilation, Pharyngitis, Hiccup, Hypoventilation, Dyspnea, Stridor Metabolism and Nutrition Increases in LDH, AST, ALT, BUN, Alkaline Phosphatase, Creatinine, Bilirubinemia, Glycosuria, Fluorosis, Albuminuria, Hypophosphatemia, Acidosis, Hyperglycemia Hemic and Lymphatic System Leucocytosis, Thrombocytopenia Skin and Special Senses Amblyopia, Pruritus, Taste Perversion, Rash, Conjunctivitis Urogenital Urination Impaired, Urine Abnormality, Urinary Retention, Oliguria See WARNINGS for information regarding malignant hyperthermia.

Post-Marketing Experience The following adverse events have been identified during post-approval use of sevoflurane. Due to the spontaneous nature of these reports, the actual incidence and relationship of sevoflurane to these events cannot be established with certainty. Central Nervous System

Seizures - Post-marketing reports indicate that sevoflurane use has been associated with seizures. The majority of cases were in children and young adults, most of whom had no medical history of seizures. Several cases reported no concomitant medications, and at least one case was confirmed by EEG. Although many cases were single seizures that resolved spontaneously or after treatment, cases of multiple seizures have also been reported. Seizures have occurred during, or soon after sevoflurane induction, during emergence, and during post-operative recovery up to a day following anesthesia.
Delirium Cardiac
Cardiac arrest
QT prolongation associated with Torsade de Pointe
Bradycardia in patients with Down syndrome Hepatic
Cases of mild, moderate and severe post-operative hepatic dysfunction or hepatitis with or without jaundice have been reported. Histological evidence was not provided for any of the reported hepatitis cases. In most of these cases, patients had underlying hepatic conditions or were under treatment with drugs known to cause hepatic dysfunction. Most of the reported events were transient and resolved spontaneously (see PRECAUTIONS ).
Hepatic necrosis
Hepatic failure Other
Malignant hyperthermia (see CONTRAINDICATIONS, WARNINGS )
Allergic reactions, such as rash, urticaria, pruritus, bronchospasm, and anaphylactic reactions (see CONTRAINDICATIONS )
Reports of hypersensitivity (including contact dermatitis, rash, dyspnea, wheezing, chest discomfort, swelling face, or anaphylactic reaction) have been received, particularly in association with long-term occupational exposure to inhaled anesthetic agents, including sevoflurane (see SAFETY AND HANDLING - Occupational Caution ). Laboratory Findings
Transient elevations in glucose, liver function tests, and white blood cell count may occur as with use of other anesthetic agents.

Sojourn

Indications

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

Sojourn

Indications

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

Interactions

Pregnancy and breastfeeding

1.0MAC) without CO

0.3MAC.

1.0MAC) without CO

1.0MAC) from Gestation Day 17 to Postnatal Day 21.

Adverse reactions

Composition

Official product information