KETAMINE G.L. PHARMA 50 MG / ML SOLUTION FOR INJECTION/INFUSION IN VIALS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Ketamine G.L. Pharma 50 mg/ml Solution for injection/infusion in vials

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Ketamine G.L. Pharma 50 mg/ml Solution for injection/infusion

Each mL of solution contains ketamine hydrochloride equivalent to 50 mg ketamine.

Each 5 mL vial contains 250 mg ketamine.

Each 10 mL vial contains 500 mg ketamine.

Each 20 mL vial contains 1,000 mg ketamine.

Excipient with known effect:

Each mL of solution contains 2.6 mg sodium.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Solution for injection or infusion

Clear, colourless solution

pH 3.5–5.0

Osmolality:

Ketamine G.L. Pharma 50 mg/ml Solution for Injection/Infusion: 360–420 mosmol/kg

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Ketamine is indicated in children, adolescents and adults.

Ketamine is recommended

– as an anaesthetic agent in diagnostic and surgical procedures. When used by intravenous (i.v.) or intramuscular (i.m.) injection, ketamine is best suited for short procedures. With additional doses, or by intravenous infusion (see section 4.3), ketamine 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 catheterisation 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

Posology

Note

All doses are given in terms of ketamine base.

Preoperative preparations

Ketamine 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 glycopyrrolate) or another drying agent should be given at an appropriate interval prior to induction to reduce ketamine-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

As with other general anaesthetic agents, the individual response to ketamine 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 i.v. injection, the patient should be in a supported position during administration. An i.v. dose of 2 mg/kg of bodyweight usually produces surgical anaesthesia within 30 seconds after injection and the anaesthetic effect usually lasts 5–10 minutes. An i.m. dose of 10 mg/kg of bodyweight usually produces surgical anaesthesia within 3–4 minutes following injection and the anaesthetic effect usually lasts 12–25 minutes. Return to consciousness is gradual.

A. Ketamine G.L. Pharma as the sole anaesthetic agent

Intravenous infusion (see section 4.3)

The use of Ketamine G.L. Pharma 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 ketamine is suitable for administration by infusion.

For the preparation of an infusion the following solutions are suitable: sodium chloride 0.9% solution for injection

sodium chloride and dextrose solution for injection (sodium chloride 0.18% w/v and dextrose 4% w/v)

Ringer’s solution for injection

Lactated Ringer’s solution for injection

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

lnduction

lntravenous route

The initial dose of ketamine administered i.v. may range from 1–4.5 mg/kg body weight (in terms of ketamine base). The average amount required to produce 510 minutes of surgical anaesthesia has been 2.0 mg/kg. It is recommended that i.v. 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

In obstetrics, for vaginal delivery or in caesarean section, i.v. doses ranging from 0.21.0 mg/kg are recommended (see section 4.6).

Intramuscular route

The initial dose of Ketamine G.L. Pharma administered intramuscularly may range from 6.5–13 mg/kg (in terms of ketamine 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 12–25 minutes of surgical anaesthesia.

Dosage in obstetrics

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.

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 Ketamine G.L. Pharma by either the intravenous or intramuscular rou­te.

Each additional dose is from Î4 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 ketamine 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. Ketamine G.L. Pharma as induction agent prior to the use of other general anaesthetics

Induction is accomplished by a full intravenous or intramuscular dose of ketamine as defined above. If Ketamine G.L. Pharma has been administered intravenously and the principal anaesthetic is slow-acting, a second dose of Ketamine G.L. Pharma may be required 5–8 minutes following the initial dose. If Ketamine G.L. Pharma 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 Ketamine G.L. Pharma.

C. Ketamine G.L. Pharma as supplement to anaesthetic agents

Ketamine G.L. Pharma is clinically compatible with the commonly used general and local anaesthetic agents when an adequate respiratory exchange is maintained. The dose of Ketamine G.L. Pharma 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 ketamine.

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 (5–10 mg i.v. in an adult). A hypnotic dose of a thiobarbiturate (50–100 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.

Special populations

Paediatric population

Ketamine G.L. Pharma in vials must not be used in the paediatric population (see section 4.3).

Elderly (over 65 years)

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

Hepatic impairment

Dose reductions should be considered in patients with cirrhosis or other types of liver impairment (see section 4.4).

Method of administration

Intravenous or intramuscular use.

Intravenous infusion after dilution.

For special restrictions for vials in the paediatric population, for intravenous infusion and for volumes larger than 15 ml, see section 4.3.

For instructions on dilution of the medicinal product before administration as an infusion, see section 6.6

4.3 Contraindications

– Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

– Patients in whom an elevation of blood pressure would constitute a serious hazard (see section 4.8)

– Severe coronary or myocardial disease

– Eclampsia or pre-eclampsia

– Cerebrovascular accident or cerebral trauma

– Ketamine G.L. Pharma in vials must not be used (because of the content of the excipient benzethonium chloride):

o in the paediatric population

o for infusion (in all patient populations)

o in larger volumes than 15 ml in single doses (in all patient populations)

4.4 Special warnings and precautions for use

Ketamine should be used only in hospitals or under the supervision of an experienced medically qualified anaesthetist 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 ketamine, 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.

As the pharyngeal and laryngeal reflexes generally 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 ketamine anaesthesia under experimental conditions, in clinical practice aspiration is seldom a problem.

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

When ketamine 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.

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

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

– 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 ketamine anaesthesia, ketamine should be used with special caution in patients with preanaesthetic elevated CSF 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 ketamine, 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 20–25% 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 given ketamine on a long-term basis (one month up to several years). Ketamine is not indicated nor recommended for long term use. Hepatotoxicity has also been reported in patients with extended use (longer than 3 days).

Drug abuse and dependence

The abuse of ketamine has been reported. These reports suggest that ketamine produces a variety of symptoms including (but not limited to) flashbacks, hallucinations, dysphoria, anxiety, insomnia, or disorientation. Moreover, 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 an existing or a history of drug abuse or dependence.

Therefore the use of ketamine should be closely supervised, and it should be prescribed and administered with special 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 ketamine.

Ketamine is chemically incompatible with barbiturates and diazepam (see section 6.2).

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 muscle relaxants like 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 H1-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.

In combination with xanthine derivatives (e.g. aminophylline, theophylline) a lowering of the seizure threshold may occur. Therefore, concomitant administration should be avoided. Unpredictable extensor-type seizures have been reported with concurrent administration of these agents.

Generally, CYP3A4 inhibitors cause hepatic clearance to decrease. This leads to increased plasma concentrations of CYP3A4 substrates such as ketamine.

Coadministration of ketamine with medicinal products that inhibit the CYP3A4 enzyme may require a reduction in ketamine dosage to achieve the desired clinical effect.

Generally, CYP3A4 inducers cause hepatic clearance to increase. This leads to decreased plasma concentrations of CYP3A4 substrates such as ketamine.

Coadministration of ketamine with medicinal products that induce the CYP3A4 enzyme may require an increase in ketamine dosage to achieve the desired clinical effect.

4.6 Fertility, pregnancy and lactation

Pregnancy

Ketamine 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 i.v. 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 i.v. doses greater than 2 mg/kg.

Data are lacking for i.m. injection and maintenance infusion of ketamine in the parturient population, and recommendations cannot be made. Available data are presented in section 5.2.

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

Breast-feeding

The safe use of ketamine during lactation has not been established. Therefore the use is not recommended.

4.7 Effects on ability to drive and use machines

Patients should be cautioned that driving motor vehicles, operating machinery or working in hazardous situations 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:

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

– You have taken it according to the instructions given by the prescriber and in

the information provided with the medicine and

– It was not affecting your ability to drive safely

4.8 Undesirable effects

The following adverse events have been reported.

The frequencies are defined as follows: 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 (cannot be estimated from available data).

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:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

4.9 Overdose

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

Symptoms

Respiratory depression can result from an overdosage of ketamine.

Management

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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: General anaesthetics

ATC code: N01AX03

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 producing somatosensory blockade. It may selectively depress the thalamo-neocortical 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 10–15 minutes, which is associated with the duration of the anaesthetic effect (about 20 minutes). Plasma ketamine concentrations are about 1.8–2.0 jig/mL at 5 minutes after an i.v. bolus injection of 2 mg/kg dose, and about 1.7–2.2 jig/mL at 15 minutes after an i.m. injection of 6 mg/kg dose in adults and children.

In parturients receiving an i.m. 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 |jg/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 these results for humans is not known.

Published studies in animals (including primates) at doses resulting in light to moderate anaesthesia demonstrated that the use of anaesthetic agents during the period 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

Ketamine G.L. Pharma 50 mg/ml Solution for Injection/Infusion in vials

Benzethonium chloride

Hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

Water for injection

6.2 Incompatibilities

Ketamine is chemically incompatible with barbiturates and diazepam because of precipitate formation. 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

30 months

Vials: For single use only. Discard any unused product at the end of each operating session.

After dilution: Chemical and physical stability has been demonstrated for 48 hours at 25°C.

From a 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 12 hours at 2–8°C, unless reconstitution/di­lution has taken place in controlled and validated aseptic conditions.

For further information see section 6.6.

6.4 Special precautions for storage

Do not freeze.

Store in the original package in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Vials (type 1) closed with chlorobutyl rubber stoppers and sealed with aluminium/ polypropylene flip-off caps.

Ketamine G.L. Pharma 50 mg/ml Solution for Injection/Infusion in vials

Packs of 5, 10 or 20 mL vials in boxes of 1, 5, 10, 15, 20, 50, or 100.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

If required, Ketamine G.L. Pharma can be diluted with

– sodium chloride 0.9% solution for injection

– sodium chloride and dextrose solution for injection (sodium chloride 0.18% w/v and dextrose 4% w/v)

– Ringer’s solution for injection

– Lactated Ringer’s solution for injection

No evidence of incompatibility was observed between Ketamine G.L. Pharma and representative brands of injectable forms of the following drugs when stored over a 48 hour period at ambient temperature using sodium chloride 0.9% solution for injection as diluent

– morphine hydrochloride

– oxycodone hydrochloride

– hydromorphone hydrochloride

Use only if the solution is clear and colourless and without precipitate.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

G.L. Pharma GmbH,

Schlossplatz 1,

8502 Lannach,

Austria

8 MARKETING AUTHORISATION NUMBER(S)

PL 21597/0069

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

25/07/2019