1. Name Of The Medicinal Product
Bupivacaine Hydrochloride Injection B.P. 0.375 % w/v
2. Qualitative And Quantitative Composition
Solution for Injection containing 0.395 % w/v Bupivacaine Hydrochloride B.P; Ph.Eur equivalent to 0.375 % w/v anhydrous bupivacaine hydrochloride.
3. Pharmaceutical Form
Clear, colourless aqueous, sterile solution in 10 ml and 20 ml translucent plastic ampoules
4. Clinical Particulars
4.1 Therapeutic Indications
Bupivacaine Hydrochloride Injection B.P. 0.375% w/v may be used for the production of local anaesthesia by peripheral nerve block(s), or by central neural block (caudal or lumbar epidural) for analgesia in labour.
4.2 Posology And Method Of Administration
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Every precaution should be taken to avoid an accidental intravascular injection; careful aspiration is essential. For epidural anaesthesia, a test dose of 3-5 ml of bupivacaine containing adrenaline is recommended, since an intravascular injection of an adrenaline-containing solution may be recognised by an increase in heart rate. Verbal contact with the patient and repeated measurements of heart rate (ECG) should be maintained following the test dose. Aspiration should be repeated prior to administration of the main dose. The main dose should be injected slowly in incremental doses of 25 to 50 mg/minute, while keeping in constant contact with the patient. If toxic symptoms or signs of an intrathecal blockade occur, the injection should be stopped immediately.
The lowest dosage required to achieve anaesthesia should be given. However, the dosage will vary and will depend on 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 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 to150mg Bupivacaine Hydrochloride. Doses of up to 50mg 2-hourly may subsequently be used. A maximum dose of 2mg/kg should not be exceeded in any four hour period and the total dose over 24 hours should not exceed 400mg.
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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Children: Not recommended
4.3 Contraindications
Bupivacaine hydrochloride solutions are contra-indicated in patients with a known hypersensitivity to local anaesthetic agents of the amide group or to other components of the injectable formulation. Solutions of bupivacaine hydrochloride are contra-indicated for intravenous regional anaesthesia (Bier's block).
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, subacute combined degeneration of the cord due to pernicious anaemia, and cerebral or spinal tumors. Tuberculosis of the spine. Pyogenic infection of the skin at or adjacent to the site of lumbar puncture. Cardiogenic or hypovolaemic shock. Coagulation disoders or ongoing anticoagulant therapy. Epidural and spinal anaesthesia is contra-indicated in patients with an expanding cerebral lesion, a tumor, cyst or abscess, which may, if the intracranial pressure is suddenly altered, cause obstruction to the cerebrospinal fluid or blood circulation (the pressure cone).
4.4 Special Warnings And Precautions For Use
Before any nerve block is attempted, intravenous access for resuscitation purposes should be established. Adequate resuscitative equipment (oxygen, suction, means of intubation and appropriate emergency drugs) must be available. Epidural and spinal block techniques should only be carried out by clinicians with the necessary knowledge and experience.
There have been reports of cardiac arrest with difficult resuscitation or death during the use of bupivacaine for epidural anaesthesia in obstetrical patients. Resuscitation has been difficult or impossible despite adequate preparation and appropriate management. Cardiac arrest has occurred after convulsions resulting from systemic toxicity, presumably following inadvertent intravascular injection. Regardless of the site of injection or overdosage, inadvertent 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 (with anaphylactic shock developing in most severe instances). Patients allergic to ester-type local anaesthetics such as procaine have not shown cross-sensitivity to amide-type agents such as bupivacaine.
Since bupivacaine is metabolised in the liver, it should be used cautiously in patients with liver disease or with reduced liver blood flow. Local anaesthetics should be used with caution for epidural or spinal anaesthesia in the following situations: severe shock, hypovolaemia, dehydration, hypotension below 90mm systolic or a level less than 30% of their average systolic blood pressure, gross hypertension, marked obesity, senility, cerebral atheroma, myocardial degeneration, toxaemia and severe ischaemic heart disease (especially with a history of recent infarction) because of the dangers of hypotension.
Similar caution is required in cases of impaired cardiovascular conduction, such as patients with a fixed cardiac output (severe valvular stenosis, heart block, beta-blocking therapy), resulting in decreased ability to respond to dilatation of the vascular bed or to compensate for functional changes associated with the prolongation of A-V conduction produced by local anaesthetics.
Epidural and spinal anaesthesia with any local anaesthetic can cause hypotension and bradycardia which should be anticipated and appropriate precautions taken. These may include preloading the circulation with crystalloid or colloid solution. If hypotension develops, it should be treated with posture, pressor drugs e.g. ephedrine 10-15mg intravenously in divided doses, intravenous infusions, atropine or glycopyrrolate in the presence of severe bradycardia, and oxygen. Severe hypotension may result from hypovolaemia due to haemorrhage or dehydration or aorta-caval occlusion in patients with massive ascites, large abdominal tumors or late pregnancy. Marked hypotension should be avoided in patients with cardiac decompensation.
Patients with hypovolaemia due to any cause may develop sudden and severe hypotension during epidural or spinal anaesthesia.
Epidural and spinal anaesthesia, properly performed, is generally well tolerated by obese patients and by those with obstructive lung disease. However, patients with a splinted diaphragm which interferes with breathing, such as those with hydramnios, large ovarian or uterine tumors, pregnancy, ascites or omental obesity are at risk from hypoxia due to respiratory inadequacy and aortocaval compression due to tumor mass. Lateral tilt, oxygen and mechanical ventilation should be used when indicated. Dosage should be reduced in such patients. Patients who are breathless from any cause e.g. pleural effusion, may become hypoxic, especially if the level of anaesthesia is so high as to cause paralysis of the intercostal muscles.
Septicaemia can increase the risk of intraspinal abscess formation in the postoperative period.
Paracervical block may have a greater adverse effect on the foetus that 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. lignocaine, tocainide or beta-blocking drugs, since their toxic effects may be additive.
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 embryological effect in rabbits if bupivacaine is administered in pregnancy. Bupivacaine should not therefore be given in early pregnancy unless the benefits are considered to outweigh the risks.
Foetal bradycardia may occur following paracervical nerve block. Labour may be prolonged leading to the need for caesarean section.
4.7 Effects On Ability To Drive And Use Machines
In general, it is sufficient to allow 2-4 hours post nerve block or until full functions have returned following regional nerve block. In many situations, patients receive a sedative or other C.N.S. depressant drug e.g. diazepam, midazolam to allow the block to be performed. One must allow adequate time for the effects of these drugs to clear. Depending on dosage, local anaesthetics may have a very mild effect on mental function and co-ordination even in the absence of overt CNS toxicity and may temporarily impair locomotion and alertness.
4.8 Undesirable Effects
Serious systemic adverse reactions are rare, but may occur in connection with overdosage or unintentional intravascular injection.
Allergic skin and systemic reactions are very rare but have been reported. They include e.g. urticaria, face oedema, and brochospasm. Life threatening anaphylactic reactions have also been documented.
Bupivacaine causes systemic toxicity similar to that observed with other local anaesthetic agents. It is caused by high plasma concentration 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 subarachnoid 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 phosphatase and bilirubin has been observed following repeated injections or infusions of bupivacaine. If signs of hepatic dysfunction are observed during treatment with bupivacaine, the drug should be discontinued.
4.9 Overdose
Acute systemic toxicity
With accidental intravascular injection, the toxic effect will be obvious within <0.5-3 min., while with overdosage, peak plasma concentrations may not be reached for 20-30 min, and signs of toxicity are therefore delayed. Toxic reactions originate mainly in the central nervous and the cardiovascular systems.
Central nervous system toxicity is a graded response with symptoms and signs of escalating severity. The first symptoms are circumoral paraesthesia, numbness of the tongue, light-headedness, hyperacusis and tinnitus. Visual disturbance and muscular tremors are more serious and precede the onset of generalized convulsions. These signs must not be mistaken for a neurotic behaviour. Unconsciousness and grand mal convulsions may follow and can last from a few seconds to several minutes. Hypoxia and hypercarbia occur rapidly following convulsions due to the increased muscular activity together with the interference with normal respiration and loss of the airway. In severe cases, apnoea may occur. Acidosis increases the toxic effects of local anaesthetics.
Recovery is due to redistribution of the local anaesthetic drug from the central nervous system and metabolism. Recovery may be rapid unless large amounts of the drug have been injected.
Cardiovascular effects are only seen in patients with high systemic concentrations. Severe hypotension, bradycardia, arrhythmia and cardiovascular collapse may be the result in such cases.
Generally cardiovascular toxic effects are preceded by signs of toxicity in the central nervous system, unless the patient is receiving a general anaesthetic or is heavily sedated with drugs such as benzodiazepine or barbiturate.
Treatment of acute toxicity
Treatment of acute toxicity should be instituted at the latest when twitches occur. Necessary drugs and equipment should be immediately available. The objectives of treatment are to maintain oxygenation, stop the convulsions and to support the circulation.
Oxygen must be given and assisted ventilation if necessary (mask and bag). An anticonvulsant should be given i.v. if the convulsions do not stop spontaneously in 15-20 seconds. Thiopental 100-150mg i.v. will abort the convulsions rapidly. Alternatively diazepam 5-10mg i.v. may be used but its action is slower. Suxamethonium will stop the muscle convulsions rapidly, but will require tracheal intubation and controlled ventilation, and should be used by those familiar with these procedures.
If cardiovascular depression is evident (hypotension, bradycardia), ephedrine 5-10mg i.v. should be given and may be repeated if necessary after 2-3 min.
Should cardiac arrest occur, immediate cardiopulmonary resuscitation should be instituted. Optimal oxygenation and ventilation and circulatory support as well as treatment of acidosis are of vital importance, since hypoxia and acidosis will increase the systemic toxicity of local anaesthetics. Adrenaline should be given intravenously as soon as possible and repeated if necessary.
Cardiac arrest due to bupivacaine can be resistant to electrical defibrillation and resuscitation should be continued for a prolonged period.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Bupivacaine Hydrochloride is a long acting local anaesthetic of the amide type. It prevents the generation and conduction of the nerve impulse by decreasing the permeability of the nerve cell membrane to sodium ions. As well as blocking conduction in nerve axons in the peripheral nervous system, local anaesthetics interfere with the function of all organs in which conduction or transmission of impulses occur. Following absorption, bupivacaine may cause stimulation of the CNS followed by depression and, in the cardiovascular system, it acts primarily on the myocardium where it may decrease electrical excitability, conduction rate and force of contraction.
5.2 Pharmacokinetic Properties
Like other local anaesthetics, the rate of systemic absorption of bupivacaine is dependent upon the total dose and concentration administered, the route of administration and the vascularity of the tissue locally. Bupivacaine is about 95% bound to plasma proteins, mainly to alpha-1-acid glycoprotein at low concentrations and to albumin at high concentrations. It has a half-life of 1.5 to 5 hours in adults and about 8 hours in neonates. Local anaesthetics are distributed to some extent to all body tissues, with higher concentrations found in highly perfused organs such as liver, heart and brain.
Bupivacaine is metabolised in the liver and is excreted in the urine mainly as metabolites, with only 5 to 6% as unchanged drug. The drug crosses the placenta.
5.3 Preclinical Safety Data
No further relevant information other than which is included in other sections of the Summary of Product Characteristics
6. Pharmaceutical Particulars
6.1 List Of Excipients
Sodium Chloride
Sodium Hydroxide
Water for Injection
6.2 Incompatibilities
Bupivacaine Hydrochloride Injection should not be mixed with other drugs. The solution must not be stored in contact with metal e.g. needles or metal parts of syringes as dissolved metal ions may cause swelling at site of the injection.
6.3 Shelf Life
3years
6.4 Special Precautions For Storage
Protect from light
Store at 25oC.
6.5 Nature And Contents Of Container
Translucent plastic ampoule, the plastic is manufactured from polypropylene Ph.Eur. The ampoules are packed in individual thermoformed sterile polypropylene lidded trays, which are then packed in cardboard cartons.
Pack sizes: 10, 20, 50 and 100 x 10ml sterile wrapped ampoules
10, 20, 50 and 100 x 20ml sterile wrapped ampoules
6.6 Special Precautions For Disposal And Other Handling
Use as directed by the physician.
Keep out of reach of children.
If only part used, discard the remaining solution.
ADMINSTRATIVE DATA
7. Marketing Authorisation Holder
Antigen International Ltd.
Roscrea
Co.Tipperary
Ireland
8. Marketing Authorisation Number(S)
PL 02848/0183.
9. Date Of First Authorisation/Renewal Of The Authorisation
19 May 1997.
10. Date Of Revision Of The Text
November 2002.
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