For the use of a Registered Medical Practitioner, Hospital or a Laboratory only
LIDOCAINE HYDROCHLORIDE INJECTION USP 2% W/V
LIDOCAN INJECTION
COMPOSITION
Each ml contains:
Lidocaine Hydrochloride USP 2 % w/v
Sodium Chloride BP 6 mg
Methylparaben BP 1 mg (as preservative)
Water for Injections BP q.s.
DESCRIPTION
A clear, colourless to almost colorless solution.
PHARMACODYNAMIC
Anaesthetics, local, amides.
ATC code: N01BB02.
Mechanism of action
Local and regional anaesthesia
Lidocaine is a local anaesthetic agent of the amide type.
Lidocaine reduces the permeability of cell membranes for cations, in particular sodium ions, at higher concentrations also for potassium ions. This leads, depending on the concentration of lidocaine, to reduced excitability of the nerve fibres because the increase of sodium permeability producing the action potential is slowed down. From inside the cell the lidocaine molecule enters the open sodium channel and blocks it by binding to a specific receptor. A direct effect of incorporation of lidocaine in the cell membrane is much less relevant.
Because lidocaine, before reaching its site of action, must pass into the cell, its effect depends on its pKa and on the environmental pH, i.e. on the proportion of the free base which is the moiety predominantly migrating through the lipophilic membranes of nerve fibres.
In inflamed tissue the local anaesthetic effect is reduced due to the lower pH in such regions.
PHARMACOKINETICS
Absorption
Plasma levels depend on the site and mode of administration. However, there is a poor relationship between the amount of local anaesthetic injected and peak plasma levels. After intravenous administration the bio-availability is 100%.
Maximum concentrations are achieved within latest 30 minutes, in the majority of patients maximum concentrations are met within 10-20 minutes.
After intramuscular injection of 400 mg of lidocaine hydrochloride monohydrate for intercostal block, the maximum plasma concentration (Cmax) has been determined to be 6.48 mg/l, attained after 5 – 15 min (tmax).
After intravenous administration, onset of the therapeutic effect of lidocaine is rapid. Therapeutic plasma concentrations are reached within 1 – 2 min. The effect of a bolus injection lasts for 10 – 20 min; in order to maintain the therapeutic effect of lidocaine, its administration must be continued in the form of an intravenous infusion.
After continuous infusion and when no loading dose is given the steady state of plasma concentration was achieved not earlier than 5 hours (range, 5 – 10 hours) of beginning of the infusion. However, therapeutic concentrations had already been achieved after 30 – 60 min.
After subcutaneous administration, Cmax values reached 4.91 mg/l (vaginal injection) or 1.95 mg/l (abdominal injection), respectively. In a study involving 5 healthy volunteers, after maxillar-buccal infiltration anaesthesia with 36 mg of lidocaine hydrochloride monohydrate, using a 2% solution, the Cmax value reached 0.31 mg/l.
After epidural injection the measured maximum plasma concentrations do not seem to be directly proportional to the dose applied. Administration of 400 mg resulted in Cmax values of 3 – 4 mg/l.
No data are available on pharmacokinetics after intrathecal administration.
Distribution
Lidocaine follows a biphasic elimination kinetic. After intravenous administration the drug substance is first rapidly distributed from the central compartment into intensively perfused tissues and organs (α-distribution phase). This phase is followed by redistribution into skeletal muscles and adipose tissue. The half-life time during the α-distribution phase is approximately 4-8 minutes. Distribution into peripheral tissues is predicted to occur within 15 min.
The plasma protein binding rate is approximately 60 – 80 per cent in adults. It is dependent on the drug concentration and additionally on the concentration of the α-1-acid glycoprotein (AAG). The AAG is an acute phase protein that is binding free lidocaine and may be increased e.g. after trauma, surgery or burns depending on the pathophysiological condition of the patient. To the contrary it had been shown that AAG concentrations are low in neonates and patients suffering from liver impairment leading to a marked reduction of lidocaine plasma protein binding.
The distribution volume may be altered in patients suffering from further diseases, e.g. heart insufficiency, liver insufficiency or renal insufficiency.
Biotransformation
Besides distribution of Lidocaine in other compartments (e.g. cerebrospinal fluid), the drug is rapidly metabolised in the liver by mono-oxygenases mainly via oxidative desalkylation, hydroxylation at the aromatic ring and hydrolysis of the amide bond. Hydroxylated derivatives undergo conjugation. In total, approximately 90 % of lidocaine are metabolised to 4-hydroxy-2,6-xylidine, to 4-hydroxy-2,6-xylidine glucuronide and to a lower degree to the active metabolites monoethyl glycine xylidide (MEGX) and glycine xylidide (GX). The latter may accumulate during longer lasting infusions or in the presence of severe renal insufficiency due to their longer half life time as compared to lidocaine itself. In the presence of liver diseases, the metabolic rate may be reduced to 10 – 50 per cent of normal.
Results with human liver microsomes and recombinant human CYP isoforms demonstrated that CYP1A2 and CYP3A4 enzymes are the major CYP isoforms involved in lidocaine N-deethylation.
The hepatic blood flow appears to limit the rate of lidocaine metabolism. As a consequence, the plasma t1/2 of lidocaine and its metabolites may be prolonged and significant effects on pharmacokinetics and dosage requirements of lidocaine are to be expected in patients with impaired liver perfusion, e.g. after acute myocardial infarction, in the presence of cardiac insufficiency, liver disease or congestive heart failure.
Elimination
Less than – 10 per cent of lidocaine are excreted unchanged in urine, the remaining proportion in the form of the metabolites.
The elimination half-life is 1.5 – 2 hours in healthy adults and approximately 3 hours in newborns.
The half-lives of the active metabolites MEGX and GX are about 2-6 hours and 10 hours, respectively. Since their plasma t1/2 are longer than that of lidocaine, accumulation of metabolites, particularly GX, may occur during prolonged infusion.
Additionally, the elimination rate depends on the pH; it can be increased by acidification of the urine. The plasma clearance is about 0.95 l/min.
THERAPEUTIC INDICATION
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.
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.
DOSAGE AND 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:
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 liter upward in venous blood.
The lethal plasma concentration for humans is in the range 6 to 33 mg lidocaine per liter.
CONTRAINDICATION
General
- Hypersensitivity to the active substance, amide-type local anaesthetics, or to any of the excipients.
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.
WARNING AND PRECAUTIONS
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, cardiac insufficiency, bradycardia, impaired respiratory function and severe shock.
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 cannula.
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.
PREGNANCY, LACTATION AND ABILITY TO DRIVE
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.
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.
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.
DRUG 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.
Pharmacokinetic interactions
- Medicinal products that alter the hepatic blood flow, cardiac output or peripheral distribution of lidocainemay 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.
ADVERSE 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.
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: 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), Not Known (frequency cannot be established from the available data).
| Local And Regional Anaesthesia: | ||
| System Organ Class | Frequency | Adverse Reactions |
| Blood and the Lymphatic system disorder | 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. incontinence), headache accompanied by tinnitus and photophobia.
Cranial nerves 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 disorder and administration site conditions | Rare | Shivering (after epidural use). |
PRESENTATION
LIDOCAN Injections are supplied in 30 ml flint, Type I USP, Tubular vial.
STORAGE AND OTHER INFORMATION
Store in a cool and dry place. Protect from light.
Store at below 30°C temperature.
Caution: Not to be used if container is found leaking or solution is hazy or contain any visible solid particles. Keep this medicine out of the sight and reach of children.
CFS/I/00