INFORMATION FOR HEALTH PROFESSIONALS
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0.5% Marcain® Dental with Adrenaline 1:200,000 is a clear, colourless, sterile, particle-free, isotonic aqueous solution. It contains sodium metabisulphite as an antioxidant. The pH of the solution is 3.3-5.0. 0.5% Marcain® Dental with Adrenaline 1:200,000 is paraben-free and for single use only. Remaining unused contents should be discarded.
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.
Local anaesthetic medicines may have similar effects on excitable membranes in the brain and myocardium. If excessive amounts of medicine reach the systemic circulation rapidly, symptoms and signs of toxicity will appear, emanating mainly from the central nervous and cardiovascular systems.
Central nervous system toxicity usually precedes the cardiovascular effects as it occurs at lower plasma concentrations. Direct effects of local anaesthetics on the heart include slow conduction, negative inotropism and eventually cardiac arrest.
The addition of a vasoconstrictor such as adrenaline may decrease the rate of absorption of bupivacaine.
Bupivacaine is a long-acting, amide-type local anaesthetic chemically related to lignocaine and mepivacaine. It is approximately four times as potent as lignocaine. The onset of the blockade is slower than with lignocaine, especially when anaesthetising large nerves.
Bupivacaine has a pKa of 8.1 and is extensively bound to plasma proteins. 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 onset of action following dental injections is usually 2-10 minutes and anaesthesia may last two or three times longer than with lignocaine or mepivacaine for dental use, in many patients up to 7 hours. The duration of anaesthetic effect is prolonged by the addition of adrenaline 1:200 000.
The plasma concentration of bupivacaine depends upon the dose, the route of administration and the vascularity of the injection site. Absorption may be slowed by the addition of adrenaline.
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 h and an intermediate hepatic extraction ratio of 0.4 following experimental IV administration in adults. The terminal elimination half-life is prolonged in the newborn to approximately 8 hours. In children over 3 months the elimination half-life is similar to that in adults. Bupivacaine is mainly bound to alpha-1-acid glycoprotein in plasma with a plasma binding of 96%.
An increase in alpha-1-acid glycoprotein, which occurs postoperatively after major surgery, may cause an increase in the total plasma concentration of bupivacaine. The level of free medicine will remain the same. This explains why total plasma concentrations above the apparent toxic threshold level of 2.6-3.0 mg/L are well tolerated.
Following IV administration bupivacaine is excreted in the urine principally as metabolites with about 6% as unchanged medicine.
Various pharmacokinetic parameters can be significantly altered by a number of factors including the presence of hepatic and renal disease, route of administration, age of the patient and certain concomitant medication.
0.5% Marcain® Dental with Adrenaline 1:200,000 is indicated for the production of local anaesthesia in routine dental procedures and oral surgery by means of infiltration and nerve block techniques.
As with all local anaesthetics, 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 and the physical condition of the patient.
The lowest dosage that results in effective anaesthesia should be used. For specific techniques and procedures refer to standard textbooks.
The 0.5% concentration with adrenaline is recommended for infiltration and block injection in the maxillary and mandibular area when a longer duration of local anaesthetic action is desired such as for oral surgical procedures generally associated with significant postoperative pain. The average dose 2.2 mL (11 mg) per injection site will usually suffice. An occasional second dose of 2.2 mL (11 mg) may be used if necessary to produce adequate anaesthesia after making allowance for 2 to 10 minutes onset time (see Pharmacokinetics).
The lowest effective dose should be employed and time should be allowed between injections. It is recommended that the total dose for all injection sites, spread out over a single dental sitting should not ordinarily exceed 90 mg for a healthy adult patient (8 x 2.2 mL cartridges of 0.5% Marcain® Dental with Adrenaline 1:200,000). Injections should be made slowly and with frequent aspirations.
0.5% Marcain® Dental with Adrenaline 1:200,000 in dentistry cannot be recommended for children younger than 12 years of age. A reduced dosage based on body weight and surface area should be used. The dosage should be calculated for each patient individually and modified in accordance with the dentist's experience and knowledge of the patient.
Debilitated or elderly patients, including those with partial or complete heart block, advanced liver disease or severe renal dysfunction should be given a reduced dosage commensurate with their physical condition (see WARNINGS AND PRECAUTIONS).
The safe use of bupivacaine during pregnancy has not been established. Although bupivacaine has been used extensively for dental procedures during pregnancy with no reports of ill effects to mother or foetus, there are no adequate well controlled studies in pregnant women of the effect of bupivacaine on the developing foetus. It should therefore be used cautiously during pregnancy.
Adrenaline has been given to large numbers of pregnant women and women of child-bearing age without any proven increase in the frequency of malformation or other indirect harmful effects on the foetus having been observed.
Adrenaline may delay the second stage of labour by inhibiting uterine contractions.
Bupivacaine enters breast milk but in such small quantities at therapeutic dose levels that there is generally little risk of affecting the child.
Depending on the dosage, local anaesthetics may have a mild effect on mental function and co-ordination and may temporarily impair locomotion and co-ordination.
Reactions to bupivacaine are similar in character to those observed with other local anaesthetics of the amide type.
These adverse reactions are, in general, dose-related and may be due to high plasma levels as a result of excessive dosage, rapid absorption, delayed elimination or metabolism, or inadvertent intravascular injection. Pronounced acidosis, hyperkalaemia or hypoxia in the patient may increase the risk and severity of toxic reactions.
Such reactions are systemic in nature and involve the central nervous system and/or the cardiovascular system (see OVERDOSAGE).
Ventricular arrhythmia, ventricular fibrillation, sudden cardiovascular collapse and death have been reported when 0.5% Marcain® Dental with Adrenaline 1:200,000 has been utilised for local anaesthetic procedures that may result in high systemic concentrations of bupivacaine.
The following are the most commonly reported adverse effects irrespective of the route of administration.
CNS manifestations are excitatory and/or depressant and may be characterised by light-headedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred vision, vomiting, sensations of heat, cold or numbness, twitching, tremor, 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 agent 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 and 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 medicines 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. (See Overdosage).
Allergy to amide type local anaesthetics is very rare but may present as cutaneous lesions, urticaria, odema or anaphylaxis. Patients allergic to ester derivatives of para-aminobenzoic acid (procaine, tetracaine, benzocaine etc.) have not shown cross sensitivity to agents of the amide type.
Sodium metabisulphite is included in solutions containing adrenaline and may also cause this type of reaction.
The incidence of adverse neurological reactions associated with the use of local anaesthetics is very low.
Local anaesthetics of the amide type, such as bupivacaine should be used with caution in patients receiving anti-arrhythmic medicines (e.g. Mexiletine) since potentiation of cardiac effects may occur.
The following interactions may occur with adrenaline-containing solutions:-
Solutions containing adrenaline should be used with extreme caution in patients receiving tricyclic antidepressants, phenothiazines, monoamine oxidase inhibitors, butyrophenones or some antihistamines and thyroid hormones as severe sustained hypertension or hypotension and/or potentiation of adrenaline-induced cardiovascular effects may result.
Adrenaline-containing solutions should not be used in the presence of oxytocic agents of the ergot-type as they are known to interact to produce severe, persistent hypertension and its sequelae.
Solutions containing adrenaline should be used with caution in the presence of adrenergic neuron blocking agents (e.g. guanethidine, debrisoquine, bethanidine).
Serious cardiac arrhythmias and acute pulmonary oedema if hypoxia is present may occur if preparations containing adrenaline are employed in patients during or following the administration of chloroform, halothane, cyclopropane, trichlorethylene, or other halogenated compounds.
Solutions containing adrenaline may enhance the toxic effects of cardiac glycosides which may result in arrhythmias.
Solutions containing adrenaline may interact with quinidine resulting in cardiac arrhythmias.
Adrenaline induced hyperglycaemia may lead to loss of blood sugar control in diabetic patients treated with hypoglycaemic agents.
Acute emergencies associated with the use of local anaesthetics are generally related to high plasma levels or to unintended subarachnoid injection of the local anestetic solution (See ADVERSE EFFECTS and WARNINGS AND PRECAUTIONS).
With accidental intravascular injections of local anaesthetics, the toxic effects will be obvious within 1-3 minutes. With overdosage, peak plasma concentration 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, light-headedness, hyperacusis and tinnitus. Visual disturbance 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 which may last from a few seconds to several minutes. Hypoxia and hypercapnia 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.
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 stopped immediately.
Treatment will be required if convulsions occur. All medicines and equipment should be immediately available. The objectives of treatment are to maintain oxygenation, stop the convulsions and support the circulation. Oxygen must be given and ventilation assisted if necessary (mask and bag). An anticonvulsant should be given IV if the convulsions do not stop spontaneously in 15-20 seconds, Thiopentone 100-150 mg IV will abort the convulsions rapidly.
Alternatively diazepam 5-10 mg IV may be used, although its action is slower. Suxamethonium will stop the muscle convulsions rapidly, but will require tracheal intubation and controlled ventilation, and should only be used by those familiar with these procedures.
18 months
Stored at or below 25°C. Do not freeze. Protect from light.
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 0.5% Marcain® Dental with Adrenaline 1:200,000 solutions and metal surfaces such as metal bowls, cannulae and syringes with metal parts.
Adrenaline-containing solutions should not be re-autoclaved. Surface sterilisation using pure, undiluted isopropyl alcohol (91%) or 70% ethyl alcohol (USP) may be carried out if desired.
Prescription Medicine
0.5% Marcain® Dental with Adrenaline 1:200,000, 50 x 2.2 mL.
Sponsor:
Dentsply (NZ) Limited
C/O Russell McVeagh
48 Shortland Street, Auckland
Distributor:
Dentsply New Zealand
C/- ProPharma
58 Richard Pearse Drive, Airport Oaks
Auckland
Freephone: 0800 809 074
23 December 2004