Marcain with Fentanyl: Indications, Dosage, Precautions, Adverse Effects
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Marcain with Fentanyl - Product Information

Manufacture: AstraZeneca
Country: Australia
Condition: Pain, Postoperative Pain
Class: Local injectable anesthetics, Narcotic analgesics
Form: Liquid solution, Intraosseous (IO)
Ingredients: bupivacaine hydrochloride, fentanyl citrate, sodium chloride, sodium hydroxide or hydrochloric acid for ph adjustment, water for injections

Name of the Medicine

The active ingredients in Marcain 0.125% with fentanyl 5μg/mL are bupivacaine hydrochloride and fentanyl citrate.

The CAS number for bupivacaine hydrochloride is 14252-80-3. The chemical name for bupivacaine hydrochloride is (RS)-1-butyl-2-piperidylformo-2’,6’-xylidide hydrochloride monohydrate. Bupivacaine has a pKa of 8.1 and is more lipid soluble than lignocaine. The Australian approved name is bupivacaine hydrochloride or bupivacaine hydrochloride anhydrous. The chemical name for fentanyl citrate is N-(1-phenethyl-4-piperidyl) propionanilide citrate. The CAS number for fentanyl citrate is 990-73-8. The Australian approved name is fentanyl citrate.

The chemical structures are:


Description

Bupivacaine is classed as a membrane stabilising agent and is a local anaesthetic of the amide type.

Fentanyl is an opioid agonist analgesic with a rapid onset of effect and short duration of action after single or infrequent doses.

Marcain 0.125% with fentanyl 5μg/mL is a sterile, isotonic aqueous solution containing bupivacaine hydrochloride, fentanyl citrate, sodium chloride and water for injections with nominal osmolality of 298mOsmol/kg. The pH of the solution is adjusted with sodium hydroxide or hydrochloric acid to remain between 4.0-6.5 during the approved shelf-life.

Marcain 0.125% with fentanyl 5 μg/mL contains no antimicrobial agent. Each vial and ampoule should be used only once and any residue discarded. Each Polybag is intended for single use only, not exceeding 24 hours; any solution remaining should be discarded.

Pharmacology

Bupivacaine

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 drugs may have similar effects on excitable membranes in the brain and myocardium. If excessive amounts of drug reach the systemic circulation rapidly, symptoms and signs of toxicity will appear, emanating mainly from the central nervous system and cardiovascular systems.

p>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.

Indirect cardiovascular effects, e.g. hypotension and bradycardia, may occur after epidural or spinal administration depending on the extent of the concomitant sympathetic block.

Fentanyl

Fentanyl is a opioid analgesic. The principal actions of therapeutic value are analgesia and sedation. Alterations in respiratory rate and alveolar ventilation associated with opioid analgesics may last longer than the analgesic effect. The duration and degree of respiratory depression is dose related. As the dose of opioid is increased, the decrease in pulmonary exchange becomes greater. Large doses may produce apnoea.

Histamine assays and skin wheal testing in man indicate that clinically significant histamine release rarely occurs with fentanyl. Fentanyl appears to have less emetic activity than either morphine or pethidine. Fentanyl preserves cardiac stability and blunts stress-related hormonal changes at higher doses. Fentanyl produces minimal cortical depression and may act by filling receptor sites located in the thalamus, midbrain and spinal cord.

A specific morphine antagonist (e.g. nalorphine) produces reversal of respiratory, cardiovascular, miotic and motor incoordination effects and also produces reversal of analgesia, euphoria and sedation. Cholinergic effects such as bradycardia are reversed by atropine.

Pharmacokinetics

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 and has a longer duration of action than lignocaine. The onset of the blockade is slower than with lignocaine, especially when anaesthetising large nerves. When bupivacaine is used in low concentrations (≤ 2.5 mg/mL) there is less effect on motor nerve fibres and the duration of action is shorter. This may be an advantage for prolonged pain relief, e.g. in labour or postoperatively.

The plasma concentration of bupivacaine depends upon the dose, the route of administration and the vascularity of the injection site. After peripheral nerve block, caudal or epidural administration, peak plasma levels of bupivacaine in the blood are reached within 30 to 45 minutes, followed by a decline to insignificant levels during the next 3 to 6 hours. In children rapid absorption (plasma concentrations are in the order of 1 - 1.5 mg/L after a dose of 3 mg/kg) is seen with caudal block.

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 following experimental IV administration in adults. The terminal elimination half-life is prolonged in the newborn to approximately 8 hours. In children aged over 3 months the elimination half-life is similar to that in adults. Bupivacaine is mainly bound to α1-acid glycoprotein in plasma with a plasma binding of 96%.

Absorption of bupivacaine from the epidural space occurs in 2 phases; the first phase is in the order of 7 minutes and the second is in 6 hours. The slow absorption is rate-limiting in the elimination of bupivacaine, which explains why the apparent elimination half-life after epidural administration is longer than after intravenous administration.

An increase in α1 -acid glycoprotein, which occurs postoperatively after major surgery, may cause an increase in the total plasma concentration of bupivacaine.The level of free drug will remain the same. This explains why total plasma concentrations above the apparent toxic threshold level of 2.6-3.0 mg/L are apparently well tolerated in this situation.

Bupivacaine is excreted in the urine principally as metabolites with about 6% as unchanged drug. Following epidural administration, the urinary recovery of unchanged bupivacaine is about 0.2%, of pipecolylxylidine (PPX) about 1% and of 4-hydroxy-bupivacaine about 0.1% of the administered dose.

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.

Fentanyl

The pharmacokinetics of fentanyl can be described by a three-compartment model, with a distribution time of 1.7 minutes, redistribution of 13 minutes and a terminal elimination half-life of 219 minutes. The volume of distribution for fentanyl is 4 L/kg.

Fentanyl accumulates in skeletal muscle and fat, and is released slowly into the blood.

Fentanyl plasma protein binding capacity increases with increasing ionisation of the drug. Alterations in pH may affect its distribution between plasma and the central nervous system.

Fentanyl is primarily transformed in the liver, catalyzed by CYP3A4, and demonstrates a high first pass clearance with approximately 75% of an intravenous dose excreted in urine, primarily as inactive metabolites with less than 10% representing the unchanged drug. Approximately 9% of the dose is recovered in the faeces, primarily as metabolites.

Indications

Marcain 0.125% with fentanyl 5μg/mL is intended for post-operative or obstetric epidural analgesia.

Contraindications

  1. Allergy or hypersensitivity to amide type local anaesthetics, fentanyl or other ingredients contained in Marcain 0.125% with fentanyl 5μg/mL solution (see DESCRIPTION)
  2. Epidural and spinal anaesthesia is contraindicated in patients with uncorrected hypotension.
  3. Local anaesthetic techniques must not be used when there is infection in the region of the proposed injection and/or in the presence of septicaemia.
  4. As with all bupivacaine solutions, bupivacaine is contraindicated in obstetric paracervical block, intravenous regional anaesthesia (Bier’s block) and all intravenous infusions.
  5. Fentanyl must not be administered to patients who are taking or have taken a mono-amine oxidase inhibitor (including selegiline) within the previous fourteen days (see INTERACTIONS).
  6. Fentanyl should not be used in patients susceptible to respiratory depression, or patients in whom respiratory reserve is significantly depleted (e.g comatose patients who may have head injuries or a brain tumour). Fentanyl may obscure the clinical course of patients with head injury.
  7. General contraindications related to epidural anaesthesia, regardless of the local anaesthetic used, should be taken into account.

Precautions

  1. WHEN MARCAIN 0.125% WITH FENTANYL 5μg/mL IS USED, RESUSCITATIVE EQUIPMENT AND DRUGS, INCLUDING OXYGEN AND AN OPIOID ANTAGONIST SHOULD BE IMMEDIATELY AVAILABLE IN ORDER TO MANAGE POSSIBLE ADVERSE REACTIONS INVOLVING THE CARDIOVASCULAR, RESPIRATORY OR CENTRAL NERVOUS SYSTEMS. BECAUSE OF THE POSSIBILITY OF HYPOTENSION AND BRADYCARDIA FOLLOWING MAJOR BLOCKS, AN IV CANNULA SHOULD BE INSERTED BEFORE THE SOLUTION IS INJECTED. DELAY IN PROPER MANAGEMENT OF DOSE-RELATED TOXICITY, UNDER-VENTILATION FROM ANY CAUSE AND/OR ALTERED SENSITIVITY MAY LEAD TO THE DEVELOPMENT OF ACIDOSIS, CARDIAC ARREST AND DEATH.
  2. INJECTION SHOULD ALWAYS BE MADE SLOWLY WITH FREQUENT ASPIRATIONS TO AVOID INADVERTENT INTRAVASCULAR INJECTION WHICH CAN PRODUCE TOXIC EFFECTS (SEE DOSAGE AND ADMINISTRATION - TEST DOSE).
  3. Careful and constant monitoring of cardiovascular and respiratory vital signs and the patient’s state of consciousness should be accomplished after each local anaesthetic injection. It should be kept in mind that at such times restlessness, anxiety, tinnitus, dizziness, blurred vision, tremors, depression or drowsiness may be early warning signs of CNS toxicity.
  4. LOW MOLECULAR WEIGHT HEPARINS AND HEPARINOIDS (Spinal/Epidural Haematomas) – When neuraxial anaesthesia (epidural / spinal anaesthesia) is employed, patients anti-coagulated or scheduled to be anti-coagulated with low molecular weight heparins or heparinoids are at risk of developing an epidural or spinal haematoma which can result in long-term or permanent paralysis. The risk of these events is increased by the use of indwelling epidural catheters, traumatic or repeated epidural/spinal puncture, and the concomitant use of drugs affecting haemostasis such as NSAIDs, platelet inhibitors or other anticoagulants. Patients should be frequently monitored for signs and symptoms of neurological impairment.
  5. The safety and efficacy of Marcain 0.125% with fentanyl 5μg/mL depends on proper dosage, correct technique and adequate precautions. Standard textbooks should be consulted regarding specific techniques and precautions for epidural anaesthetic/analgesic procedures.
  6. The lowest dosage that results in effective analgesia should be used (see DOSAGE AND ADMINISTRATION). Repeated injection of Marcain 0.125% with fentanyl 5μg/mL may cause accumulation of bupivacaine or fentanyl or their metabolites and result in toxic effects. Tolerance to bupivacaine and fentanyl varies considerably between individuals. Elderly, young or debilitated patients, including those with partial or complete conduction block, advanced liver disease or severe renal impairment, should be given reduced doses commensurate with their age and physical condition.
  7. Marcain 0.125% with fentanyl 5μg/mL is not recommended in children as experience is limited.
  8. Marcain 0.125% with fentanyl 5μg/mL should be given with caution to patients with epilepsy, impaired cardiac conduction, bradycardia, severe shock or digitalis intoxication. It should also be administered with caution to patients with impaired cardiovascular function as they may be less able to compensate for functional changes associated with the prolongation of AV conduction produced by these local anaesthetics. Patients being treated with class III anti-arrhythmic drugs (eg amiodarone) should be under close surveillance and ECG monitoring since cardiac effects may be additive. Fentanyl may produce bradycardia which can be treated according to standard clinical practice. In patients with Stokes-Adams syndrome or Wolff-Parkinson-White syndrome extreme care should be taken to avoid accidental arteriovenous injection.
  9. Marcain 0.125% with fentanyl 5μg/mL should be used with caution in patients with severe impairment of respiratory function, e.g. severe bronchial asthma. In such patients opioid agonists, such as fentanyl, may further decrease respiratory drive, increase airway resistance and increase cerebrospinal fluid pressure. Patients should be monitored for signs of respiratory depression and appropriate countermeasures taken as necessary.
  10. Local anaesthetics should be given with caution (if at all) to patients with pre-existing neurological or neuromuscular disease e.g. myasthenia gravis. Use with extreme caution in epidural, caudal and spinal analgesia when there are serious diseases of the CNS or of the spinal cord, e.g. meningitis, spinal fluid block, cranial or spinal haemorrhage, tumours, poliomyelitis, syphilis, tuberculosis or metastatic lesions of the spinal cord.
  11. Bupivacaine is eliminated primarily by hepatic metabolism and changes in hepatic function may have significant consequences. Bupivacaine has an intermediate clearance which depends on its unbound fraction and intrinsic metabolic clearance. Marcain 0.125% with fentanyl 5μg/mL should therefore be used with caution in patients with severe hepatic disease.
  12. Bupivacaine should be used with caution in patients with severe renal dysfunction because acidosis and reduced plasma protein concentration, which are frequently seen in these patients, may increase the risk of systemic toxicity. Patients with hyperthyroidism are also more susceptible to toxicity with bupivacaine.
  13. Inadvertent intravascular or subarachnoid injection may produce adverse reactions similar to systemic toxicity.
  14. Fentanyl has abuse potential. Psychological and physical dependence may occur with repeated or prolonged dosing.
  15. Hyperglycaemia has been reported with opioid agonists. This should be considered when diabetics require treatment with these agents.
  16. Opioid agonists may cause spasm of the sphincter of Oddi.
  17. Marcain 0.125% with fentanyl 5μg/mL may cause drowsiness and general impairment of co-ordination. Ambulatory patients should be supervised.

Carcinogenicity, Mutagenicity, Impairment of Fertility

Long-term animal studies with bupivacaine and/or fentanyl to assess carcinogenic potential have not been conducted.

Formal studies of mutagenic potential have not been carried out.

Effects on fertility with either agent have not been determined.

Use in Pregnancy Category C

Bupivacaine and fentanyl cross the placental barrier. However, concentrations of bupivacaine in umbilical veins are lower than those found in the maternal circulation.

Bupivacaine has been effectively used for analgesia during labour and adverse effects on the course of labour or delivery are rare. It has been suggested that blood glucose levels should be checked in newborns after obstetric regional anaesthesia.

Opioid agonist analgesics may cause respiratory depression in the new born infant. Withdrawal symptoms in newborn infants have been reported with prolonged use of opioids.

The safe use of bupivacaine and fentanyl during pregnancy, other than labour, has not been established. Although bupivacaine has been used extensively for surgical procedures during pregnancy with no reports of ill effects to mother or fetus, there are no adequate and well-controlled studies in pregnant women on the effect of bupivacaine or fentanyl on the developing fetus. Bupivacaine with fentanyl should therefore be used cautiously during pregnancy other than labour.

Use In Lactation

Bupivacaine passes into breast milk. The amount of bupivacaine appearing in breast milk from a nursing mother receiving parenteral bupivacaine is unlikely to lead to a significant accumulation of the parent drug in the breast-fed infant.

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).

The remote possibility of an idiosyncratic or allergic reaction in the breast-fed infant from bupivacaine remains to be determined.

Insignificant amounts of fentanyl have been detected in breast milk following intravenous administration. No detectable levels of fentanyl were found in breast milk after a single epidural dose. There are no data available regarding the passage of fentanyl into breast milk following epidural infusion.

Interactions with other Medicines

Anti-arrhythmic drugs

Local anaesthetics of the amide type, such as bupivacaine, should be used with caution in patients receiving antiarrhythmic drugs, e.g. mexiletine and lignocaine since potentiation of cardiac effects may occur. Specific interaction studies with bupivacaine and anti-arrhythmic drugs class III (eg amiodarone) have not been performed, but caution should be advised (see PRECAUTIONS).

CNS Depressants

The depressant effects of fentanyl are potentiated by other CNS depressants such as alcohol, barbiturates, tranquilizers, benzodiazepines, neuroleptics, opioids and general anaesthetics. When fentanyl is used in conjunction with other CNS depressants, the dosage should be reduced.

Neuroleptics

When a neuroleptic such as droperidol is used with fentanyl, pulmonary arterial pressure may be decreased. Hypotension can occur and, possibly, hypovolaemia (which should be managed with appropriate parenteral fluids). The following adverse reactions have also been reported: chills, shivering, restlessness, hypertension, postoperative hallucinatory episodes, and transient periods of mental depression. Extrapyramidal symptoms (dystonia, akathisia and oculogyric crisis) have been observed up to 24 hours postoperatively. When they occur, extrapyramidal symptoms can usually be controlled with antiparkinson agents.

MAO inhibitors

Severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics. Since the safety of bupivacaine and fentanyl in this regard has not been established, it should not be administered to patients who have received MAO inhibitors within 14 days, (see CONTRAINDICATIONS).

Nitrous oxide

Nitrous oxide has been reported to produce cardiovascular depression when given with high doses of fentanyl.

Amiodarone

Profound bradycardia, sinus arrest and hypotension have occurred when patients receiving amiodarone have been given fentanyl.

Beta-Adrenergic Blockers and Calcium Channel Blockers

The combination of calcium channel blockers and beta-adrenergic blockers during fentanyl anaesthesia should be used with caution since severe hypotension has been reported to occur.

Coadministration of the following drugs may enhance or prolong the effects of fentanyl: azole antifungals, macrolide antibiotics and protease inhibitors such as Ritonavir.

Coadministration of the following drugs may decrease the plasma concentration of fentanyl: phenytoin.

Coadministration of sibutramine hydrochloride with fentanyl may increase the risk of serotonin syndrome (hypertension, hypothermia, myoclonus and mental status changes).

The concurrent administration of fentanyl and naltrexone precipitates opioid withdrawal symptoms.

Effects on Laboratory Tests

There is no information available concerning the effect of Marcain with fentanyl on laboratory tests.

Adverse Effects

The adverse reactions to Marcain 0.125% with fentanyl 5μg/mL are similar to those observed with the individual agents.

Bupivacaine

Adverse reactions to bupivacaine are rare in the absence of overdosage or inadvertent intravascular injection. These adverse reactions are similar in character to those observed with other amide type local anaesthetics and pertain mainly to the central nervous system and the cardiovascular system. Adverse reactions to bupivacaine are in general, dose-related and may result from high plasma levels caused by excessive dosage, rapid absorption, delayed elimination, altered metabolism or inadvertent intravascular injection or may result from a hypersensitivity, idiosyncrasy or diminished tolerance on the part of the patient.

Pronounced acidosis, hyperkalaemia, *hypocalcaemia or hypoxia in the patient may increase the risk and severity of toxic reactions.

Fentanyl

Adverse reactions to fentanyl are similar to those observed with other opioid agonist analgesics.

More Common Reactions

Central Nervous System:

CNS manifestations resulting from bupivacaine with fentanyl are excitatory and/or depressant and may be characterised by light-headedness, nervousness, apprehension, agitation, difficulty swallowing, slurred speech, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred vision, nausea, vomiting, sensations of heat, cold or numbness, disorientation, twitching, muscular rigidity, myclonic movements, tremors, convulsions, unconsciousness and respiratory depression and apnoea.

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 System:

Cardiovascular manifestations following inadvertent intravascular injection are usually depressant and are characterised by bradycardia, hypotension and cardiovascular collapse, which may lead to cardiac arrest, (see OVERDOSAGE).

Neurologic:

In the practice of caudal or lumbar epidural block, occasional unintentional penetration of the subarachnoid space by the catheter may occur. Subsequent adverse effects may depend partially on the amount of drug administered intrathecally.

These 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 when caudal or lumbar epidural block has been attempted. Backache and headache have also been noted following use of these anaesthetic procedures.

Inadvertent subarachnoid injection may lead to CNS depression, respiratory arrest and cardiovascular collapse.

Skin:

Pruritus, urticaria

Less Common Reactions

Central Nervous System:

Postoperative mental depression, paradoxical CNS excitation, delerium.

Cardiovascular System:

Cardiac arrhythmias.

Allergic:

Cutaneous lesions, oedema, bronchospasm, laryngospasm, anaphylactoid reactions.

Other:

Miosis, diaphoresis, spasm of the sphincter of Oddi.

Dosage and Administration

The lowest dosage that results in effective analgesia should be used and should be based on the status of the patient and the analgesia required.

RECOMMENDED DOSAGES FOR MARCAIN 0.125% WITH FENTANYL 5μg/mL FOR INFUSION FOR ANALGESIA IN THE AVERAGE HEALTHY 70KG ADULT PATIENT.

PROCEDUREVOLUME DOSE
bupivacaine fentanyl
OBSTETRICS/GYNAECOLOGY
Epidural/caudal (vaginal delivery, vacuum extraction, first, second stage)
Bolus dose, if required6-10 mL7.5 - 12.5 mg30-50 μg
followed by Epidural infusion4- 10 mL/hr5 - 12.5 mg/hr20-50 μg/hr
POSTOPERATIVE ANALGESIA
Epidural Bolus dose, if required 6- 10 mL7.5 - 12.5 mg30-50 μg
followed by Epidural infusion4-10 mL/hr5 - 12.5 mg/hr20-50 μg/hr
MAXIMUM HOURLY DOSE (infusion + bolus)
10 mL12.5 mg50 μg

* for up to 48 hours

Note:

1. Recommended doses

Tolerability varies widely between patients. The dose administered must therefore be tailored to the individual patient and procedure. Careful observation of the patient must be maintained. When calculating the dosage for post-operative analgesia, the use of intra-operative bupivacaine and/or fentanyl (or other opioid agonist analgesic) should be taken into account. When given by bolus injection, doses should not be repeated more frequently than every 3 hours. The rapid injection of a large volume of Marcain 0.125% with fentanyl 5μg/mL solution should be avoided and fractional doses should be used when feasible.

2. Hypotension

During epidural analgesia, a marked fall in blood pressure may be seen, possibly due to the use of excessive doses, improper positioning of the patient or accidental disposition of local anaesthetic within the subarachnoid space. Hypotension and bradycardia may occur as a result of sympathetic blockade.

3. Test dose

For epidural analgesia, a test dose of 3-5 mL of a local anaesthetic solution, preferably containing up to 15 micrograms of adrenaline, should be administered. Verbal contact and repeated monitoring of heart rate and blood pressure should be maintained for 5 minutes following the test dose after which, in the absence of signs of subarachnoid or intravascular injection, the main dose may be given.

Use of a test dose containing adrenaline may have further advantages in that an intravascular injection of adrenaline will be quickly recognised by an increase in heart rate, usually within about 40 seconds. To detect this, the heart rate and rhythm should be monitored with an electrocardiogram. An accidental intrathecal injection may be recognised by signs of a spinal block.

Use in Children

Experience with Marcain 0.125% with fentanyl 5μg/mL in children is limited and its use is not recommended.

Use in Debilitated or Elderly Patients

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 PRECAUTIONS)

Overdosage

Acute emergencies associated with the use of local anaesthetics are generally related to high plasma levels or to unintended subarachnoid injection of the local anaesthetic solution (see ADVERSE REACTIONS).

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.

Symptoms of Acute Toxicity

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.

Signs of 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.

Respiratory Depression: Overdosage due to Marcain 0.125% with fentanyl 5μg/mL may result in narcosis (which may be preceded by marked skeletal muscle rigidity), cardiorespiratory depression accompanied by cyanosis, followed by a fall in body temperature, circulatory collapse, coma and possibly death.

Treatment of Overdosage

If signs of acute systemic toxicity appear, injection of the infusion solution 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 (eg. thiopentone) or a benzodiazepine (eg. diazepam) may be administered iv. 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.

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.

If cardiovascular depression occurs (hypotension, bradycardia), appropriate treatment with intravenous fluids, vasopressor, inotropic agents and/or lipid emulsion should be considered. Children should be given doses commensurate with age and weight.

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.

To counteract the pressor effects of adrenaline, use rapidly acting vasodilators, for instance nitrates or б-blocking agents.

Respiratory depression can be managed by assisted or controlled respiration or where appropriate by the administration of an opioid antagonist such as naloxone. The duration of respiratory depression of doses of fentanyl employed during anaesthesia is usually longer than the duration of opioid antagonist action. Consult the individual product information before administering opioid antagonists.

Presentation and Storage Conditions

Marcain 0.125% with fentanyl 100µg/20mL

Marcain 0.125% with fentanyl 1000µg/200mL

(bupivacaine hydrochloride anhydrous 0.125% (1.25mg/mL) with fentanyl (as citrate) 5 μg/mL)

20 mL x 5 Polyamp DuoFit® ampoules in Sterile AstraZeneca Theatre Pack™

20mL x 5 Top Hat® single dose vial in sterile AstraZeneca Theatre Pack™.^

200 mL x 5 Polybag® infusion bags in sterile AstraZeneca Theatre Pack™.^

^Not currently marketed.

Storage

Store below 30C. 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 0.125% with fentanyl 5μg/mL and metal surfaces, such as metal bowls, cannulae and syringes with metal parts.

Solutions showing discolouration or particulate matter and unused portions of solutions should be discarded.

Name and Address of the Sponsor

AstraZeneca Pty Ltd

ABN 54 009 682 311

Alma Road, North Ryde

NSW 2113 Australia

Poison Schedule of the Medicine

S8

Date of Approval

Date of TGA approval: 3 January 2006

Date of most recent amendment: 4 July 2012

Marcain, Polyamp DuoFit, Polybag and Sterile AstraZeneca Theatre Pack are trade marks of the AstraZeneca group of companies.