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2%W/V Lidocaine Injection Bp

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

2% w/v Lidocaine Injection BP.

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ampoule contains    2ml    5ml    10ml    20ml

Lidocaine Hydrochloride H2O    40mg    100mg    200mg    400mg

3.    PHARMACEUTICAL FORM

Solution for intracutaneous, subcutaneous, intramuscular, perineural and epidural injection and for intravenous injection.

4.    CLINICAL PARTICULARS

4.1.    Therapeutic indications

Nerve block anaesthesia.

Treatment of severe symptomatic ventricular tachycardia if judged to be life-threatening by the doctor.

4.2.    Posology and method of administration Recommended dosage schedule

Nerve block anaesthesia Adults:

Unless directed otherwise, up to 200 mg of Lidocaine hydrochloride, corresponding to approx. 10 ml 2% w/v Lidocaine Injection BP, are given to adults.

The maximum daily dose is 200 mg of Lidocaine hydrochloride.

Children:

The dosage should be calculated in ml per kg body weight. Unless prescribed otherwise, children are administered up to 4 mg of Lidocaine hydrochloride, corresponding to approx. 0.2 ml of 2 % w/v Lidocaine Injection BP.

The maximum daily dose is 4 mg of Lidocaine hydrochloride per kg B.W.

When Lidocaine is used in obstetrics, it must be remembered that pregnant women need 1/3 less of local anaesthetics.

The dose should be reduced in patients with heart failure, liver diseases, in patients receiving drugs which enhance the effects of Lidocaine (see interactions) and in patients who are more than 60 years old.

As a matter of principle, the lowest possible dose and concentration of the local anaesthetic should be used.

Antiarrhythmic therapy

Adults:

Unless directed otherwise, initially 70-100 mg (1-1.5 mg/kg B.W.) of Lidocaine hydrochloride are injected slowly i.v.

The maximum injection rate is 25 mg/min., corresponding to approx. 1.5 ml of 2 % w/v Lidocaine Injection BP per minute.

If the first injection is ineffective, a second dose - one third to half of the initial dose - may be injected after 5 - 10 minutes.

Within one hour, not more than 200 - 300 mg of Lidocaine hydrochloride should be given, corresponding to approx. 10.0 - 15.0 ml of 2 % w/v Lidocaine Injection BP.

For maintenance of therapeutic plasma levels of Lidocaine hydrochloride (1.5 - 5 pg/ml), Lidocaine hydrochloride is infused at a dose of 20 - 50 pg per kg BW per min, corresponding to 0.001- 0.0025 ml per kg B.W per min.

For preparation of Lidocaine infusions, 1000 mg of Lidocaine hydrochloride (50 ml of 2% w/v Lidocaine Injection BP) may be added to 500 ml of appropriate glucose or sodium chloride infusion solutions. A 70 kg patient is to receive 1 - 2 ml of such infusion per min, corresponding to 2-4 mg Lidocaine hydrochloride per min.

As a general rule, the dosage should be guided by the individual requirements and the therapeutic effect.

After prolonged infusion of Lidocaine (more than 12 hours) the serum half life time of Lidocaine will be increased and accumulation should therefore be considered; the dosage should then be reduced accordingly.

The dose should be reduced in patients with heart failure, liver diseases, in patients receiving drugs which enhance the effects of Lidocaine (see "Interactions"), during pregnancy, and in patients who are more than 60 years old.

Renal insufficiency, as a rule, does not require specific dose adjustment. however, such patients should be monitored for toxic effects caused by accumulation of efficacious metabolites.

Children

The safety and the efficacy of the use of Lidocaine in children have not been sufficiently established. The American Heart Association, in their Standards and Guidelines for Cardio-pulmonary Resuscitation and Emergency Cardiology of 1985, recommend an initial dose of 1 mg/kg BW and subsequently, if required, infusion of 20 - 50 pg/kg BW/min. For ensuring sufficiently high plasma levels of Lidocaine, a second dose of 1 mg/kg BW may be injected prior to infusion.

Method of administration

Nerve block anaesthesia

Intracutaneous, subcutaneous, intramuscular, perineural and epidural injection for nerve block anaesthesia.

The injection must be performed under repeated aspiration attempts.

When injection in the spinal chord region is intended, a small test dose should be given 5 min prior to the full dose in order to exclude subarachnoidal injection.

Every local anaesthetic procedure must be performed under strictly aseptic conditions.

Before undertaking any local anaesthetic procedure, venous access is recommended. Appropriate instruments and drugs for emergency treatment should be made available.

Antiarrhythmic therapy

Slow intravenous injection.

Intravenous infusion after dilution with appropriate amounts of a suitable vehicle solution.

Administration of Lidocaine should be accompanied by continuous monitoring of ECG, blood pressure and respiration. Extension of the P-Q time or QRS broadening or further extension of an already broadened QRS complex occurring during administration of Lidocaine may indicate beginning overdosage, necessitating revision of treatment. Therapy with Lidocaine must also be discontinued after aggravation of cardiac arrhythmia. In emergency situations, if bradycardia is excluded, injection of Lidocaine may be performed under continuous monitoring of the heart rate.

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

In critical cases and during prolonged therapy monitoring of Lidocaine plasma levels and adjusting to 3 (1.5 - 5) pg/ml is recommended. The exact dosage must be determined for each patient individually.

The infusion should be discontinued as soon as the cardiac rhythm has been stabilised or first signs of overdosage are observed.

When using Lidocaine preparations it should be considered that until now no Class-I antiarrhythmic agent has been proved to have a life-time prolonging effect.

Notice'.

In narcotised patients central nervous disorders may remain unrecognised and cardiac side effects may suddenly occur.

During prolonged therapy with Lidocaine infusions water and electrolyte balance should be monitored.

4.3. Contraindications

2% w/v Lidocaine Injection must not be used in cases of:

-    Severely disturbed cardiac conduction (sinu-atrial, atrioventricular or intraventricular blocks of higher degree, e.g. 2nd and 3rd degree A-V block),

-    Use during the first three months after myocardial infarction or in conditions of reduced cardiac output (left ventricular output less than 35 per cent of normal),

-    Bradycardia with heart rate below 50 BPM.

-    ADAMS-STOKES Syndrome

-    WOLFF-PARKINSON-WHITE Syndrome,

-    Hypersensitivity to amide-type local anaesthetics,

-    Suspicion of hereditary tendency to malignant hyperthermia,

Additionally, in nerve block anaesthetics, 2 % w/v Lidocaine Injection BP must not be used in the following conditions:

-    Disorders of blood coagulation, anticoagulant therapy,

-    Infections in the region of injection,

-    Uncooperative patient.

4.4. Special warnings and precautions for use Special warnings

In narcotised patients central nervous disorders may remain unrecognised and cardiac side effects may suddenly occur.

During prolonged therapy with Lidocaine infusions water and electrolyte balance should be monitored.

Special precautions for use

Especially careful medical monitoring is mandatory if 2 % w/v Lidocaine Injection BP is used in the following conditions:

-    Disorders of cardiac impulse generation and conduction (Sick Sinus Syndrome, 1st degree A-V block, Bundle Branch Block),

-    Hypoxia,

-    Respiratory depression,

-    Increased tendency to convulsions,

-    Hypovolaemia,

-    Shock,

-    Diseases of liver and kidneys,

-    Myocardial weakness (cardiac insufficiency),

-    Severe hypotension (systolic blood pressure below 90 mm Hg).

Before undertaking any local anaesthetic procedure, venous access is recommended. Appropriate instruments and drugs for emergency treatment should be made available.

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

Beta blockers (e.g. propranolol, metoprolol), cimetidine, and noradrenaline have a synergetic effect on the action of Lidocaine; in acidosis, the plasma concentration of free Lidocaine is increased. These conditions may necessitate dose reduction.

If 2 % w/v Lidocaine Injection BP is combined with other anti-arrhythmic agents such as beta blockers or calcium antagonists, the inhibitory effect on cardiac conduction and contractility may be enhanced.

If 2 % w/v Lidocaine Injection BP and inhalation narcotics are given simultaneously, there may be mutual synergisms regarding their depressive effects.

If epinephrine or noradrenaline are given additionally, but separately, frequency or seriousness of side effects on the heart may be markedly increased.

Drugs stimulating the hepatic metabolism of drug substances by microsomal enzyme induction, e.g. phenobarbital or phenytoin, reduce the efficacy of Lidocaine.

Lidocaine may have a synergetic effect on peripheral muscle relaxants, especially suxamethonium chloride.

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.

4.6. Pregnancy and lactation

Lidocaine crosses the placental barrier. During pregnancy, 2% w/v Lidocaine Injection should only be used if the expected benefits clearly outweigh potential hazards. The doses applied should be as low as possible. 2% w/v Lidocaine Injection should also be used very cautiously in obstetrics, especially in situations of foetal hypoxia and acidosis.

Lidocaine is secreted into breast milk. Therefore, caution should be exercised when administering 2% w/v Lidocaine Injection to nursing women. In general, however, nursing does not have to be discontinued.

4.7. Effects on ability to drive and use machines

Because of the effects of Lidocaine on the C.N.S. impaired ability to drive or to operate machinery must be considered.

Therefore, after use of 2 % w/v Lidocaine Injection BP in surgery, operative dentistry or after procedures involving the use on extended body areas, the physician has to decide whether the patient is fit for driving or operating machines.

4.8 Undesirable effects

Frequently, especially under too rapid administration, central nervous disorders are observed, such as sleepiness, dizziness, vertigo, confusion, blurred vision, dysarthria, dysphagia, tinnitus, trembling, flushing, chills, tingling and skin paraesthesia, further restlessness, irritability, euphoria, hallucinations and depression. Frequently observed gastro-intestinal disorders include anorexia, nausea, and vomiting. These adverse effects are more frequent under rapid onset of systemic effects of lidocaine hydrochloride.

If undesirable effects are observed, the rate of administration of lidocaine must be reduced or administration must be discontinued.

Rarely, neurological complications following central nervous blocks -mainly spinal anaesthesia - may occur such as persistent anaesthesia, paraesthesia, paresis or plegia of the lower extremities and loss of sphincter control (e.g. cauda equina syndrome).

After spinal anaesthesia, transient pain in the lower extremities and lower back pain is commonly observed. The pain may last several (up to 5) days and will resolve spontaneously.

Proarrhythmic effects becoming manifest as alterations or aggravation of the originally present arrhythmia may lead to severe impairment of cardiac action possibly followed by cardiac arrest.

Rarely, especially in cases of overdosage, serious adverse effects such as muscular convulsions, possibly up to spasms of the entire body, impaired consciousness up to coma, respiratory depression or even arrest, drop of blood pressure, bradycardia, tachyarrhythmia and shock are observed.

Foetal bradycardia in connection with the use of lidocaine hydrochloride in obstetrics has been reported.

Allergic reactions such as exanthema, urticaria, oedema, hypotension and

anaphylactic shock have been observed sporadically.

In elderly patients the incidence of side 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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9. Overdose

Minor overdosage mainly affects the C.N.S. symptoms (see "Undesirable Effects") which disappear in most cases after discontinuation of the administration of Lidocaine.

Gross overdosage will cause convulsions, disturbance of consciousness and even coma, respiratory depression, shock, myocardial conduction disorders or blocks.

Treatment:

Immediately discontinue administration!

Give respiratory support; ensure sufficient ventilation and patency of the respiratory tract; if required, perform mouth-to-mouth or mouth-to-nose ventilation; give oxygen.

Immediately start cardio-pulmonary resuscitation, if necessary.

For treatment of spasms / convulsions give diazepam or a short-acting barbiturate, institute artificial respiration.

In case of sudden drop of blood pressure ensure appropriate positioning of the patient (head-down position); give vasopressors and volume replacement fluids. Adrenaline and analeptics acting on the C.N.S. are contraindicated.

For bradycardias give atropine i.v. For therapy of A-V Blocks orciprenaline may be given; transient pacemaker therapy may be instituted if necessary.

There is no specific antidote.

Lidocaine cannot be eliminated by haemodialysis.

5.


PHARMACOLOGICAL PROPERTIES

The local anaesthetic effect of Lidocaine results from blockage of the sodium channels of neural fibres. Impulse generation and conduction are suppressed and the sensation of pain is discontinued without effects on consciousness. The anaesthesising effect is reversible and confined to the area of application.

The sensitivity of neural fibres to Lidocaine depends on their diameter; thin fibres are anaesthesized earlier than thicker ones. The order of loss of nerve function is as follows: pain, temperature, touch and pressure. The order of return of nerve function is inverse, i.e. return of pain sensation is latest.

In inflamed tissues, the efficacy of Lidocaine may be reduced due to the lower pH in such tissues.

Lidocaine is also a class Ib antiarrhythmic agent (acc. to VAUGHAN-WILLIAMS). In membranes of myocardial fibres Lidocaine inhibits the fast sodium influx and increases the potassium influx. In PURKINYE fibres the duration of action potentials and their effective refractory time are shortened while impulse conduction is slowed down. Impulse conduction in the sinus node and supraventricular regions remains virtually unaffected.

In the myocardium, the excitation and fibrillation thresholds are raised. Lidocaine suppresses heterotopic pacemakers and action potentials originating from delayed potentials, and tachyarrhythmias caused by circus rhythm. The antiarrhythmic effect is particularly marked in tachycardia. The effect of Lidocaine is enhanced if the resting potential is less negative, e.g. in hyperkalaemia and/or myocardial ischaemia. In situations of a more negative resting potential or hyperpolarisation e.g. due to hypokalaemia; the effect of Lidocaine is reduced.

The effects of Lidocaine on myocardial contractility, blood pressure, and cardiac output are very small. Patients with impaired function of the sinus node, however, may respond particularly markedly to the conduction suppressing effect of Lidocaine. Reduced coronary blood flow may be increased after correction of the arrhythmia.

5.2. Pharmacokinetic properties

Onset of the local anaesthetic effect of Lidocaine is rapid, i.e. within less than 5 min. Its duration is between 1 and 2 hours. The elimination of Lidocaine from the region of application depends on tissue perfusion. Due to the concentration gradient in the area of application Lidocaine diffuses into the surrounding tissue, into blood vessels and is eventually washed away by the bloodstream.

After intravenous administration, onset of the anti arrhythmic effect of Lidocaine is rapid. Maximum plasma concentrations are reached within 1 - 2 min. The effect of a bolus injection lasts for 10 - 20 min; in order to maintain the antiarrhythmic effect of Lidocaine, its administration must be continued in the form of an infusion. The therapeutic plasma concentration should be between 1.5 and 6 pg/l. Beyond 6 pg/l, toxic effects on the C.N.S. and the cardiovascular system are to be expected.

The plasma protein binding is 60 - 80 % in adults, 20 - 40 % in adolescents and about 25 % in newborns.

Intravenously administered Lidocaine is rapidly distributed in highly perfused organs (lungs, kidneys, liver, heart) and is re-distributed in muscles and adipose tissue. The distribution volume is 1.3 - 1.8 l/kg; it is greater in newborns and in patients with hepatic or renal insufficiency; it is lower in patients with cardiac insufficiency.

Most of an administered Lidocaine dose (90 - 95 %) is hepatically metabolised by de-salkylation to monoethyl glycine xylidide (MEGX) and further to glycine xylidide (GX). MEGX has a weak anti arrhythmic potential. Both metabolites are potentially toxic. The degree of formation of 2,6-xylidine is not exactly known. Metabolism of Lidocaine strongly depends on liver perfusion. Vasoactive substances, e.g. glucagon or isoprenaline increase the hepatic perfusion and consecutively the elimination of Lidocaine.

The elimination of Lidocaine from the plasma is biphasic with an initial half life time of approx. 10 min. (distribution phase) and a terminal half life time of 1.5 - 3 h. (elimination phase). The half life time of Lidocaine is prolonged in new-borns (2.9 - 3 h), in patients with cardiac and particularly with hepatic insufficiency (3-19 h).

When Lidocaine is infused continuously, the half life time is extended to 3 - 5 h. The half life time of the metabolites are longer than that of Lidocaine (MEGX, 2 h, GX, 10 h). In situations of renal insufficiency, further extension of the half life time and accumulation of GX in the plasma must be considered.

5 - 10 % of Lidocaine are excreted unchanged in urine; the remaining proportion in the form of the metabolites. The predominant metabolite in urine is 4-hydroxy-2,6-xylidine (65 %).

Lidocaine passes the placental barrier and in foetal blood its concentration is about 60 % of that in maternal blood. Because of the low protein binding in fetal blood the concentration of free Lidocaine is about 1.4 times that of the maternal value.

Lidocaine is metabolised by the foetus; the half life time is about 3 hours.

Lidocaine appears in breast-milk. Its concentration is about 40 % of the concentration in maternal blood.

The toxic effects of Lidocaine become manifest in the central nervous system and the cardiovascular system.

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.

The basic causes of high plasma concentrations are actual overdose of Lidocaine, injection into a vein or artery and too rapid resorption from the injection site.

Depending on the individual sensitivity toxic reactions occur from a concentration of approx. 4-6 ^g Lidocaine/ml venous blood.

The lethal concentration for humans is in the range 6 to 33 ^g Lidocaine/ml.

Animal experiments have not provided any evidence of embryo-toxicity or teratogenicity.

There are findings indicating a mutagenic effect of Lidocaine. These indications come from in vitro tests with the metabolite 2,6 -xylidine at very high, almost toxic concentrations. There does not appear to be any relevance for the therapeutic administration.

In a carcinogenicity study of the metabolite 2-6 xylidine in rats, applying excessively high doses, benign and malignant tumours were detected particularly in the nasal cavity. The significance of this result for humans is unclear, but high dose administration over long periods should be avoided.

6. PHARMACEUTICAL PARTICULARS 6.1. List of excipients

Sodium chloride, sodium hydroxide, water for injections

6.2. Incompatibilities

Lidocaine hydrochloride is incompatible with solutions containing sodium bicarbonate, with injectable preparations of amphotericin B, sulfadiazine sodium, methohexital sodium, cephazolin sodium, phenytoin, and other

alkaline solutions. Therefore, 2 % Lidocaine Injection BP must not be mixed with such solutions.

6.3. Shelf life

2 ml: 18 months 5 ml: 24 months 10 ml: 30 months 20 ml: 30 months

6.4. Special precautions for storage

Do not store above 25°C.

6.5. Nature and contents of container

2 % w/v Lidocaine Injection BP is supplied in plastic ampoules of low-density polyethylene (Mini-Plasco) of 2 ml, 5 ml, 10 ml, 20 ml.

6.6. Instruction for use/handling

The product is supplied in single-dose containers. Note:

Disinfect the exterior of the ampoule prior to use.

7. MARKETING AUTHORISATION HOLDER

B. Braun Melsungen AG Carl-Braun-Strasse 1 D-34212 Melsungen.

Germany

8.


MARKETING AUTHORISATION NUMBER(S)

PL 03551/0013.

9. DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

20 September 1996.

10 DATE OF REVISION OF THE TEXT

14/04/2015