4.1. Therapeutic indications

Lidocaine 10 mg/ml (1 % w/v) in indicated for:

-local anaesthesia and peripheral nerve block in adults and children above 2 years,

-intravenous regional anaesthesia for upper extremities in adults.

4.2. Posology and method of administration

Lidocaine should only be used by or under the supervision of doctors with experience of anaesthesia and resuscitative skills. Facilities for resuscitation should be available when administering anaesthetics.

The dose should be adjusted according to the response of the patient, the site of administration, and the expected duration of the surgical procedure.

The lowest concentration and smallest dose producing the required effect should be given.

Adults

• Local anaesthesia and peripheral nerve block anaesthesia

For infiltration anaesthesia and peripheral nerve blocks, the usual total dose of lidocaine is 3–5 mg/kg.

The generally maximum recommended total dose of lidocaine should not exceed 200 mg, but depending on the procedure and patient factors, higher maximum doses may be required.

The volume of the solution used plays a role in the size of the area of spread of anaesthesia.

If used intravenously to prevent pain induced by medicinal products upon injection, Lidocaine should be administered at a dose of 10 to 40 mg via short bolus prior to the painful procedure. In this case, the administered dose represents a volume of less than half of the 10 ml pre-filled syringe. The excess must be emptied from the 10 ml syringe prior to injection. Smaller syringes, which are more appropriate for administration of the recommended dose, should be taken into consideration.

• Intravenous regional anaesthesia (IVRA) for upper extremities

The usual total dose of lidocaine is 3 mg/kg.

Depending on the procedure and patient factors, 100-200 mg should be used. The maximum single dose should not exceed 200 mg and 3 mg/kg.

The pharmaceutical form (pre-filled syringe) is not considered suitable for IVRA of the lower extremities.

Special populations

Elderly

For elderly patients, the doses are calculated individually according to the patients' age and body weight. Doses may need adaptation as cardiac output and hepatic blood flow decrease with advanced age indicating a decreased clearance of lidocaine (see section 5.2).

Patients with renal impairment

Patients should be monitored as renal impairment may cause toxic effects due to the accumulation of active metabolites (see section 4.4 and 5.2). The dose may need to be adapted due to reduced clearance and increased half-life of lidocaine.

Patients with hepatic impairment

The dose may need to be reduced by up to a half in patients with cardiac or hepatic insufficiency (see section 4.4).

Patients with cardiac insufficiency

The dose may need to be reduced by up to a half in patients with cardiac or hepatic insufficiency (see section 4.4).

Other special population

Doses may need to be reduced in patients with poor general condition or in those with reduced protein binding capacity (resulting e.g. from renal insufficiency, liver insufficiency, cancer, pregnancy).

• Paediatric population Local anaesthesia and peripheral nerve block anaesthesia

Children and adolescents (2-18 years)

For infiltration anaesthesia and peripheral nerve blocks, the doses are calculated individually according to the patients' age, body weight and the nature of the procedure.

The usual dosage for children (2-11 years) and adolescents (12-18 years) is 3-4 mg/kg body weight. For calculation, the average age weight is to be considered for overweight children.

The administered dose may represent a volume of less than half 10 ml syringe. The required dose should be calculated and the excess dose must be emptied from the 10 ml syringe prior to injection in the child. For the dose remaining in the syringe, slow incremental injections are recommended.

The behavior of the child during treatment has to be monitored carefully.

Children younger aged less than 2 years

Lidocaine should not be used in children aged less than 2 years as safety and efficacy have not been established.

If used intravenously to prevent pain induced by medicinal products upon injection, the posology for adolescents (12-18 years) is the same as for adults.

Lidocaine should not be used intravenously in children aged less than 12 years because of safety concern of toxic reaction (see sections 4.8 and 4.9).

• Intravenous regional anaesthesia (IVRA) for upper extremities

Lidocaine should not be used in children and adolescents aged less than 18 years because of safety concern of toxic reaction (see sections 4.8 and 4.9).

Method of administration

The method of administration varies according to the procedure.

Lidocaine may be administered by intravenous injection (intravenous use) or infiltration (intradermal, subcutaneous, or submucosal use) injection into the surroundings of peripheral nerves.

Lidocaine is a ready to administer pre-filled syringe which is not designed for administration with an electronic syringe pump.

Intravenous regional anaesthesia (IVRA)

Proper tourniquet technique specific to the extremities is essential in the performance of intravenous regional anaesthesia.

4.3. Contraindications

• Hypersensitivity to the active substance, amide-type local anaesthetics or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Lidocaine should be used with caution in patients with:

• epilepsy: patients with cerebral seizure disorders must be monitored very closely for manifestation of central nervous symptoms. Also low doses of lidocaine can cause increased convulsive readiness.

• renal or liver insufficiency;

• myasthenia gravis;

• block of the cardiac conduction system due to the fact that local anaesthetics may suppress atrioventricular conduction;

• patients with reduced cardiovascular function;

• bradycardia;

• respiratory depression;

• the elderly and generally debilitated patients.

• coagulopathy or treatment with anticoagulants (eg. Heparin), NSAIDs or plasma substitutes as accidental injury of blood vessels may lead to serious bleedings.

Inadvertent intravascular administration or overdoses may cause high lidocaine blood concentrations responsible for acute central nervous and cardiovascular toxic symptoms.

Accidental intravascular injections in the head and neck areas may cause cerebral symptoms even at low doses.

Caution should also be exercised if the local anaesthetic is to be injected into inflamed (infected) tissue because of increased systemic absorption due to higher blood flow and decreased effect due to the lower pH of infected tissue.

There have been post-marketing reports of chondrolysis in patients receiving post- operative 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.

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

After removing the tourniquet after intravenous regional anaesthesia (IVRA) there is an increased risk of adverse effects. The tourniquet should not be loosened within 20 minutes of injection.

This medicinal product contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per 5 ml pre-filled syringe, that is to say essentially “sodium-free”.

This medicine contains 1.2 mmol (28 mg) sodium per 10 ml pre-filled syringe, equivalent to 1.4 % of the WHO recommended maximum daily intake of 2g sodium for an adult.

4.5. Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactions

Class I antiarrhythmics

Simultaneous administration of lidocaine and other class I antiarrhythmics should be avoided because of the risk that serious cardiac adverse effects occur.

Other anti-arrhythmics

If lidocaine is combined with other anti-arrhythmic medicinal products such as beta receptor blockers or calcium channel blockers, the inhibitory effect on atrioventricular and intraventricular conduction and on contractility may be enhanced.

Combination with other local anaesthetics

Combination of different local anaesthetics may lead to additive effects on the cardiovascular and the central nervous system.

Muscle relaxants

The effect of muscle relaxants (e.g. Suxamethonium) is prolonged by lidocaine.

Sedatives, hypnotics

Lidocaine should be administered with due caution to patients receiving medication with sedatives that also affect the function of the CNS and therefore may alter the toxicity of lidocaine. There may be an additive effect between the local anaesthetic effect and sedatives or hypnotics.

Volatile anaesthetics

If lidocaine and volatile anaesthetics are given simultaneously, the depressive effects of both may be intensified.

Medicinal products that can lower the seizure threshold

As lidocaine itself may reduce the seizure threshold co-administration with other medicinal products lowering the seizure threshold (e.g. tramadol or bupropion) may increase the risk of seizures.

Medicinal products that can raise the seizure threshold

Simultaneously administered diazepam raises the threshold for Lidocaine to produce convulsions. This must be kept in mind when monitoring patients for signs of toxicity of Lidocaine.

Vasoconstrictors:

The local anaesthetic effect is prolonged by combination with a vasoconstrictor, e.g. epinephrine. If lidocaine is given as antiarrhythmic agent, additional medication with epinephrine or norepinephrine may lead to potentiation of the cardiac undesirable effects.

Pharmacokinetic interactions

Lidocaine is mainly metabolized via the cytochrome P 450 isoenzymes CYP 3A4 and CYP 1A2 (see section 5.2). Concomitant administration with active substances that are substrates, inhibitors or inducers of hepatic enzymes, isoenzyme CYP3A4 and CYP1A2, may have an influence on the pharmacokinetics of lidocaine and thus also on its effect.

Inhibitors of CYP 3A4 and/or CYP 1A2

Concurrent administration of lidocaine with inhibitors of CYP3A4 and/or CYP1A2 may lead to accelerated plasma concentrations of lidocaine. Increased plasma levels have been reported for e.g:

• Amiodarone (CYP3A4 inhibitor): Amiodarone decreases hepatic metabolism of lidocaine, thus leading to the risk of increase of lidocaine levels, with subsequent increase of neurological and cardiovascular toxicity. Clinical monitoring, ECG and eventually control of plasma concentration of lidocaine should be performed. If needed dosage of lidocaine should be monitored during and after amiodarone therapy.

• Cimétidine (CYP3A4 and CYP1A2 inhibitor): Cimetidine used at doses equal or higher than 800 mg/day: increase of plasma concentration of lidocaine with subsequent increase of neurological and cardiovascular toxicity. Clinical survey, ECG and eventually control of plasma concentration of lidocaine should be performed. If needed dosage of lidocaine should be monitored during and after cimetidine therapy.

• Fluvoxamine (CYP3A4 and CYP1A2 inhibitor): Increase of lidocaine levels, thus enhancing risk of neurological and cardiovascular toxicity. Clinical monitoring, ECG and eventually control of plasma concentration of lidocaine should be performed. If needed dosage of lidocaine should be monitored during and after the association.

• Betablockers (except esmolol): Lidocaine intravenous: increase of lidocaine levels, with subsequent increase of neurological and cardiovascular toxicity. Clinical monitoring, ECG and eventually control of plasma concentration of lidocaine should be performed. If needed dosage of lidocaine should be monitored during and after betablockers therapy.

• Other known inhibitors of CYP3A4: protease inhibitors (e.g. ritonavir), macrolides antibiotics (e.g. erythromycine), antifungals (e.g. ketoconazole, itraconazole).

• Other known inhibitors of CYP1A2: ciprofloxacin.

Inducers of CYP 3A4 and/or CYP 1A2

Active substances inducing CYP3A4 and/or CYP 1A2 such as barbiturates (mainly phenobarbital), carbamazepine, phenytoin or primidone, accelerate the plasmatic clearance of lidocaine and thus reduce the efficacy of lidocaine.

Other pharmacokinetic interactions

Medicinal products that alter the metabolism, hepatic blood flow, cardiac output or peripheral distribution of lidocaine may influence plasma levels of lidocaine.

Medicinal products that cause hypokalaemia

The electrophysiological effects of lidocaine are highly dependent on the extracellular potassium concentration and can be almost completely blocked by hypokalemia.

Concomitant use of medicinal products that can cause severe hypokalemia (e.g. acetazolamide, loop diuretics and thiazides) should therefore be avoided or used under careful monitoring of serum potassium concentration.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of lidocaine in pregnant women.

Lidocaine passes the placenta (see section 5.2). It is reasonable to assume that a large number of pregnant women and women of child-bearing age have been given lidocaine. No specific disturbances to the reproductive process have so far been reported, e.g., no increased incidence of malformations, or direct or indirect effect on the foetus. However, the risks for humans are not completely investigated.

Animal studies have shown reproductive toxicity (see section 5.3).

In short term use during pregnancy and at delivery the benefits should be weighed against the risks. Paracervical blockade or pudendal blockade with lidocaine increases the risk of reactions such as bradycardia/tachycardia in the foetus. The heart rate of the foetus must therefore be carefully monitored.

Lactation

Lidocaine is excreted into human breastmilk in small amounts. The use of lidocaine at recommended doses is unlikely to affect the breast-fed child. Breast-feeding can therefore be continued during treatment with lidocaine.

Fertility

No human data on the effect of lidocaine on fertility are available.

4.7. Effects on ability to drive and use machines

Lidocaine may have influence on the ability to drive and use machines. After injection of local anaesthetics a transient sensory loss and/or motor blockade, may occur. Until the effects subside patients should not drive vehicles or use machines.

4.8. Undesirable effects

Summary of the safety profile

The frequency and severity of the undesirable effects of lidocaine depend upon the dose, the method of administration and the patient's individual sensitivity.

The undesirable effects related to local anaesthetics are rare in the absence of an overdose, abnormal rapid systemic absorption or accidental intravascular injection; in such cases, they can be very serious, in particular in terms of cardiac and neurologic function.

Adverse reactions caused by lidocaine may be difficult to distinguish from the physiological effects of the nerve block (e.g. hypotension, bradycardia), events caused directly (e.g. neurological lesions) or indirectly by needle puncture.

Symptoms of local toxicity may occur after the administration of lidocaine. Systemic adverse effects may be expected at plasma concentrations of lidocaine exceeding 5-10 mg/l. They become manifest in the form of both CNS symptoms and cardiovascular symptoms.

The possible undesirable effects after administration of lidocaine as local anaesthetic are largely the same as those produced by other amide-type local anaesthetics

Tabulated list of adverse reactions

The adverse reactions listed in this section fall in to the following frequency categories: 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).

The following table lists adverse reactions associated with the use of lidocaine as anaesthetic.

System Organ Class

Very Common

Common

Uncommon

Rare

Very rare

Frequency Not known

Blood and lymphatic system disorders

Methaemoglobinaemia

Immune system disorders

allergic reaction*, anaphylactoid reactions, bronchospasm, and in severe cases anaphylactic shock

Nervous system disorders

Paresthesia, loss of consciousness. Transient neurological symptoms.

Neuropathy, convulsions (overdose) persistent anaesthesia, paresis, headache accompanied by tinnitus and photophobia. Cranial nerve lesions, neurosensory deafness. Regional applications in the thoracic or head/neck region may induce sympathetic blockade resulting in transient symptoms such as Horner’s syndrome, Harlequin syndrome.

Cardiac disorders

bradycardia

Arrhythmia, myocardial depression or possibly cardiac arrest (overdose or inadvertent intravascular injection)

Eye disorders

Double vision

Respiratory, thoracic and mediastinal disorders

Respiratory depression

Vascular disorders

hypotension, hypertension

Gastrointestinal disorders

nausea

vomiting

Skin and subcutaneous tissue disorders

rash , urticaria, oedema

* Skin testing for allergy to lidocaine is not considered to be reliable

Paediatric population

Frequency, type and severity of adverse reactions in children are expected to be the same as in adults.

Other special populations

In elderly patients the incidence of undesirable effects may be increased.

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 Yellow Card Scheme.

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Depending on the individual sensitivity, toxic reactions occur from a concentration of approximately 5 - 10 mg lidocaine per litre upward in venous blood.

The lethal plasma concentration for humans is in the range 6 to 33 mg lidocaine per litre.

An overdose, or an accidental intravascular injection can produce excessive plasma concentrations of lidocaine; this results in signs of acute toxicity, which can lead to very serious undesirable effects. The toxic effects of lidocaine depend on the level of the plasma concentration; the higher the plasma concentration and the more rapid its rise, the more frequent and more serious are the toxic reactions. Such toxic reactions concern the central nervous system and the cardiovascular system.

Symptoms

Low toxic overdoses of lidocaine result in stimulation of the CNS. Gross overdose, producing high toxic plasma concentrations, causes depression of the central functions.

Central nervous system toxicity is a graded response with symptoms and sign of escalating severity.

Initially, symptoms are observed such as: dizziness, vertigo, agitation, hallucination, euphoria, apprehension, yawning, logorrhoea, headaches, nausea, vomiting, labial paraesthesia, numbness of the tongue, tinnitus and dysarthria, impaired hearing and vision.

Other subjective central nervous system symptoms include: disorientation, occasional feeling of drowsiness. Tachycardia, hypertension and flushing have also been reported.

These signs of alarm necessitate attentive surveillance: muscular twitching, tremors, shivering, and generalised seizures. Simultaneously administered diazepam raises the threshold for lidocaine to produce convulsions. This must be kept in mind when monitoring patients for signs of toxicity of lidocaine.

In cases of very high dose administered: generalised depression of central nervous system, respiratory depression, coma and respiratory arrest.

Cardiovascular toxicity may be seen in severe cases: cardiac rhythm disorders such as ventricular extrasystole, ventricular fibrillation, unpalpable pulse, pallor, major bradycardia, disorders of atrioventricular conduction, decrease in cardiac contractility, hypotension and cardiac arrest.

Treatment

If signs of acute toxicity occur during administration of the local anaesthetic, administration of the anaesthetic should be stopped immediately. Intravenous fluid should be given in order to prevent hypoxia and acidosis, which potentiate local anaesthetic systemic toxicity (LAST) and exacerbate progression to cardiovascular collapse and seizure.

If convulsions occur, oxygenation should be maintained and circulation should be supported. If required, an anticonvulsant should be administered. Use of intravenous lipid emulsion should be considered.

If cardiovascular depression is evident (hypotension, bradycardia) treatment with intravascular fluid substitution, vasopressoric, chronotropic and/or inotropic drugs should be taken in consideration.

In case of circulatory arrest, immediate cardiopulmonary resuscitation should be initiated. For a successful outcome prolonged resuscitative efforts may be required.

Patients having manifested signs of LAST should be monitored for at least 12 hours, because cardiovascular depression can persist or recur after treatment.

Centrally acting analeptics are contra-indicated.

There is no specific antidote.

Lidocaine cannot be eliminated by haemodialysis.