Sevorane AF
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Sevorane AF - Scientific Information

Manufacture: AbbVie
Country: Canada
Condition: Surgery
Class: Analgesics
Form: Liquid solution, Inhaler
Ingredients: sevoflurane

Pharmaceutical Information

Drug Substance

Proper name:sevoflurane
Chemical name:fluoromethyl 2,2,2-trifluoro-l-(trifluoromethyl)ethyl ether
Molecular formula and molecular mass:C4H3F7O200.05
Structural formula:

Physicochemical properties:Sevoflurane, a nonflammable and nonexplosive liquid administered by vaporization, is a halogenated general inhalation anesthetic drug. Sevoflurane is nonpungent. It is miscible with ethanol, ether, chloroform and petroleum benzene, and it is slightly soluble in water.

Sevoflurane has the following physical and chemical properties:

Boiling Point at 760 mm Hg58.6°C
Specific Gravity at 20°C1.520 - 1.525
Vapor Pressure*157 mm Hg at 20°C
197 mm Hg at 25°C
317 mm Hg at 36°C
Distribution Partition Coefficients at 37°C:
Blood/Gas0.63 - 0.69
Olive Oil/Gas47.2 - 53.9
* Vapor pressure (mm Hg) is calculated using the equation: Log10Pvap = A+B/T, where A = 8.086; B = -1726.68; T = °C + 273.16°K (Kelvin)

Mean Component/Gas Partition Coefficients at 25°C for Polymers Used Commonly in Medical Applications:

Conductive rubber14.0
Butyl rubber7.7
Polyvinyl chloride17.4

Clinical Trials

Study Results

Cardiovascular Effects

SEVORANE AF (sevoflurane) was studied in 14 healthy volunteers (18 to 35 years old) comparing sevoflurane-O2 (Sevo/O2) to sevoflurane-O2/N2O (Sevo/O2/N2O) during 7 hours of anesthesia. During controlled ventilation, hemodynamic parameters measured are shown in, Figure 1, Figure 2, Figure 3, and Figure 4.

Figure 1. Heart Rate – SEVORANE AF does not produce an increase in heart rate with or without nitrous oxide at doses less than 2 MAC.

Figure 2. Mean Arterial Pressure – The decrease in mean arterial pressure seen with SEVORANE AF with or without nitrous oxide is dose dependent at all MAC values.

Figure 3. Systemic Vascular Resistance – The decrease in systemic vascular resistance seen with SEVORANE AF with or without nitrous oxide is dose dependent at all MAC values.

Figure 4. Cardiac Index - SEVORANE AF has a dose-related cardiac depressant effect with or without nitrous oxide.

A study investigating the epinephrine-induced arrhythmogenic effect of SEVORANE AF versus isoflurane in adult patients undergoing transsphenoidal hypophysectomy (N = 40) demonstrated that the threshold dose of epinephrine (i.e., the dose at which the first sign of arrhythmia was observed) producing multiple ventricular arrhythmias was 5 mcg/kg in both groups.

Cardiovascular Surgery / Coronary Artery Bypass Graft (CABG) Surgery

SEVORANE AF was compared to isoflurane as an adjunct with opioids in a multicentre study of 273 patients undergoing CABG surgery. The average MAC dose was 0.49 for SEVORANE AF and 0.53 for isoflurane. No statistical differences were observed between the two treatment groups with respect to incidence (SEVORANE AF 7%, isoflurane 11%) and duration (SEVORANE AF approx. 18 minutes, isoflurane approx. 17 minutes) of ischemic events, number of patients with diagnosis of myocardial infarction (SEVORANE AF 8%, isoflurane 10%), time to hemodynamic stability (SEVORANE AF approx. 5 hours, isoflurane approx. 6 hours), or use of cardioactive drugs (SEVORANE AF 53%, isoflurane 47%).

Non-Cardiac Surgery Patients at Risk for Myocardial Ischemia

Sevoflurane-N2O was compared to isoflurane-N2O for maintenance of anesthesia in a multicentre study of 214 patients who were at mild-to-moderate risk for myocardial ischemia who underwent elective non-cardiac surgery. The average MAC dose was 0.49 for both drugs. No statistical differences were observed between the treatment groups for the incidence of any hemodynamic variation (tachycardia, bradycardia, hypertension, hypotension, and ischemia without hemodynamic abnormality). No statistical differences were observed between the two regimens with respect to intra-operative incidence of myocardial ischemia (SEVORANE AF 6%, isoflurane 3%) or post-operative incidence of ischemic events (SEVORANE AF 10%, isoflurane 16%). No statistical differences were observed between the treatment groups for the incidences of study drug-related adverse experience by body system or by COSTART term (SEVORANE AF 60%, isoflurane 61%). There was one death in SEVORANE AF group while four deaths occurred in the isoflurane group. None of these deaths were considered by the investigator to be drug-related.

Pediatric Anesthesia

The concentration of SEVORANE AF required for maintenance of general anesthesia is age-dependent. See DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment. Incidences of bradycardia (more than 20 beats/min less than normal) is lower for SEVORANE AF (3%) than for halothane (7%). Emergence times for SEVORANE AF are faster than with halothane (12 vs 19 minutes, respectively). A higher incidence of agitation occurs with SEVORANE AF (208/837 patients or 25%) when compared with halothane (114/661 patients or 17%).

Detailed Pharmacology

Methyl ethers have proven to be a successful series of anesthetics because of several characteristics: molecular stability, non-flammability, lack of arrhythmogenicity, lack of neuronal excitation, relative cardiovascular stability, large lethal to anesthetic concentration ratio, minimal effect on cerebral blood flow at low concentrations and minimal end-organ effects. In addition to these characteristics, sevoflurane exhibits a low blood solubility with a blood gas partition coefficient of 0.63 to 0.69 at 37°C and has a pleasant, non-irritating odor. These qualities provide a rapid and smooth inhalational induction of, and rapid recovery from, anesthesia.

Equipotent doses of sevoflurane and isoflurane produce similar effects on cerebral blood flow (CBF), cerebral metabolic rate for oxygen (CMRO2), intracranial pressure (ICP) and electroencephalogram patterns (EEG). In contrast, after short-term exposure, sevoflurane administration (1 MAC) produces a smaller increase in ICP than does an equipotent concentration of halothane.

Anesthesia with sevoflurane is both time- and concentration-dependent and involves suppression of cerebral cortex activity (loss of awareness and motor reflexes), suppression of the cerebellum and mesencephalon (loss of righting reflex, corneal reflex), suppression of the spinal cord (loss of the tail pinch response), and suppression of the medulla oblongata (depression of respiration).

Sevoflurane suppresses heart rate and arterial blood pressure in a dose-dependent fashion. In general, the hemodynamic/cardiovascular effects of sevoflurane are comparable to those of isoflurane. However, a more pronounced tachycardia was observed in dogs exposed to 1.2 MAC sevoflurane than those animals exposed to 1.2 MAC isoflurane. The magnitude of myocardial contractile depression observed in dogs during sevoflurane anesthesia was similar to those previously reported for isoflurane and desflurane; however, sevoflurane appears to cause less depression of the inotropic state than that reported for halothane.

Sevoflurane does not appear to have any remarkable coronary vasodilatory effects, does not negatively affect the blood flow distribution in areas of local myocardial ischemia, and, therefore, does not appear to exacerbate myocardial ischemia. Sevoflurane does not reduce collaterally-derived myocardial perfusion or cause coronary steal.

At clinical concentrations in the absence of pacing, sevoflurane does not affect atrioventricular (A-V) conduction. Sevoflurane appears to have a lower risk for the potentiation of epinephrine-induced arrhythmias, or other pressoramine-induced arrhythmias, than either halothane or enflurane.

The administration of epinephrine during sevoflurane anesthesia does not appear to be associated with the production of ventricular arrhythmia. In a dog model, halothane was more sensitizing to the myocardium in the presence of pressoramines than was sevoflurane. Also, in the same dog model, ventricular fibrillation was observed with epinephrine and norepinephrine under halothane, no ventricular fibrillation was produced under sevoflurane anesthesia in this study.

Mean MAC for sevoflurane has been determined as 2.2% in rats, 2.3% in mice, 3.61 to 3.7% in rabbits, 2.36% in dogs, 2.58% in cats, and 2.12% in newborn swine.

Sevoflurane will trigger malignant hyperthermia (MH) in susceptible pigs; however, it is a weak trigger. The onset of MH is slow and easily reversible. In contrast, halothane triggers MH in susceptible pigs much sooner and more strongly than does sevoflurane.


Acute Toxicity

Five laboratory animal species (rat, mouse, rabbit, dog, monkey) have been studied to determine the acute toxic effects and median lethal concentration of sevoflurane via the inhalation route and, in rodents, by oral, and parenteral routes. Calculated median lethal concentrations for 1-hour inhalation exposure ranged from 5.8% in the rat to 10.6% in rabbits. Prolongation of exposure lowered the LC50 within each species. See Table 1.

Table 1. Summary of Calculated Median Lethal Concentrations
SpeciesInhalation LC50
1 hour3 hours

Sevoflurane was virtually non-toxic orally (LD50 10.8 to 24.3 mL/kg) and parenterally (LD50 6.3 to 11.7 mL/kg). No significant differences in response to sevoflurane were detected between males and females. Neonatal rodents were shown to be more tolerant to acute exposures than adults.

Dyspnea and cyanosis appeared to be the primary cause of death following acute inhalation exposure in all species studied. There was no clear organ pathology associated with acute sevoflurane exposure in these studies even at lethal concentrations.

Subchronic Toxicity

Repeated exposure studies have confirmed the absence of any specific organ toxicity associated with non-lethal concentrations of sevoflurane. Rats and monkeys have been exposed for up to 3 hours/day, 3 days/week, for 8 weeks at concentrations ranging from 0.1 to 1.0 MAC (0.22 to 2.2%) and 1.0 to 2.5 MAC (2 to 5%), respectively. Dogs have been repeatedly anesthetized (3 hours/day, 5 days/week for 2 weeks) at concentrations of up to 5%.

Dogs and monkeys in these studies revealed no evidence of autonomic or central nervous system stimulation, cardiac arrhythmia or unexpected cardiorespiratory depression. Bradycardia was rarely reported in dogs, and was never observed in monkeys. Clinical observations, hematology and pathology were unremarkable, indicating no adverse effects.

Reproduction and Teratology

There were no significant effects on male and female reproductive capabilities at exposure concentrations of up to 1.0 MAC (2.2%) in a classic Segment I reproduction study. Systemic toxicity, as manifested by reductions in body weight gain, was observed in the males at exposures > 0.5 MAC (1.1%) and at exposures > 0.3 MAC (0.66%) in females.

Fetal body weights were slightly reduced at these maternally toxic exposure levels (> 0.3 MAC), and an increase in skeletal variations at the highest exposure level, a common occurrence in this species, was also observed.

Developmental toxicity (Segment II and III) studies in rats indicate that sevoflurane is not a selective developmental toxicant. Similar to what was observed in the rat reproduction study, reductions in fetal and neonatal body weights and increased skeletal variations were observed only at maternally toxic concentrations of 1.0 MAC (2.2%). No effects on offspring viability, behaviour or reproductive capability was observed.

In rabbits, no developmental toxicity was observed at maternally toxic concentrations of up to 1.0 MAC (1.8%). Mutagenicity studies indicate that sevoflurane is not mutagenic when tested both in vitro and in vivo.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies on carcinogenesis have not been performed. No mutagenic effect was noted in the Ames test and no chromosomal aberrations were induced in cultured mammalian cells.

Special Toxicity Studies

Compound A

In Wistar rats the LC50 of Compound A was 1050 to 1090 ppm in animals exposed for 1 hour and 400 to 420 ppm in animals exposed for 3 hours (median lethal concentrations were approximately 1070 and 330 to 490 ppm, respectively). In rats exposed to 30, 60, or 120 ppm of Compound A in an eight week chronic toxicity study (24 exposures, 3 hours/exposure), no apparent evidence of toxicity was observed other than loss of body weight in females on the last study day.

Sprague-Dawley rats were administered Compound A via nose-only inhalation exposure in an open system (25, 50, 100 or 200 ppm [0.0025 to 0.02%] of Compound A alone or in combination with 2.2% sevoflurane. Control groups were exposed to air. The threshold, at which reversible alterations in urinary and clinical parameters indicative of renal changes (concentration-dependent increases in BUN, creatinine, glucose, protein/creatinine ratios and N-acetyl-glucosamidase/ creatinine ratios) were observed, was 114 ppm Compound A. Histological lesions were reversible as indicated by histological examinations and by urinalysis surrogate markers (ketones, occult blood, glucose, NAG/creatinine, protein/creatinine).

Since the uptake of inhalational agents in small rodents is substantially higher than in humans, higher levels of drug, Compound A (degradant of sevoflurane) or 2-bromo-2-chloro-1,1-difluoro ethylene (BCDFE) (degradant/metabolite of halothane) would be expected in rodents. Also, the activity of the key enzyme (β-lyase) involved in haloalkene nephrotoxicity is tenfold greater in the rat than it is in humans.

In the clinical situation, the highest concentration of Compound A in the anesthesia circuit with soda lime as the CO2 absorbant was 15 ppm in pediatrics and 32 ppm in adults. However, concentrations to 61 ppm have been observed in patients attached to systems with Baralyme as the CO2 absorbant with no evidence of renal dysfunction.

Compound B

In the clinical situation, the concentration of Compound B detected in the anesthesia circuit did not exceed 1.5 ppm. Inhalation exposure to Compound B at concentrations of up to 2400 ppm (0.24%) for 3 hours resulted in no adverse effects on renal parameters or tissue histology in Wistar rats.