SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Lidocaine 10 mg/ml Solution for injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of solution for injection contains 10 mg lidocaine hydrochloride.

Each 2 ml of solution for injection contains 20 mg lidocaine hydrochloride. Each 5 ml of solution for injection contains 50 mg lidocaine hydrochloride. Each 10 ml of solution for injection contains 100 mg lidocaine hydrochloride. Each 20 ml of solution for injection contains 200 mg lidocaine hydrochloride.

Excipient(s) with known effect:

1 ml of solution for infusion contains approximately 0.119 mmol sodium. For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Solution for Injection

A clear and colourless solution or almost colourless solution

pH of the solution is between 5.00 and 7.00 and osmolarity of the solution is

276.49 mosmol/kg

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Local and regional anesthesia, minor and major nerve blocks.

4.2 Posology and method of administration

The dosage should be adjusted according to the response of the patient and the site of administration. The lowest concentration and smallest dose producing the required effect should be given. The maximum dose for healthy adults should not exceed 200mg.

The volume of the solution used plays a role in the size of the area of spread of anaesthesia. In case it is desirable to administer a larger volume with a lower concentration, than the standard solution has to be diluted with a saline solution (NaCl 0.9%). This dilution should take place just before administration.

Children and elderly or debilitated patients require smaller doses, commensurate with age and physical status.

Single doses of Lidocaine (for anaesthesia other than spinal) should not exceed 5 mg/kg (with a maximum of 200 mg) in adults or children 12 - 18 years of age.

The following doses are recommended for adults:

	10 mg/ml	20 mg/ml
Infiltration- anaesthesia: Small procedures	2-10 ml(20-100 mg)
Large procedures	10-20 ml (100200 mg)	5-10 ml(100-200 mg)
Nerve blockade	3-20 ml(30-200 mg)	1.5-10 ml (30200 mg)
Fingers/toes	2-4 ml (20-40 mg)	2-4 ml (40-80 mg)
Epidural, lumbar	25-30 ml (250300 mg)
Caudal, thoracic block	20-30 ml (200300 mg)
Regional anaesthesia	Maximal 5 ml (50 mg)	Maximal 2.5 ml (50 mg)

Children below 1 year of age:

There is limited experience in children below 1 year of age. The maximum dosage for children (1 to 12 years of age) is 5 mg/kg BW of a 1% solution.

4.3 Contraindications

Known hypersensitivity to anaesthetics of the amide type.

Complete heart block

Hypovolaemia

4.4 Special warnings and precautions for use

Lidocaine should be administered by persons with resuscitative skills and equipment. Facilities for resuscitation should be available when administering local anaesthetics.

It should be used with caution in patients with myasthenia gravis, epilepsy, congestive heart failure, bradycardia or respiratory depression, including where agents are known to interact with Lidocaine either to increase its availability, or additive effects (e.g. phenytoin) or prolong its elimination (e.g. hepatic or end renal insufficiency where the metabolites of Lidocaine may accumulate).

Patients treated with anti-arrhythmic drugs class III (e.g. amiodarone) should be under close surveillance and ECG monitoring considered, since cardiac effects may be additive (see section 4.5).

There have been post-marketing reports of chondrolysis in patients receiving postoperative intra-articular continuous infusion of local anaesthetics. The majority of reported cases of chondrolysis have involved the shoulder joint. Due to multiple contributing factors and inconsistency in the scientific literature regarding mechanism of action, causality has not been established. Intra-articular continuous infusion is not an approved indication for lidocaine.

Intramuscular Lidocaine may increase creatinine phosphokinase concentrations which can interfere with the diagnosis of acute myocardial infarction. Lidocaine has been shown to be porphyrinogenic in animals and should be avoided in persons suffering from porphyria.

The effect of Lidocaine may be reduced if it is injected into inflamed or infected areas.-

Hypokalaemia, hypoxia and disorder of acid-base balance should be corrected before treatment with intravenous lidocaine begins.

Certain local anaesthetic procedures may be associated with serious adverse reactions, regardless of local anaesthetic drug used.

Central nerve blocks may cause cardiovascular depression, especially in the presence of hypovolaemia, and therefore epidural anaesthesia should be used with caution in patients with impaired cardiovascular function.

Epidural anaesthesia may lead to hypotension and bradycardia. This risk can be reduced by preloading the circulation with crystalloidal or colloidal solutions. Hypotension should be treated promptly.

Paracervical block can sometimes cause foetal bradycardia or tachycardia and careful monitoring of the foetal heart rate is necessary (see section 4.6).

Injections in the head and neck regions may be made inadvertently into an artery causing cerebral symptoms even at low doses.

Retrobulbar injections may rarely reach the cranial subarachnoid space, causing serious/severe reactions including cardiovascular collapse, apnoea, convulsions and temporary blindness.

Retro- and peribulbar injections of local anaesthetics carry a low risk of persistent ocular motor dysfunction. The primary causes include trauma and/or local toxic effects on muscles and/or nerves.

The severity of such tissue reactions is related to the degree of trauma, the concentration of the local anaesthetic and the duration of exposure of the tissue to local anaesthetic. For this reason, as with all local anaesthetic, the lowest effective concentration and dose of local anaesthetic should be used.

Lidocaine solution for injection is not recommended for use in neonates. The optimum serum concentration of lidocaine required to avoid toxicity, such as convulsions and cardiac arrhythmias, in this age group is not known.

Intravascular injection that is not indicated should be avoided.

Use with caution in:

-    patients with coagulopathy. Treatment with anticoagulants (eg. Heparin), NSAIDs or plasma substitutes causes increased bleeding tendency. Accidental injury of blood vessels may lead to serious bleedings. If necessary bleeding time and activated partial thromboplastin (aPTT), quicktest and platelet count should be checked.

-    patients with incomplete or complete block of the cardiac conduction system

-    due to the fact that local anaesthetics may suppress atrioventricular conduction

-    patients with cerebral seizure disorders must be monitored very closely for manifestation of central nervous symptoms. Also low doses of lidocain hydrochloride can cause increased convulsive readiness. In patients with Melkersson-Rosenthal Syndrome allergic and toxic reactions of the nervous system on local anaesthetics may occur more frequently.

-    third trimester of preqnancypregnancy

Lidocaine 10mg/ml solution for injection is not approved for intrathecal administration (subarachnoidal anaesthesia).

4.5 Interaction with other medicinal products and other forms of interaction

Lidocaine toxicity is enhanced, by the co-administration of cimetidine and propranolol requiring a reduction in the dosage of lidocaine. Both drugs decrease hepatic blood flow. Also, cimetidine depresses microsomial activity. Ranitidine produces a small reduction in Lidocaine clearance. Increase in serum levels of lidocaine may also occur with anti-viral agents (e.g. amprenavir, atazanavir, darunavir, lopinavir).

Hypokalaemia caused by diuretics may antagonize the action of lidocaine if administered concomitantly (see section 4.4).

Lidocaine should be used with caution in patients receiving other local anaesthetics or agents structurally related to amide-type local anaesthetics (e.g. anti-arrhythmics, such as mexiletine, tocainide), since the systemic toxic effects are additive. Specific interaction studies with lidocaine and class III antiarrhythmic drugs (e.g. amiodarone) have not been performed, but caution is advised.

There may be an increased risk of ventricular arrhythmia in patients treated concurrently with antipsychotics which prolong or may prolong the QT interval (e.g. pimozide, sertindole, olanzapine, quetiapine, zotepine), prenylamine, adrenaline (if accidently injected intravenously)) or 5HT3 antagonists (e.g. tropisetron, dolasetron).

Concomitant use of quinupristin/dalfopristin may increase lidocaine levels with a subsequent increased risk of ventricular arrhythmias and therefore should be avoided.

There may be an increased risk of enhanced and prolonged neuromuscular blockade in patients treated concurrently with muscle relaxants (e.g. suxamethonium).

Cardiovascular collapse has been reported following the use of bupivacaine in patients on treatment with verapamil and timolol; Lidocaine is closely related to bupivacaine.

Dopamine and 5 hydroxytryptamine reduce the convulsant threshold to Lidocaine.

Narcotics are probably proconvulsants and this would support the evidence that Lidocaine reduces the seizure threshold to fentanyl in man.

Opioid-antiemetic combination sometimes used for sedation in children could reduce the convulsant threshold to Lidocaine and increase the CNS depressant effect.

While adrenaline when used in conjunction with Lidocaine might decrease vascular absorption, it greatly increase the danger of ventricular tachycardia and fibrillation if accidentally injected intravenously.

Co-administration of other antiarrhythmic drugs, beta-blockers and calcium antagonists may cause an additive inhibitory effect on AV conduction, intraventricular conduction and contractility.

Co-administration of vasoconstrictive drugs leads to a longer duration of action of lidocaine.

Concomitant administration of lidocaine and secale alkaloids (eg. ergotamine) may cause a severe decrease in blood pressure.

Caution should be taken in the use of sedatives that also affect the function of the central nervous system and may alter the effect of local anaesthetics.

Caution is advised when antiepileptic drugs (phenytoin), barbiturates and other enzyme inhibitors, which were taken over a longer time, because it can lead to lower efficiency and therefore higher dose requirements of lidocaine.

Intravenous administration of phenytoin on the other hand may increase the cardiodepressive effect of lidocaine.

The analgesic effect of local anaesthetics may be potentiated by opioids and clonidine.

Ethyl alcohol, especially chronic abuse, can decrease the effect of local anaesthetics.

4.6 Fertility, pregnancy and lactation

Fertility

There are no human data regarding potential effects of lidocaine on fertility.

Pregnancy

Lidocaine can be administered during pregnancy and lactation. The dose limit prescribed should be strictly observed. Epidural anaesthesia with lidocaine is contraindicated in obstetrics in case of crisis or pre-existing bleeding.

Lidocaine has been used in a large number of pregnant women and women of childbearing age. There were no specific reproductive disorders, i.e. there was no increased incidence of malformations.

Foetal side effects of local anesthetics, such as foetal bradycardia, could occur after paracervical block, because high concentrations may reach the foetus._Lidocaine is therefore not applicable in obstetrics at concentrations above 1%.

Animal studies have revealed no evidence of harm to the foetus.

Lactation

Lidocaine is excreted in small amounts into breast milk and the oral bioavailability of lidocaine is very poor. Therefore, the amount that reaches the infant via breast milk is expected to be very low and thus the potential for harm for the infant is very low.

4.7 Effects on ability to drive and use machines

After injection of local anesthetics a transient sensory loss or and/or motor blockade, may occur. Until the effects subside patients should not drive vehicles or operate machines.

4.8 Undesirable effects

The adverse reactions are described according to the MedDRA system organ class as below.

Frequencies are defined using the following convention:

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), not known (cannot be estimated from the available data).

In common with other local anaesthetics, adverse reactions to Lidocaine are rare and are usually the result of raised plasma concentrations due to accidental intravascular injection, excessive dosage or rapid absorption from highly vascular areas, or may result from a hypersensitivity, idiosyncrasy or diminished tolerance on the part of the patient. Systemic toxicity mainly involves the central nervous system and/or the cardiovascular system (see also 4.9 Overdose).

Immune system disorders

Hypersensitivity reactions (allergic or anaphylactoid reactions, anaphylactic shock) -see also Skin & subcutaneous tissue disorders). Skin testing for allergy to Lidocaine is not considered to be reliable.

Nervous system & Psychiatric disorders

Neurological signs of systemic toxicity include dizziness or light-headedness, nervousness, tremor, circumoral paraesthesia, tongue numbness, drowsiness, convulsions, coma.

Nervous system reactions may be excitatory and or depressant. Signs of CNS stimulation may be brief, or may not occur at all, so that the first signs of toxicity may be confusion and drowsiness, followed by coma and respiratory failure.

Neurological complications of spinal anaesthesia include transient neurological symptoms such as pain of the lower back, buttock and legs. These symptoms usually develop within twenty-four hours of anaesthesia and resolve within a few days. Isolated cases of arachnoiditis or cauda equine syndrome, with persistent paraesthesia, bowel and urinary dysfunction, or lower limb paralysis have been reported following spinal anaesthesia with

lidocaine and other similar agents. The majority of cases have been associated with hyperbaric concentrations of Lidocaine or prolonged spinal infusion.

Eye disorders

Blurred vision, diplopia and transient amaurosis may be signs of lidocaine toxicity.

Bilateral amaurosis may also be a consequence of accidental injection of the optic nerve sheath during ocular procedures. Orbital inflammation and diplopia have been reported following retro or peribulbar anaesthesia (see section 4.4 Special warnings and precautions for use)

Ear and labyrinth disorders

Tinnitus, hyperacusis.

Cardiac and vascular disorders

Cardiovascular reactions are depressant and may manifest as hypotension, bradycardia, myocardial depression, cardiac arrhythmias and possibly cardiac arrest or circulatory collapse.

Hypotension may accompany spinal and epidural anesthesia. Isolated cases of bradycardia and cardiac arrest have also been reported.

Respiratory, thoracic and mediastinal disorders

Dyspnoea, bronchospasm, respiratory depression, respiratory arrest.

Gastrointestinal disorders

Nausea, vomiting.

Skin & subcutaneous tissue disorders

Rash, urticaria, angioedema, face oedema.

4.9 Overdose

Symptoms of acute systemic toxicity

Central nervous system toxicity presents with symptoms of increasing severity. Patients may present initially with circumoral paraesthesia, numbness of the tongue, light-headedness, hyperacusis and tinnitus. Visual disturbance and muscular tremors or muscle twitching are more serious and precede the onset of generalised convulsions. These signs must not be mistaken for neurotic behaviour. Unconsciousness and grand mal convulsions may follow, which may last from a few seconds to several minutes. Hypoxia and hypercapnia occur rapidly following convulsions due to increased muscular activity, together with the interference with normal respiration. In severe cases, apnoea may occur. Acidosis increases the toxic effects of local anaesthetics.

Effects on the cardiovascular system may be seen in severe cases. Hypotension, bradycardia, arrhythmia and cardiac arrest may occur as a result of high systemic concentrations, with potentially fatal outcome.

Recovery occurs as a consequence of redistribution of the local anaesthetic drug from the central nervous system and metabolism and may be rapid unless large amounts of the drug have been injected.

Treatment of acute toxicity

If signs of acute systemic toxicity appear, injection of the anaesthetic should be stopped immediately.

Treatment will be required if convulsions, CNS depression and cardiotoxicity occurs. The objectives of treatment are to maintain oxygenation, stop the convulsions and support the circulation. A patent airway should be established and oxygen should be administered, together with assisted ventilation (mask and bag) if necessary. The circulation should be maintained with infusions of plasma or intravenous fluids. Where further supportive treatment of circulatory depression is required, use of a vasopressor agent may be considered although this involves a risk of CNS excitation. Convulsions may be controlled by the intravenous administration of Diazepam (0,1mg/kg i.v.) or Thiopentone Sodium (1-3mg/kg i.v.), bearing in mind that anticonvulsant drugs may also depress respiration and the circulation. Prolonged convulsions may jeopardize the patient’s ventilation and oxygenation and early endotracheal intubation should be considered. If cardiac arrest should occur, standard cardiopulmonary resuscitation procedures should be instituted. Continual optimal oxygenation and ventilation and circulatory support as well as treatment of acidosis are of vital importance.

Dialysis is of negligible value in the treatment of acute overdosage with lidocaine.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic groups: Anaesthetics, local; Amides ATC code: N01BB02

Lidocaine is a short-acting amide-type local anesthetic. The mechanism of action is based on a decreased permeability of the membrane of the neuron for sodium ions. As a consequence of this, the depolarization rate is decreased and the threshold of excitation is increased, resulting in a reversible local numbness. Lidocaine is used to provide anaesthesia by nerve blockade at various sites in the body and in the control of dysrhythmias. It has a rapid onset of action (about one minute following intravenous injection and fifteen minutes following intramuscular injection) and rapidly spreads through the surrounding tissues. The effect lasts about ten to twenty minutes and about sixty to ninety minutes following intravenous and intramuscular injection respectively.

5.2 Pharmacokinetic properties

Absorption

Lidocaine is absorbed rapidly from the gastro-intestinal canal but only low amounts reached the circulation due to the first-pass effect in the liver.

The systemic absorption of Lidocaine is determined by the site of injection, the dosage and its pharmacological profile. The maximum blood concentration occurs following intercostal nerve blockade followed in order of decreasing concentration, the lumbar epidural space, brachial plexus site and subcutaneous tissue. The total dose injected regardless of the site is the primary determinant of the absorption rate and blood levels achieved. There is a linear relationship between the amount of Lidocaine injected and the resultant peak anaesthetic blood levels.

Distribution

Lidocaine is bound to plasma proteins, including a 1-acid glycoprotein (AAG) and albumin. The extent of binding is variable but is about 66%. The AAG plasma level is low in neonates and the free biologically active lidocaine fraction is relatively high in neonates.

The drug crosses the blood-brain and placental barriers probably as a result of passive diffusion

Metabolism

Lidocaine is metabolised in the liver and about 90% of a given dose undergoes N-dealkylation to form monoethylglycinexylidide (MEGX) and glycinexylidide GX), both of which may contribute to the therapeutic and toxic effects of lidocaine. The pharmacologic and toxic effects of MEGX and GX are comparable but lesser in strength than those of lidocaine. GX has a longer hafl-life ( about 10 hours) than lidocaine and can accumulate with chronic administration.

Further metabolism occurs and metabolites are excreted in the urine with less than 10% as unchanged lidocaine.

Elimination

The elimination half-life of lidocaine following an intravenous bolus injection in healthy adult subjects is 1 - 2 hours. The elimination half-life of glycinexylidide is approximately 10 hours and that of monoethylglycinexylidide is 2 hours.

Special population groups

The pharmacokinetics of lidocaine can be influenced by conditions affecting the liver function due to its rapid metabolism. The half-life can be increased by a factor of 2 or more in patients with hepatic dysfunction.

Renal function impairment has no effect on the pharmacokinetics of lidocaine but may lead to the accumulation of its metabolites.

In neonates, the a 1-acid glycoprotein levels are low and protein binding may be reduced. As the free fraction may be higher, the use of lidocaine in neonates is not recommended.

5.3 Preclinical safety data

Genotoxicity studies with lidocaine did not indicate a mutagenic potential.

In some genotoxicity tests, weak evidence of mutagenicity was observed for a metabolite of lidocaine, 2,6-xylidine (2,6-dimethylanilline). In long-term toxicology studies, the metabolite 2,6-xylidine induced carcinogenic effects at high doses. Possibly, these effects are relevant for humans. Therefore, lidocaine should not be used at high doses for a long period of time.

Otherwise, preclinical studies did not reveal relevant information other than which is already included in other sections of the Summary of Product Characteristics.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Sodium chloride (As a tonicity agent)

0.1 M Hydrochloric acid (for pH adjustment)

0.1 M Sodium hydroxide (for pH adjustment)

Water for injections

6.2 Incompatibilities

Lidocaine has been found to be incompatible when mixed with amphotericin, methohexitone and glyceryl trinitrate. It is not advisable to mix Lidocaine with other agents.

6.3    Shelf life

2 years

6.4    Special precautions for storage

Do not store above 25°C. Do not refrigerate or freeze.

Nature and contents of container

Clear glass ampoules and clear glass vials with rubber stopper and flip-off seal.

The 2ml and 5ml glass ampoules are available in pack of 5, 10 and 25, 10ml ampoule available in pack of 5 and 10 and 20ml vial available in pack of 1 and 10.

6.6 Special precautions for disposal

For I.V., I.M. or S.C. injection.

Use as directed by the doctor.

For single use only. Discard any unused contents.

7 MARKETING AUTHORISATION HOLDER

CLARIS LIFESCIENCES UK LIMITED

CREWE HALL

CREWE

CHESHIRE

CW1 6UL

UNITED KINGDOM

8    MARKETING AUTHORISATION NUMBER(S)

PL 20568/0038

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

14/02/2013

10    DATE OF REVISION OF THE TEXT

12/03/2015