In the event of overdosage, the following action should be taken: Stop drug administration, establish a clear airway and initiate assisted or controlled ventilation with pure oxygen and maintain adequate cardiovascular function.
Sevorane should not be used in patients with known or suspected sensitivity to Sevorane or other halogenated anaesthetics (e.g. history of liver function disorder, fever or leucocytosis of unknown cause after anaesthesia with one of these agents).
Sevorane is also contraindicated in patients with known or suspected genetic susceptibility to malignant hyperthermia.
Sevorane is contraindicated in patients in whom general anaesthesia is contraindicated.
Sevorane is stable when stored under normal room lighting conditions. No discernible degradation of Sevorane occurs in the presence of strong acids or heat. Sevorane is not corrosive to stainless steel, brass, aluminum nickel-plated brass, chrome-plated brass or copper beryllium alloy.
Chemical degradation can occur upon exposure of inhaled anaesthetics to CO2 absorbent within the anaesthesia machine. When used as directed with fresh absorbents, degradation of Sevorane is minimal and degradants are undetectable or non-toxic. Sevorane degradation and subsequent degradant formation are enhanced by increasing absorbent temperature, desiccated CO2 absorbent (especially potassium hydroxide-containing, e.g. Baralyme®), increased Sevorane concentration and decreased fresh gas flow. Sevorane can undergo alkaline degradation by two pathways. The first results from the loss of hydrogen fluoride with the formation of pentafluoroisopropanyl fluoromethyl ether (PIFE or more commonly known as Compound A). The second pathway for degradation of Sevorane occurs only in the presence of desiccated CO2 absorbents and leads to the dissociation of Sevorane into hexafluoroisopropanol (HFIP) and formaldehyde. HFIP is inactive, non-genotoxic, rapidly glucoronidated, cleared and has toxicity comparable to Sevorane. Formaldehyde is present during normal metabolic processes. Upon exposure to a highly desiccated absorbent, formaldehyde can further degrade into methanol and formate. Formate can contribute to the formation of carbon monoxide in the presence of high temperature. Methanol can react with compound A to form the methoxy addition product Compound B. Compound B can undergo further HF elimination to form Compounds C,D and E. With highly desiccated absorbents, especially those containing potassium hydroxide (e.g Baralyme®) the fomation of formaldehyde, methanol, carbon monoxide, Compound A and perhaps some of its degradants, Compounds B,C and D may occur.
Summary of the safety profile
As with all potent inhaled anaesthetics, Sevorane may cause dose-dependent cardio-respiratory depression. Most adverse reactions are mild to moderate in severity and are transient in duration. Nausea, vomiting and delirium are commonly observed in the post-operative period, at a similar incidence to those found with other inhalation anaesthetics. These effects are common sequelae of surgery and general anaesthesia which may be due to the inhalational anaesthetic, other agents administered intra-operatively or post-operatively and to the patient's response to the surgical procedure.
The most commonly reported adverse reactions were as follows:
In adult patients: hypotension, nausea and vomiting;
In elderly patients: bradycardia, hypotension and nausea; and
In paediatric patients: agitation, cough, vomiting and nausea.
Tabulated summary of adverse reactions
All adverse reactions at least possibly relating to Sevorane from clinical trials and post-marketing experience are presented in the following table by MedDRA System Organ Class, Preferred Term and frequency. The following frequency categories are used: Very common (>1/10); common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000); very rare (<1/10,000), including isolated reports. Post-marketing adverse reactions are reported voluntarily from a population with an unknown rate of exposure. Therefore it is not possible to estimate the true incidence of adverse events and the frequency is “unknownâ€. The type, severity and frequency of adverse reactions in Sevorane patients in clinical trials were comparable to adverse reactions in reference-drug patients.
Adverse Reaction Data Derived From Clinical Trials and Post-marketing Experience
| Summary of Most Frequent Adverse Drug Reactions in Sevorane Clinical Trials and Post-marketing Experience | ||
| System Organ Class | Frequency | Adverse Reactions |
| Immune system disorders | Unknown | Anaphylactic reaction 1 Anaphylactoid reaction Hypersensitivity 1 |
| Blood and lymphatic system disorders | Uncommon | Leukopenia Leukocytosis |
| Psychiatric disorders | Very Common Uncommon | Agitation Confusional state |
| Nervous system disorders | Common
Unknown | Somnolence Dizziness Headache Convulsion 2, 3 Dystonia |
| Cardiac disorders | Very Common Common Uncommon
Unknown | Bradycardia Tachycardia Atrioventricular block complete Atrial fibrillation Arrythmia Ventricular extrasystoles Supraventricular extrasystoles Extrasystoles Cardiac arrest 4 QT prolongation associated with Torsade |
| Vascular disorders | Very Common Common | Hypotension Hypertension |
| Respiratory, thoracic and mediastinal disorders | Very Common Common
Uncommon
Unknown | Cough Respiratory disorder Laryngospasm Apnoea Hypoxia Asthma Bronchospasm Dyspnoea 1 Wheezing 1 Pulmonary oedema |
| Gastrointestinal disorders | Very Common
Common | Nausea Vomiting Salivary hypersecretion |
| Renal and urinary disorders | Uncommon
Unknown | Urinary retention Glycosuria Renal failure acute |
| Hepato-biliary disorders | Unknown | Hepatitis 1, 2 Hepatic failure 1, 2 Hepatic necrosis 1, 2 |
| Skin and subcutaneous tissue disorders | Unknown | Dermatitis contact 1 Pruritus Rash 1 Swelling face 1 Urticaria |
| Musculoskeletal and connective tissue disorders | Unknown | Muscle twitching |
| General disorders and administration site conditions | Common
Unknown | Chills Pyrexia Hypothermia Chest discomfort 1 Hyperthermia malignant 1, 2 |
| Investigations | Common
Uncommon | Blood glucose abnormal Liver function test abnormal 5 White blood cell count abnormal Aspartate aminotransferase increased Blood fluoride increased6 Alanine aminotransferase increased Blood creatinine increased Blood lactate dehydrogenase increased |
| Injury, poisoning and procedural complications | Common | Hypothermia |
- Description of selected adverse reactions.
- Paediatric population.
4 There have been very rare post-marketing reports of cardiac arrest in the setting of Sevorane use.
5 Occasional cases of transient changes in hepatic function tests were reported with Sevorane and reference agents.
6 Transient increases in serum inorganic fluoride levels may occur during and after Sevorane anaesthesia. See Description of selected adverse reactions below.
Description of selected adverse reactions
Transient increases in serum inorganic fluoride levels may occur during and after Sevorane anaesthesia. Concentrations of inorganic fluoride generally peak within two hours of the end of Sevorane anaesthesia and return within 48 hours to pre-operative levels. In clinical trials, elevated fluoride concentrations were not associated with impairment of renal function.
Rare reports of post-operative hepatitis exist. In addition, there have been rare post-marketing reports of hepatic failure and hepatic necrosis associated with the use of potent volatile anaesthetic agents, including Sevorane. However, the actual incidence and relationship of Sevorane to these events cannot be established with certainty.
Rare reports of hypersensitivity (including contact dermatitis, rash, dyspnoea, wheezing, chest discomfort, swelling face, or anaphylactic reaction) have been received, particularly in association with long-term occupational exposure to inhaled anaesthetic agents, including Sevorane.
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.
Paediatric population
The use of Sevorane has been associated with seizures. Many of these have occurred in children and young adults starting from 2 months of age, most of whom had no predisposing risk factors. Clinical judgment should be exercised when using Sevorane in patients who may be at risk for seizures.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme:
Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Animal studies have shown that hepatic and renal circulation are well maintained with Sevorane.
Sevorane decreases the cerebral metabolic rate for oxygen (CMRO2) in a fashion analogous to that seen with isoflurane. An approximately 50% reduction of CMRO2 is observed at concentrations approaching 2.0 MAC. Animal studies have demonstrated that Sevorane does not have a significant effect on cerebral blood flow.
In animals, Sevorane significantly suppresses electroencephalographic (EEG) activity comparable to equipotent doses of isoflurane. There is no evidence that Sevorane is associated with epileptiform activity during normocapnia or hypocapnia. In contrast to enflurane, attempts to elicit seizure-like EEG activity during hypocapnia with rhythmic auditory stimuli have been negative.
Compound A was minimally nephrotoxic at concentrations of 50-114 ppm for 3 hours in a range of studies in rats. The toxicity was characterised by sporadic single cell necrosis of the proximal tubule cells. The mechanism of this renal toxicity in rats is unknown and its relevance to man has not been established. Comparable human thresholds for Compound A-related nephrotoxicity would be predicted to be 150-200 ppm. The concentrations of Compound A found in routine clinical practice are on average 19 ppm in adults (maximum 32 ppm) with use of Soda lime as the CO2 absorbent.
Developmental toxicity studies have been performed in pregnant rats and rabbits at doses up to 1 MAC for three hours per day. Reduced foetal body weights concomitant with increased skeletal variations were noted in rats only at maternally toxic concentrations. No adverse foetal effects were observed in rabbits. In fertility studies in rats at doses up to 1 MAC no effects on male and female reproductive capabilities were observed.
Published studies in pregnant and juvenile animals suggest that the use of anaesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of rapid brain growth or synaptogenesis may result in neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis when used for longer than 3 hours. These studies included anaesthetic agents from a variety of drug classes. The clinical significance of these nonclinical findings is yet to be determined.
Sevorane is indicated for induction and maintenance of general anaesthesia in adult and paediatric patients for inpatient and outpatient surgery.
Pharmaco-therapeutic group: Anaesthetics, general - ATC code: N01A
Changes in the clinical effects of Sevorane rapidly follow changes in the inspired concentration.
Cardiovascular Effects
As with all other inhalation agents Sevorane depresses cardiovascular function in a dose related fashion. In one volunteer study, increases in Sevorane concentration resulted in decrease in mean arterial pressure, but there was no change in heart rate. Sevorane did not alter plasma noradrenaline concentrations in this study.
Nervous System Effects
No evidence of seizure was observed during the clinical development programme.
In patients with normal intracranial pressure (ICP), Sevorane had minimal effect on ICP and preserved CO2 responsiveness. The safety of Sevorane has not been investigated in patients with a raised ICP. In patients at risk for elevations of ICP, Sevorane should be administered cautiously in conjunction with ICP-reducing manoeuvres such as hyperventilation.
Paediatric
Some published studies in children have observed cognitive deficits after repeated or prolonged exposures to anaesthetic agents early in life. These studies have substantial limitations, and it is not clear if the observed effects are due to the anaesthetic/sedation drug administration or other factors such as the surgery or underlying illness. In addition, more recent published registry studies did not confirm these findings.
- Preclinical safety data).The low solubility of Sevorane 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 Sevorane is metabolised. The rapid and extensive pulmonary elimination of Sevorane minimises the amount of anaesthetic available for metabolism. Sevorane 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 then rapidly conjugated with glucuronic acid and excreted in the urine.
The metabolism of Sevorane 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 Sevorane anaesthesia. Generally, concentrations of inorganic fluoride peak within 2 hours of the end of Sevorane anaesthesia and return within 48 hours to pre-operative levels.
Sevorane may cause respiratory depression, which may be augmented by narcotic premedication or other agents causing respiratory depression. Respiration should be supervised and if necessary, assisted.
Sevorane should be administered only by persons trained in the administration of general anaesthesia. Facilities for maintenance of a patent airway, artificial ventilation, oxygen enrichment and circulatory resuscitation must be immediately available.
The concentration of Sevorane being delivered from a vaporiser must be known exactly. As volatile anaesthetics differ in their physical properties, only vaporisers specifically calibrated for Sevorane must be used. The administration of general anaesthesia must be individualised based on the patient's response. Hypotension and respiratory depression increase as anaesthesia is deepened.
Malignant Hyperthermia
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 clinical syndrome is signalled by hypercapnia, and may include muscle rigidity, tachycardia, tachypnoea, cyanosis, arrhythmias, and/or unstable blood pressure. Some of these nonspecific signs may also appear during light anaesthesia, acute hypoxia, hypercapnia and hypovolaemia.
In clinical trials, one case of malignant hyperthermia was reported. In addition, there have been postmarketing reports of malignant hyperthermia. Some of these reports have been fatal.
Treatment includes discontinuation of triggering agents (e.g. Sevorane), administration of intravenous dantrolene sodium (consult prescribing information for intravenous dantrolene sodium for additional information on patient management), and application of supportive therapy. Such therapy includes vigorous efforts to restore body temperature to normal, respiratory and circulatory support as indicated, and management of electrolyte-fluid-acid-base abnormalities. Renal failure may appear later, and urine flow should be monitored and sustained if possible.
Perioperative Hyperkalemia
Use of inhaled anaesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in paediatric patients during the postoperative period. Patients with latent as well as overt neuromuscular disease, particularly Duchenne muscular dystrophy, appear to be most vulnerable. Concomitant use of succinylcholine has been associated with most, but not all, of these cases. These patients also experienced significant elevations in serum creatine kinase levels and, in some cases, changes in urine consistent with myoglobinuria. Despite the similarity in presentation to malignant hyperthermia, none of these patients exhibited signs or symptoms of muscle rigidity or hypermetabolic state. Early and aggressive intervention to treat the hyperkalaemia and resistant arrhythmias is recommended, as is subsequent evaluation for latent neuromuscular disease.
Isolated reports of QT prolongation, very rarely associated with torsade de pointes (in exceptional cases, fatal), have been received. Caution should be exercised when administering Sevorane to susceptible patients.
Isolated cases of ventricular arrhythmia were reported in paediatric patients with Pompe's disease.
Caution should be exercised in administering general anaesthesia, including Sevorane, to patients with mitochondrial disorders.
Hepatic
Very rare cases of mild, moderate and severe post-operative hepatic dysfunction or hepatitis with or without jaundice have been reported from postmarketing experiences.
Clinical judgment should be exercised when Sevorane is used in patients with underlying hepatic conditions or under treatment with drugs known to cause hepatic dysfunction.
Patients with repeated exposures to halogenated hydrocarbons, including Sevorane, within a relatively short interval may have an increased risk of hepatic injury.
General
During the maintenance of anaesthesia, increasing the concentration of Sevorane 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 Sevorane. Particular care must be taken when selecting the dosage for patients who are hypovolaemic, hypotensive, or otherwise hemodynamically compromised, e.g., due to concomitant medications.
As with all anaesthetics, maintenance of haemodynamic stability is important to avoid myocardial ischaemia in patients with coronary artery disease.
Caution should be observed when using Sevorane during obstetric anaesthesia because the relaxant effect on the uterus could increase the risk of uterine bleeding.
The recovery from general anaesthesia should be assessed carefully before patients are discharged from the recovery room. Rapid emergence from anaesthesia is generally seen with Sevorane so early relief of postoperative pain may be required. Although recovery of consciousness following Sevorane administration generally occurs within minutes, the impact on intellectual function for two or three days following anaesthesia has not been studied. As with other anaesthetics, small changes in moods may persist for several days following administration. Rapid emergence in children may be associated with agitation and lack of co-operation (in about 25% of cases).
Replacement of Desiccated CO2 Absorbents:
Rare cases of extreme heat, smoke, and/or spontaneous fire in the anaesthesia machine have been reported during Sevorane use in conjunction with the use of desiccated CO2 absorbent, specifically those containing potassium hydroxide (e.g Baralyme). An unusually delayed rise or unexpected decline of inspired Sevorane concentration compared to the vaporiser setting may be associated with excessive heating of the CO2 absorbent canister.
An exothermic reaction, enhanced Sevorane degradation, and production of degradation products can occur when the CO2 absorbent becomes desiccated, such as after an extended period of dry gas flow through the CO2 absorbent canisters. Sevorane degradants (methanol, formaldehyde, carbon monoxide, and Compounds A, B, C, and D) were observed in the respiratory circuit of an experimental anaesthesia machine using desiccated CO2 absorbents and maximum Sevorane concentrations (8%) for extended periods of time (> 2 hours). Concentrations of formaldehyde observed at the anaesthesia respiratory circuit (using sodium hydroxide containing absorbents) were consistent with levels known to cause mild respiratory irritation. The clinical relevance of the degradants observed under this extreme experimental model is unknown.
If a health care professional suspects that the CO2 absorbent has become desiccated, it must be replaced before subsequent use of volatile anaesthetics (such as Sevorane). It must be taken into account that the colour indicator does not always change after desiccation has taken place. Therefore, the lack of significant colour change should not be taken as an assurance of adequate hydration. CO2 absorbents should be replaced routinely regardless of the state of the colour indicator.
Renal Impairment:
Because of the small number of patients with renal insufficiency (baseline serum creatinine greater than 1.5mg/dL) studied, the safety of Sevorane administration in this group has not been fully established. Therefore, Sevorane should be used with caution in patients with renal insufficiency.
)Neurosurgery & Neuromuscular Impairment:
In patients at risk from elevation of intra-cranial pressure, Sevorane should be administered cautiously in conjunction with techniques to lower intra-cranial pressure (e.g. hyperventilation).
Seizures:
Rare cases of seizures have been reported in association with Sevorane use.
-Paediatric population).Paediatric population:
The use of Sevorane has been associated with seizures. Many have occurred in children and young adults starting from 2 months of age, most of whom had no predisposing risk factors. Clinical judgment should be exercised when using Sevorane in patients who may be at risk for seizures.
Dystonic movements in children have been observed.
As with other agents, patients should be advised that performance of activities requiring mental alertness, such as operating a motor vehicle or hazardous machinery, may be impaired for some time after general anaesthesia.
Patients should not be allowed to drive for a suitable period after Sevorane anaesthesia.
Premedication should be selected according to the need of the individual patient, and at the discretion of the anaesthetist.
Surgical Anaesthesia:
Sevorane should be delivered via a vaporiser specifically calibrated for use with Sevorane so that the concentration delivered can be accurately controlled. MAC (minimum alveolar concentration) values for Sevorane decrease with age and with the addition of nitrous oxide. The table below indicates average MAC values for different age groups.
| Table 1: MAC values for Adults and Paediatric patients according to age | ||
| Age of Patient (years) | Sevorane in Oxygen | Sevorane in 65% N2O/35% O2 |
| 0 - 1 months* | 3.3% | 2.0%** |
| 1 - < 6 months | 3.0% | |
| 6 months - < 3 years | 2.8% | |
| 3 - 12 | 2.5% | |
| 25 | 2.6% | 1.4% |
| 40 | 2.1% | 1.1% |
| 60 | 1.7% | 0.9% |
| 80 | 1.4% | 0.7% |
* Neonates are full term gestational age. MAC in premature infants has not been determined.
** In 1 - <3 year old paediatric patients, 60% N2O/40% O2 was used.
Induction:
Dosage should be individualised and titrated to the desired effect according to the patient's age and clinical status. A short acting barbiturate or other intravenous induction agent may be administered followed by inhalation of Sevorane. Induction with Sevorane may be achieved in oxygen or in combination with oxygen-nitrous oxide mixtures. In adults inspired concentrations of up to 5% Sevorane usually produce surgical anaesthesia in less than 2 minutes. In children, inspired concentrations of up to 7% Sevorane usually produce surgical anaesthesia in less than 2 minutes. Alternatively, for induction of anaesthesia in unpremedicated patients, inspired concentrations of up to 8% Sevorane may be used.
Maintenance:
Surgical levels of anaesthesia may be sustained with concentrations of 0.5 - 3% Sevorane with or without the concomitant use of nitrous oxide.
Emergence:
Emergence times are generally short following Sevorane anaesthesia. Therefore, patients may require early post-operative pain relief.
Older people:
MAC decreases with increasing age. The average concentration of Sevorane to achieve MAC in an 80 year old is approximately 50% of that required in a 20 year old.
Paediatric population:
Refer to Table 1 for MAC values for paediatric patients according to age.
Sevorane should be administered via a vaporiser calibrated specifically for Sevorane using a key filling system designed for Sevorane specific vaporisers or other appropriate Sevorane specific vaporiser filling systems.
Carbon dioxide absorbents should not be allowed to dry out when inhalational anaesthetics are being administered. Some halogenated anaesthetics have been reported to interact with dry carbon dioxide absorbent to form carbon monoxide. However, in order to minimise the risk of formation of carbon monoxide in re-breathing circuits and the possibility of elevated carboxyhaemoglobin levels, CO2 absorbents should not be allowed to dry out. There have been rare cases of excessive heat production, smoke and fire in the anaesthetic machine when Sevorane has been used in conjunction with a desiccated (dried out) CO2 absorbent. If the CO2 absorbent is suspected to be desiccated it should be replaced.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements
