Each 250 ml contains: Seveoflurane, USP 100% v/v.
The formulation contains sevoflurane (C4H3F7O), which is a halogenated general inhalation anaesthetic drug. Sevoflurane is a non-flammable, pleasant smelling, non-explosive and volatile liquid.
Sevoflurane is a clear, colourless, stable liquid containing no additives or chemical stabilizers. It is nonpungent, miscible with ethanol, ether, chloroform and petroleum benzene, and it is slightly soluble in water.
No discernible degradation occurs in the presence of strong acids or heat.
Sevoflurane is not corrosive to stainless steel, brass, aluminum, nickel plated brass, chrome plated brass or copper beryllium alloy.
Physical properties constant of sevoflurane are as under: Gram molecular weight: 200.0.
Boiling point at 760 mmHg: 58.5°C.
Refractive Index n20: 1.2740-1.2760.
Saturated Vapour pressure at 20°C: 157.0 mmHg.
Odor: non-irritating, similar to ether.
Additives/Chemical stabilizers: None.
Stability in Moist Soda Lime at 40°C / 60°C / 80°C: Unstable.
Partition Co-efficients at normal body temperature: Water : Gas: 0.36; Blood : Gas: 0.63-0.69; Olive Oil : Gas: 47.2-53.9; Brain : Blood: 1.7; Heart : Blood: 1.78; Liver : Blood: 1.85; Kidney : Blood: 1.15.
Mean Partition coefficients at 25°C - component/gas: Conductive rubber: 14.0; Butyl rubber: 7.7; Polyvinylchloride: 17.4; Polyethylene: 1.3; Purity by gas chromatography: 99.975% or better; Flammability: Not flammable.
Pharmacology: Sevoflurane is an inhalation anaesthetic agent for use in induction and maintenance of general anaesthesia. Administration has been associated with smooth, rapid loss of consciousness during inhalation induction and a rapid recovery following discontinuation of anaesthesia. Minimum alveolar concentration (MAC) of sevoflurane in oxygen reported for a 40-year-old adult is 2.1%. The MAC of sevoflurane decreases with age and with the addition of nitrous oxide.
Induction is accomplished with a minimum of excitement or of signs of upper respiratory irritation, no evidence of excessive secretions within the tracheobronchial tree and no central nervous system stimulation.
Changes in the depth of sevoflurane anaesthesia rapidly follow changes in the inspired concentration. The times for induction and recovery were reduced in paediatric patients who received sevoflurane in clinical studies.
The depth of anaesthesia changes rapidly following changes in the inspired concentration of Sevoflurane. Emergence and recovery are particularly rapid. Therefore, patients may require early post-operative pain relief.
As with all other inhalation agents sevoflurane depresses cardiovascular function in a dose related fashion. No evidence of seizure has been documented.
Sevoflurane had minimal effect on intracranial pressure (ICP) and preserved CO2, responsiveness in patients with normal ICP. Its safety has not been investigated in patients with a raised ICP. Sevoflurane should be administered cautiously in conjunction with ICP-reducing manoeuvres such as hyperventilation in those patients who are at risk for elevations of ICP.
The low solubility of sevoflurane in blood should result in alveolar concentrations which rapidly increase upon induction and rapidly decrease upon cessation of the inhaled agent.
In humans <5% of the absorbed sevoflurane is metabolised. The rapid and extensive pulmonary elimination of Sevoflurane minimises the amount of anaesthetic available for metabolism. Sevoflurane is defluorinated via cytochrome p450 (CYP)2E1 resulting in the production of hexafluoroisopropanol (HFIP) with release of inorganic fluoride and carbon dioxide (or a one carbon fragment). HFIP is hen rapidly conjugated with glucuronic acid and excreted in the urine.
The metabolism of sevoflurane may be increased by known inducers of CYP2E1 (e.g. Isoniazid and alcohol), but it is not inducible by barbiturates.
Transient increases in serum inorganic fluoride levels may occur during and after Sevoflurane anaesthesia. Generally, concentrations of inorganic fluoride peak within hours of the end of sevoflurane anaesthesia and return within 48 hours to pro-operative levels.
Pharmacokinetics: Sevoflurane is absorbed on inhalation. The blood/gas partition coefficient up to 5% of the absorbed dose of sevoflurane is metabolized in the liver cytochrome P450 isoenzyme CYP2E1 and defluorinated to its major metabolites H-- isopropanol (HFIP), inorganic fluoride, and carbon dioxide. HFIP is rapidicated with glucuronic acid eliminated in the urine. Sevoflurane crosses the placenta.
For Induction and maintenance of general anaesthesia for in-patient and out-patient surgery in both adults and children.
Premedication should be selected at the discretion of the anaesthetist, taking into consideration the need of the individual patient. The use of anticholinergic drugs is, a matter of choice.
Dosage should be individualised and titrate to the desired effect according to the patient's age and clinical status.
Anaesthesia can be induced in adults and children with sevoflurane.
A short acting barbiturate or other intravenous induction agent may be administered followed by inhalation of sevoflurane.
Induction with sevoflurane may be achieved in oxygen or in combination with oxygen-nitrous oxide mixtures.
In adults, inspired concentrations of up to 5% sevoflurane usually produce surgical anaesthesia in less than 2 minutes.
In children, inspired concentrations of up to 7% sevoflurane usually produce surgical anaesthesia in less than 2 minutes.
Alternatively, for Induction of anaesthesia in unpremedicated patients, inspired concentrations of up to 8% sevoflurane may be used.
Surgical levels of anaesthesia can usually be achieved with concentrations of 0.5-3% sevoflurane with or without the concomitant use of nitrous oxide.
To maintain surgical anaesthesia in these patients, lesser concentrations of sevoflurane are normally required. See as follows for MAC values. MAC (minimum alveolar concentration) values for sevoflurane decrease with age and with the addition of nitrous oxide.
The table as follows indicates average MAC values for different age groups: See table.
Click on icon to see table/diagram/image
Emergence times are generally short following sevoflurane anaesthesia. Therefore, patients may require early post-operative pain relief.
In the event of overdosage: stop drug administration, establish a clear airway and initiate assisted or controlled ventilation with pure oxygen and maintain adequate cardiovascular function.
Sevoflurane should not be used in patients with known sensitivity to sevoflurane and in patients with known or suspected genetic susceptibility to malignant hyperthermia.
Sevoflurane should be administered only by trained personnel in the administration of general anaesthesia.
Ensure that facilities for maintenance of a patent airway, artificial ventilation, oxygen enrichment and circulatory resuscitation are immediately available.
Sevoflurane should be delivered via a vaporiser specifically calibrated for use with sevoflurane so that the concentration delivered can be accurately controlled. Hypotension and respiratory depression increase as anaesthesia is deepened.
Sevoflurane should be used with caution in patients with renal insufficiency.
Sevoflurane may present an increased risk in patients with known sensitivity to volatile halogenated anaesthetic agents.
Rare cases of seizures have been reported in association with sevoflurane use.
Maintenance of anaesthesia: During the maintenance of anaesthesia, increasing the concentration of sevoflurane produces dose-dependent decreases in blood pressure. Excessive decrease in blood pressure may be related to depth of anaesthesia and in such instances may be corrected by decreasing the inspired concentration of sevoflurane.
Malignant Hyperthermia: The recovery from general anaesthesia should be assessed carefully before patients are discharged from the recovery room. In susceptible individuals, potent inhalation anaesthetic agents may trigger a skeletal muscle hypermetabolic state leading to high oxygen demand and the clinical syndrome known as malignant hyperthermia. The syndrome may include non-specific features such as muscle rigidity, tachycardia, tachypnoea, cyanosis, arrhythmias and unstable blood pressure. Treatment includes discontinuation of triggering agents (e.g. Sevoflurane), administration of intravenous dantrolene sodium, and application of supportive therapy. Renal failure may appear later, and urine flow should be monitored and sustained if possible.
Perioperative hyperkalaemia: Use of inhaled anaesthetic agents has been associated with very rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in children during the postoperative period. The condition has been described in patients with latent as well as overt neuromuscular disease, particularly Duchenne muscular dystrophy. Use of suxamethonium has been associated with most, but not all of these cases. These patients showed evidence of muscle damage with increased serum creatine kinase concentration and myoglobinuria. These patients did NOT have classical signs of malignant hyperthermia such as muscle rigidity, rapid increase in body temperature, or increased oxygen uptake and carbon dioxide production. Prompt and vigorous treatment for hyperkalaemia and arrhythmias is recommended. Subsequent evaluation for latent neuromuscular disease is indicated.
Renal Function: 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. Limited pharmacology data in these patients appear to suggest that the half-life of sevoflurane may be increased. The clinical significance is unknown at this time. Thus, sevoflurane should be used with caution in these patients.
Hepatic Function: Results of evaluations of laboratory parameters (e.g., ALT, AST, alkaline phosphatase, and total bilirubin, etc.), as well as investigator-reported incidence of adverse events relating to liver function, demonstrate that sevoflurane can be administered to patients with normal or mild-to-moderately impaired hepatic function. However, patients with severe hepatic dysfunction were not investigated. Occasional cases of transient changes in postoperative hepatic function tests were reported with both sevoflurane and reference agents. Sevoflurane was found to be comparable to isoflurane with regard to these changes in hepatic function.
Very rare cases of mild, moderate and severe post-operative hepatic dysfunction or hepatitis with or without jaundice have been reported from post marketing experiences. Clinical judgement should be exercised when sevoflurane is used in patients with underlying hepatic conditions or under treatment with drugs known to cause hepatic dysfunction.
Compound A: Sevoflurane produces low levels of Compound A (pentafluoroisopropenyl fluoromethyl ether (PIFE)) and trace amounts of Compound B (pentafluoromethoxy isopropyl fluoromethyl ether (PMFE)), when in direct contact with CO2, absorbents. Levels of Compound A Increase with: increase in canister temperature; increase in anaesthetic concentration; decrease in gas flow rate an increase more with the use of Baralyme rather than Soda lime. (See also Pharmaceutical precautions as follows).
It is reported from some studies in rats, nephrotoxicity was seen in animal exposed to levels of Compound A in excess of those usually soon in routine clinical practice. The mechanism of this renal toxicity in rats is unknown and its relevance o man has not been established.
Replacement of Desiccated CO2 Absorbents: The exothermic reaction that occurs with sevoflurane and CO2 absorbents is increased when the CO2, absorbent becomes desiccated, such as after an extended period of dry gas flow through the CO2 absorbent canisters. Rare cases of extreme heat, smoke and/or spontaneous fire in the anesthesia machine have been reported during sevoflurane use in conjunction with the use of desiccated CO2 absorbent. An unusually delayed rise or unexpected decline of inspired sevoflurane concentration compared to the vaporize setting may be associated with excessive heating of the CO2 absorbent canister.
When a clinician suspects that the CO2 absorbent may be desiccated, it should be replaced before administration of sevoflurane. The color indicator of most CO2 absorbents does not necessarily change as a result of desiccation. Therefore, the lack of significant color change should not be taken as an assurance of adequate hydration. CO2 absorbents should be replaced routinely regardless of the state of the color indicator.
Laboratory findings: Transient elevations in glucose and white blood cell count may occur as with use of other anaesthetic agents.
Occasional cases of transient changes in hepatic function tests were reported with sevoflurane.
Pharmaceutical precautions: Sevoflurane is chemically stable. As with some halogenated anaesthetics, minor degradation occurs through direct contact with CO2 absorbents. The extent of degradation is clinically insignificant and no dose adjustments or change in clinical practice is necessary when rebreathing circuits are used. Higher levels of compound A are obtained when using Baralyme rather than Soda lime.
Effects on driving ability and operation of machinery: As with other anaesthetic agents, patients should be advised that performance of activities requiring mental alertness, such as operating hazardous machinery, may be impaired for some time after general anaesthesia. Patients should not be (lowed to drive for a suitable period after sevoflurane anaesthesia.
Use in Pregnancy & Lactation: Sevoflurane should be used during pregnancy only if clearly needed. It is not known whether sevoflurane is excreted in human milk therefore caution should be exercised when sevoflurane is administered to a nursing woman.
Generally well tolerated. Most adverse events are mild to moderate in severity and transient.
Nausea and vomiting are commonly observed in the post-operative period at a similar incidence to those found in other inhalation anaesthetics. In addition to nausea and vomiting, other frequent adverse events were: in adults, hypotension; in elderly, hypotension and bradycardia; in children, agitation and increased cough.
Less frequent adverse events associated with sevoflurane administration were agitation, somnolence, chills, bradycardia, dizziness, increased salivation, respiratory disorder, hypertension, tachycardia, laryngismus, fever, headache, hypothermia, increased SGOT. Occasionally reported adverse effects associated with the administration of sevoflurane administration include: arrhythmias, increased LDH, increased SGPT, hypoxia, apnoea, leukocytosis, ventricular extrasystoles, supraventricular extrasystoles, asthma, confusion, increased creatinine, urinary retention, glycosuria, atrial fibrillation, complete AV block, bigeminy, leucopenia. Allergic reactions, such as rash, urticaria, pruritus, bronchospasm, anaphylactic or anaphylactoid reactions have also been reported. As with all potent inhaled anaesthetics, sevoflurane may cause dose-dependent cardiorespiratory depression.
Convulsions may occur extremely rarely following sevoflurane administration particularly in children. There have been very rare reports of pulmonary oedema.
The action of non-depolarising muscle relaxants is markedly potentiated with sevoflurane, therefore, when administered with sevoflurane, dosage adjustments of these agents should be made.
Sevoflurane is similar to isoflurane in the sensitisation of the myocardium to the arrhythmogenic effect of exogenously administered adrenaline.
MAC values for Sevoflurane decrease with the addition of nitrous oxide as indicated in the table on 'Effect of Age on MAC of Sevoflurane' under Dosage & Administration. As with other agents, lesser concentrations of sevoflurane may be required following use of an intravenous anaesthetic e.g. propofol. The metabolism of Sevoflurane may be increased by known inducers of CYP2E1 (e.g. isoniazid and alcohol), but it is not inducible by barbiturates.
Instructions for use: Some halogenated anaesthetics have been reported to interact with dry carbon dioxide absorbent to form carbon monoxide. To date there is no evidence that this can occur with sevoflurane. However, in order to minimise the risk of formation of carbon monoxide in re-breathing circuits and the possibility of elevated carboxy-haemoglobin levels, carbon dioxide absorbents should not be allowed to dry out.
Store at temperatures not exceeding 25°C. Do not refrigerate. Keep cap tightly closed.
Shelf Life: The shelf life of Sevoflurane (Sojourn) is 60 months when stored at the recommended storage conditions.
N01AB08 - sevoflurane ; Belongs to the class of halogenated hydrocarbons. Used as general anesthetics.
Volatile liqd for inhalation (bottle) 100% v/v (clear, colourless) x 250 mL.