1. Name Of The Medicinal Product
Marcain Polyamp Steripack 0.25%.
2. Qualitative And Quantitative Composition
Bupivacaine Hydrochloride BP 2.64mg/ml equivalent to bupivacaine hydrochloride anhydrous 2.5mg/ml.
3. Pharmaceutical Form
Injection.
4. Clinical Particulars
4.1 Therapeutic Indications
Marcain 0.25%, 0.375% 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.
A list of indications and the suggested dose and strength of solution appropriate for each are shown in the table below.
Marcain 0.75% solution produces a more prolonged motor block than 0.25%, 0.375% or 0.5% solutions and is, therefore, recommended for epidural anaesthesia for surgical purposes. Epidural anaesthesia is usually maintained for 3 to 4 hours.
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 3-5ml 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, 25-50mg/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 150mg bupivacaine hydrochloride. Doses of up to 50mg 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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If total amount greater than 20ml reduce concentration to 0.2%.
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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).
0.75% solution is contra-indicated for epidural use in obstetrics.
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 obstetrical patients. In most cases, this has followed use of the 0.75% concentration. Resuscitation has been difficult or impossible despite apparently adequate preparation and appropriate management. Cardiac arrest has occurred after convulsions resulting from systemic toxicity, presumably following unintentional intravasular injection. The 0.75% concentration should be reserved for surgical procedures where a high degree of muscle relaxation and prolonged effect are necessary.
Epidural blockade and large nerve plexus blocks should only be employed by those with the necessary training and experience.
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 10-15mg 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.
Clinicians who perform retrobulbar blocks should be aware that there have been reports of respiratory arrest following local anaesthetic injection. Prior to retrobulbar block, necessary equipment, drugs and personnel should be immediately available as with all other regional procedures.
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.
Serious cardiac arrhythmias may occur if preparations containing a vasoconstrictor drug are employed in patients during or following the administration of chloroform, halothane, cyclopropane, trichlorethylene or other related agents.
4.6 Pregnancy And Lactation
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.
Bupivacaine enters the mother's milk, but in such small quantities that there is no risk of affecting the child at therapeutic dose levels. 4.7 Effects on ability to drive and use machines
None stated.
4.8 Undesirable Effects
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, 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. Usually these will be preceded or accompanied by major CNS toxicity, i.e. convulsions, but in rare cases cardiac arrest has occurred without prodromal CNS effects.
Epidural anaesthesia itself can cause adverse reactions regardless of the local anaesthetic agent used. These include hypotension and bradycardia due to sympathetic blockade and/or vasovagal fainting.
In severe cases cardiac arrest may occur.
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.
4.9 Overdose
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 200mg or diazepam 5 to 10mg. Alternatively succinylcholine 50mg - 100mg 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 30mg, 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 10-15mg 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
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 is a well established active ingredient.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Sodium chloride, sodium hydroxide and water for injections.
6.2 Incompatibilities
None stated.
6.3 Shelf Life
24 months.
6.4 Special Precautions For Storage
Store below 30ºC.
6.5 Nature And Contents Of Container
10ml and 20ml polypropylene ampoules (Steripack). Cartons contain 5 or 10 ampoules.
6.6 Special Precautions For Disposal And Other Handling
For single use only. Discard any unused solution.
7. Marketing Authorisation Holder
Astra Pharmaceuticals Ltd.,
600 Capability Green,
Luton, LU1 3LU, UK.
8. Marketing Authorisation Number(S)
PL 0017/0305.
9. Date Of First Authorisation/Renewal Of The Authorisation
First granted 19/4/93; renewed 22-09-98.
10. Date Of Revision Of The Text
13th December 2001
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