4.1. Therapeutic indications

Local and regional anaesthesia: 2% w/v Lidocaine Injection BP is indicated in adults, adolescents and children over 2 years of age. In children under 2 years only limited data are available (see section 4.2).

Severe symptomatic ventricular tachycardia or tachy-arrhythmia, if assessed to be life-threatening: 2% w/v Lidocaine Injection BP is indicated in adults, adolescents and children over 2 years of age. In children under 2 years only limited data are available (see section 4.2).

4.2. Posology and method of administration

Posology

Local and regional anaesthesia

As a matter of principle the smallest possible dose that produces adequate anaesthesia should be administered. The dosage should be adjusted individually according to the particulars of each case.

Adults

When injected into tissues with marked systemic absorption, without combination with a vasoconstrictor, a single dose of lidocaine hydrochloride monohydrate should not exceed 4.5 mg/kg body weight (BW) (or 300 mg). If combined with a vasoconstrictor, 7 mg/kg BW (or 500 mg) of lidocaine hydrochloride monohydrate per single dose should not be exceeded.

For the clinical uses listed below, recommendations for single doses and strengths of the injection solution to be administered to adults with average body weight (70 kg) are as follows:

Type of anaesthesia

Concentration [%]

Usual volume [ml]

Maximum dose [mg]

Infiltration

0.5-1

300

500 (with epinephrine)

Major nerve blocks

1-2

30-50

500 (with epinephrine)

Minor nerve blocks

1

5-20

200

Epidural

1-2

15-30*

500 (with epinephrine)

Spinal

1.5 or 5 in 7.5% glucose

1-2

100

Intravenous regional anaesthesia (IVRA)

-upper limb

-lower limb

0.5

0.25

40

50-100

*1.5 ml per segment in average

For prolongation of anaesthesia lidocaine may be combined with a vasoconstrictor, e.g. epinephrine. Addition of epinephrine at a concentration of 1:100 000 to 1:200 000 has proven useful.

Paediatric population

For children, the doses are calculated individually according to the patient's age, body weight and the nature of the procedure. Up to 5 mg/kg BW may be administered. With the addition of epinephrine, up to 7 mg/kg can be used. In children with a high body weight a gradual reduction of the dosage is often necessary and should be based on the ideal body weight. Standard textbooks should be consulted for factors affecting specific block techniques and for individual patient requirements. For anaesthesia in children, only a low strength (0.5% w/v) of the local anaesthetic should be used. To achieve a complete motor block, a higher strength (1% w/v) may be required.

Lidocaine should be used with caution in children younger than two years of age as there are limited data to support the safety and efficacy of this product in this patient population at this time.

Elderly patients

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

Other special patient groups

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

• In patients with severe renal insufficiency the dose may need to be adapted due to reduced clearance and increased half-life of lidocaine (see section 5.2).

• Patients with liver diseases show reduced tolerance towards amide-type local anaesthetics. This may be due to reduced hepatic metabolism and decreased protein synthesis resulting in a lower protein binding rate of the local anaesthetic. Dose reduction is advisable in such cases.

• The dose should be reduced in patients showing clinical signs of cardiac insufficiency. Nevertheless, local or regional nerve blockage can be the anaesthetic method of choice in such patients.

• During pregnancy, the dose may need to be reduced depending on the type of anaesthesia. Regional anaesthetic blocks in which usually large doses are required should be avoided during the first trimester. For use in anaesthetic blocks in which smaller doses are administered the dosage may need to be reduced because of the altered anatomical and physiological characteristics in late pregnancy.

Antiarrhythmic therapy

Adults

The dosage must be adjusted according to individual requirements and the therapeutic effect.

Bolus:

Usual loading doses are 50-100 mg or 1-1.5 mg/kg BW of lidocaine hydrochloride monohydrate as direct intravenous injection, corresponding to approximately 2.5 – 5 ml or 0.05 - 0.075 ml/kg BW of Lidocaine B.Braun 20 mg/ml.

The rate of injection should not exceed 25-50 mg/min, corresponding to approximately 1.25 – 2.5 ml/min of 2 % w/v Lidocaine Injection BP.

If the therapeutic effect of the first dose is insufficient within the first 5 - 10 minutes, the initial dose may be repeated once or twice up to a maximum dose of 200 - 300 mg in 1 hour.

Maintenance:

To maintain therapeutic plasma lidocaine concentrations (1.5 - 5 µg/ml), lidocaine hydrochloride monohydrate is infused at a rate of 20 - 50 µg/kg BW/min (about 1 - 4 mg/min), corresponding to approximately 0.001- 0.0025 ml/kg BW/min.

Infusions can be prepared by adding 1000 mg of lidocaine hydrochloride monohydrate, corresponding to 50 ml of 2% w/v Lidocaine Injection BP, to 500 ml of glucose solution or physiological saline.

The infusion should be terminated as soon as the patient's basic cardiac rhythm appears to be stable or at the earliest signs of toxicity. It should rarely be necessary to continue the infusion beyond 24 hours. As soon as possible, patients should be changed to an oral antiarrhythmic agent for maintenance therapy.

Paediatric patients

The safety and the efficacy of the use of lidocaine in children have not yet been definitely established. The dose should be adapted according to the clinical situation and the nature of the procedure.

Infants and children may be given an initial IV bolus of 0.5 - 1 mg/kg BW. This dose may be repeated according to the response of the patient, but the total dose should not exceed 3-5 mg/kg BW. If required, a maintenance IV infusion of 10 – 50 µg/kg BW/min may be given via an infusion pump.

For advanced cardiovascular life support in children, the recommended dosage is an initial rapid IV or intraosseous injection (i.e. bolus) of 1 mg/kg BW up to a maximum initial dose of 100 mg.

If ventricular tachycardia or ventricular fibrillation is not corrected following defibrillation (or cardioversion) and an initial recommended dose of lidocaine, an IV or intraosseous infusion should be started at a rate of 20 - 50 µg/kg BW/min.

Elderly patients

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

Other special patient groups

Cardiac insufficiency, hepatic insufficiency, co-medication, pregnancy

The dose should be reduced in patients with cardiac insufficiency, hepatic insufficiency, in patients receiving drugs that intensify the effects of lidocaine (see section 4.5) and during pregnancy (see section 4.6). See also section 5.2.

Renal insufficiency

Renal insufficiency as a rule does not require specific dose adjustment. However, such patients should be monitored for toxic effects caused by accumulation of active metabolites. In cases of severe renal insufficiency the dose may need to be adapted (see also section 5.2).

Method of administration

Local and regional anaesthesia

Intradermal, intramuscular, subcutaneous or submucosal use (infiltration), perineural (injection into the surroundings of peripheral nerves), epidural or spinal use. Intravenous use regarding intravenous regional anaesthesia (Bier`s block). Every local anaesthetic procedure should only be carried out by personnel adequately skilled in the respective anaesthetic technique.

Antiarrhythmic therapy

Intravenous use. Intraosseous use

Administer as slow intravenous injection or intravenous infusion after dilution in a suitable vehicle solution.

Because of the relatively short duration of action of lidocaine, the injection should be followed by continuous infusion, if possible, using an infusion pump.

4.3. Contraindications

General

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

Local and regional anaesthesia

The special contraindications for spinal and epidural anaesthesia must also be observed:

● uncorrected hypovolaemia

● coagulopathy (acquired, induced, genetic)

● increased intracranial pressure

● intracranial or intraspinal haemorrhage.

Antiarrhythmic therapy

● Severe conduction disorders

● Myocardial infarction within the preceding 3 months or markedly decreased cardiac output unless there is life threatening ventricular cardiac arrhythmia.

4.4. Special warnings and precautions for use

General

In the case of known allergy towards other amide-type local anaesthetics, group allergy towards lidocaine should be considered.

Lidocaine should only be used with particular caution in patients with liver or kidney diseases or with myasthenia gravis, impaired cardiac conduction (see also section 4.3), cardiac insufficiency, bradycardia, impaired respiratory function and severe shock. See also section 4.2.

In general, prior to injection of lidocaine, it must be made sure that all equipment for resuscitation and emergency medication for the treatment of toxic reactions are instantly available.

Patients with epilepsy should be carefully monitored for the occurrence of central nervous symptoms. An increased tendency to convulsions should be considered even with doses below maximum.

Local and regional anaesthesia

Sudden arterial hypotension may occur as a complication of spinal and epidural anaesthesia, in particular in elderly patients.

Particular 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.

A risk of post-spinal headache is associated with spinal anaesthesia mainly in adolescents and in adults up to the age of 30 years. This risk of post-spinal headache can be markedly reduced by choosing sufficiently thin injection cannulae.

After removing the tourniquet after intravenous regional anaesthesia there is an increased risk of adverse effects. Therefore the local anaesthetic should be drained off in several portions.

During anaesthetic procedures in the neck and head region patients are at increased risk of central nervous toxic effects of the drug. See also section 4.8.

Antiarrhythmic therapy

In acidosis, the plasma protein binding of lidocaine is reduced and therefore the concentration of free lidocaine is increased. Hence the effect of lidocaine may be intensified in acidosis.

Hypokalaemia, hypoxia and disorders of acid-base balance need to be corrected prior lidocaine is used in patients who require large doses of antiarrhythmic agents.

During prolonged parenteral therapy with lidocaine, fluid balance, serum electrolytes and acid-base balance should be monitored regularly.

Administration of lidocaine should be accompanied by continuous monitoring of ECG, blood pressure, state of consciousness and respiration. Especially adjustment of the dose of the anti-arrhythmic drug requires careful cardiological monitoring. Cardiological emergency equipment must be available. If one or more parameters indicate worsening of cardiac function, revision of therapy, which may include discontinuation of lidocaine, is necessary.

Note:

In narcotised patients central nervous disorders may remain unrecognised and cardiac adverse effects may suddenly occur without other previous warning symptoms.

Special warnings/ precautions regarding excipients

2 ml, 5 ml and 10 ml ampoule:

This medicinal product contains less than 1 mmol (23 mg) per ampoule, that is to say essentially 'sodium free'.

20 ml ampoule:

This medicinal product contains 43.7 mg sodium per ampoule, equivalent to 2.2% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

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

Pharmacodynamic interactions

● 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 side effects.

● 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.

● Muscle relaxants

The effect of muscle relaxants is prolonged by lidocaine.

● Combination with other local anaesthetics

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

● Volatile anaesthetics

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

● Class I antiarrhythmic agents

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

● Other anti-arrhythmic agents

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

● 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.

Pharmacokinetic interactions

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

● Beta receptor blockers, vasoconstrictors, cimetidine

Beta receptor blockers (e.g. propranolol, metoprolol, see also below), cimetidine (see also below) and vasoconstrictors like norepinephrine reduce cardiac output and/or hepatic blood flow and therefore reduce the plasma clearance of lidocaine prolonging its elimination half life. Therefore, due account should be taken of the possibility of accumulation of lidocaine.

● As lidocaine is mainly metabolized via the cytochrome P450 isoenzymes CYP3A4 and CYP1A2 concurrently administered drug 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 CYP3A4 and/or CYP1A2

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. erythromycine, fluvoxamine, amiodarone, cimetidine, protease inhibitors.

Inducers of CYP3A4 and/or CYP 1A2

Drugs inducing CYP3A4 and/or CYP 1A2, e.g. barbiturates (mainly phenobarbital), carbamazepine, phenytoin or primidone, accelerate the plasmatic clearance of lidocaine and thus reduce the efficacy of lidocaine.

Substrates of CYP 3A4 and/or CYP1A2

Co-administration with other substrates of CYP3A4 and/or CYP1A2 may lead to increased plasma levels of the drugs.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or a limited amount of data from the use of lidocaine in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see 5.3).

However, lidocaine rapidly crosses the placenta. Therefore high plasma concentrations of lidocaine in the mother`s plasma may cause central nervous depression, alteration of the peripheral vascular tone and cardiac function in the foetus/neonate.

Lidocaine should only be used in pregnancy if there is an imperative indication . Then doses should be as low as possible.

Local and regional anaesthesia

Use of lidocaine for epidural, pudendal, caudal or paracervical block may cause varying degrees of foetal and neonatal toxicity (e.g. bradycardia, hypotonia or respiratory depression). An accidental subcutaneous injection of lidocaine in the foetus during paracervical or perineal block may cause apnoea, hypotension and convulsive fits and may thus put the newborn at vital risk.

In general lidocaine in strengths of 10 mg/ml should be preferred during pregnancy.

Breast-feeding

Lidocaine/ metabolites are excreted in small amounts into human milk, but at therapeutic doses of 2 % w/v Lidocaine Injection BP no effects on the breastfed newborns/infants are anticipated.

Fertility

No data available

4.7. Effects on ability to drive and use machines

In general, 2 % w/v Lidocaine Injection BP has negligible influence on the ability to drive and use machines. However, when outpatient anaesthesia affects areas of the body involved in driving or operating machinery, patients should be advised to avoid these activities until normal function is fully restored. So when using this medicinal product, the doctor has to assess in each individual case whether a patient is able to take part in traffic or to operate machinery.

4.8. Undesirable effects

General

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

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 (see also section 4.9).

Considering the method of administration, systemic undesirable effects are more frequently associated with the use of lidocaine as antiarrhythmic agent.

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

Undesirable effects are listed according to their frequencies 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)

Not known:

(frequency cannot be estimated from the available data)

Local and regional anaesthesia

Blood and the lymphatic system disorders

Not known:

Methaemoglobinaemia

Immune system disorders

Rare:

Anaphylactic reactions manifesting as urticaria, oedema, bronchospasm, respiratory distress and circulatory symptoms up to anaphylactic shock.

Nervous system disorders

Common:

Transient neurological symptoms especially pain after spinal and epidural anaesthesia (up to 5 days).

Rare:

Neurological complications following central nervous blocks – mainly spinal anaesthesia – such as persistent anaesthesia, paraesthesia, paresis up to paraplegia, Cauda equina syndrome (i.e. bilateral leg weakness up to paraplegia, saddle anaesthesia, urinary retention and fecal incontinence), headache accompanied by tinnitus and photophobia.

Cranial nerve lesions, neurosensory deafness (if administered in head and neck regions).

Not known:

Horner’s syndrome, associated with epidural anaesthesia or regional applications in the head/neck region.

Gastrointestinal disorder

Very common:

Nausea, vomiting

Injury, poisoning and procedural complications

Rare:

Trauma, transient radicular irritation due to spinal anaesthesia, compression of the spinal cord after development of haematoma

General disorders and administration site conditions

Rare:

Shivering (after epidural use)

Antiarrhythmic therapy

The most frequently seen undesirable effects after administration of lidocaine as antiarrhythmic agent are those on the nervous system. Further heart function and circulation may be affected. Most of the reactions observed are associated with high injection speed or infusion rate.

Immune system disorders

Rare:

Anaphylactic reactions manifesting as urticaria, oedema, bronchospasm, respiratory distress and circulatory symptoms up to anaphylactic shock.

Psychiatric disorders

Common:

Confusion, restlessness, irritability, euphoria, hallucinations and depression

Very common:

Dysphoria

Nervous system disorders

Common:

Somnolence, dizziness, vertigo, dysarthria, tinnitus, trembling, tingling and paraesthesia (skin), blurred vision

Rare:

Muscular twitching, up to generalised convulsions, depressed level of consciousness up to coma

Cardiac disorders

Rare:

Bradycardia, atrioventricular block up to cardiac arrest

Very rare:

Ventricular tachycardia

Vascular disorders

Rare:

Hypotension

Gastrointestinal disorders

Very common:

Nausea, vomiting, dysphagia

Respiratory, thoracic and mediastinal disorders

Rare:

Respiratory depression or even arrest.

Paediatric population

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

Elderly patients

In elderly patients the incidence of undesirable effects may be increased (see section 4.4).

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

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.

Depending on the individual sensitivity, toxic reactions occur from a concentration of approximately 5 – 9 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.

Symptoms

Effects on the CNS:

Low toxic overdoses of lidocaine result in stimulation of CNS.

Gross overdose, producing high toxic plasma concentrations, causes depression of the central functions.

Two phases of lidocaine intoxication can be distinguished:

Stimulation

At the beginning of intoxication with lidocaine patients mainly show symptoms of excitation: unrest, vertigo, disturbances of hearing and vision, unpleasant perioral sensations, agitation, hallucination, euphoria, paraesthesias (e.g. circumoral paraesthesia and numbness of the tongue), dizziness, tinnitus, blurred visions, nausea, vomiting, dysarthria. Shivering and muscular twitching may be signs of imminent attacks of generalized convulsion. Subconvulsive plasma levels of lidocaine often also lead to sleepiness and sedation. Tachycardia, hypertension and flushing may occur as a sign of initial stimulation of the sympathetic nervous system.

Depression

During progress of the intoxication of the CNS increasing impairment of the brain stem functions appears in the form of respiratory depression and coma, even up to death.

Effects on cardiovascular circulation:

Unpalpable pulse, pallor, hypotension, bradycardia, arrhythmias, cardiovascular collapse, ventricular fibrillation, cardiac arrest.

Sudden hypotension often is the first sign of cardiovascular toxicity of lidocaine. The hypotension is mainly caused by the reduction or block of cardiac impulse conduction. These toxic effects, however, are less relevant than those on the CNS.

Treatment

The occurrence of central nervous or cardiovascular symptoms demands the following emergency treatment:

• Immediately discontinue administration!

• Ensure patency of the airways

• Supply additional oxygen. If necessary provide artificial ventilation with pure oxygen – assisted or controlled – initially via mask and air bag, then intubate. The oxygen therapy must be continued until all vital functions have returned to normal

• Monitor blood pressure, pulse and pupil width carefully

• Maintain the circulation by sufficient supply of intravenous fluid

• Immediately start cardio-pulmonary resuscitation, if necessary.

These measures are also applicable in the case of accidental total spinal anaesthesia, first manifesting as unrest, whispering voice and sleepiness. The latter can proceed to unconsciousness and respiratory arrest.

Further therapeutic measures include the following:

Acute life-threatening hypotension should be treated with intravenous vasopressors.

Bradycardia caused by increased vagal tone should be treated with intravenous atropine. Convulsions not reacting to sufficient oxygenation should be treated with intravenous benzodiazepines or ultra-short-acting barbiturates.

Centrally acting analeptics are contra-indicated.

There is no specific antidote.

Lidocaine cannot be eliminated by haemodialysis.