KETALAR INJECTION 10 MGML

רזייפ יא ףא יפ מ"עב לארשי הקיטבצמרפ

רקנש 'חר

.ד.ת ,

12133

לארשי ,חותיפ הילצרה

46725

:לט

972-9-9700500

:סקפ

972-9-9700501

רבוטקוא

2018

,ה/דבכנ ת/חקור ,ה/אפור

ולעב ןוכדע לע ךעידוהל וננוצרב

אפורל

(אפורל ןולע תנוכתמב ןכרצל ןולע)

לש

רישכתה :םי

Ketalar injection 10mg/ml

Ketalar 50mg/ml injection

:ליעפה ביכרמה

Ketamine (as hydrochloride) 10mg/mL

Ketamine (as hydrochloride) 50mg/ml

Indicated for:

As the sole anaesthetic agent for diagnostic and surgical procedures.

When used by intravenous or intramuscular injection, Ketalar is best suited for short procedures. With

additional doses, or by intravenous infusion, Ketalar 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 procedure: 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 movement 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 reduction, manipulation femoral pinning, amputations and biopsies.

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

Cardiac catheterization procedures.

Caesarian section: as an induction agent in the absence of elevated blood pressure. Anaesthesia in the

asthmatic patient, either to minimise the risk of an attack of bronchospasm developing or in the presence of

bronchospasm where anaesthesia cannot be delayed.

:אפורל ןולעב םיירקיעה םינוכדעה ןלהל

4.5

Interaction with other medicinal products and other forms of interaction

Prolonged recovery time may occur if barbiturates and/or narcotics are used concurrently with

Ketalar

Ketalar

is chemically incompatible with barbiturates and diazepam because of precipitate

formation. Therefore, these should not be mixed in the same syringe or infusion fluid.

Diazepam is known to increase the half-life of ketamine and prolongs its pharmacodynamic effects.

Dose adjustments may therefore be needed.

Ketamine may potentiate the neuromuscular blocking effects of atracurium and tubocurarine

including respiratory depression with apnoea.

The use of halogenated anaesthetics concomitantly with ketamine can lengthen the elimination half-

life of ketamine and delay recovery from anaesthesia. Concurrent use of ketamine (especially in high

doses or when rapidly administered) with halogenated anaesthetics can increase the risk of

developing bradycardia, hypotension or decreased cardiac output.

The use of ketamine with other central nervous system (CNS) depressants (e.g. ethanol,

phenothiazines, sedating H

– blockers or skeletal muscle relaxants) can potentiate CNS depression

and/or increase risk of developing respiratory depression. Reduced doses of ketamine may be

required with concurrent administration of other anxiolytics, sedatives and hypnotics.

Ketamine has been reported to antagonise the hypnotic effect of thiopental.

Patients taking thyroid hormones have an increased risk of developing hypertension and tachycardia

when given ketamine.

Concomitant use of antihypertensive agents and ketamine increases the risk of developing

hypotension.

Sympathomimetics (directly or indirectly acting) and vasopressin may enhance the

sympathomimetic effects of ketamine.

Concomitant use with ergometrine may lead to an increase in blood pressure.

When ketamine and theophylline or aminophylline are given concurrently, a clinically significant

reduction in the seizure threshold may be is observed. Unpredictable extensor-type seizures have

been reported with concurrent administration of these agents.

Drugs that inhibit CYP3A4 enzyme activity generally decrease hepatic clearance, resulting in

increased plasma concentration of CYP3A4 substrate medications, such as ketamine.

Coadministration of ketamine with drugs that inhibit CYP3A4 enzyme may require a decrease in

ketamine dosage to achieve the desired clinical outcome.

Drugs that induce CYP3A4 enzyme activity generally increase hepatic clearance, resulting in

decreased plasma concentration of CYP3A4 substrate medications, such as ketamine.

Coadministration of ketamine with drugs that induce CYP3A4 enzyme may require an increase in

ketamine dosage to achieve the desired clinical outcome.

.הרמחה םיווהמ בוהצ עקרב םישגדומה םייונישה ינוכדעו עדימ תטמשה ,עדימ תפסות םיללוכה םיפסונ םייוניש ועצוב ,ןכ ומכ .הרמחה םיווהמ םניאש חסונ

ולעה

דועמה ןכ

חלשנ

ךרוצל תואירבה דרשמל מוסרפ

:תואירבה דרשמ רתאבש תופורתה רגאמב

https://www.old.health.gov.il/units/pharmacy/trufot/index.asp?safa=h

ולע תלבקל ,ןיפוליחל םינ

אלמ םי

ספדומ םי

חל תונפל ןתינ יא ףא יפ רזייפ תרב מ"עב לארשי הקיטבצמרפ

רקנש

.ד.ת ,

12133

,חותיפ הילצרה

46725

רבב ,הכ

ידובע לטרוא

הנוממ תחקור

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

Ketalar

Injection 10 mg/ml

Ketalar

50 mg/ml Injection

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 1 ml of solution contains:

Ketalar

Injection 10mg/ml: ketamine (as hydrochloride) equivalent to 10 mg

ketamine base per ml.

Excipient(s) with known effect: Each 1 ml contains 2.6 mg of sodium

Ketalar

50mg/ml Injection: ketamine (as hydrochloride) equivalent to 50 mg

ketamine base per ml.

For the full list of excipients see section 6.1.

3

PHARMACEUTICAL FORM

Solution for Injection or Infusion

A clear solution for injection or infusion.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

As the sole anaesthetic agent for diagnostic and surgical procedures. When used by

intravenous or intramuscular injection, Ketalar

is best suited for short procedures.

With additional doses, or by intravenous infusion, Ketalar

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.

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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.

4.2

Posology and method of administration

Preoperative preparations

While vomiting has been reported following ketamine administration, some airway

protection may be afforded because of active laryngeal-pharyngeal reflexes.

However, since aspiration may occur with ketamine and since protective reflexes may

also be diminished by supplementary anesthetics and muscle relaxants, the possibility

of aspiration must be considered. Ketamine is recommended for use in the patient

whose stomach is not empty when, in the judgment of the practitioner, the benefits of

the drug outweigh the possible risks.

Premedications with an anticholinergic agent (e.g., atropine, scopolamine, hyoscine,

or glycopyrrolate) or another drying agent should be given at an appropriate interval

prior to induction to reduce ketalar-induced hypersalivation.

Midazolam, diazepam, lorazepam, or flunitrazepam used as a premedicant or as an

adjunct to ketamine, have been effective in reducing the incidence of emergence

reactions.

Onset and duration

Because of rapid induction following intravenous injection, the patient should be in a

supported position during administration.

The onset of action of ketamine is rapid; an intravenous dose of 2 mg/kg of body

weight usually produces surgical anaesthesia within 30 seconds after injection and the

anaesthetic effect usually lasts 5 to 10 minutes. If a longer effect is desired, additional

increments can be administered intravenously or intramuscularly to maintain

anesthesia without producing significant cumulative effects.

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Intramuscular doses, from experience primarily in pediatric patients, in a range of 9

mg/kg to 13 mg/kg usually produce surgical anesthesia within 3 to 4 minutes

following injection, with the anesthetic effect usually lasting 12 to 25 minutes.

Dosage:

As with other general anesthetic agents, the individual response to ketamine is

somewhat varied depending on the dose, route of administration, and age of patient,

so that dosage recommendation cannot be absolutely fixed. The drug should be

titrated against the patient's requirements.

Supplementary Agents:

Ketamine is clinically compatible with the commonly used general and local

anesthetic agents when an adequate respiratory exchange is maintained.

The regimen of a reduced dose of ketamine supplemented with diazepam can be used

to produce balanced anesthesia by combination with other agents such as nitrous

oxide and oxygen.

General Anesthesia Induction

Intravenous Route:

Adults

: The initial dose of Ketamine administered intravenously may range from 1

mg/kg to 4.5mg/kg. The average amount required to produce 5 to 10 minutes of

surgical anaesthesia has been 2.0 mg/kg.

Alternatively, in adult patients an induction dose of 1.0 mg to 2.0 mg/kg intravenous

ketamine at a rate of 0.5 mg/kg/min may be used for induction of anesthesia. In

addition, diazepam in 2 mg to 5 mg doses, administered in a separate syringe over 60

seconds, may be used. In most cases, 15 mg of intravenous diazepam or less will

suffice. The incidence of psychological manifestations during emergence, particularly

dream-like observations and emergence delirium, may be reduced by this induction

dosage program.

Rate of Administration: It is recommended that ketamine be administered slowly

(over a period of 60 seconds). More rapid administration may result in respiratory

depression and enhanced pressor response.

Intramuscular Route:

Adults

: The initial dose of ketamine administered intramuscularly may range from 6.5

mg/kg to 13 mg/kg. A dose of 10 mg/kg will usually produce 12 to 25 minutes of

surgical anaesthesia.

Dosage in Hepatic Insufficiency:

Dose reductions should be considered in patients with cirrhosis or other types of liver

impairment (see section

4.4 Special warnings and Precautions for Use –

General).

Maintenance of General Anaesthesia

The maintenance dose should be adjusted according to the patient's anesthetic needs

and whether an additional anesthetic agent is employed.

Increments of one-half to the full induction dose may be repeated as needed for

maintenance of anesthesia. However, it should be noted that purposeless and tonic-

clonic movements of extremities may occur during the course of anesthesia. These

movements do not imply a light plane and are not indicative of the need for additional

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doses of the anesthetic. It should be recognized that the larger the total dose of

ketamine administered, the longer will be the time to complete recovery.

Adult patients induced with ketamine augmented with intravenous diazepam may be

maintained on ketamine given by slow microdrip infusion technique at a dose 0.1

mg/minute to 0.5 mg/minute, augmented with diazepam 2 to 5 mg administered

intravenously as needed. In many cases 20 mg or less of intravenous diazepam total

for combined induction and maintenance will suffice. However, slightly more

diazepam may be required depending on the nature and duration of the operation,

physical status of the patient, and other factors. The incidence of psychological

manifestations during emergence, particularly dream-like observations and

emergence delirium, may be reduced by this maintenance dosage program.

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section

6.1.Ketalar

is contraindicated in persons in whom an elevation of blood pressure

would constitute a serious hazard (see section 4.8). Ketalar

should not be used in

patients with eclampsia or pre-eclampsia, severe coronary or myocardial disease,

cerebrovascular accident or cerebral trauma.

4.4

Special warnings and precautions for use

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 Ketalar

, 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 Ketalar

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, Ketalar

should be

supplemented with an agent which obtunds visceral pain.

When Ketalar

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.

Ketalar

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

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

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Ketamine 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 ketamine 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

Ketalar

anaesthesia, Ketalar

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

ketamine.

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 (ketamine

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(see section 4.8).

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, ketamine

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, ketamine 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 Ketalar

, 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

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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, acute kidney injury,

hydronephrosis, and ureteral disorders have been reported in patients being given

ketamine on a long term basis, especially in the setting of ketamine abuse. These

adverse reactions develop in patients receiving long-term ketamine treatment after a

time ranging from 1 month to several years).

Ketamine 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

Ketalar

has been reported as being a drug of abuse. Reports suggest that ketamine

produces a variety of symptoms including, but not limited to, flashbacks,

hallucinations, dysphoria, anxiety, insomnia, or disorientation. Adverse effects have

also been reported: see “Long-Term Use”.

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 Ketalar

should be closely supervised and it should be prescribed and

administered with caution.

4.5

Interaction with other medicinal products and other forms of interaction

Prolonged recovery time may occur if barbiturates and/or narcotics are used

concurrently with Ketalar

Diazepam is known to increase the half-life of ketamine and prolongs its

pharmacodynamic effects. Dose adjustments may therefore be needed.

Ketalar

is chemically incompatible with barbiturates and diazepam because of

precipitate formation. Therefore, these should not be mixed in the same syringe or

infusion fluid.

Ketamine may potentiate the neuromuscular blocking effects of atracurium and

tubocurarine including respiratory depression with apnoea.

The use of halogenated anaesthetics concomitantly with ketamine can lengthen the

elimination half-life of ketamine and delay recovery from anaesthesia. Concurrent use

of ketamine (especially in high doses or when rapidly administered) with halogenated

anaesthetics can increase the risk of developing bradycardia, hypotension or

decreased cardiac output.

The use of ketamine with other central nervous system (CNS) depressants (e.g.

ethanol, phenothiazines, sedating H

– blockers or skeletal muscle relaxants) can

potentiate CNS depression and/or increase risk of developing respiratory depression.

Reduced doses of ketamine may be required with concurrent administration of other

anxiolytics, sedatives and hypnotics.

Ketamine has been reported to antagonise the hypnotic effect of thiopental.

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Patients taking thyroid hormones have an increased risk of developing hypertension

and tachycardia when given ketamine.

Concomitant use of antihypertensive agents and ketamine increases the risk of

developing hypotension.

Sympathomimetics (directly or indirectly acting) and vasopressin may enhance the

sympathomimetic effects of ketamine.

Concomitant use with ergometrine may lead to an increase in blood pressure.

When ketamine and theophylline or aminophylline are given concurrently, a

clinically significant reduction in the seizure threshold may be

observed.

Unpredictable extensor-type seizures have been reported with concurrent

administration of these agents.

Drugs that inhibit CYP3A4 enzyme activity generally decrease hepatic clearance,

resulting in increased plasma concentration of CYP3A4 substrate medications, such

as ketamine. Coadministration of ketamine with drugs that inhibit CYP3A4 enzyme

may require a decrease in ketamine dosage to achieve the desired clinical outcome.

Drugs that induce CYP3A4 enzyme activity generally increase hepatic clearance,

resulting in decreased plasma concentration of CYP3A4 substrate medications, such

as ketamine. Coadministration of ketamine with drugs that induce CYP3A4 enzyme

may require an increase in ketamine dosage to achieve the desired clinical outcome.

4.6

Fertility, pregnancy and lactation

Pregnancy

Ketalar

crosses the placenta. This should be borne in mind during operative obstetric

procedures in pregnancy. No controlled clinical studies in pregnancy have been

conducted. The use in pregnancy has not been established, and such use is not

recommended, with the exception of administration during surgery for abdominal

delivery or vaginal delivery.

Some neonates exposed to ketamine at maternal intravenous doses ≥ 1.5 mg/kg

during delivery have experienced respiratory depression and low Apgar scores

requiring newborn resuscitation.

Marked increases in maternal blood pressure and uterine tone have been observed at

intravenous doses greater than 2 mg/kg.

Data are lacking for intramuscular injection and maintenance infusion of ketamine in the

parturient population, and recommendations cannot be made. Available data are

presented in section 5.2.

Lactation

The safe use of ketamine during lactation has not been established, and such use is

not recommended.

Studies in animals have shown reproductive toxicity (see section 5.3).

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4.7

Effects on ability to drive and use machines

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. 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

4.8

Undesirable effects

The following adverse events have been reported:

MedDRA

System Organ Class

Frequency†

Undesirable Effects

Immune system disorders

Rare

Anaphylactic reaction*

Metabolism and nutrition

disorders

Uncommon

Anorexia

Psychiatric disorders

Common

Hallucination, Abnormal dreams,

Nightmare, Confusion, Agitation,

Abnormal behaviour

Uncommon

Anxiety

Rare

Delirium*, Flashback*, Dysphoria*,

Insomnia, Disorientation*

Nervous system disorders

Common

Nystagmus, Hypertonia, Tonic-clonic

movements

Eye disorders

Common

Diplopia

Not known

Intraocular pressure increased

Cardiac disorders

Common

Blood pressure increased, Heart rate

increased

Uncommon

Bradycardia, Arrhythmia

Vascular disorders

Uncommon

Hypotension

Respiratory, thoracic and

mediastinal disorders

Common

Respiratory rate increased

Uncommon

Respiratory depression, Laryngospasm

Rare

Obstructive airway disorder*,

Apnoea*

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Gastrointestinal disorders

Common

Nausea, Vomiting

Rare

Salivary hypersecretion*

Hepatobiliary disorders

Not known

Liver function test abnormal, Drug-

induced liver injury**

Skin and subcutaneous

tissue disorders

Common

Erythema, Rash morbilliform

Renal and urinary

disorders

Rare

Cystitis*, Haemorrhagic cystitis*

General disorders and

administration site

conditions

Uncommon

Injection site pain, Injection site rash

†

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. Any suspected adverse events should be reported to the Ministry of Health

according to the National Regulation by using an online form

https://sideeffects.health.gov.il

4.9

Overdose

Respiratory depression can result from an overdosage of ketamine 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.

Ketalar

has a wide margin of safety; several instances of unintentional

administration of overdoses of Ketalar

(up to 10 times that usually required) have

been followed by prolonged but complete recovery.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

ATC Code: N01AX03, Pharmacotherapeutic group: Other general anaesthetics.

Ketamine is a rapidly acting general anaesthetic for intravenous or intramuscular use

with a distinct pharmacological action. Ketamine 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:

Ketamine induces sedation, immobility, amnesia and marked analgesia. The

anaesthetic state produced by ketamine has been termed “dissociative anaesthesia” in

that it appears to selectively interrupt association pathways of the brain before

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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 ketamine, 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 ketamine.

Ketamine has sympathomimetic activity resulting in tachycardia, hypertension,

increased myocardial and cerebral oxygen consumption, increased cerebral blood

flow and increased intracranial and intraocular pressure. Ketamine is also a potent

bronchodilator. Clinical effects observed following ketamine administration include

increased blood pressure, increased muscle tone (may resemble catatonia), opening of

eyes (usually accompanied by nystagmus) and increased myocardial oxygen

consumption.

5.2

Pharmacokinetic properties

Absorption

Ketamine is rapidly absorbed following intramuscular administration.

Distribution

Ketamine is rapidly distributed into perfused tissues including brain and placenta.

Animal studies have shown ketamine 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

ketamine 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

ketamine concentrations are about 1.8 to 2.0

g/mL at 5 minutes after an intravenous

bolus injection of 2 mg/kg dose, and about 1.7 to 2.2

g/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 ketamine from maternal artery to umbilical vein was 47% at

the time of delivery (1.72 versus 0.75 µg/mL). Average delivery time for these

parturients was 12 minutes from the time of ketamine 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 ketamine N-demethylation to norketamine 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.

5.3

Preclinical safety data

Animal research has shown that ketamine 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.

Published studies in animals (including primates) at doses resulting in light to

moderate anaesthesia demonstrate that the use of anaesthetic agents during the period

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of rapid brain growth or synaptogenesis results in cell loss in the developing brain

that can be associated with prolonged cognitive deficiencies. The clinical significance

of these nonclinical findings is not known.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Ketalar

Injection 10mg/ml:

sodium chloride, benzethonium chloride, water for

injections, nitrogen

Ketalar

50mg/ml Injection:

benzethonium chloride, water for injections,

nitrogen

6.2

Incompatibilities

Ketalar

is chemically incompatible with barbiturates and diazepam because of

precipitate formation. Therefore, these should not be mixed in the same syringe or

infusion fluid.

6.3

Shelf life

The expiry date of the product is indicated on the packaging materials. For single use

only. Discard any unused product at the end of each operating session.

After dilution the solutions should be used immediately.

6.4

Special precautions for storage

Store below 25°C. Protect from light. Do not freeze.

6.5

Nature and contents of container

Ketalar

Injection 10 mg/ml: 20 ml neutral clear glass vial with rubber closure and

aluminium flip-off cap containing 20 ml of solution as 10 mg ketamine base per ml.

Ketalar

50 mg/ml Injection: 10 ml neutral clear glass vial with rubber closure and

aluminium flip-off cap containing 10 ml of solution as 50 mg ketamine base per ml.

6.6

Instructions for use/handling

Dilution: To prepare a dilute solution containing 1 mg of ketamine per mL,

aseptically transfer 10 mL (50 mg/mL vial) to 500 mL of 5% dextrose injection, or

sodium chloride (0.9%) for injection, and mix well. The resultant solution will

contain 1 mg of ketamine per mL. A 1 mg/mL solution of ketamine in dextrose 5%

or sodium chloride 0.9% is stable for 24 hours.

The fluid requirements of the patient and duration of anesthesia must be considered

when selecting the appropriate dilution of ketamine. If fluid restriction is required,

ketamine can be added to a 250 mL infusion as described above to provide a ketamine

concentration of 2 mg/mL.

Ketamine vials in the 10 mg/mL concentration are not recommended for dilution.

7 Manufacturer:

Ketalar LPD CC 190320

2019-0053982

Page 12 of 12

Siegfried Hameln GmbH, Hameln, Germany

8 License Holder:

Pfizer PFE Pharmaceuticals Israel Ltd., 9 Shenkar St, Herzliya Pituach 46725.

9 License Number:

Ketalar

Injection 10 mg/ml: 110-91-21856

Ketalar

50 mg/ml Injection: 110-99-21857

The content of this leaflet was approved by the Ministry of Health in July 2017 and updated

according to the guidelines of the Ministry of Health in March 2020