INFORMATION FOR HEALTH PROFESSIONALS
Home | Consumers | Health Professionals | Regulatory | Other | Hot Topics | Search
Home | Consumers | Health Professionals | Regulatory | Other | Hot Topics | Search
Infusion solution: a clear, colourless, particle-free solution containing 1.25 mg/mL bupivacaine HCl and 2 mcg/mL fentanyl citrate, with a pH of 4.0-6.5 in a 100 mL or 200 mL Polybag.
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.
Indirect cardiovascular effects (hypotension, bradycardia) may occur after epidural or spinal administration depending on the extent of the concomitant sympathetic block.
Fentanyl is a narcotic analgesic.
A dose of 100 mcg of fentanyl is approximately equivalent in analgesic activity to 10 mg of morphine or 75 -100 mg of pethidine administered IV or IM. The principal actions of therapeutic value are analgesia and sedation. Alterations in respiratory rate and alveolar ventilation associated with narcotic analgesics may last longer than the analgesic effect. As the dose of narcotic is increased, the decrease in pulmonary exchange becomes greater. Large doses may produce apnoea. Fentanyl appears to have less emetic activity than either morphine or pethidine. Histamine assays and skin wheal testing in man indicate that clinically significant histamine release rarely occurs with fentanyl. Recent assays in man show no clinically significant histamine release at doses up to 50 mcg/kg (0.05 mg/kg or 1 mL/kg). Fentanyl preserves cardiac stability and blunts stress-related hormonal changes at higher doses.
Bupivacaine is a long acting, amide type local anaesthetic chemically related to lignocaine and mepivacaine. It is approximately four times as potent as lignocaine.
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.
In concentrations of 5 mg/mL it has a long duration of action, from 2-5 hours following a single epidural injection and up to 12 hours after peripheral nerve blocks. The onset of blockade is slower than with lignocaine, especially when anaesthetising large nerves.
When used in low concentrations (2.5 mg/mL or less) there is less effect on motor nerve fibres and the duration of action is shorter. Low concentrations may, however, be used with 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 injection of Marcain solutions for caudal, epidural or peripheral nerve block in man, 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.
Intercostal blocks give the highest peak plasma concentration due to a rapid absorption (maximum plasma concentrations in the order of 1-4 mg/L after a 400 mg dose), while subcutaneous abdominal injections give the lowest plasma concentration. Epidural and major plexus blocks are intermediate. In children rapid absorption and high plasma concentrations (in the order of 1-1.5 mg/L after a dose of 3 mg/kg) are 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 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%.
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 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.
Bupivacaine is excreted in the urine principally as metabolites with about 6% as unchanged medicine. 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.
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 is 4 L/kg.
Fentanyl plasma protein binding capacity decreases with increasing ionisation of the agent. Alterations in pH may affect its distribution between plasma and the central nervous system. It accumulates in skeletal muscle and fat, and is released slowly into the blood. Fentanyl is primarily biotransformed in the liver. Approximately 75% of an intravenous dose is excreted in urine as metabolites with less than 10% representing the unchanged medicine. Approximately 9% of the dose is recovered in the faeces, primarily as metabolites.
As with other narcotic analgesics, the duration of the respiratory depressant effect of fentanyl may be longer than the analgesic effect. The following observations have been reported concerning altered respiratory response to CO2 stimulation following administration of fentanyl to man:
MARCAIN WITH FENTANYL for epidural infusion is intended for post-operative analgesia, except where specifically contraindicated.
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 infusion for analgesia in the average, healthy, 70 kg adult patient.
Postoperative Analgesia: epidural
| VOLUME | BUPIVACAINE | FENTANYL 2 mcg/mL | |
|---|---|---|---|
| Epidural infusion (for up to 48 hours) |
6-15 mL/hr | 7.5 - 18.75 mg/hr | 12-30 mcg/hr |
Toxic doses vary widely between patients. Careful observation of the patient must therefore be maintained. It is recommended that a single dose of bupivacaine at any time should not exceed 2 mg/kg. However, the dose administered must be tailored to the individual patient and procedure, and the maximum dose quoted here should be used as a guide only.
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 maximum daily dosage should not exceed 400 mg bupivacaine in a 70 kg adult, whether administered by bolus injection and/or by infusion.
The rapid injection of a large volume of MARCAIN WITH FENTANYL solution should be avoided and fractional doses should be used when feasible.
During epidural analgesia, a marked fall in blood pressure and/or intercostal paralysis 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.
For epidural analgesia, a 3-5 mL test dose of a local anaesthetic, preferably containing up to 15 mcg of adrenaline (e.g. 3 mL Marcain 0.5 % with Adrenaline 1:200,000), should be administered. Verbal contact and repeated monitoring of the heart rate and blood pressure should be maintained for 5 minutes after 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 spinal block.
Prior to connection to an infusion set, aspiration should be repeated. The infusion rate should be slow, with continual assessment of the patient. If toxic symptoms or signs occur, the infusion should be stopped immediately.
Experience with MARCAIN WITH FENTANYL in children is limited and its use is not recommended.
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).
Narcotic analgesics may cause respiratory depression in the newborn infant. These products should only be used during labour after weighing the needs of the mother against the risk to the foetus.
MARCAIN WITH FENTANYL will cross the placenta rapidly. A lower foetal maternal ratio (0.2-0.4) than for other local anaesthetics (e.g. lignocaine, prilocaine) has been observed for bupivacaine. Fentanyl has been shown to have an umbilical cord to maternal vein ratio of 0.06 to 0.44. Opioid agonist analgesics may cause respiratory depression in the newborn infant. During the last 2-3 hours before expected delivery, these products should therefore only be used after weighing the needs of the mother against the risk to the foetus.
There is no information on the safe use of bupivacaine and/or fentanyl during pregnancy and these products should only be used during pregnancy if the potential benefit justifies the potential risk to the foetus.
With recommended doses, bupivacaine enters breast milk but in such small quantities at therapeutic dose levels that there is generally no risk of affecting the child.
At maternal serum levels of up to 0.45 mcg/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 mcg/mL).
Following fentanyl 100 mcg administered as a single bolus epidural dose there was no detectable excretion of medicine into breast milk.
Depending on dosage, local anaesthetics may have a very mild effect on mental function 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.
Adverse reactions 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). Inadvertent subarachnoid injection may lead to cardiovascular collapse, CNS depression and respiratory arrest. Reactions to fentanyl are similar to those observed with other opioid agonist analgesics.
Light-headedness, nervousness, dizziness, blurred vision, tremor, tinnitus, oral numbness, disorientation, nausea and vomiting, respiratory depression (related to fentanyl), apnoea, muscular rigidity, bradycardia and pruritis. If these respiratory and cardio-vascular effects remain untreated, respiratory arrest, circulatory depression, or cardiac arrest could occur.
If respiratory depression occurs, assisted or controlled respiration will provide adequate ventilation without reversing analgesia. Respiratory depression can be immediately reversed by opioid antagonists (e.g. naloxone) which, it should be noted, will also reverse the central analgesia due to fentanyl, although the epidural analgesia may not be altered.
Muscular rigidity may be associated with reduced pulmonary compliance and/or apnoea, laryngospasm or bronchospasm. Prompt reversal of this effect can be achieved with the intravenous administration of an appropriate single dose of a muscle relaxant such as suxamethonium. Assisted or controlled respiration is required to provide ventilation after the use of muscle relaxants.
Bradycardia and other cholinergic effects may occur and can be controlled with the appropriate dose of atropine. The inclusion of atropine or other anticholinergic agents in the pre-anaesthetic regimen tends to reduce the occurrence of such effects.
More serious but less common reactions that reflect an overdosage of bupivacaine are convulsions, unconsciousness, respiratory depression or arrest, hypotension, cardio-vascular collapse and bradycardia which may lead to cardiac arrest.
Other less common reactions which may occur include: Hypertension, hypotension, emesis, miosis, laryngospasm, diaphoresis, itching and euphoria.
High doses of fentanyl may produce motor stimulation and bronchospasm.
The incidence of adverse neurological reactions associated with the use of local anaesthetics is very low. Neurological reactions after regional anaesthesia have included persistent anaesthesia, paraesthesia, weakness, paralysis of the lower extremities and loss of sphincter control. Reactions to bupivacaine are similar in character to those observed with other local anaesthetics of the amide type.
Allergy to amide type local anaesthetics is very rare but may present as allergic dermatitis, bronchospasm or anaphylaxis.
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.
Other CNS depressant agents, e.g. barbiturates, neuroleptics, opioid agonists and general anaesthetics, will have additive or potentiating effects when used with MARCAIN WITH FENTANYL. When patients have received such agents, the dose of MARCAIN WITH FENTANYL required will be less than usual. Likewise, following the administration of MARCAIN WITH FENTANYL, the dose of other CNS depressant agents should be reduced (see Precautions).
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.
Severe and unpredictable potentiation by MAO inhibitors has been reported with opioid agonist analgesics. Since the safety of MARCAIN WITH FENTANYL in this regard has not been established, the use of MARCAIN WITH FENTANYL in patients who have received MAO inhibitors within 14 days is not recommended (see Contraindications).
Nitrous oxide has been reported to produce cardiovascular depression when given with high doses of fentanyl.
Profound bradycardia, sinus arrest and hypotension have occurred when patients receiving amiodarone have been given fentanyl for anaesthesia.
Acute systemic toxicity: With accidental intravascular injections, the toxic effect will be obvious within 1-3 minutes, while with overdosage, peak plasma concentrations may not be reached for 20-30 minutes depending on the site of injection with signs of toxicity thus being 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 generalised convulsions. These signs must not be mistaken for a neurotic behaviour. Unconsciousness and grand mal convulsions may follow which may 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 medicine from the central nervous system and metabolism. Recovery may be rapid unless large amounts of the medicine have been injected.
Effects on the cardiovascular system may be seen in severe cases. Hypotension, bradycardia, arrhythmia and even cardiac arrest may occur as a result of high systemic concentrations.
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 medicines such as a benzodiazepine or barbiturate.
Overdosage due to fentanyl 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.
If signs of acute systemic toxicity appear, injection of the local anaesthetic should be immediately stopped.
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 sec. 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.
If cardiovascular depression is evident (hypotension, bradycardia), ephedrine 5-10 mg IV should be given and repeated, if necessary, after 2-3 min.
Should circulatory 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 (0.1-0.2 mg intravenous or intracardiac) should be given as soon as possible and repeated, if necessary.
In the presence of hypoventilation or apnoea, oxygen should be administered and respiration assisted or controlled as necessary. A patent airway must be maintained.
The patient should be carefully observed for 24 hours; body warmth and adequate fluid intake should be maintained.
If severe or persistent hypotension occurs, the possibility of hypovolaemia should be considered and managed with appropriate parenteral fluid therapy.
A specific narcotic antagonist, such as nalorphine or naloxone, should be available for use as indicated to manage respiratory depression. This does not preclude the use of more immediate countermeasures. The duration of respiratory depression following overdosage of fentanyl is usually longer than the duration of narcotic antagonist action.
Polybag: 24 months.
Store below 30°C. 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 of MARCAIN WITH FENTANYL solutions and metal surfaces such as metal bowls, cannulae and syringes with metal parts. Solutions showing discolouration and unused portions of solutions should be discarded.
Controlled Drug B3.
MARCAIN 0.125% with FENTANYL 2 mcg/mL
100 and 200 mL Polybag® infusion bags Astra Theatre Pack® (5's)
The active ingredients of MARCAIN WITH FENTANYL are 2-piperidine-carboxamide, 1-butyl-N-(2, 6-dimethyl-phenyl) - monohydrochloride, monohydrate (bupivacaine HCl) and N-(1-phenethyl-4-piperidyl) propionanilide citrate (fentanyl citrate).
AstraZeneca Limited
303 Manukau Rd, Epsom
P O Box 1301
Auckland
Phone: 09 623 6300
4 February 2002