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SUMMARY OF PRODUCT CHARACTERISTICS
1.
NAME OF THE MEDICINAL PRODUCT
Ketamin Abcur 10 mg/ml, solution for injection
Ketamin Abcur 50 mg/ml, solution for injection
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml solution for injection contains ketamine hydrochloride equivalent to 10 mg ketamine.
1 ampoule of 5 ml contains ketamine hydrochloride equivalent to 50 mg ketamine.
Each ml solution for injection contains ketamine hydrochloride equivalent to 50 mg ketamine.
1 ampoule of 5 ml contains ketamine hydrochloride equivalent to 250 mg ketamine.
1 ampoule of 10 ml contains ketamine hydrochloride equivalent to 500 mg ketamine.
Excipients with known effect: contains 0,29 mmol sodium (6,6 mg) per ml sodium.
For the full list of excipients, see section 6.1.
3.
PHARMACEUTICAL FORM
Solution for injection (injection).
Clear colourless solution
4.
CLINICAL PARTICULARS
4.1
Therapeutic indications
Induction and maintenance of anaesthesia for diagnostic and surgical procedures either as a single
anaesthetic agent or in combination with other anaesthetic agents. Prior to the induction or to supplement
regional anaesthesia.
4.2
Posology and method of administration
Ketamin Abcur should only be administered by or under supervision of medically qualified anaesthetists.
Equipment to ensure the vital functions should be available.
Premedication: Atropine or glycopyrrolate should be given preoperatively to inhibit mucus secretion.
Benzodiazepine derivate such as midazolam, as premedication (intravenous or rectal), can be given to
supress the initial hyperkinetic circulation and reduce the frequency of anxiety during awakening.
Posology
Intramuscular: For intramuscular administration the higher strength, Ketamin Abcur 50 mg/ml, should be
chosen to minimize the volume.
i.m. injection
Induction
Maintenance
Dose (mg/kg body weight)
10.0 (6.5–13.5)
½ the induction dose
Onset time(min)
3-5
Duration(min)
12-25
Intravenous: Administration of the initial intravenous dose should be slow (at least 60 seconds). More rapid
administration may result in transient respiratory depression.
1
i.v. injection
Induction
Maintenance
Dose (mg/kg body weight)
2.0 (1.0–4.5)
½ the induction dose or transition to
infusion. See below.
Onset time (min)
1
Duration(min)
5-15
Conversion table: Dose in mg/kg body weight to dose in ml/kg body weight
Dose
mg/kg body weight
Dose
ml/kg body weight
Dose
ml/kg body weight
1.0
2.0
4.5
6.5
10.0
13.5
Ketamin Abcur 10 mg/ml
0.10
0.20
0.45
0.65
1.00
1.35
Ketamin Abcur 50 mg/ml
0.02
0.04
0.09
0.13
0.20
0.27
Infusion: Infusion gives a more even course of anaesthesia. The total dose of ketamine is often lower than
with intermittent injections and awakening occurs faster. During ventilation with oxygen/nitrous oxide, a
dose of ketamine in the lower range may be sufficient.
Infusion
Induction
Maintenance
Dose
2.0-6.0 mg/kg body weight
2.0-6.0 mg/kg body weight and hour
The dose above is equivalent to about 1 drop/kg body weight and minute of ketamine 1 mg/ml solution for
infusion.
Dosing in obstetrics: For use in obstetrics, during vaginal delivery or cesarean section, an intravenous dose
in the interval 0.2-1.0 mg/kg is recommended, see section 4.6.
Dosing in hepatic impairment: Dose reduction should be considered for patients with cirrhosis or hepatic
impairment for other reasons (see section 4.4).
Dosing in renal impairment
Dose reduction is usually not required.
Paediatric population
The safety and efficay in children below 18 years have not yet been established.
Combination with other anaesthetic agents: Ketamine can advantageously be combined with benzodiazepine
derivates, such as midazolam. Ketamine and midazolam can be mixed in the same infusion (10 ml Ketamin
Abcur 50 mg/ml + 7.5 ml midazolam 5 mg/ml per 500 ml solution for infusion).
Induction (i.v. injection)
ketamine
midazolam
2 mg/kg body weight
0.15 mg/kg kroppsvikt
Maintenance (continuous infusion)
ketamine
midazolam
1 mg/kg bodyweight and hour
0.075 mg/kg body weight and hour
2
Method of administration
For instructions on dilution of the medicinal product before administration, see section 6.6.
4.3
Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Patients whom an elevation of blood pressure would constitute a serious hazard.
Eclampsia or pre-eclampsia.
4.4
Special warnings and precautions for use
Ketamin Abcur should be used with caution in patients with:
- hypovolemia, dehydration or heart disease, especially coronary artery disease (e.g. congestive heart
failure, myocardial ischemia and myocardial infarction), because of the substantial increase in
myocardial oxygen consumption.
- mild to moderate hypertension and tachyarrhythmias.
- elevated cerebrospinal fluid pressure and injuries and diseases of the central nervous system, since an
increase in cerebrospinal fluid pressure has been reported during ketamine anaesthesia.
- increased intraocular pressure (e.g. glaucoma) and examination or surgery of the eye, where an increase
in intraocular pressure is undesirable.
- chronic or acute alcohol intoxication.
- neutrotic traits or pschiatric history ( e.g. schizophrenia and acute psychosis).
- acute intermittent porphyria.
- hyperthyroidism or patients receiving thyroid replacement (increased risk of hypertension and
tachycardia).
- pulmonary or upper respiratory infection (ketamine sensitises the gag reflex, potentially causing
laryngospasm).
- intracranial lesions, head injury, damage to the eyeball or hydrocephalus.
The induction of the anaesthesia is accompanied by occasional tachycardia, elevation of the blood pressure
and cardiac output, which return to baseline within 15 minutes after the injection. The median peak rise of
the blood pressure in clinical studies has ranged from 20 to 25 percent of the initial values. Depending on the
condition of the patient, this elevation of the blood pressure may be considered an adverse reaction or a
beneficial effect of ketamine.
After outpatient anaesthesia the patient should be accompanied home and should not drink alcohol for the
next 24 hours.
Ketamine is metabolised in the liver and hepatic clearance is required for termination of the clinical effects.
A prolonged duration of action may occur in patients with cirrhosis or other types of liver impairment. Dose
reduction should be considered in these patients.
Liver toxicity has been reported in patients after prolonged use (>3 days).
Ketamine has been given as a single agent with good safety when the ventricle has not been emptied. As the
need for additional anaesthetics or muscle relaxants cannot always be predicted it is recommended that the
patient fasts for 4-6 hours prior to surgery to prevent aspiration. Because pharyngeal reflexes usually remains
active, mechanical stimulation of the pharynx should be avoided unless muscle relaxants with proper
attention are used.
Cases of cystitis including haemorrhagic cystitis have been reported in patients being given ketamine on a
long term basis (outside the current indication). This adverse reaction develops in patients receiving long
term ketamine treatment after a time ranging from 1 month to several years.
Abuse and dependence
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Ketamine 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. Cases of cystitis, including haemorrhagic cystitis have also been reported. Dependence and
tolerance may develop in individuals with a history of drug abuse and dependence. Therefore ketamine
should be prescribed and administered with caution.
Ketamin Abcur contains sodium
10 mg/ml: 1 ampoule of 5 ml contains less than 1 mmol sodium (23 mg), i.e. essentially ‘sodium-free’,
4.5
Interaction with other medicinal products and other forms of interaction
Ketamine may increase the effect of coadministered opioids causing increased CNS- and/or respiratory
depression.
Theophylline
Since there is clinical and experimental evidence of lowered seizure threshold at the combination of
theophylline and ketamine combination with theophylline should be avoided. Unpredictable extensor-type
seizures have been reported with concurrent administration of these agents.
Neuromuscular blockers
Ketamine may potentiate and prolong the effect of neuromuscular blocking agents (e g suxametonium and
atracurium) causing prolonged muscle relaxation and/or respiratory depression.
Diazepam
Premedication with diazepam prolongs the half-life of ketamine with enhanced efficacy as a result. The
combination may require dose adjustment.
Vasopressin
At concurrent administration of ketamine and vasopressin synergetic increase in the blood pressure been
observed.
Barbiturates, narcotics, inhalation anaesthetics, alcohol, muscular relaxants
Prolonged recovery time may occur if barbiturates, narcotics and inhalation anaesthetics are used
concurrently with ketamine. 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.
Concurrent administration of ketamine and other sedatives (e.g. ethanol, phenothiazines, sedating H1blockers or muscle relaxants) can potentiate CNS depression and/or increase risk of 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.
Thyroid hormones
Patients taking thyroid hormones have an increased risk of developing hypertension and tachycardia when
given ketamine.
Antihypertensive agents
Concomitant use of antihypertensive agents and ketamine increase the risk of developing hypotension.
Medicinal products that inhibit the enzyme activity of CYP3A4 usually decrease hepatic clearance which
may cause increased plasma concentrations of CYP3A4 substrates such as ketamine. A dose reduction of
ketamine may be required in case of concomitant administration with CYP3A4 inhibitors (e g itraconazole,
fluconazole, clarithromycin, erythromycin, verapamil, diltiazem).
Medicinal products that induce the enzyme activity of CYP3A4 usually increase hepatic clearance which
may cause decreased plasma concentrations of CYP3A4 substrates such as ketamine. A dose increase of
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ketamine may be required in case of concomitant administration with CYP3A4 inducers (eg phenytoin,
carbamazepine, St John´s Wort).
4.6
Fertility, pregnancy and lactation
Pregnancy
No controlled clinical studies in pregancy have been conducted. The safe use in pregnancy has not been
established, and such use is not recommended, with the exception of administration during surgery for
abdominal or vaginal delivery. Ketamine readily crosses the placenta.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 observerd at intravenous doses greater than 2 mg/kg.
Breastfeeding
Ketamine is excreted in the breast milk, but the risk for the infant seems unlikely with therapeutic doses.
Since necessary data is lacking the use cannot be recommended.
4.7
Effects on ability to drive and use machines
After treatment with ketamine the ability to react may be impaired. This should be considered when alertness
is required, e.g. when driving a car.
Patients should not drive motor vehicles or operate machinery at least 24 hours after anaesthesia with
ketamine.
4.8
Undesirable effects
The adverse reactions are mostly related to dose and rate of injection and are reversible. CNS adverse events
are more common if Ketamin Abcur is given as a single anaesthetic.
The following adverse reactions have been observed and reported in treatment with ketamine.
Frequency description: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to<1/100),
rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (frequency cannot be estimated from
available data).
MedDRA
system organ class
database
Common
(1/100, <1/10)
Immune system
disorders
Metabolism and
nutrition disorders
Psychiatric disorders
Uncommon
(1/1 000,
<1/100)
Rare
(1/10 000,
<1/1 000)
anaphylactic
reaction*
anorexia
anxiety
Nervous system
disorders
hallucination,
abnormal dreams,
nightmare,
confusion,
agitation,
abnormal
behaviour
nystagmus, tonic
clonic movements
delirium*,
flashback*,
dysphoria*,
insomnia,
disorientation
Eye disorders
diplopia
increased
intraocular
pressure
5
Not known
(frequency cannot
be estimated from
available data)
MedDRA
system organ class
database
Common
(1/100, <1/10)
Uncommon
(1/1 000,
<1/100)
Cardiac disorders
increased blood
pressure,
increased heart
rate
bradycardia,
arrhythmia
Vascular disorders
Rare
(1/10 000,
<1/1 000)
hypotension
Respiratory, thoracic
and mediastinal
disorders
increased
respiratory rate
Gastrointestinal
disorders
nausea, vomiting,
salivary
hypersecration*
respiratory
depression,
laryngospasm
obstructive airway
disorder*, apnoea*
Hepatobilary
disorders
Skin and
subctaneous tissue
disorders
Musculoskeletal and
connective tissue
disorders
General disorders
and administration
site conditions
Not known
(frequency cannot
be estimated from
available data)
abnormal liver
function test
drug induced liver
damage**
erythema, rash
mobilliform
exanthem
increased muscle
tonus
injection site pain,
injection site rash
*AE frequency estimated from post-marketing safety database
** After prolonged use (>3 days) or drug abuse
Awakening from the anaesthesia is often accompanied by vivid dreams, with or without psychomotor
activity, which can be manifested in nightmares or hallucinations, confusion, emergence delirium (often with
dissociative or floating sensation) and irrational behaviour. The incidence of these reactions is reduced by
combination of Ketamin Abcur and benzodiazepine derivate. Transient respiratory depression due to CNS
disorders can be seen at intravenous induction and is dependent on dose and rate of injection.
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 national reporting system listed in Appendix V*.
4.9
Overdose
Clinical signs of overdose are convulsions, cardiac arrest and respiratory depression.
Respiratory depression should be treated with assisted or controlled ventilation until adequate spontaneous
respiration is restored.
Convulsion should be treated with intravenous diazepam. If this treatment does not give the desired result is
intravenous administration of phenytoin or thiopental recommended.
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No specific antidote is available.
5.
PHARMACOLOGICAL PROPERTIES
5.1
Pharmacodynamic properties
Pharmacotherapeutic group: general anaesthetic, ATC code: N01AX03
Ketamin Abcur contains the active substance ketamine in racemic form. Ketamine gives a dissociative
anaesthesia by selectively interrupting association pathways in the brain. The analgesic effect in sub
anaesthetic doses is probably due to interactions with biogenic amine- and endogenous opioid systems.
Ketamine do not usually affect the reflex of the pharynx and larynx and the muscle tone remains normal or
increases slightly. Cardiovascular and respiratory stimulating effects admit ketamine to be given to high-risk
patients in hypovolemic shock. The bronchodilation action of ketamine allows use in patients with asthma
bronchiale and the respiratory treatment of status astmaticus. The effect on the secretion and the
gastrointestinal tract is attenuated by premedication with anticholinergics. The analgesic effect can be
utilized as a complement to regional anaesthesia or in mass casualty situations/disasters. Ketamine is
clinically compatible with the commonly used anaesthetics and muscle relaxants provided that respiration is
maintained.
An intravenous dose of 2.0 mg/kg body weight provides surgical anaesthesia within one minute after
injection and the anaesthetic effect persists for 5-15 minutes. Intramuscular dosing 10.0 mg/kg body weight
gives surgical anaesthesia within 3-5 minutes after injection with a duration of 12-25 minutes. To achieve
prolonged anaesthesia or analgesia Ketamin Abcur may be given via drip infusion or syringe pump for even
administration. Intravenous or intramuscular administration can be repeated.
5.2
Pharmacokinetic properties
Absorption
Ketamine is rapidly absorbed following intramuscular administration.The bioavailability following
intramuscular administration is 90 %.
Distribution
The binding to plasma proteins is about 50 %. The lipid solubility is high. Ketamine easily passes the
placenta and is quickly distributed to highly perfused tissues (e g heart, lung and brain), followed by muscle
tissues and then fat. Ketamine has a biphasic plasma profile with a distribution phase lasting for 45 minutes
and with distribution half-life of 10-15 minutes, which clinically corresponds to the anaesthetic effect.
Maximum plasma concentrations are approximately 0.6-0.7 µg/ml and levels in cerebrospinal fluid are
approximately 0.2 µg/ml 1-2 hours after an intravenous ketamine dose of 1 mg/kg.
Biotransformation
Degradation of ketamine occurs in the liver. The plasma half-life is about 80 minutes in adults, slightly
shorter for children.
Ketamine is N-demetylated in the liver (via the cytochrome P450 system) and hydroxylated on the
cyclohexane ring resulting in water soluble conjugates that are excreted in the urine. CYP3A4 is the primary
enzyme responsible for N-demethylation of ketamine to norketamine in human liver microsomes, and the
enzymes CYP2B6 and CYP2C9 contribute to a small extent. Additional oxidation occurs with formation of
cyclohexanon derivates. The nonconjugated N-demethylated metabolite has been demonstrated to have less
than 1/6 of the potency of ketamine. The nonconjugated demethylcyclohexanone derivative has been
demonstrated to have less than 1/10 of the potency of ketamine.
Elimination
Results from adults show that approximately 91% of the dose is recovered in urine and faeces.
7
5.3
Preclinical safety data
There are no preclinical data considered relevant to clinical safety beyond data included in other sections of
this Summary of Product Characteristics.
6.
PHARMACEUTICAL PARTICULARS
6.1
List of excipients
10 mg/ml:
Sodium chloride
Water for injections
50 mg/ml:
Water for injections
6.2
Incompatibilities
Ketamin Abcur is chemically incompatible with barbiturates and diazepam because of formation of
precipitate. Therefore, these should not be mixed in the same syringe or infusion fluid.
This medicinal product must not be mixed with other medicinal products except those mentioned in section
6.6.
6.3
Shelf life
Before first opening:3 years
After opening: Chemical and physical in-use stability has been demonstrated for 48 hours at 25°C. From
microbiological point of view, the product should be used immediately. If not used immediately, in-use
storage times and conditions prior to use are the responsibility of the user and would normally not be longer
than 24 hours at 2 to 8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic
conditions.
6.4
Special precautions for storage
No special storage conditions.
6.5
Nature and contents of container
Ketamin Abcur 10 mg/ml:
Ketamin Abcur 50 mg/ml:
5 ml glass ampoules (type I) in boxes of 5, 10, 20, 50 or 100 ampoules.
5 ml glass ampoules (type I) in boxes of 5, 10, 20, 50 or 100 ampoules.
10 ml glass ampoules (type I) in boxes of 5, 10, 20, 50 or 100 ampoules.
Not all pack sizes may be marketed.
6.6
Special precautions for disposal and other handling
Ketamin Abcur can be diluted with 50 mg/ml (5%) glucose solution and 9 mg/ml (0.9%) sodium chloride.
Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.
7.
MARKETING AUTHORISATION HOLDER
8
Abcur AB
Box 1452
251 14 Helsingborg
Sweden
8.
MARKETING AUTHORISATION NUMBER(S)
<[To be completed nationally]>
9.
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
10.
DATE OF REVISION OF THE TEXT
22 December 2015
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