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MARCAIN SPINAL 0.5% HEAVY. A sterile, hyperbaric solution which is clear, colourless and particle-free, with a specific gravity of 1.026 at 20°C. The pH has been adjusted to 4.0 to 6.0. Contains 80 mg/mL glucose (8% w/v), and 5 mg/mL bupivacaine hydrochloride (0.5% w/v) per mL solution.
MARCAIN 0.5%: A sterile, aqueous, isobaric solution which is clear, colourless and particle free. The relative density of the solution is 1.004 at 20°C. The pH has been adjusted to 4.0 to 6.5. Contains 5 mg/mL (0.5% w/v) bupivacaine hydrochloride.
Bupivacaine is a local anaesthetic of the amide type, chemically related to mepivacaine. Bupivacaine, like other local anaesthetics, causes a reversible blockade of impulse propagation along nerve fibres by preventing the inward movement of sodium ions through the nerve membrane. Local anaesthetics of the amide type are thought to act within the sodium channels of the nerve membrane.
Given as a spinal anaesthetic, bupivacaine has a rapid onset and a medium to long duration. The duration is dose-dependent. It is approximately four times more potent and toxic than lignocaine.
MARCAIN 0.5% and MARCAIN SPINAL 0.5% HEAVY have a rapid onset and long duration of action. The duration of analgesia from the isobaric solution is 3-4 hours in the lower thoracic and lumbar segments, and that from the hyperbaric solution is between 2-3 hours in the T10 - T12 segments.
MARCAIN 0.5% produces muscle relaxation in the lower limbs which lasts 3-4 hours, somewhat shorter than the duration of sensory blockade.
MARCAIN SPINAL 0.5% HEAVY produces moderate muscle relaxation in the lower extremities lasting 2-3 hours. Motor blockade of the abdominal muscles makes the solution suitable for performance of abdominal surgery lasting 1.5-2 hours. The duration of motor blockade does not exceed the duration of analgesia.
MARCAIN 0.5% is slightly hyperbaric (compared to cerebrospinal fluid) at 20°C and slightly hypobaric at 37°C. Practically it may be considered isobaric as its spread is only marginally affected by gravity. MARCAIN 0.5% will produce a lower level of block, for a longer duration, than the hyperbaric solution.
MARCAIN SPINAL 0.5% HEAVY is hyperbaric and its initial spread in the subarachnoid space is affected by gravity. The duration of anaesthesia tends to be shorter due to the larger intrathecal distribution and the consequently lower mean concentration.
Bupivacaine has a pKa of 8.1 and is extensively bound to plasma proteins (95%). Bupivacaine exhibits a high degree of lipid solubility with an oil/water partition coefficient of 27.5. These factors contribute to its prolonged duration of action.
The rate of hydrolysis in spinal fluid is slow. The majority of a dose is removed from the subarachnoid space by the venous drainage system and a smaller amount through the lymphatic system
The maximum plasma concentration is approximately 0.4 mg/L for every 100 mg injected, this is due to slow absorption from the subarachnoid space and the small dose required for spinal anaesthesia. This means that even the maximum recommended dose (20 mg) would result in plasma levels of less than 0.1 mg/L.
Bupivacaine has a total plasma clearance of 0.58 L/min, a volume of distribution at steady state of 73 L, an elimination half-life of 2.7 hours and an intermediate hepatic extraction ratio of 0.40. Clearance of bupivacaine is almost entirely due to liver metabolism, and depends upon both liver blood flow and enzyme activity. The major pathway is thought to be N-dealkylation to 2,6-pipecoloxylidide (PPX). Only 6% of bupivacaine is excreted unchanged in the urine, the main metabolites being PPX and its derivatives.
Unbound bupivacaine readily crosses the placenta in equilibrium with the mother. Only about 5% of bupivacaine is unbound and available for transfer and foetal protein binding is low compared to the mother so that the total plasma concentration (free plus bound) will be lower in the foetus than in the mother.
MARCAIN 0.5% and MARCAIN SPINAL 0.5% HEAVY are indicated for intrathecal (subarachnoid, spinal) anaesthesia for surgical and obstetrical procedures.
MARCAIN 0.5% is indicated for lower limb, including hip surgery, lasting 2 to 4 hours where muscle relaxation is desired or needed.
MARCAIN SPINAL 0.5% HEAVY is indicated for lower abdominal surgery (including Caesarean section), urological and lower limb, including hip surgery, lasting 1.5 to 3 hours.
The following dosage recommendations should be regarded as a guide for use in the average adult. The patient's physical status and concomitant medication should be considered when deciding the dose, and the lowest dose required for adequate anaesthesia should be used. Duration varies with dose, while segmental spread may be difficult to predict, especially with the isobaric (plain) solution.
The dose should be reduced in the elderly and in patients in the late stages of pregnancy.
The spread of anaesthesia obtained with both MARCAIN 0.5% and MARCAIN SPINAL 0.5% HEAVY is dependent on several factors, the most important being volume of solution injected, position of patient and rate of injection.
Note:
Spinal injections should only be made after the subarachnoid space has been clearly identified by lumbar puncture. No drug should be injected until clear cerebrospinal fluid (CSF) is seen to escape from the spinal needle or it is detected by aspiration.
During spinal anaesthesia, a marked fall in blood pressure and/or intercostal paralysis may be seen, possibly due to the use of excessive doses or improper positioning of the patient. Hypotension and bradycardia may occur as a result of sympathetic blockade.
Standard textbooks should be consulted with respect to techniques for administration of MARCAIN for spinal anaesthesia.
Marcain 0.5% and Marcain Spinal 0.5% Heavy may be used in children.
One of the differences between small children and adults is a relatively high CSF volume in infants and neonates, requiring a relatively larger dose/kg to produce the same level of block as compared to adults.
| Body Weight (kg) | Dose (mg/kg) |
|---|---|
| < 5 | 0.40-0.50 mg/kg |
| 5 to 15 | 0.30-0.40 mg/kg |
| 15 to 40 | 0.25-0.30 mg/kg |
General contraindications related to intrathecal anaesthesia should be taken into account:
Arthritis and other diseases of the vertebral column are relative contraindications due to technical difficulties in performing a spinal injection.
It is reasonable to assume that a large number of pregnant women and women of child-bearing age have been given bupivacaine. No specific disturbances to the reproductive process have so far been reported, e.g. no increased incidence of malformations.
It should be noted that the dose should be reduced in patients in the late stages of pregnancy (see DOSAGE AND ADMINISTRATION).
Local anaesthetics cross the placental barrier rapidly. A lower foetal/maternal ratio (0.2 - 0.4) than for other local anaesthetics has been observed for bupivacaine.
With recommended doses, bupivacaine enters breast milk in such small quantities that there is generally no risk of affecting the breast-fed child.
At maternal serum levels of up to 0.45 µg/mL produced by the epidural use of bupivacaine for vaginal delivery, bupivacaine could not be detected in breast milk during the first 24 hours after delivery (detection limit 0.02 µg/mL).
Besides the direct anaesthetic effect, local anaesthetics may have a very mild effect on mental function and coordination even in the absence of overt CNS toxicity and may temporarily impair locomotion and alertness.
The adverse reaction profile for MARCAIN 0.5% SPINAL is similar to those for other long acting local anaesthetics administered intrathecally. 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, bradycardia, temporary urinary retention), events caused directly (e.g. nerve trauma) or indirectly (e.g. epidural abscess) by the needle puncture or events associated to cerebrospinal leakage (eg. postdural puncture headache).
| Very Common (>1/10) |
Cardiac disorders: | Hypotension, bradycardia |
|---|---|---|
| Gastrointestinal disorders: | Nausea | |
| Common (>1/100 <1/10) |
Nervous system disorders: | Postdural puncture headache |
| Gastrointestinal disorders: | Vomiting | |
| Renal and urinary disorders: |
Urinary retention, urinary incontinence | |
| Uncommon (>1/1,000 <1/100) |
Nervous system disorders: | Paraesthesia, paresis, dysaesthesia |
| Musculoskeletal, connective tissue and bone disorders: | Muscle weakness, back pain | |
| Rare (<1/1,000) |
Cardiac disorders: | Cardiac arrest |
| Immune system disorders: | Allergic reactions, anaphylactic shock | |
| Nervous system disorders: | Total spinal block (unintentional), paraplegia, paralysis, neuropathy, arachnoiditis. | |
| Respiratory disorders: | Respiratory depression |
Severe adverse reactions following spinal bupivacaine are rare but may occur in connection with extensive (total) spinal blockade. Total spinal blockade will result in cardiovascular and respiratory depression. The cardiovascular depression is caused by an extensive sympathetic blockade which may result in profound hypotension and bradycardia, or even cardiac arrest. Ventilatory depression is caused by blockade of respiratory muscles including the diaphragm.
In view of the low dosage employed, systemic adverse reactions are rarely associated with spinal anaesthesia. The following types are the most commonly reported:
CNS manifestations are excitatory and/or depressant and may be characterised by light-headedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred vision, nausea, vomiting, sensations of heat, cold or numbness, urinary retention, paraesthesia, dysaesthesia, twitching, tremors, convulsions, unconsciousness, respiratory depression and/or arrest, agitation, difficulty swallowing and slurred speech.
The excitatory manifestations may be very brief or may not occur at all, in which case the first manifestation of toxicity may be drowsiness merging into unconsciousness and respiratory arrest. Drowsiness following administration of bupivacaine is usually an early sign of a high blood level of the drug and may occur as a result of rapid absorption. In unconscious patients, circulatory collapse should be watched as CNS effects may not be apparent as an early manifestation of toxicity may in some cases progress to frank convulsions and ultimately lead to respiratory depression and/or arrest. It is crucial to have resuscitative equipment and anticonvulsant drugs available to manage such patients. (see OVERDOSAGE -Treatment of Overdosage)
Cardiovascular manifestations are usually depressant and are characterised by bradycardia, hypotension, and cardiovascular collapse, which may lead to cardiac arrest.
Regional anaesthesia may lead to maternal hypotension.
Allergic reactions are characterised by cutaneous lesions, urticaria, oedema or anaphylactoid reactions. Allergy to amide type local anaesthetics is very rare. If such a reaction occurs, it should be managed by conventional means. The detection of sensitivity by skin testing is of doubtful value.
The incidences of adverse reactions associated with the use of local anaesthetics may be related to the total dose of local anaesthetic administered and are also dependent on the particular drug used, the route of administration and the physical status of the patient.
Adverse effects experienced subsequent to spinal administration of local anaesthetic may include spinal block of varying magnitude (including total spinal block), hypotension secondary to spinal block, loss of bladder and bowel control and loss of perineal sensation and sexual function. Persistent motor, sensory and/or autonomic (sphincter control) deficit of some lower spinal segments with slow recovery (several months) or incomplete recovery have been reported in rare instances.
Pronounced acidosis, hyperkalaemia, hypocalcaemia or hypoxia in the patient may increase the risk and severity of toxic reactions.
The effects of systemic overdose and unintentional intravascular injection may involve the central nervous system and/or the cardiovascular system (see OVERDOSAGE). Inadvertent subarachnoid injection of high doses of local anaesthetic may lead to CNS depression, respiratory arrest and cardiovascular collapse.
Bupivacaine should be used with caution in patients receiving agents structurally related to local anaesthetics, eg certain anti-arrhythmics such as lignocaine, mexiletin, tocainide, since the systemic toxic effects are additive. Specific interaction studies with bupivacaine and anti-arrhythmic medicines class III (eg amiodarone) have not been performed, but caution should be advised (see WARNINGS AND PRECAUTIONS).
Acute emergencies associated with the use of local anaesthetics are generally related to high plasma levels (see ADVERSE REACTIONS and PRECAUTIONS). Since the dose required for spinal anaesthesia is so small (20% or less than that required for epidural anaesthesia), acute systemic toxicity is extremely unlikely and has not been reported.
With accidental intravascular injections of local anaesthetics, the toxic effects will be obvious within 1 - 3 minutes. With overdosage, peak plasma concentrations may not be reached for 20 - 30 minutes, depending on the site of injection and toxic signs will be delayed. Toxic reactions mainly involve the central nervous and 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, lightheadedness, hyperacusis and tinnitus. Visual disturbances and muscular tremors are more serious and precede the onset of generalised convulsions. These signs must not be mistaken for neurotic behaviour.
Unconsciousness and grand mal convulsions may follow. These may last from a few seconds to several minutes. Hypoxia and hypercapnia occur rapidly following convulsions due to increased muscular activity, together with the interference with normal respiration and loss of the airway. In severe cases, apnoea may occur. Acidosis, hyperkalaemia, hypocalcaemia and hypoxia increase and extend 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 toxicity indicates a more severe situation. Hypotension, bradycardia, arrhythmia and even cardiac arrest may occur as a result of high systemic concentrations of local anaesthetics.
Cardiovascular toxic effects are generally 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 benzodiazepines or barbiturates.
If signs of acute systemic toxicity appear, injection of the local anaesthetic should be immediately stopped.
If convulsions occur then immediate attention is required for the maintenance of patent airway and assisted or controlled ventilation with oxygen, via a positive airway pressure delivery system mask. Adequacy of the circulation should then be evaluated, bearing in mind that drugs used to treat convulsions depress the circulation when administered intravenously.
Should convulsions persist despite adequate respiratory support, and if the status of the circulation permits, appropriate anticonvulsant medication such as an ultra-short acting barbiturate (e.g. thiopentone) or a benzodiazepine (e.g. diazepam) may be administered IV. The clinician should be familiar with these anticonvulsant drugs prior to use of local anaesthetics.
If ventricular fibrillation or cardiac arrest occurs, effective cardiovascular resuscitation treatment must be instituted and maintained for a prolonged period if necessary. Optimal oxygenation and ventilation, and circulatory support as well as treatment of acidosis are of vital importance.
MARCAIN should be stored at 25°C or below. Do not freeze.
Local anaesthetics react with certain metals and cause the release of their respective ions which, if injected, may cause severe local irritation. Adequate precautions should be taken to avoid prolonged contact between MARCAIN and metal surfaces such as metal bowls, cannulae and syringes with metal parts.
The ampoules are designed for single use only, any unused portions of solutions should be discarded. The solution should be used immediately after opening the ampoule. Solutions showing discolouration should not be used.
Incorrect autoclaving causes decomposition of glucose which may result in a decreased duration of anaesthesia of the hyperbaric solution. It is advisable not to re-autoclave ampoules of MARCAIN SPINAL 0.5% HEAVY.
Glass ampoules: 3 years
Prescription Medicine
Marcain 0.5% and Marcain Spinal 0.5% Heavy
Packs of 5 x 4 mL glass ampoules in pre-sterilised AstraZeneca Theatre Packs®.
The active ingredient in MARCAIN is 2-piperidine carboxamide, 1-butyl-N-(2,6-dimethylphenyl)-monohydrochloride, monohydrate.
Based on conventional studies with bupivacaine of safety pharmacology, single and repeated dose toxicity, reproduction toxicity, mutagenic potential and local toxicity, no hazards for humans were identified other than those which can be expected on the basis of the pharmacodynamic action of high doses of bupivacaine (eg. CNS signs and cardiotoxicity).
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