Consumer medicine information

Marcain with Fentanyl

Bupivacaine hydrochloride; Fentanyl

BRAND INFORMATION

Brand name

Marcain with Fentanyl

Active ingredient

Bupivacaine hydrochloride; Fentanyl

Schedule

S8

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Marcain with Fentanyl.

What is in this leaflet

This leaflet answers some of the common questions people ask about MARCAIN with FENTANYL. It does not contain all the information that is known about MARCAIN with FENTANYL.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor will have weighed the risks of you being given MARCAIN with FENTANYL against the benefits they expect it will have for you.

If you have any concerns about being given this medicine, ask your doctor or pharmacist.

Keep this leaflet. You may need to read it again.

What MARCAIN with FENTANYL is for

MARCAIN with FENTANYL is used after surgery to treat post-operative pain.

It can also be used to make childbirth less painful.

MARCAIN belongs to a group of medicines called local anaesthetics. When injected, it makes the nerves nearby unable to pass messages to the brain and will therefore prevent or relieve pain.

FENTANYL belongs to a group of medicines called narcotic analgesics. It is a powerful drug used to relieve pain.

MARCAIN with FENTANYL is a combination of the two drugs and produces anaesthesia (loss of feeling) and analgesia (pain relief).

Your doctor will have explained why you are being treated with MARCAIN with FENTANYL and told you what dose you will be given.

Follow all directions given to you by your doctor carefully. They may differ from the information contained in this leaflet.

Your doctor may prescribe this medicine for another use. Ask your doctor if you want more information.

As it contains fentanyl, MARCAIN with FENTANYL can be addictive, but when it is used only to relieve or prevent pain it is unlikely to become habit forming.

Before you are given MARCAIN with FENTANYL

When you must not have it

Ask your doctor about the risks and benefits of being given MARCAIN with FENTANYL while you are pregnant or breastfeeding. We do not know if it is safe for you to be given it while you are pregnant. However, it can be used during childbirth.

Your baby can take in very small amounts of MARCAIN with FENTANYL from breast milk if you are breastfeeding, but it is unlikely that the amount available to the baby will do any harm.

MARCAIN with FENTANYL will only be used if the solution is clear, the package is undamaged and the use by (expiry) date marked on the pack has not been passed.

MARCAIN with FENTANYL is not recommended for use in children. There is only limited information about its use in children.

Before you are given it

You must tell your doctor if:

  1. you have any allergies to
  • any ingredients listed at the end of this leaflet
  • other local anaesthetics e.g. lignocaine
  • other strong pain killers e.g. morphine or pethidine
If you have an allergic reaction, you may get a skin rash, hay fever or an asthma attack.
  1. you have any of these medical conditions
  • problems with your blood pressure or circulation
  • problems with the clotting of your blood, blood poisoning
  • heart, nerve, liver or kidney problems
  • diseases of the cerebrospinal system, such as meningitis, tumours, poliomyelitis, degeneration of the spinal cord
  • certain conditions of the back e.g. tumours, osteomyelitis, arthritis and spondylitis
  • problems with your breathing such as severe asthma, severe bronchitis or emphysema
  • a history of fits or head injuries
  • neuromuscular disease e.g. myasthenia gravis (muscle weakness)
  • thyroid problems

It may not be safe for you to be given MARCAIN with FENTANYL if you have any of these conditions.

Taking other medicines

Tell your doctor if you are taking any other medicines, including

  • medicines used to treat irregular heart beats, e.g. mexiletine, lignocaine or amiodarone
  • low molecular weight heparin or other medicines used to prevent blood clots.
  • sedatives, sleeping tablets
  • antidepressant treatment with monoamine oxidase (MAO) inhibitors, e.g. tranylcypromine, even if you are within 14 days of stopping such treatment; Other anti-depressant drugs, migraine medicines and sibutramine (medicines for weight loss). Taking these medicines with MARCAIN with FENTANYL may cause a serious condition called Serotonin Syndrome (a sudden increase in body temperature, very high blood pressure, rigid muscles, mental status changes, nausea, vomiting and/ or fits)
  • medicines that you buy at the chemist, supermarket or health food shop.

These medicines may affect the way MARCAIN with FENTANYL works.

Your doctor or pharmacist can tell you what to do if you are taking any of these medicines.

If you have not told your doctor about any of these things, tell them before you are given any MARCAIN with FENTANYL.

How MARCAIN with FENTANYL is given

MARCAIN with FENTANYL will be injected by your doctor into the epidural space, near your spinal cord, through a space between vertebrae in your lower back. A thin tube will be inserted so a continuous dose can be given over a period of time.

This is called an EPIDURAL INFUSION and it will result in a feeling of numbness in your lower body, in an area that may seem unrelated to the site of injection.

MARCAIN with FENTANYL should not be injected directly into the blood.

The dosage you will be given will depend on your body size, age and the type of pain relief required.

Your doctor will have had a lot of experience injecting MARCAIN with FENTANYL or other similar drugs and will choose the best dose for you. They will be willing to discuss this decision with you.

Overdose (taking too much)

The doctor giving you MARCAIN with FENTANYL will be experienced in the use of this type of drug, so it is unlikely that you will be given an overdose. However, if you are particularly sensitive to MARCAIN with FENTANYL, or the dose is accidently injected directly into your blood, you may develop problems for a short time with your sight or hearing. You may get a numb feeling in or around the mouth, feel dizzy or stiff, or have twitchy muscles.

Whenever you are given MARCAIN with FENTANYL, equipment will be available to care for you if an overdose happens.

While you are being given it

Things to be careful of

Be careful driving or operating machinery after you have been given MARCAIN with FENTANYL. You may be drowsy and your reflexes may be slow.

Do not drink alcohol while you are being given MARCAIN with FENTANYL. If you drink alcohol while you are being given MARCAIN with FENTANYL your blood pressure may drop making you feel dizzy and faint.

Please talk to your doctor or pharmacist about these possibilities if you think they may bother you.

Side effects

Tell your doctor or nurse as soon as possible if you do not feel well while you are being given MARCAIN with FENTANYL.

MARCAIN with FENTANYL will prevent or relieve pain in most people, but it may have unwanted side-effects. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Ask your doctor, nurse or pharmacist to answer any questions you may have.

Tell your doctor or nurse if you notice any of the following and they worry you:

  • nervousness
  • dizziness
  • blurred vision
  • drowsiness
  • ringing in the ears
  • numbness
  • feeling strange (disoriented)
  • nausea (feeling sick), vomiting
  • constipation
  • itching

These are all mild side effects of MARCAIN with FENTANYL.

After an epidural injection you may develop a headache or backache which is not related to the medicine used. These can, on rare occasions, last for some months after the injection is given.

If MARCAIN with FENTANYL is given wrongly, or you are very sensitive to it, it sometimes causes

  • fits
  • unconsciousness
  • breathing problems
  • low blood pressure
  • slow heart beat
  • clammy and cold skin
  • collapse

These are all serious side effects. You may need urgent medical attention

Some people may get other side effects while being given MARCAIN with FENTANYL.

Tell your doctor if you notice anything else that is making you feel unwell.

After using it

Storage

MARCAIN with FENTANYL will be stored by your doctor or pharmacist under the recommended conditions.

It should be kept in a cool dry place where the temperature stays below 30 degrees C.

Disposal

Any MARCAIN with FENTANYL which is not used will be disposed of in a safe manner by your doctor or pharmacist.

Product description

Each MARCAIN with FENTANYL contains Bupivacaine hydrochloride 1.25 mg/mL (as monohydrate) plus

fentanyl 5 microgram/mL (as citrate) as the active ingredients, plus

Sodium Chloride

Sodium Hydroxide or Hydrochloric Acid for pH adjustment

Water for Injections

MARCAIN with FENTANYL is available as 20mL polypropylene ampoules in sterile theatre packs.

Sponsor

Aspen Pharmacare Australia Pty Ltd
34-36 Chandos St
St Leonards NSW 2065
Australia

MARCAIN (1.25 mg/mL) with FENTANYL (5 microgram/mL)

20 mL ampoule Aust R 123384

This leaflet was revised in Sep 2018

Trademarks are owned by or licensed to the Aspen group of companies.

Published by MIMS November 2018

BRAND INFORMATION

Brand name

Marcain with Fentanyl

Active ingredient

Bupivacaine hydrochloride; Fentanyl

Schedule

S8

 

1 Name of Medicine

Bupivacaine hydrochloride with fentanyl (as citrate).

2 Qualitative and Quantitative Composition

Marcain 0.125% with Fentanyl 5 microgram/mL is a sterile, isotonic aqueous solution containing bupivacaine hydrochloride (as monohydrate) 1.25 mg/mL and fentanyl (as citrate) 5 microgram/mL as the active ingredients. They also contain sodium chloride and water for injections with nominal osmolality of 298 mOsmol/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.

3 Pharmaceutical Form

A clear, colourless solution for injection or infusion.

4 Clinical Particulars

4.1 Therapeutic Indications

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

4.2 Dose and Method of 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. (See Table 1.)

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 intraoperative 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 5 microgram/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 microgram 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.

Paediatric use.

Experience with Marcain 0.125% with Fentanyl 5 microgram/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 Section 4.4 Special Warnings and Precautions for Use.)

4.3 Contraindications

1. Allergy or hypersensitivity to amide type local anaesthetics, fentanyl or other ingredients contained in Marcain 0.125% with Fentanyl 5 microgram/mL solution (see Section 6.1 List of Excipients).
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 Section 4.5 Interactions with Other Medicines and Other Forms of 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.

4.4 Special Warnings and Precautions for Use

1. When Marcain 0.125% with Fentanyl 5 microgram/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 Section 4.2 Dose and Method of 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 anticoagulated 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 5 microgram/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 Section 4.2 Dose and Method of Administration). Repeated injection of Marcain 0.125% with Fentanyl 5 microgram/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 5 microgram/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 (e.g. 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.
8. Marcain 0.125% with Fentanyl 5 microgram/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.
9. 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.
10. Inadvertent intravascular or subarachnoid injection may produce adverse reactions similar to systemic toxicity.
11. Fentanyl has abuse potential. Psychological and physical dependence may occur with repeated or prolonged dosing.
12. Hyperglycaemia has been reported with opioid agonists. This should be considered when diabetics require treatment with these agents.
13. Opioid agonists may cause spasm of the sphincter of Oddi.
14. Marcain 0.125% with Fentanyl 5 microgram/mL may cause drowsiness and general impairment of coordination. Ambulatory patients should be supervised.
15. Epidural anaesthesia may lead to hypotension and bradycardia. Hypotension should be treated promptly.
16.

Serotonin syndrome.

Caution is advised when fentanyl is coadministered with drugs that affect the serotonergic neurotransmitter systems.
The development of a potentially life-threatening serotonin syndrome may occur with the concomitant use of serotonergic drugs such as Selective Serotonin Re-uptake Inhibitors (SSRIs) and Serotonin Norepinephrine Reuptake Inhibitors (SNRIs), and with drugs which impair metabolism of serotonin (including Monoamine Oxidase Inhibitors [MAOIs]), antidepressants, migraine medicines and sibutramine. This may occur within the recommended dose.
Serotonin syndrome may include mental-status changes (e.g. agitation, hallucinations, coma), autonomic instability (e.g. tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g. hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhoea).
If serotonin syndrome is suspected, rapid discontinuation of fentanyl should be considered.

Use in hepatic impairment.

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 5 microgram/mL should therefore be used with caution in patients with severe hepatic disease.

Use in renal impairment.

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.

Use in the elderly.

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.

Paediatric use.

Marcain 0.125% with Fentanyl 5 microgram/mL is not recommended in children as experience is limited.

Effects on laboratory tests.

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

4.5 Interactions with Other Medicines and Other Forms of Interactions

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 (e.g. amiodarone) have not been performed, but caution should be advised (see Section 4.4 Special Warnings and Precautions for Use).

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 Section 4.3 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.

Serotonin syndrome.

Opioids can interact with antidepressants and migraine medicines to cause a serious central nervous system reaction called serotonin syndrome, in which high levels of the chemical serotonin build up in the brain and cause toxicity.
Coadministration of sibutramine hydrochloride with fentanyl may increase the risk of serotonin syndrome (hypertension, hypothermia, myoclonus and mental status changes).
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.
The concurrent administration of fentanyl and naltrexone precipitates opioid withdrawal symptoms.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Effects on fertility with either agent have not been determined.
(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 newborn 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.
 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 microgram/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 microgram/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.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

The adverse reactions to Marcain 0.125% with Fentanyl 5 microgram/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, myoclonic 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 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 drugs available to manage such patients. (See Section 4.9 Overdose, Treatment of overdosage.)

Cardiovascular system.

Tachycardia, arrhythmia. 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 Section 4.9 Overdose).

Eye disorders.

Visual disturbance.

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.

Respiratory, thoracic and mediastinal disorders.

Laryngospasm, bronchospasm and apnoea.

Skin.

Pruritus, urticaria.

Less common reactions.

Central nervous system.

Postoperative mental depression, paradoxical CNS excitation, delirium.

Allergic.

Cutaneous lesions, oedema, anaphylactoid reactions.

Respiratory, thoracic and mediastinal disorders.

Hyperventilation, hiccups, cough.

Gastrointestinal disorders.

Constipation.

Other.

Miosis, diaphoresis, spasm of the sphincter of Oddi.
When a neuroleptic is used with fentanyl, the following adverse reactions may be observed: chills and/or shivering, restlessness, postoperative hallucinatory episodes and extrapyramidal symptoms (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

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 Section 4.8 Adverse Effects (Undesirable Effects)).
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.

It 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.

It 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 5 microgram/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 (e.g. thiopentone) or a benzodiazepine (e.g. 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 α-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.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

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

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

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.

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

5.3 Preclinical Safety Data

Genotoxicity.

Formal studies of mutagenic potential have not been carried out.

Carcinogenicity.

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

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

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 5 microgram/mL and metal surfaces, such as metal bowls, cannulae and syringes with metal parts.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
Solutions showing discolouration or particulate matter and unused portions of solutions should be discarded.
Marcain 0.125% with Fentanyl 5 microgram/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.

6.4 Special Precautions for Storage

Store below 30°C. Do not freeze.

6.5 Nature and Contents of Container

Marcain 0.125% with Fentanyl 100 microgram/20 mL.

Bupivacaine hydrochloride 1.25 mg/mL (as monohydrate) with fentanyl 5 microgram/mL (as citrate).
20 mL x 5 Polyamp DuoFit ampoules in Sterile Theatre Pack;
20 mL x 5 Top Hat single dose vial in Sterile Theatre Pack.#

Marcain 0.125% with Fentanyl 1000 microgram/200 mL.

Bupivacaine hydrochloride 1.25 mg/mL (as monohydrate) with fentanyl 5 microgram/mL (as citrate).
200 mL x 5 Polybag infusion bags in Sterile Theatre Pack.#
(#Not currently marketed.)

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

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 monohydrate or bupivacaine hydrochloride.
The chemical name for fentanyl citrate is N-(1-phenethyl-4-piperidyl) propionanilide citrate. The Australian approved name is fentanyl citrate.

Chemical structure.

The chemical structures are:

CAS number.

The CAS number for bupivacaine hydrochloride is 14252-80-3.
The CAS number for fentanyl citrate is 990-73-8.

7 Medicine Schedule (Poisons Standard)

S8.

Summary Table of Changes