Calypsol

Calypsol is indicated in children and in adults.

Calypsol is recommended:

As an anaesthetic agent for diagnostic and surgical procedures. When used by intravenous or intramuscular injection, Calypsol is best suited for short procedures. With additional doses, or by intravenous infusion, Calypsol can be used for longer procedures. If skeletal muscle relaxation is desired, a muscle relaxant should be used and respiration should be supported.

For the induction of anaesthesia prior to the administration of other general anaesthetic agents. To supplement other anaesthetic agents.

Specific areas of application or types of procedures:

When the intramuscular route of administration is preferred.

Debridement, painful dressings, and skin grafting in burned patients, as well as other superficial surgical procedures.

Neurodiagnostic procedures such as pneumoencephalograms, ventriculograms, myelograms, and lumbar punctures.

Diagnostic and operative procedures of the eye, ear, nose, and mouth, including dental extractions.

Note: Eye movements may persist during ophthalmological procedures.

Anaesthesia in poor-risk patients with depression of vital functions or where depression of vital functions must be avoided, if at all possible.

Orthopaedic procedures such as closed reductions, manipulations, femoral pinning, amputations, and biopsies.

Sigmoidoscopy and minor surgery of the anus and rectum, circumcision and pilonidal sinus.

Cardiac catheterization procedures.

Caesarean section; as an induction agent in the absence of elevated blood pressure.

Anaesthesia in the asthmatic patient, either to minimise the risks of an attack of bronchospasm developing, or in the presence of bronchospasm where anaesthesia cannot be delayed.

For intravenous infusion, intravenous injection or intramuscular injection.

NOTE: All doses are given in terms of Calypsol base

Adults, elderly (over 65 years) and children:

For surgery in elderly patients Calypsol has been shown to be suitable either alone or supplemented with other anaesthetic agents.

Preoperative preparations

Calypsol has been safely used alone when the stomach was not empty. However, since the need for supplemental agents and muscle relaxants cannot be predicted, when preparing for elective surgery it is advisable that nothing be given by mouth for at least six hours prior to anaesthesia.

Premedication with an anticholinergic agent (e.g. atropine, hyoscine or glycopyrolate) or another drying agent should be given at an appropriate interval prior to induction to reduce Calypsol- induced hypersalivation.

Midazolam, diazepam, lorazepam, or flunitrazepam used as a premedicant or as an adjunct to Calypsol, have been effective in reducing the incidence of emergence reactions.

Onset and duration

As with other general anaesthetic agents, the individual response to Calypsol is somewhat varied depending on the dose, route of administration, age of patient, and concomitant use of other agents, so that dosage recommendation cannot be absolutely fixed. The dose should be titrated against the patient's requirements.

Because of rapid induction following intravenous injection, the patient should be in a supported position during administration. An intravenous dose of 2 mg/kg of bodyweight usually produces surgical anaesthesia within 30 seconds after injection and the anaesthetic effect usually lasts 5 to10 minutes. An intramuscular dose of 10 mg/kg of bodyweight usually produces surgical anaesthesia within 3 to 4 minutes following injection and the anaesthetic effect usually lasts 12 to 25 minutes. Return to consciousness is gradual.

A. Calypsol as the sole anaesthetic agent

Intravenous Infusion

The use of Calypsol by continuous infusion enables the dose to be titrated more closely, thereby reducing the amount of drug administered compared with intermittent administration. This results in a shorter recovery time and better stability of vital signs.

A solution containing 1 mg/ml of Calypsol in dextrose 5% or sodium chloride 0.9% is suitable for administration by infusion.

General Anaesthesia Induction

An infusion corresponding to 0.5 - 2 mg/kg as total induction dose.

Maintenance of anaesthesia

Anaesthesia may be maintained using a microdrip infusion of 10 - 45 microgram/kg/min (approximately 1 - 3 mg/min).

The rate of infusion will depend on the patient's reaction and response to anaesthesia. The dosage required may be reduced when a long acting neuromuscular blocking agent is used.

Intermittent Injection

Induction

Intravenous Route

The initial dose of Calypsol administered intravenously may range from 1 mg/kg to 4.5 mg/kg (in terms of Calypsol base). The average amount required to produce 5 to 10 minutes of surgical anaesthesia has been 2.0 mg/kg. It is recommended that intravenous administration be accomplished slowly (over a period of 60 seconds). More rapid administration may result in respiratory depression and enhanced pressor response.

Dosage in Obstetrics

Intramuscular Route

The initial dose of Calypsol administered intramuscularly may range from 6.5 mg/kg to 13 mg/kg (in terms of Calypsol base). A low initial intramuscular dose of 4 mg/kg has been used in diagnostic manoeuvres and procedures not involving intensely painful stimuli. A dose of 10 mg/kg will usually produce 12 to 25 minutes of surgical anaesthesia.

Dosage in Hepatic Insufficiency:

Dosage in Obstetrics

Data are lacking for intramuscular injection and maintenance infusion of Calypsol in the parturient population, and recommendations cannot be made.

Maintenance of general anaesthesia

Lightening of anaesthesia may be indicated by nystagmus, movements in response to stimulation, and vocalization. Anaesthesia is maintained by the administration of additional doses of Calypsol by either the intravenous or intramuscular route.

Each additional dose is from ½ to the full induction dose recommended above for the route selected for maintenance, regardless of the route used for induction.

The larger the total amount of Calypsol administered, the longer will be the time to complete recovery.

Purposeless and tonic-clonic movements of extremities may occur during the course of anaesthesia. These movements do not imply a light plane and are not indicative of the need for additional doses of the anaesthetic.

B. Calypsol as induction agent prior to the use of other general anaesthetics

Induction is accomplished by a full intravenous or intramuscular dose of Calypsol as defined above. If Calypsol has been administered intravenously and the principal anaesthetic is slow- acting, a second dose of Calypsol may be required 5 to 8 minutes following the initial dose. If Calypsol has been administered intramuscularly and the principal anaesthetic is rapid-acting, administration of the principal anaesthetic may be delayed up to 15 minutes following the injection of Calypsol.

C. Calypsol as supplement to anaesthetic agents

Calypsol is clinically compatible with the commonly used general and local anaesthetic agents when an adequate respiratory exchange is maintained. The dose of Calypsol for use in conjunction with other anaesthetic agents is usually in the same range as the dosage stated above; however, the use of another anaesthetic agent may allow a reduction in the dose of Calypsol.

D. Management of patients in recovery

Following the procedure the patient should be observed but left undisturbed. This does not preclude the monitoring of vital signs. If, during the recovery, the patient shows any indication of emergence delirium, consideration may be given to the use of diazepam (5 to 10 mg I.V. in an adult). A hypnotic dose of a thiobarbiturate (50 to 100 mg I.V.) may be used to terminate severe emergence reactions. If any one of these agents is employed, the patient may experience a longer recovery period.

Calypsol is contra-indicated in persons in whom an elevation of blood pressure would constitute a serious hazard.

Calypsol should not be used in patients with eclampsia or pre-eclampsia, severe coronary or myocardial disease, cerebrovascular accident or cerebral trauma.

To be used only in hospitals by or under the supervision of experienced medically qualified anaesthetists except under emergency conditions.

As with any general anaesthetic agent, resuscitative equipment should be available and ready for use.

Respiratory depression may occur with overdosage of Calypsol, in which case supportive ventilation should be employed. Mechanical support of respiration is preferred to the administration of analeptics.

The intravenous dose should be administered over a period of 60 seconds. More rapid administration may result in transient respiratory depression or apnoea and enhanced pressor response.

Because pharyngeal and laryngeal reflexes usually remain active, mechanical stimulation of the pharynx should be avoided unless muscle relaxants, with proper attention to respiration, are used.

Although aspiration of contrast medium has been reported during Calypsol anaesthesia under experimental conditions (Taylor, P A and Towey, R M, Brit. Med. J. 1971, 2: 688), in clinical practice aspiration is seldom a problem.

In surgical procedures involving visceral pain pathways, Calypsol should be supplemented with an agent which obtunds visceral pain.

When Calypsol is used on an outpatient basis, the patient should not be released until recovery from anaesthesia is complete and then should be accompanied by a responsible adult.

Calypsol should be used with caution in patients with the following conditions:

- Use with caution in the chronic alcoholic and the acutely alcohol-intoxicated patient.

- Calypsol is metabolised in the liver and hepatic clearance is required for termination of clinical effects. A prolonged duration of action may occur in patients with cirrhosis or other types of liver impairment. Dose reductions should be considered in these patients. Abnormal liver function tests associated with Calypsol use have been reported, particularly with extended use (>3 days) or drug abuse.

- Since an increase in cerebrospinal fluid (CSF) pressure has been reported during Calypsol anaesthesia, Calypsol should be used with special caution in patients with preanaesthetic elevated cerebrospinal fluid pressure.

- Use with caution in patients with globe injuries and increased intraocular pressure (e.g. glaucoma) because the pressure may increase significantly after a single dose of Calypsol.

- Use with caution in patients with neurotic traits or psychiatric illness (e.g. schizophrenia and acute psychosis)

- Use in caution in patients with acute intermittent porphyria.

- Use in caution in patients with seizures.

- Use in caution in patients with hyperthyroidism or patients receiving thyroid replacement (increased risk of hypertension and tachycardia)

- Use in caution in patients with pulmonary or upper respiratory infection (Calypsol sensitises the gag reflex, potentially causing laryngospasm)

- Use in caution in patients with intracranial mass lesions, a presence of head injury, or hydrocephalus.

Emergence Reaction

The psychological manifestations vary in severity between pleasant dream-like states, vivid imagery, hallucinations, nightmares and emergence delirium (often consisting of dissociative or floating sensations). In some cases these states have been accompanied by confusion, excitement, and irrational behaviour which a few patients recall as an unpleasant experience..

Emergence delirium phenomena may occur during the recovery period. The incidence of these reactions may be reduced if verbal and tactile stimulation of the patient is minimised during the recovery period. This does not preclude the monitoring of vital signs.

Cardiovascular

Because of the substantial increase in myocardial oxygen consumption, Calypsol should be used in caution in patients with hypovolemia, dehydration or cardiac disease, especially coronary artery disease (e.g. congestive heart failure, myocardial ischemia and myocardial infarction). In addition Calypsol should be used with caution in patients with mild-to-moderate hypertension and tachyarrhythmias.

Cardiac function should be continually monitored during the procedure in patients found to have hypertension or cardiac decompensation.

Elevation of blood pressure begins shortly after the injection of Calypsol, reaches a maximum within a few minutes and usually returns to preanaesthetic values within 15 minutes after injection. The median peak rise of blood pressure in clinical studies has ranged from 20 to 25 percent of preanaesthetic values. Depending on the condition of the patient, this elevation of blood pressure may be considered a beneficial effect, or in others, an adverse reaction.

Long-Term Use

Cases of cystitis including haemorrhagic cystitis have been reported in patients being given Calypsol on a long term basis. This adverse reaction develops in patients receiving long term Calypsol treatment after a time ranging from 1 month to several years. Calypsol is not indicated nor recommended for long term use. Hepatotoxicity has also been reported in patients with extended use (> 3 days).

Drug Abuse and Dependence

Calypsol has been reported as being a drug of abuse. Reports suggest that Calypsol produces a variety of symptoms including, but not limited to, flashbacks, hallucinations, dysphoria, anxiety, insomnia, or disorientation. Cases of cystitis including haemorrhagic cystitis and cases of hepatotoxicity have also been reported. If used on a daily basis for a few weeks, dependence and tolerance may develop, particularly in individuals with a history of drug abuse and dependence. Therefore the use of Calypsol should be closely supervised and it should be prescribed and administered with caution.

Patients should be cautioned that driving a car, operating hazardous machinery or engaging in hazardous activities should not be undertaken for 24 hours or more after anaesthesia.

This medicine can impair cognitive function and can affect a patient's ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

- The medicine is likely to affect your ability to drive

- Do not drive until you know how the medicine affects you

- It is an offence to drive while under the influence of this medicine

- However, you would not be committing an offence (called 'statutory defence') if:

o The medicine has been prescribed to treat a medical or dental problem and

o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

o It was not affecting your ability to drive safely

The following Adverse Events have been reported:

†Common (>1/100 to <1/10); Uncommon (>1/1,000 to <1/100); Rare (>1/10,000 to <1/1,000); Not known (frequency cannot be estimated from the available data)

* AE frequency estimated from post-marketing safety database

** Extended period use (> 3 days) or drug abuse

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 at: www.mhra.gov.uk/yellowcard.

Respiratory depression can result from an overdosage of Calypsol hydrochloride. Supportive ventilation should be employed. Mechanical support of respiration that will maintain adequate blood oxygen saturation and carbon dioxide elimination is preferred to administration of analeptics.

Calypsol has a wide margin of safety; several instances of unintentional administration of overdoses of Calypsol (up to 10 times that usually required) have been followed by prolonged but complete recovery.

Pharmacotherapeutic group: Other general anesthetics.

ATC Code: N01A X03

Calypsol is a rapidly acting general anaesthetic for intravenous or intramuscular use with a distinct pharmacological action. Calypsol hydrochloride produces dissociative anaesthesia characterised by catalepsy, amnesia, and marked analgesia which may persist into the recovery period. Pharyngeal-laryngeal reflexes remain normal and skeletal muscle tone may be normal or can be enhanced to varying degrees. Mild cardiac and respiratory stimulation and occasionally respiratory depression occur.

Mechanism of Action:

Calypsol induces sedation, immobility, amnesia and marked analgesia. The anaesthetic state produced by Calypsol has been termed “dissociative anaesthesia” in that it appears to selectively interrupt association pathways of the brain before producing somesthetic sensory blockade. It may selectively depress the thalamoneocortical system before significantly obtunding the more ancient cerebral centres and pathways (reticular-activating and limbic systems). Numerous theories have been proposed to explain the effects of Calypsol, including binding to N-methyl-D-aspartate (NMDA) receptors in the CNS, interactions with opiate receptors at central and spinal sites and interaction with norepinephrine, serotonin and muscarinic cholinergic receptors. The activity on NMDA receptors may be responsible for the analgesic as well as psychiatric (psychosis) effects of Calypsol. Calypsol has sympathomimetic activity resulting in tachycardia, hypertension, increased myocardial and cerebral oxygen consumption, increased cerebral blood flow and increased intracranial and intraocular pressure. Calypsol is also a potent bronchodilator. Clinical effects observed following Calypsol administration include increased blood pressure, increased muscle tone (may resemble catatonia), opening of eyes (usually accompanied by nystagmus) and increased myocardial oxygen consumption.

Absorption

Calypsol is rapidly absorbed following intra-muscular administration.

Distribution

Calypsol is rapidly distributed into perfused tissues including brain and placenta. Animal studies have shown Calypsol to be highly concentrated in body fat, liver and lung.

In humans at an intravenous bolus dose of 2.5 mg/kg, the distribution phase of Calypsol lasts about 45 minutes, with a half-life of 10 to 15 minutes, which is associated with the duration of the anaesthetic effect (about 20 minutes). Plasma Calypsol concentrations are about 1.8 to 2.0 μg/mL at 5 minutes after an intravenous bolus injection of 2 mg/kg dose, and about 1.7 to 2.2 μg/mL at 15 minutes after an intramuscular injection of 6 mg/kg dose in adults and children.

In parturients receiving an intramuscular dose of 250 mg (approximately 4.2 mg/kg), placental transfer rate of Calypsol from maternal artery to umbilical vein was 47% at the time of delivery (1.72 versus 0.75 µ g/mL). Average delivery time for these parturients was 12 minutes from the time of Calypsol injection to vaginal delivery of a newborn.

Biotransformation

Biotransformation takes place in liver. Termination of anaesthetic is partly by redistribution from brain to other tissues and partly by metabolism. CYP3A4 enzyme is the primary enzyme responsible for Calypsol N-demethylation to norCalypsol in human liver microsomes; with CYP2B6 and CYP2C9 enzymes as minor contributors.

Elimination

Elimination half-life is approximately 2-3 hours, and excretion renal, mostly as conjugated metabolites.

Animal research has shown that Calypsol can induce NMDA antagonist-induced neuronal cell death in juvenile animals (apoptosis) when administered in high doses, for prolonged periods, or both. In some cases this led to abnormalities in behaviour, learning and memory. The relevance of this finding to human use is unknown.

Calypsol is chemically incompatible with barbiturates and diazepam because of precipitate formation. Therefore, these should not be mixed in the same syringe or infusion fluid.

For single use only. Discard any unused product.