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)
Bradycardia 5%, Hypotension 4%, Tachycardia 2%
Laryngospasm 8%, Airway obstruction 8%, Breathholding 5%, Cough Increased 5%
Pediatric Patients (N = 507)
Tachycardia 6%, Hypotension 4%
Breathholding 5%, Cough Increased 5%, Laryngospasm 3%, Apnea 2%
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%
Hypotension 11%, Hypertension 2%, Bradycardia 5%, Tachycardia 2%
Somnolence 9%, Agitation 9%, Dizziness 4%, Increased salivation 4%
Nausea 25%, Vomiting 18%
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
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
Crying, Nervousness, Confusion, Hypertonia, Dry Mouth, Insomnia
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
Skin and Special Senses
Amblyopia, Pruritus, Taste Perversion, Rash, Conjunctivitis
Urination Impaired, Urine Abnormality, Urinary Retention, Oliguria
See WARNINGS for information regarding malignant hyperthermia.
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.
• Cardiac arrest
• QT prolongation associated with Torsade de Pointe
• Bradycardia in patients with Down syndrome
• 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
• 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).
• Transient elevations in glucose, liver function tests, and white blood cell count may occur as with use of other anesthetic agents.
In the event of overdosage, or what may appear to be overdosage, the following action should be taken: discontinue administration of sevoflurane, maintain a patent airway, initiate assisted or controlled ventilation with oxygen, and maintain adequate cardiovascular function.
The concentration of sevoflurane being delivered from a vaporizer should be known. This may be accomplished by using a vaporizer calibrated specifically for sevoflurane. The administration of general anesthesia must be individualized based on the patient’s response.
Replacement of Desiccated CO 2 Absorbents
When a clinician suspects that the CO 2 absorbent may be desiccated, it should be replaced. The exothermic reaction that occurs with sevoflurane and CO 2 absorbents is increased when the CO 2 absorbent becomes desiccated, such as after an extended period of dry gas flow through the CO 2 absorbent canisters (see PRECAUTIONS).
No specific premedication is either indicated or contraindicated with sevoflurane. The decision as to whether or not to premedicate and the choice of premedication is left to the discretion of the anesthesiologist.
Sevoflurane has a nonpungent odor and does not cause respiratory irritability; it is suitable for mask induction in pediatrics and adults.
Surgical levels of anesthesia can usually be achieved with concentrations of 0.5 — 3% sevoflurane with or without the concomitant use of nitrous oxide. Sevoflurane can be administered with any type of anesthesia circuit.
Table 9. MAC Values for Adults and Pediatric Patients According to Age
Age of Patient (years)
Sevoflurane in Oxygen
Sevoflurane in 65% N 2 O/35% O 2
0 — 1 months #
1 — < 6 months
6 months — < 3 years
3 — 12
# Neonates are full-term gestational age. MAC in premature infants has not been determined.
@ In 1 — < 3 year old pediatric patients, 60% N 2 O/40% O 2 was used.
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