1. Name Of The Medicinal Product
Marcain 0.25% with Adrenaline (5 mcg/ml) (1:200,000).
2. Qualitative And Quantitative Composition
Each ml contains Bupivacaine hydrochloride equivalent to anhydrous bupivacaine hydrochloride 2.5 mg per ml (25 mg per 10 ml ampoule) and Adrenaline tartrate equivalent to adrenaline 5 micrograms per ml (50 micrograms per 10 ml ampoule).
For excipients, see 6.1
3. Pharmaceutical Form
Solution for injection
4. Clinical Particulars
4.1 Therapeutic Indications
Marcain 0.25% and 0.5% solutions are used for the production of local anaesthesia by percutaneous infiltration, peripheral nerve block(s) and central neural block (caudal or epidural), that is, for specialist use in situations where prolonged anaesthesia is required. Because sensory nerve block is more marked than motor block, Marcain is especially useful in the relief of pain, e.g. during labour.
4.2 Posology And Method Of Administration
The utmost care should be taken to prevent an accidental intravascular injection, always including careful aspiration. For epidural anaesthesia, a test dose of 3-5 ml of bupivacaine containing adrenaline should be administered, since an intravascular injection of adrenaline will be quickly recognised by an increase in heart rate. Verbal contact and repeated measurement of heart rate should be maintained throughout a period of 5 minutes following the test dose. Aspiration should be repeated prior to administration of the total dose. The main dose should be injected slowly, 25-50 mg/min, in incremental doses under constant contact with the patient. If mild toxic symptoms occur, the injection should be stopped immediately.
The dosage varies and depends upon the area to be anaesthetised, the vascularity of the tissues, the number of neuronal segments to be blocked, individual tolerance and the technique of anaesthesia used. The lowest dosage needed to provide effective anaesthesia should be administered. For most indications, the duration of anaesthesia with Marcain solutions is such that a single dose is sufficient.
The maximum dosage must be determined by evaluating the size and physical status of the patient and considering the usual rate of systemic absorption from a particular injection site. Experience to date indicates a single dose of up to 150 mg bupivacaine hydrochloride. Doses of up to 50 mg 2-hourly may subsequently be used. The dosages in the following table are recommended as a guide for use in the average adult. For young, elderly or debilitated patients, these doses should be reduced.
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Lumbar epidural |
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* With continuous (intermittent) techniques, repeat doses increase the degree of motor block. The first repeat dose of 0.5% may produce complete motor block for intra-abdominal surgery.
4.3 Contraindications
Bupivacaine hydrochloride solutions are contra-indicated in patients with a known
hypersensitivity to local anaesthetic agents of the amide type or to other components of the injectable formulation.
Solutions of bupivacaine hydrochloride are contra-indicated for intravenous regional anaesthesia (Bier's-block).
Solutions containing adrenaline are contra-indicated in patients with thyrotoxicosis or severe heart disease, particularly when tachycardia is present.
Solutions of bupivacaine hydrochloride with adrenaline should not be used in connection with anaesthesia in areas of the body supplied by end arteries or otherwise having a compromised blood supply such as digits, nose, external ear, penis, etc.
Epidural anaesthesia, regardless of the local anaesthetic used, has its own contra-indications which include:
Active disease of the central nervous system such as meningitis, poliomyelitis, intracranial haemorrhage, sub-acute combined degeneration of the cord due to pernicious anaemia and cerebral and spinal tumours. Tuberculosis of the spine. Pyogenic infection of the skin at or adjacent to the site of lumbar puncture. Cardiogenic or hypovolaemic shock. Coagulation disorders or ongoing anticoagulation treatment.
4.4 Special Warnings And Precautions For Use
There have been reports of cardiac arrest with difficult resuscitation or death during use of bupivacaine for epidural anaesthesia in obstetric patients or peripheral nerve blockade. In some instances, resuscitation has been difficult or impossible despite apparently adequate preparation and appropriate management. Major peripheral nerve blocks may require the administration of a large volume of local anaesthetic in areas of high vascularity, often close to large vessels where there is an increased risk of intravascular injection and/or systemic absorption. This may lead to high plasma concentrations. Cardiac arrest has occurred after convulsions resulting from systemic toxicity, presumably following unintentional intravascular injection.
Epidural blockade and large nerve plexus blocks should only be employed by those with the necessary training and experience.
Before any nerve block is attempted, intravenous access for resuscitation purposes should be established. Clinicians should have received adequate and appropriate training in the procedure to be performed and should be familiar with the diagnosis and treatment of side effects, systemic toxicity or other complications. Adequate resuscitation equipment should be available whenever local or general anaesthesia is administered.
Overdosage or accidental intravenous injection may give rise to toxic reactions.
Injection of repeated doses of bupivacaine hydrochloride may cause significant increases in blood levels with each repeated dose due to slow accumulation of the drug. Tolerance varies with the status of the patient. Debilitated, elderly or acutely ill patients should be given reduced doses commensurate with their physical status.
Only in rare cases have amide local anaesthetics been associated with allergic reactions (in most severe instances anaphylactic shock).
Patients allergic to ester-type local anaesthetic drugs (procaine, tetracaine, benzocaine, etc.) have not shown cross-sensitivity to agents of the amide type such as bupivacaine.
Local anaesthetics should be used with caution for epidural anaesthesia in patients with impaired cardiovascular function since they may be less able to compensate for functional changes associated with the prolongation of A-V conduction produced by these drugs.
Since bupivacaine is metabolised in the liver, it should be used cautiously in patients with liver disease or with reduced liver blood flow.
Epidural anaesthesia with any local anaesthetic can cause hypotension and bradycardia which should be anticipated and appropriate precautions taken. These may include pre-loading the circulation with crystalloid or colloid solution. If hypotension develops it should be treated with a vasopressor such as ephedrine 10-15 mg intravenously. Severe hypotension may result from hypovolaemia due to haemorrhage or dehydration, or aorto-caval occlusion in patients with massive ascites, large abdominal tumours or late pregnancy. Marked hypotension should be avoided in patients with cardiac decompensation.
Patients with hypovolaemia due to any cause can develop sudden and severe hypotension during epidural anaesthesia.
Epidural anaesthesia can cause intercostal paralysis and patients with pleural effusions may suffer respiratory embarrassment. Septicaemia can increase the risk of intraspinal abscess formation in the postoperative period.
Paracervical block may have a greater adverse effect on the foetus than other nerve blocks used in obstetrics. Due to the systemic toxicity of bupivacaine special care should be taken when using bupivacaine for paracervical block.
Small doses of local anaesthetics injected into the head and neck, including retrobulbar, dental and stellate ganglion blocks, may produce systemic toxicity due to inadvertent intra-arterial injection.
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Retrobulbar injections may very occasionally reach the cranial subarachnoid space causing temporary blindness, cardiovascular collapse, apnoea, convulsions etc. These must be diagnosed and treated promptly.
Retro- and peribulbar injections of local anaesthetics carry a low risk of persistent ocular muscle 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 the local anaesthetic. For this reason, as with all local anaesthetics, the lowest effective concentration and dose of local anaesthetic should be used. Vasoconstrictors, and other additives may aggrevate tissue reactions and should be used only when indicated.
Solutions containing adrenaline should be used with caution in patients with hypertension, arteriosclerotic heart disease, cerebrovascular insufficiency or diabetes.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Bupivacaine should be used with care in patients receiving anti-arrhythmic drugs with local anaesthetic activity, e.g. lidocaine since their toxic effects may be additive.
Solutions containing adrenaline should be used with caution in those patients receiving drugs known to produce blood pressure alterations, i.e. MAO inhibitors, tricyclic antidepressants, phenothiazines, etc., as severe and sustained hypotension or hypertension may occur.
Solutions containing adrenaline should be used with caution in patients undergoing general anaesthesia with inhalation agents such as halothane, due to the risk of serious cardiac arrhythmias.
Non-cardioselective betablockers such as propranolol enhance the pressor effects of adrenaline, which may lead to severe hypertension and bradycardia.
4.6 Pregnancy And Lactation
Bupivacaine enters the mother's milk, but in such small quantities that there is no risk of affecting the child at therapeutic dose levels.
There is no evidence of untoward effects in human pregnancy. In large doses there is evidence of decreased pup survival in rats and an embryological effect in rabbits if Marcain is administered in pregnancy. Marcain should not therefore be given in early pregnancy unless the benefits are considered to outweigh the risks.
4.7 Effects On Ability To Drive And Use Machines
None stated.
4.8 Undesirable Effects
The adverse reaction profile for Marcain is similar to those for other long acting local anaesthetics. Adverse reactions caused by the drug per se are difficult to distinguish from the physiological effects of the nerve block (e.g. decrease in blood pressure, bradychardia), events caused directly (e.g. nerve trauma) or indirectly (e.g. epidural abscess) by the needle puncture.
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Serious systemic adverse reactions are rare, but may occur in connection with overdosage or unintentional intravascular injection.
Bupivacaine causes systemic toxicity similar to that observed with other local anaesthetic agents. It is caused by high plasma concentrations as a result of excessive dosage, exceptionally rapid absorption or, most commonly, inadvertent intravascular injection. Pronounced acidosis or hypoxia may increase the risk and severity of toxic reactions. Such reactions involve the central nervous system and the cardiovascular system. CNS reactions are characterised by numbness of the tongue, light-headedness, dizziness, blurred vision and muscle twitch, followed by drowsiness, convulsions, unconsciousness and possibly respiratory arrest.
Cardiovascular reactions are related to depression of the conduction system of the heart and myocardium leading to decreased cardiac output, heart block, hypotension, bradycardia and sometimes ventricular arrhythmias, including ventricular tachycardia, ventricular fibrillation and cardiac arrest. Sudden cardiovascular collapse and death have been reported when Marcain has been used for local anaesthetic procedures that may result in high systemic concentrations of bupivacaine. Usually these cardiovascular events will be preceded or accompanied by major CNS toxicity, i.e. convulsions, but in rare cases cardiac arrest has occurred without prodromal CNS effects.
Accidental sub-arachnoid injection can lead to very high spinal anaesthesia possibly with apnoea and severe hypotension.
Neurological damage is a rare but well recognised consequence of regional and particularly epidural and spinal anaesthesia. It may be due to several causes, e.g. direct injury to the spinal cord or spinal nerves, anterior spinal artery syndrome, injection of an irritant substance, or an injection of a non-sterile solution. These may result in localised areas of paraesthesia or anaesthesia, motor weakness, loss of sphincter control and paraplegia. Occasionally these are permanent.
Hepatic dysfunction, with reversible increases of SGOT, SGPT, alkaline phosphates and bilirubin, has been observed following repeated injections or long-term infusions of bupivacaine. If signs of hepatic dysfunction are observed during treatment with bupivacaine, the drug should be discontinued.
4.9 Overdose
Treatment of side effects:
Treatment of a patient with systemic toxicity consists of arresting convulsions and ensuring adequate ventilation with oxygen, if necessary by assisted or controlled ventilation (respiration). If convulsions occur they must be treated promptly by intravenous injection of thiopentone 100 to 200 mg or diazepam 5 to 10 mg. Alternatively succinylcholine 50 mg - 100 mg i.v. may be used providing the clinician is capable of performing endotracheal intubation and managing a fully paralysed patient.
Once convulsions have been controlled and adequate ventilation of the lungs ensured, no other treatment is generally required. If hypotension is present, however, a vasopressor, preferably one with inotropic activity, e.g. ephedrine 15 to 30 mg, should be given intravenously.
Cardiac arrest due to bupivacaine can be resistant to electrical defibrillation and resuscitation must be continued energetically for a prolonged period.
High or total spinal blockade causing respiratory paralysis and hypotension during epidural anaesthesia should be treated by ensuring and maintaining a patent airway and giving oxygen by assisted or controlled ventilation.
Hypotension should be treated by the use of vasopressors, e.g. ephedrine 10-15 mg intravenously and repeated until the desired level of arterial pressure is reached. Intravenous fluids, both electrolytes and colloids, given rapidly can also reverse hypotension.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
ATC code: N01B B51
Bupivacaine is a potent amide local anaesthetic with a prolonged duration of action. It affects sensory nerves more than motor nerves and is ideal for producing analgesia without motor blockade.
5.2 Pharmacokinetic Properties
In adults, the terminal half-life of bupivacaine is 3.5 hours. The maximum blood concentration varies with the site of injection and is highest after intercostal nerve blockade.
Total dose, rather than concentration, is an important determinant of peak blood levels.
Bupivacaine is biodegraded in the liver and only 6% is excreted unchanged in the urine.
5.3 Preclinical Safety Data
Bupivacaine hydrochloride and adrenaline tartrate are well established active ingredients.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Sodium metabisulphite, sodium chloride, hydrochloric acid and water for injections.
6.2 Incompatibilities
None known.
6.3 Shelf Life
10 ml ampoules - 18 months
6.4 Special Precautions For Storage
Do not store above 25°C
6.5 Nature And Contents Of Container
10 ml glass ampoules - blister packed
6.6 Special Precautions For Disposal And Other Handling
None known.
7. Marketing Authorisation Holder
AstraZeneca UK Ltd.
600 Capability Green
Luton
LU1 3LU
UK
8. Marketing Authorisation Number(S)
PL17901/0140
9. Date Of First Authorisation/Renewal Of The Authorisation
12 August 2002 / 5th November 2003
10. Date Of Revision Of The Text
5th November 2003
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