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MercuryPharma

PACKAGE LEAFLET: INFORMATION FOR THE USER

Prilotekal®

prilocaine hydrochloride

Read all of this leaflet carefully before you are given this medicine.

Keep this leaflet.You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

1.    What Prilotekal is and what it is used for

2.    Before Prilotekal is given

3.    How Prilotekal is given

4.    Possible side effects

5.    How to store Prilotekal

6.    Further information

1.    What Prilotekal is and what it is used for

Prilotekal contains a medicine called prilocaine hydrochloride. This belongs to a group of medicines called local anaesthetics. Prilotekal is used to anaesthetise (numb) specific parts of the body and prevent pain during surgery.

2.    Before Prilotekal is given Do not use Prilotekal if you:

-    are allergic (hypersensitive) to prilocaine hydrochloride or any of the other ingredients of Prilotekal (see Section 6: Further information),

-    have problems with your heart,

-    suffer from severe anaemia (a blood problem which means you have too few red blood cells),

-    suffer from shock,

-    have a problem with blood pigment levels called ‘methaemoglobinaemia’. You must not be given Prilotekal if any of the above apply to you. If you are not sure, talk to your doctor before you are given Prilotekal.

Take special care with Prilotekal

and speak to your doctor before having Prilotekal if you:

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Prilotekal®

prilocaine hydrochloride

MercuryPharma

SUMMARY OF PRODUCT CHARACTERISTICS

Prilotekal®

1.    Name of the medicinal product

Prilotekal^®

2.    Qualitative and quantitative composition

1 ml of solution for injection contains 20 mg of prilocaine hydro -chloride (equivalent to 2%)

1 ampoule with 5 ml solution, contains 100 mg of prilocaine hydrochloride Excipients:

0.0086 mg sodium per 1 ml

For a full list of excipients, see section 6.1.

3.    Pharmaceutical form

Solution for injection. Clear, colourless solution.

4.    Clinical Particulars

4.1    Therapeutic indications - Spinal anaesthesia

4.2    Posology and method of administration

Posology must be established on an individual basis in accordance with the characteristics of the specific case. When determining the dose, take into consideration the patient's physical condition and the concomitant administration of other medicinal products.

The duration of action is dose-dependent.

The indications relating to recommended doses are valid in adults of average height and weight (approximately 70 kg) for obtaining an effective block with one single administration. There are wide individual variations with regard to extent and duration of action. The experience of the anaesthetist and knowledge of the patient's general condition are essential for establishing the dose.

With regard to posology the following guidelines are applied: Posology Adults

As a general guideline, the maximum recommended dose is 80 mg of prilocaine hydrochloride (= 4 ml Prilotekal).

Paediatrics

Prilotekal must not be used in children and adolescents.

It is advisable to reduce the dose in patients in a compromised general condition.

In addition, in patients with established concomitant disorders (e.g. vascular occlusion, arteriosclerosis, diabetic polyneuropathy) a reduced dose is indicated.

In the case of compromised liver or kidney function a lower dosage range is recommended.

Warnings for use

The equipment, drugs and personnel capable of dealing with an emergency, e.g. maintaining the patency of the airways and administering oxygen, must be immediately available, since in rare cases severe reactions, sometimes with a fatal outcome, have been reported after using local anaesthetics, even in the absence of individual hypersensitivity in the patient's case    history.

Method of administration

Inject Prilotekal via intrathecal route into the intervertebral space L2/L3, L3/L4 and L4/L5.

Slowly inject the entire dose and check the patient's vital functions extremely carefully maintaining continuous verbal contact.

If the patient is in a seated position, the injected solution diffuses mainly in a caudal direction (in the direction of the sacrum); if the patient is lying down, the anaesthetic diffuses by gravity according to the patient's position (Trendelenburg and anti-Trendelenburg ).

In general the following points should be taken into consideration:

1.    Choose the lowest possible dose!

2.    Administer the injection slowly, after having aspirated a minimum quantity of CSF to confirm the correct position

3.    Do not inject into infected areas!

4.    Subarachnoid anaesthesia is contraindicated in patients taking anticoagulants

By means of the excipient glucose, the density of Prilotekal is 1.026 g/g at 20°C, equivalent to 1.021 g/g at 37°C.

-    have ever had a bad reaction to an anaesthetic in the past,

-    have a skin infection at or near the proposed site of the injection,

-    are suffering from any of the following:

-    diseases of the central nervous system such as meningitis, polio and problems with your spinal cord due to anaemia,

-    a severe headache,

-    brain, spine or any other tumours,

-    tuberculosis of the spine,

-    recent trauma to your spine,

-    very low blood pressure or low blood volume,

-    problems with clotting of your blood,

-    acute porphyria (a rare disease of the blood pigment),

-    fluid in your lungs,

-    septicaemia (blood poisoning),

-    have a heart condition,

-    have any liver or kidney problems,

-    suffer from neurological or neuromuscular disorders, such as multiple scleroris.

If you are not sure if any of the above apply to you, talk to your doctor before having Prilotekal.

Taking other medicines

Please tell your doctor if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

In particular, tell your doctor if you are taking any of the following medicines:

-    other local anaesthetics,

-    medicines to treat an uneven heartbeat (arrhythmia), such as amiodarone. Pregnancy and breast-feeding

Before you are given Prilotekal, tell your doctor if you are pregnant, planning to get pregnant, or if you are breast-feeding.

Ask your doctor or pharmacist for advice before taking any medicine if you are pregnant or breast-feeding.

Prilotekal should not be administered for local or regional anaesthesia during childbrith.

Driving and using machines

Prilotekal may make you feel sleepy and affect the speed of your reactions. After you have been given Prilotekal, you should not drive or use tools or machines until the next day.

Important information about some of the ingredients of Prilotekal

This medicinal product contains less than 1 mmol sodium (23 mg) per dose (maximum dose equal to 4 ml of Prilotekal), so it is essentially “sodium-free”.

101661/LF/1

4.3 Contraindications

Prilotekal must not be used in patients with

-    hypersensitivity to prilocaine hydrochloride, other amide-type local anaesthetics or to any of the excipients,

-    serious problems with cardiac conduction,

-    severe anaemia,

-    decompensated cardiac insufficiency,

-    cardiogenic and hypovolemic shock,

-    congenital or acquired methemoglobinemia.

It is also necessary to take into consideration general and specific contraindications for the technique of subarachnoid anaesthesia.

4.4 Special warnings and precautions for use

Due to the glucose content Prilotekal is only to be used for spinal anaesthesia. It is not recommended for the use in epidural anaesthesia.

Spinal anaesthesia must only be administered by (or under the supervision of) specialist medical personnel with the necessary knowledge and experience. The doctor in charge is responsible for taking the measures needed to avoid an intravascular injection.

In addition, it is essential for the doctor to know how to recognize and treat undesirable effects, systemic toxicity and other complications. If signs of acute systemic toxicity or total spinal block are observed, the injection of the local anaesthetic must be stopped immediately (see section 4.9).

Some patients require special attention in order to reduce the risk of serious undesirable effects, even when locoregional anaesthesia constitutes the optimum choice for the surgical intervention:

-    Patients with total or partial heart block, since local anaesthetics can suppress myocardial conduction.

-    Patients with high grade cardiac decompensation. The risk of methemoglobinemia must also be taken into consideration (see section 4.8).

-    Patients with advanced liver or kidney damage.

-    Elderly patients and patients in reduced general condition.

-    Patients treated with class III antiarrhythmic agents (e.g. amio -darone). These patients should be subjected to careful observation and ECG monitoring, since cardiac effects may be added (see section 4.5).

-    In patients with acute porphyria, Prilotekal should only be administered when there is a compelling indication for its use, as Prilotekal may potentially precipitate porphyria. Appropriate pre -cautions should be taken in all patients with porphyria.

Ensuring the presence of reliable venous access is recommended. As with all local anaesthetics, a drop in arterial pressure may occur and cardiac frequency may slow.

In high risk patients, the recommendation is to improve their general condition prior to the intervention.

A rare, but serious, undesirable effect of spinal anaesthesia is high or total spinal block, with consequent cardiovascular and respiratory depression. Cardiovascular depression is induced by an extended block of the sympathetic nervous system, which may induce severe hypotension and bradycardia to the point of cardiac arrest. Respiratory depression is induced by the block of the respiratory musculature and the diaphragm.

Especially in elderly patients and patients in the final period of pregnancy there is an increased risk of high or total spinal block: consequently it is advisable to reduce the anaesthetic dose. Particularly in the case of elderly patients, an unexpected drop in arterial pressure may occur as a complication of spinal anaesthesia. Rarely, neurological damage may occur after spinal anaesthesia, manifesting as paresthesia, loss of sensitivity, motor weakness and paralysis. Occasionally these symptoms persist.

There is no evidence that neurological disorder, such as multiple sclerosis, hemiplegia, paraplegia or neuromuscular disorders may be negatively influenced by spinal anaesthesia. Nevertheless, it should be used with care. Careful evaluation of the risk-benefit ratio is recommended prior to treatment.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose (maximum dose equal to 4 ml of Prilotekal), i.e. essentially “sodium-free”.

4.5    Interaction with other medicinal products and other forms of interaction

Prilocaine may potentiate the formation of methemoglobin by medicinal products known to induce methemoglobin (e.g. sulfonamides, antimalarials, sodium nitroprussiate and nitroglycerin).

In the event of the concomitant use of prilocaine and other local anaesthetics or medicinal products with a chemical structure similar to prilocaine, e.g. certain antiarrhythmics such as aprindine, lido -caine, mexiletine and tocainide, it is possible for undesirable effects to be added. No studies have been performed on interactions between prilocaine and class III antiarrhythmics (e.g. amiodarone), but care must also be taken in this case (also see section 4.4).

The combination of various local anaesthetics induces additional effects which affect the cardiovascular system and the CNS.

4.6    Pregnancy and lactation

There are no adequate data from the use of prilocaine in pregnant women. Prilocaine is able to cross the placenta. Cases of neonatal methaemoglobinaemia requiring treatment have been reported following paracervical block or pudendal anaesthesia with prilocaine during obstetric use. Cases of foetal bradycardia with fatalities have occurred with other local amide-type anaesthetics following paracervical block. Studies in animals have shown reproductive toxicity (see section 5.3). Prilotekal may therefore only be administered in cases where there is a compelling indication for its use. Use of prilocaine for paracervical block or pudendal anaesthesia should be avoided.

It is not known whether prilocaine passes into breast milk. If administration is required during lactation, breast-feeding can be resumed approximately 24 hours after treatment.

4.7    Effects on ability to drive and use machines

In the case of using Prilotekal, the doctor is responsible for deciding in each individual case if the patient can drive or use machines.

4.8    Undesirable effects

The frequency of onset of undesirable effects is classified as follows: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1000 to <1/100), rare (>1/10000 to <1/1000), very rare (<1/10000).

The possible undesirable effects due to the use of Prilotekal are generally similar to the undesirable effects of other local anaesthetics for spinal anaesthesia from the amide group. The undesirable effects induced by the medicinal product are difficult to distinguish from the physiological effects of the nerve block (e.g. reduction in arterial pressure, bradycardia, temporary urine retention), from direct effects (e.g. spinal hematoma) or the indirect effects (e.g. meningitis) of the injection or from the effects due to the loss of cerebrospinal liquid (e.g. post-spinal headache).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

3.    How Prilotekal is given

This medicine will be given to you by your doctor who will decide what dose is right for you. This will normally be between 2-4 ml (40-80 mg prilocaine hydrochloride). This dose may be reduced if you are suffering from poor health.

Prilotekal must not be used in children and adolescents.

Prilotekal is injected via the spinal route.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

4.    Possible side effects

Like all medicines, Prilotekal can cause side effects, although not everybody gets them.

All medicines can cause allergic reactions although serious allergic reactions are very rare. Any sudden wheeziness, difficulty in breathing, swelling of the eyelids, face or lips, rash or itching (especially affecting your whole body) should be reported to a doctor immediately.

Rarely (affects less than 1 in 1,000 people) a high or total spinal block may occur this may lead to heart and breathing difficulties, if you experience any such difficulty inform your doctor immediately.

Prilotekal is unlikely to cause serious side effects unless it is accidentally injected in the wrong way or used together with other local anaesthetics. If you notice any of the following effects speak to your doctor immediately:

-    numbness of the tongue, light-headedness, dizziness, shakiness and fits.

Other possible side effects:

Very common (affects more than 1 in 10 people)

-    Low blood pressure. This might make you feel dizzy or light-headed.

-    Feeling sick (nausea).

Common (affects less than 1 in 10 people)

-    Being sick (vomiting).

-    Feeling dizzy.

-    Pins and needles.

Uncommon (affects less than 1 in 100 people)

-    Itching.

-    Numbness or tingling of the skin, or reduced sensitivity to touch.

-    Back pain.

-    Temporary muscle weakness.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor.

5.    How to store Prilotekal

Keep out of the reach and sight of children.

Do not use Prilotekal after the expiry date which is stated on the ampoules and the outer carton. The expiry date refers to the last day of that month.

Do not store Prilotekal above 25°C. Do not refrigerate. Store in original pak-kage in order to protect from light.

Your doctor or the hospital will normally store Prilotekal and they are responsible for the quality of the product when it has been opened if it is not used immediately.

They are also responsible for disposing of any unused Prilotekal correctly.

6.    Further Information What Prilotekal contains

The active substance is prilocaine hydrochloride.

1 ml of solution for injection contains 20 mg of prilocaine hydrochloride (equivalent to 2%).

1 ampoule with 5 ml solution, contains 100 mg of prilocaine hydrochloride. The other ingredients are:

Glucose anhydrous

Sodium hydroxide 1N (for pH adjustment)

Water for injection

What Prilotekal looks like and contents of the pack

Solution for injection. Clear, colourless solution.

Prilotekal comes in Type I clear colourless glass ampoules.

Box of 10 ampoules each containing 5 ml of solution for injection

Marketing Authorisation Holder and Manufacturer:

Mercury Pharmaceuticals Ltd No. 1 Croydon,

12-16 Addiscombe Road,

Croydon,

CR0 0XT, UK

This leaflet was last revised in August 2010

The following information is intended for medical and healthcare professionals only:

The SPC is added at the end of the printed PL as a tear-off section.

Very common

Vascular disorders: hypotension Gastrointestinal disorders: nausea

Common

Disorders of the nervous system: paresthesia, dizziness

Gastrointestinal disorders: vomiting

Uncommon

Rare

Blood and lymphatic system disorders: methemoglobinemia, cyanosis

Immune system disorders: allergic reactions, anaphylactic reactions/ anaphylactic shock

Disorders of the nervous system: neuropathy, lesions of peripheral

nerves, arachnoiditis

Eye disorders: diplopia

Cardiac disorders: cardiac arrest, arrhythmia

Respiratory disorders: respiratory depression

The signs of intoxication from local anaesthetics are similar for any

injected preparation, both in the way in which they manifest, and in

their treatment.

In spite of the demonstrated high clinical tolerability of Prilotekal, undesirable toxic effects cannot be excluded in the presence of plasma levels above a critical threshold. These undesirable effects mainly manifest as symptoms affecting the central nervous and cardiovascular system.

The most effective prophylactic measures are scrupulous compliance with the recommended posology for Prilotekal, with it being essential for the doctor to check its action (visual and verbal contact with the patient), as well as careful aspiration prior to injecting the solution.

Mild undesirable effects (feeling dizzy or dazed) can be attributed to moderate overdose and generally resolve rapidly after reducing the dose or halting administration of Prilotekal.

Serious undesirable effects are attributable to significant overdose and/or accidental injection of local anaesthetic into a blood vessel. They manifest as symptoms affecting the central nervous system (restlessness, speech problems, disorientation, dizziness, muscle contractions, cramps, vomiting, loss of consciousness, respiratory arrest and mydriasis) and the cardiocirculatory system (raised arterial pressure and pulse frequency, arrhythmia, drop in arterial pressure, asystole) following irritation and/or depression of the cerebral cortex and the cerebral marrow (see section 4.9).

In addition, following inhibition or block of the cardiac conduction system, cardiac frequency may slow down and myocardial depression may occur.

Any problems relating to metabolism (liver) or excretion (kidney) of Prilotekal should also be considered as other possible causes of undesirable effects.

4.9 Overdose

It is unlikely that Prilotekal, at the recommended posology, will induce plasma levels capable of inducing systemic toxicity.

Acute systemic toxicity

Systemic undesirable effects, which may occur in the presence of plasma levels of more than 5-10 micrograms of prilocaine/ml, are iatrogenic, pharmacodynamic or pharmacokinetic origin and concern the central nervous system and the cardiocirculatory system. Iatrogenic undesirable effects occur due to:

-    injection of an excessive quantity of solution

-    accidental injection into a vessel

-    incorrect patient position

-    high spinal anaesthesia (marked drop in arterial pressure)

In the case of accidental intravenous administration, the toxic effect occurs within 1-3 minutes. On the contrary, in the case of overdose maximum plasma concentrations are only reached after 20-30 minutes, depending on the injection site, and the onset of signs of toxicity is delayed.

Signs of overdose can be classified into two different sets of symptoms which differ in terms of quality and intensity:

a)    Symptoms affecting the central nervous system

Generally, the first symptoms are paresthesia in the mouth area, feeling of numbness of the tongue, feeling dazed, problems with hearing and tinnitus. Visual problems and muscle contractions are more severe and precede a generalized convulsion. These signs must not be erroneously mistaken for neurotic behaviour. Subsequently loss of consciousness and tonic-clonic seizure may occur, generally lasting between a few seconds and a few minutes. The convulsions are immediately followed by hypoxia and increased levels of carbon dioxide in the blood (hypercapnia), attributable to increased muscular activity associated with respiratory problems. In serious cases respiratory arrest may occur. Acidosis potentiates the toxic effects of local anaesthetics.

The reduction or improvement of symptoms affecting the central nervous system can be attributed to the redistribution of local anaesthetics outside the CNS, with its consequent metabolism and excretion. Regression may be rapid, unless enormous quantities have been used.

b)    Cardiovascular symptoms

In serious cases cardiovascular toxicity may occur. Hypotension, bradycardia, arrhythmia and also cardiac arrest may occur in the presence of a high systemic concentration of local anaesthetics.

The first signs of toxic symptoms affecting the central nervous system generally precede toxic cardiovascular effects. This statement does not apply if the patient is under general anaesthesia or heavily sedated with medicinal products such as benzodiazepine or barbiturates.

Treatment of acute systemic toxicity

The following measures must be taken immediately:

-    Stop administration of Prilotekal.

-    Ensure an adequate supply of oxygen: keep the airways clear, administer O₂, artificial ventilation (intubation) if required.

In the event of cardiovascular depression circulation must be stabilized. If convulsions occur and do not resolve spontaneously after 15-20 seconds, the administration of an intravenous anticonvulsant is recommended.

Analeptics with a central action are contraindicated in the case of intoxication caused by local anaesthetics!

In the event of serious complications, when treating the patient it is advisable to obtain the assistance of a doctor specializing in emergency medicine and resuscitation (e.g. anaesthetist). Methemoglobinemia

Methemoglobinemia may follow the administration of prilocaine. Prilotekal is contraindicated for techniques of regional anaesthesia requiring continuous administration. The doses used in subarachnoid anaesthesia do not induce blood levels capable of inducing methemoglobinemia, which occurs if the quantity of prilocaine hydrochloride administered is equal to or higher than 600 mg.

There is a metabolite of prilocaine, o-toluidine, which can induce methemoglobin formation. In general, methemoglobin formation is clinically negligible, except in cases of extremely severe anaemia and high grade cardiac decompensation.

Patients with severe anaemia may develop hypoxia. It is important to exclude other serious causes of cyanosis, e.g. acute hypoxia and/or cardiac insufficiency.

Treatment of methemoglobinemia

Proven methemoglobinemia resolves 15 minutes after the i.v. injection of 2-4 mg/kg body weight of toluidine blue.

Additional information:

Even low concentrations of methemoglobin can alter measurements of pulsoxymetria.

5. Pharmacological properties

Prilocaine is an amide-type local anaesthetic. Prilocaine inhibits the function of the excitable structures (e.g. all types of nerve fibres [sensory, motor, autonomous nerve fibres]). It inhibits the excitability of sensory pain receptors and the conductivity of the sensory nerve fibres, at local level and in a reversible way, reducing the perception of pain and, subsequently, that of cold, heat, touch and pressure. Prilocaine reduces membrane permeability to sodium. This reduces the excitability of the nerve fibres in accordance with its concentration, through reducing the sudden peak sodium permeability, needed to form the potential for action. The effect depends on the pH of the substance and the pH of the environment. The local anaesthetic effect is due to the protonated form. In inflamed tissues, the effect of the local anaesthetics is lower because of the lower pH of the environment.

5.2 Pharmacokinetic properties

The plasma concentration should be negligible for intrathecal use. The terminal elimination half-life of prilocaine is 1.6 hours.

The plasma protein bond is approximately 55%.

The bioavailability of prilocaine at the application site is 100%.

5.3 Preclinical safety data

The therapeutic dose used locally in humans is close to the dose which is toxic in animals after intravenous administration. In animals, signs of acute toxicity are reduced activity, convulsions, dyspnea, cyanosis and death on account of cardiac insufficiency.

The subcutaneous injection of 3 ml/kg of body weight of prilocaine hydrochloride induced reversible local necrosis in the rat. At the same posology no damaging effects were observed in the monkey. The administration of 60 mg/kg body weight of prilocaine for 5 days a week for 7 weeks induced slight weight loss in the rat.

In mutagenesis tests, prilocaine did not demonstrate any mutagenic effects. The indices for a potential mutagen are based on knowledge relating to the metabolite o-toluidine, which caused genetic damage and cell proliferation (chromosome mutations, aneuploidy, DNA repair, cell conversion) in various tests in vitro.

In carcinogenicity studies performed in the rat and the mouse with high doses of the metabolite o-toluidine, an increase in the frequency of tumours of the spleen and the bladder were observed.

Neither of the results seem significant for humans in the case of the therapeutic short-term use of prilocaine; nevertheless, for safety reasons avoiding the administration of high doses over prolonged periods is recommended.

Prilocaine has no effect on the fertility of male and female rats. However, the postnatal survival of the offspring of treated females was reduced. In one study on embryotoxicity in the rat lethal effects on the foetus were observed, and dose-dependent hydronephrosis occurred in the foetuses.

6.    Pharmaceutical Particulars

6.1    List of excipients

Glucose anhydrous

Sodium hydroxide 1N (for pH adjustment)

Water for injection

6.2    Incompatibilities Not applicable.

6.3    Shelf life 3 years

The medicinal product has to be used immediately after first opening.

6.4    Special precautions for storage

Do not store above 25°C.

Do not refrigerate.

Store in original package in order to protect from light.

6.5    Nature and contents of container

Type I clear colourless glass ampoule

Box of 10 ampoules each containing 5 ml of solution for injection

6.6    Special precautions for disposal

5 ml ampoules of solution for injection are exclusively single-use. Any remaining product must be disposed of.

Do not resterilize.

The medicinal product has to be visually inspected prior to use. Only clear solutions practically free from particles should be used.

7.    Marketing authorization holder

Mercury Pharmaceuticals Ltd No. 1 Croydon,

12-16 Addiscombe Road,

Croydon,

CR0 0XT, UK

8.    Marketing authorisation number

PL 12762/0447

9. Date of first authorisation / Renewal of the authorisation

29/09/2009

10. Date of revision of the text

November 2009

101661/LF/1

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