Consumer medicine information

Marcain and Marcain with Adrenaline Injection

Bupivacaine hydrochloride

BRAND INFORMATION

Brand name

Marcain 0.125% Epidural Infusion

Active ingredient

Bupivacaine hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Marcain and Marcain with Adrenaline Injection.

What is in this leaflet

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

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 using MARCAIN against the benefits they expect it will have for you.

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

Keep this leaflet with the medicine.

You may need to read it again.

What MARCAIN is for

MARCAIN is used to prevent or relieve pain, but it will not put you to sleep.

MARCAIN is also used after surgery to relieve 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.

Depending on the amount used, MARCAIN will either totally stop pain or will cause a partial loss of feeling.

MARCAIN is sometimes combined with adrenaline to make it last longer. Adrenaline makes the blood vessels at the site of injection narrower, which keeps the MARCAIN where it is needed for a longer time.

Your doctor will have explained why you are being treated with MARCAIN 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 uses other than those listed above. Ask your doctor if you want more information.

MARCAIN is not addictive

Before you are given MARCAIN

When you must not be given it

Ask your doctor about the risks and benefits of being given MARCAIN while you are pregnant or breastfeeding.

We do not know if it is safe for you to be given it while you are pregnant. It may affect your baby if you take it early in pregnancy or in the last weeks before your baby is due. However, it can be used during childbirth.

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

MARCAIN 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.

It may have no effect at all, or worse, an entirely unexpected effect if you are given MARCAIN after the expiry date.

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
  • any other substances

If you have an allergic reaction, you may get a skin rash, hayfever, have difficulty breathing or feel faint.

  1. you have any of these medical conditions
  • problems with your blood pressure or circulation
  • blood poisoning
  • problems with the clotting of your blood
  • acidosis, or too much acid in the blood.
  • epilepsy
  • nerve problems
  • heart, liver or kidney problems
  • disease of the brain or spine
  • thyrotoxicosis
  • diabetes
  • muscle disease or weakness (e.g. myasthenia gravis)

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

Taking other medicines

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

  • medicines that control your heart beat
  • medicines used to thin the blood, including aspirin
  • low molecular weight heparin or other medicines used to prevent blood clots
  • medicines for depression
  • medicines that you buy at the chemist, supermarket or health food shop.

These medicines may affect the way MARCAIN 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.

How MARCAIN is given

MARCAIN will be injected by your doctor into the skin, near a single nerve, or into an area which contains a large number of nerves.

This will result in an area of numbness at the site of injection, near the site of injection or in an area that may seem unrelated to the site of injection. The last will be the case if you are given an EPIDURAL injection (an injection around the spinal cord) and will result in a feeling of numbness in your lower body.

If you are receiving an EPIDURAL INFUSION it 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.

MARCAIN 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 or other local anaesthetics and will choose the best dose for you. They will be willing to discuss this decision with you.

Overdose

The doctor giving you MARCAIN will be experienced in the use of local anaesthetics, so it is unlikely that you will be given an overdose.

However, if you are particularly sensitive to MARCAIN, or the dose is accidentally 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, equipment will be available to revive 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.

You may be drowsy and your reflexes may be slow.

Do not drink alcohol while you are being given MARCAIN.

If you drink alcohol while you are being given MARCAIN 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.

MARCAIN will help 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 immediately if you notice any of the following:

  • nervousness
  • dizziness
  • blurred vision
  • a tingling feeling ("pins and needles")
  • ringing in the ears
  • numbness
  • feeling strange (disoriented)
  • nausea (feeling sick), vomiting

These are all mild side effects of MARCAIN.

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

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

  • fits
  • unconsciousness
  • breathing problems
  • low blood pressure
  • slow heart beat
  • collapse

These are all serious side effects.

You may need urgent medical attention. Serious side effects are rare.

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

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

After using it

Storage

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

MARCAIN in glass should be kept in a cool dry place where the temperature stays below 25°C. MARCAIN in plastic should be kept in a cool dry place where the temperature stays below 30 °C.

Disposal

Any MARCAIN which is not used, and which is left in the container, will be disposed of in a safe manner by your doctor or pharmacist.

Product description

MARCAIN and MARCAIN WITH ADRENALINE containing solutions are clear and colourless.

Each MARCAIN solution contains Bupivacaine hydrochloride as the active ingredient,

plus,

  • Sodium chloride
  • Sodium hydroxide or hydrochloric acid for pH adjustment
  • Water for injections

Each MARCAIN WITH ADRENALINE solution contains Bupivacaine hydrochloride and Adrenaline (epinephrine) (as acid tartrate) as the active ingredients,

plus,

  • Hydrochloric acid
  • Sodium chloride
  • Sodium metabisulfite (E223)
  • Water for Injections

In the USA adrenaline is known as epinephrine.

What is in Marcain

MARCAIN 0.125% Infusion
Bupivacaine hydrochloride 1.25mg/mL
PACK SIZES 5 X 100mL
PACK TYPE Polybag®
AUST R 12424

MARCAIN 0.125% Infusion
Bupivacaine hydrochloride 1.25mg/mL
PACK SIZES 5 X 200mL
PACK TYPE Polybag®
AUST R 48374

MARCAIN 0.25%
Bupivacaine hydrochloride 2.5mg/mL
PACK SIZES 5 X 20mL
PACK TYPE Polyamp®
AUST R 48380

MARCAIN 0.25% Infusion
Bupivacaine hydrochloride 2.5mg/mL
PACK SIZES 5 X 100mL
PACK TYPE Polybag®
AUST R 11953

MARCAIN 0.25% with adrenaline 1: 400,000
Bupivacaine hydrochloride 2.5mg/mL
Adrenaline (epinephrine) 2.5microgram/mL (as acid tartrate)
PACK SIZES 5 x 20mL*
PACK TYPE single dose vial
AUST R 125878

MARCAIN 0.375%
Bupivacaine hydrochloride 3.75mg/mL
PACK SIZES 5 x 20mL
PACK TYPE Polyamp®
AUST R 52691

MARCAIN 0.5%
Bupivacaine hydrochloride 5.0mg/mL
PACK SIZES 5 x 10mL and 50 x 10mL
PACK TYPE Polyamp®
AUST R 11937

MARCAIN 0.5%
Bupivacaine hydrochloride 5.0mg/mL
PACK SIZES 5 x 20mL
PACK TYPE Polyamp®
AUST R 48328

MARCAIN 0.5% with adrenaline 1:200,000
Bupivacaine hydrochloride 5.0mg/mL
Adrenaline (epinephrine) 5microgram/mL (as acid tartrate)
PACK SIZES 5 x 20mL*
PACK TYPE single dose vial
AUST R 48329

* contains sodium metabisulfite

Not all presentations are marketed.

BRAND INFORMATION

Brand name

Marcain 0.125% Epidural Infusion

Active ingredient

Bupivacaine hydrochloride

Schedule

S4

 

1 Name of Medicine

Bupivacaine hydrochloride with or without adrenaline (epinephrine) acid tartrate.

6.7 Physicochemical Properties

The chemical name for bupivacaine hydrochloride is (2RS)-1-Butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide hydrochloride monohydrate.
Bupivacaine has a pKa of 8.1 and is more lipid soluble than lignocaine. The Australian Approved Name is bupivacaine hydrochloride monohydrate.
Epinephrine is another medicine ingredient name for adrenaline but adrenaline is mostly used in this product information.
The chemical name for adrenaline is (1R)-1-(3,4-Dihydroxyphenyl)-2-(methylamino)ethanol hydrogen (2R,3R)-2,3-dihydroxybutanedioate.
The Australian Approved Name is adrenaline (epinephrine) acid tartrate.

Chemical structure.

The chemical structure of bupivacaine hydrochloride monohydrate is:
The chemical structure of adrenaline acid tartrate is:

CAS number.

The CAS number for bupivacaine hydrochloride monohydrate is 73360-54-0. The CAS number for adrenaline acid tartrate is 51-42-3.

2 Qualitative and Quantitative Composition

Marcain solutions are available with or without adrenaline.

Marcain 0.125% epidural infusion.

Bupivacaine hydrochloride 1.25 mg/mL.

Marcain 0.25%.

Bupivacaine hydrochloride 2.5 mg/mL.

Marcain 0.25% with adrenaline 1:400,000.

Bupivacaine hydrochloride 2.5 mg/mL with adrenaline (epinephrine) 2.5 (as acid tartrate) microgram/mL.

Marcain 0.375%.

Bupivacaine hydrochloride 3.75 mg/mL.

Marcain 0.5%.

Bupivacaine hydrochloride 5 mg/mL.

Marcain 0.5% with adrenaline 1:200,000.

Bupivacaine hydrochloride 5 mg/mL with adrenaline (epinephrine) 5 (as acid tartrate) microgram/mL.
Marcain solutions for injection are sterile, isotonic aqueous solutions of bupivacaine hydrochloride in Water for Injections BP. 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 with Adrenaline solutions for injection are sterile, isotonic aqueous solutions of bupivacaine hydrochloride in Water for Injections BP. The pH of the solution is adjusted with sodium hydroxide or hydrochloric acid to remain between 3.3 - 5.0.
Marcain with Adrenaline also contains sodium metabisulfite as an antioxidant. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Clear, colourless solution for injection or infusion.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

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 the cardiovascular system.
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.
Adrenaline acts on both alpha- and beta-adrenergic receptors of tissue innervated by sympathetic nerves, except for the sweat glands and arteries of the face. It is the most important alpha-receptor activator. Adrenaline stimulates the heart to increase output; raises the systolic blood pressure; lowers diastolic blood pressure; relaxes bronchial spasm and mobilises liver glycogen, resulting in hyperglycaemia and possibly glycosuria.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Bupivacaine is a long acting, amide-type local anaesthetic chemically related to lignocaine and mepivacaine. It is approximately four times as potent as lignocaine.
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 the 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. The addition of a vasoconstrictor such as adrenaline may decrease the rate of absorption and prolong the duration of action. 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 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 concentrations. Epidural and major plexus blocks are intermediate. 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. Absorption may be slowed by the addition of adrenaline.
Bupivacaine has a total plasma clearance of 0.58 L/min, a volume of distribution at steady-state of 73 L, an elimination half-life of 2.7 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, presence or absence of adrenaline in the solution and certain concomitant medication.

5.3 Preclinical Safety Data

Genotoxicity.

Formal studies of mutagenic potential have not been carried out.

Carcinogenicity.

Long-term studies in animals of most local anaesthetics, including bupivacaine, to evaluate the carcinogenic potential have not been conducted.

4 Clinical Particulars

4.1 Therapeutic Indications

Marcain solutions are indicated for the production of local or regional anaesthesia and analgesia in individuals as follows.

Surgical anaesthesia.

Epidural block for surgery; field block (minor and major nerve blocks and infiltration).

Analgesia.

Continuous epidural infusion or intermittent bolus epidural administration for analgesia in postoperative pain or labour pain; field block (minor nerve block and infiltration).
The choice of 4 strengths, 0.125%, 0.25%, 0.375% and 0.5%, makes it possible to vary the degree of motor blockade.

4.3 Contraindications

1. Allergy or hypersensitivity to amide type local anaesthetics or sodium metabisulfite in adrenaline-containing solutions. Detection of suspected hypersensitivity by skin testing is of limited value.
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. Bupivacaine is contraindicated in obstetric paracervical block, intravenous regional anaesthesia (Bier's block) and all intravenous infusions.
5. General contraindications related to epidural anaesthesia, regardless of the local anaesthetic used, should be taken into account.
The following are additional contraindications for solutions with adrenaline.
6. Adrenaline is contraindicated in conditions where the production or exacerbation of tachycardia may prove fatal, such as thyrotoxicosis or severe heart disease, or in obstetrics when maternal blood pressure exceeds 130/80 mmHg.
7. Solutions with adrenaline must not be used for local analgesia in parts of the body with compromised blood supply or which are supplied by end arteries, such as fingers, toes, nose, ears or penis. There is a possibility of producing arterial vasoconstriction and subsequent ischaemic gangrene distal to the site of injection.
8. Solutions with adrenaline should not be used in patients with a known sensitivity to sympathomimetic amines.
9. Solutions with adrenaline should not be used in most patients with cerebral arteriosclerosis.

4.4 Special Warnings and Precautions for Use

1. When any local anaesthetic agent is used, resuscitative equipment and drugs, including oxygen, 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 local anaesthetic 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. Although intra-articular continuous infusions of local anaesthetics following arthroscopic and other surgical procedures is an unapproved use, there have been post-marketing reports of chondrolysis in patients receiving such infusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases of gleno-humeral chondrolysis have been described in paediatric and adult patients following intra-articular continuous infusions of local anaesthetics with and without adrenaline for periods of 48 to 72 hours. There is insufficient information to determine whether shorter infusion periods are not associated with these findings. The time of onset of symptoms, such as joint pain, stiffness and loss of motion can be variable, but may begin as early as the 2nd month after surgery. Currently, there is no effective treatment for chondrolysis; patients who experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement. Therefore, Marcain and Marcain with Adrenaline should not be used for postoperative intra-articular continuous infusion.
4. 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.
5. The use of local anaesthetics for major peripheral nerve block may involve the administration of large volumes in highly vascularised areas, often close to large blood vessels. As such there is an increased risk of intravascular injection and/or systemic absorption which can lead to high plasma concentrations. There have been reports of cardiac arrest or death during the use of bupivacaine for epidural anaesthesia or peripheral nerve blockade. In some instances, resuscitation has been difficult or impossible despite apparently adequate preparation and management.
6. Central nerve blocks may cause cardiovascular depression, especially in the presence of hypovolaemia. Epidural anaesthesia should be used with caution in patients with impaired cardiovascular function. Epidural anaesthesia may lead to hypotension and bradycardia. Hypotension should be treated promptly.
7. 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 NSAID, platelet inhibitors or other anticoagulants. Patients should be frequently monitored for signs and symptoms of neurological impairment.
8. The safety and efficacy of Marcain depend on proper dosage, correct technique and adequate precautions. Standard textbooks should be consulted regarding specific techniques and precautions for various regional anaesthetic procedures.
9. The lowest dosage that results in effective anaesthesia should be used (see Section 4.2 Dose and Method of Administration). Repeated injection of Marcain may cause accumulation of bupivacaine or its metabolites and result in toxic effects.
Tolerance to elevated blood levels varies with the status of the patient. 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.
10. Bupivacaine may cause acute toxicity affects on the central nervous and cardiovascular systems if utilised for local anaesthetic procedures resulting in high blood concentrations of the drug. This is especially the case after unintentional intravascular administration. Ventricular arrhythmia, ventricular fibrillation, sudden cardiovascular collapse and death have been reported in connection with high systemic concentrations of bupivacaine.
11. Bupivacaine 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 bupivacaine. Patients being treated with anti-arrhythmic drugs class III (e.g. amiodarone) should be under close surveillance and ECG monitoring since cardiac effects may be additive.
In patients with Stokes-Adams syndrome or Wolff-Parkinson-White syndrome, extreme care should be taken to avoid accidental arterio-venous injection.
12. Local anaesthetics should be given with great 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 anaesthesia 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.
13. Inadvertent intravascular or subarachnoid injection of small doses of local anaesthetics injected into the head and neck area, including retrobulbar, dental and stellate ganglion blocks, may produce adverse reactions similar to systemic toxicity seen with unintentional intravascular injections of larger doses. Injections made inadvertently into an artery may cause immediate cerebral symptoms even at low doses.
Clinicians who perform retrobulbar blocks should be aware that there have been reports of cardiovascular collapse and apnoea following the use of local anaesthetic injections for retrobulbar block. Prior to retrobulbar block, necessary equipment, drugs and personnel should be immediately available as with all other regional procedures. Retrobulbar injections may very occasionally reach the subarachnoid space, causing temporary blindness, cardiovascular collapse, apnoea, convulsions, etc. These must be diagnosed and treated promptly.
Retro- and peribulbar injections of local anaesthetics carry a low risk of persistent ocular muscle dysfunction. The primary causes include trauma and/or local toxic effects on muscles or nerves. The severity of such tissue reactions is related to the degree of trauma, the concentration of the local anaesthetic and the duration of exposure of the tissue to the local anaesthetic. For this reason, as with all local anaesthetics, the lowest effective concentration and dose of local anaesthetic should be used. Vasoconstrictors may aggravate tissue reactions and should be used only when indicated.
14. Foetal bradycardia/tachycardia frequently follows paracervical block with some amide type local anaesthetics and may be associated with foetal acidosis and hypoxia. Added risk appears to be present in prematurity, toxaemia of pregnancy and foetal distress. Careful monitoring of the foetal heart rate is necessary (see Section 4.3 Contraindications).
15. Bupivacaine should be used with caution in patients with known drug sensitivities.
16. Solutions containing adrenaline also contain sodium metabisulfite which may cause allergic type reactions including anaphylactic type symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than non-asthmatic people.
17. Solutions containing adrenaline should be used with extreme caution in patients with severe or untreated hypertension, poorly controlled thyrotoxicosis, ischaemic heart disease, heart block, cerebrovascular insufficiency, advanced diabetes and any other pathological condition that might be aggravated by the effects of adrenaline (see Section 4.3 Contraindications). Adrenaline may induce anginal pain in patients suffering from ischaemic heart disease.
18. Solutions containing adrenaline should be used with caution in patients with ventricular fibrillation, prefibrillatory rhythm, tachycardia, myocardial infarction, phenothiazine induced circulatory collapse and prostatic hypertrophy (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions and Section 4.8 Adverse Effects (Undesirable Effects)).

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. Bupivacaine 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.

Please see Section 4.2 Dose and Method of Administration, Use in debilitated or elderly patients.

Paediatric use.

Caution should be used when administering bupivacaine to children under 12 years of age.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

1. Anti-arrhythmic drugs.

Local anaesthetics of the amide type, such as bupivacaine, should be used with caution in patients receiving other local anaesthetics or agents structurally related to amide-type local anaesthetics, e.g. certain antiarrhythmic drugs such as 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).
In addition, the following interactions may occur with solutions containing adrenaline.

2. CNS acting drugs.

Solutions containing adrenaline should be used with extreme caution in patients receiving tricyclic antidepressants or monoamine oxidase (MAO) inhibitors as severe, sustained hypertension may result. The effects of adrenaline may be potentiated by some antihistamines and thyroid hormones (see Section 4.4 Special Warnings and Precautions for Use). Phenothiazines and butyrophenones may reduce or reverse the pressor effect of adrenaline.

3. Oxytocic drugs of the ergot type.

Solutions with adrenaline should not be used in the presence of oxytocic drugs of the ergot-type as they are known to interact to produce severe, persistent hypertension and its subsequent sequelae.

4. Adrenergic neuron blocking agents.

Solutions with adrenaline should be used with caution in the presence of adrenergic neuron blocking agents (e.g. guanethidine, debrisoquine, bethanidine).

5. Beta-blockers.

Non-cardioselective beta-blockers such as propranolol enhance the pressor effects of adrenaline which may lead to severe hypertension and bradycardia.

6. Inhalation anaesthetics.

Serious cardiac arrhythmias and acute pulmonary oedema if hypoxia is present may occur if preparations containing adrenaline are employed in patients during or following the administration of chloroform, halothane, cyclopropane, trichlorethylene, or other halogenated compounds.

7. Cardiac glycosides.

Solutions with adrenaline may interact with cardiac glycosides resulting in cardiac arrhythmias.

8. Quinidine.

Solutions with adrenaline may interact with quinidine resulting in cardiac arrhythmias.

9. Hypoglycaemia.

Adrenaline-induced hyperglycaemia may lead to loss of blood sugar control in diabetic patients treated with hypoglycaemic agents.

10. Alkaline solutions.

The solubility of bupivacaine is limited at pH values above 6.5. This must be taken into consideration if adding an alkaline solution since precipitation might occur at higher pH values.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Effects on fertility have not been determined.
(Category A)
After epidural administration of bupivacaine to women in labour, bupivacaine crosses the placental barrier. However, concentrations in umbilical veins are lower than those found in the maternal circulation.
Bupivacaine has been effectively used for obstetrical analgesia 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.
Foetal adverse effects due to bupivacaine, such as foetal bradycardia, seem to be most apparent in paracervical block anaesthesia. Such effects may be due to high concentrations of anaesthetic reaching the foetus (see Section 4.3 Contraindications).
The safe use of bupivacaine 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 foetus, there are no adequate and well-controlled studies in pregnant women of the effect of bupivacaine on the developing foetus. It should therefore be used cautiously during pregnancy other than labour.
Adrenaline has been given to large numbers of pregnant women and women of child-bearing age without any proven increase in the frequency of malformation or other indirect harmful effects on the foetus having been observed.
The addition of adrenaline may potentially decrease uterine blood flow and contractility, especially after inadvertent injection into maternal blood vessels.
Adrenaline may delay the second stage of labour by inhibiting uterine contractions. Adrenaline-free solutions should be used during labour for pudendal blocks.
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 possibility of an idiosyncratic or allergic reaction in the breast-fed infant from bupivacaine remains to be determined.

4.8 Adverse Effects (Undesirable Effects)

Adverse reactions to bupivacaine are rare in the absence of overdosage, exceptionally rapid absorption 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, inadvertent intravascular injection or may result from a hypersensitivity, idiosyncrasy or diminished tolerance on the part of the patient.
Serious adverse experiences are generally systemic in nature. Ventricular arrhythmias, ventricular fibrillation, sudden cardiovascular collapse and death have been reported when Marcain has been utilised for local anaesthetic procedures that may result in high systemic concentrations of bupivacaine (see Section 4.4 Special Warnings and Precautions for Use).
Pronounced acidosis, hyperkalaemia, hypocalcaemia or hypoxia in the patient may increase the risk and severity of toxic reactions.
Adverse reactions to adrenaline are similar to those observed with other sympathomimetics. These may include dizziness, unusual anxiety, nervousness, restlessness, headache, hypertension and tachycardia.

Central nervous system.

CNS manifestations are excitatory and/or depressant and may be characterised by light-headedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred vision, diplopia, nausea, vomiting, sensations of heat, cold or numbness, urinary retention, paraesthesia circumoral, paraesthesia, hyperacusis, twitching, tremors, convulsions, unconsciousness, respiratory depression and/or arrest, agitation, numbness of the tongue, difficulty swallowing and slurred speech.
The excitatory manifestations may be very brief or may not occur at all, in which case the first manifestation of toxicity may be drowsiness merging into unconsciousness and respiratory arrest. Drowsiness following administration of bupivacaine is usually an early sign of a high blood level of the drug and may occur as a result of rapid absorption. In unconscious patients, circulatory collapse should be watched as CNS effects may not be apparent as an early manifestation of toxicity may in some cases progress to frank convulsions and ultimately lead to respiratory depression and/or arrest. It is crucial to have resuscitative equipment and anticonvulsant drugs available to manage such patients (see Section 4.9 Overdose, Treatment of overdosage).

Cardiovascular.

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).

Haemodynamic.

Regional anaesthesia may lead to maternal hypotension.

Neurologic.

The incidences of adverse reactions associated with the use of local anaesthetics may be related to the total dose of local anaesthetic administered and are also dependent on the particular drug used, the route of administration and the physical status of the patient.
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 subdurally.
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.
Paresis, paraplegia, neuropathy, peripheral nerve injury and arachnoiditis have been observed.
The effects of systemic overdose and unintentional intravascular injection may involve the central nervous system and/or the cardiovascular system (see Section 4.9 Overdose). Inadvertent subarachnoid injection may lead to CNS depression, respiratory arrest and cardiovascular collapse.

Allergic.

Allergic reactions are characterised by cutaneous lesions, urticaria, oedema or anaphylactoid reactions.
Allergy to amide-type local anaesthetics is rare. Sodium metabisulfite, which is included in solutions containing adrenaline, may also cause this type of reaction. If such a reaction occurs, it should be managed by conventional means.
The detection of sensitivity by skin testing is of doubtful value.

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.

4.2 Dose and Method of Administration

As with all local anaesthetics, the dosage varies and depends upon the area to be anaesthetised, the vascularity of the tissues, the number of neuronal segments to be blocked, the depth of anaesthesia and degree of muscle relaxation required, individual tolerance, the technique of anaesthesia and the physical condition of the patient.
The lowest dosage that results in effective anaesthesia should be used. In general, surgical anaesthesia requires the use of higher concentrations and doses than those required for analgesia. The volume of the drug used will affect the extent of spread of anaesthesia.
The presentations of Marcain injection solutions are intended for single use only. Any solution remaining from an opened container should be discarded.
Table 1 is a guide to dosage. The clinician's experience and knowledge of the patient's physical status are of importance in deciding the dose. Experience to date indicates that 400 mg administered over 24 hours is well tolerated in average adults.
Marcain with Adrenaline should not be used for epidural block in labour analgesia (apart from the use as a test dose) as the benefits from the addition of adrenaline have not been shown to outweigh the risks.

Note.

1. Recommended doses.

Tolerability varies widely between patients and toxic effects may occur after any local anaesthetic procedure. Careful observation of the patient must therefore be maintained. It is recommended that the dose of bupivacaine at any time should not exceed 2 mg/kg (both plain and adrenaline containing solutions). 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.

2. Injection.

Injection of repeated doses of bupivacaine may cause significant increase in blood levels with each repeated dose, due to accumulation of the drug or its metabolites, or due to slow metabolic degradation.
The rapid injection of a large volume of local anaesthetic solution should be avoided and fractional doses should be used when feasible. For most indications the duration of Marcain is such that a single dose is sufficient.

3. Hypotension.

During thoracic, lumbar and caudal epidural anaesthesia/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 the anaesthetic within the subarachnoid space. Hypotension and bradycardia may occur as a result of sympathetic blockade.

4. Test dose.

For epidural anaesthesia, a test dose of 3 - 5 mL of a local anaesthetic solution, preferably containing up to 15 micrograms of adrenaline, (e.g. 3 mL Marcain 0.5% with Adrenaline 1:200,000) 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.
Prior to administration of the total dose, aspiration should be repeated. The main dose should be injected slowly at a rate of 25 - 50 mg/min, while closely observing the patient's vital functions and maintaining verbal contact. If toxic symptoms or signs occur, the injection should be stopped immediately.

5. Prolonged blocks.

When prolonged blocks are used, either by continuous infusion or by repeated bolus administration, the risks of reaching a toxic plasma concentration or inducing a local neural injury must be considered.

Use in children.

Experience with bupivacaine in children under the age of 12 is limited. The dosage in children should be calculated on a weight basis up to 2 mg/kg. The addition of adrenaline will prolong the duration of the block by 50 - 100%.

Use in pregnancy.

It should be noted that the dose should be reduced in patients in the late stages of pregnancy.

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).

4.7 Effects on Ability to Drive and Use Machines

Depending on the dosage, local anaesthetics may have a mild effect on mental function and coordination and may temporarily impair locomotion and coordination.

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 4.4 Special Warnings and Precautions for Use and 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.

Indicates a more severe situation. Hypotension, bradycardia, decreased cardiac output, heart block, arrhythmia and even ventricular arrhythmias, ventricular fibrillation and cardiac arrest may occur as a result of high systemic concentrations of local anaesthetics.
Overdosage with adrenaline produces a rapid rise in blood pressure which may result in cerebrovascular haemorrhage, cardiac arrhythmia leading to ventricular fibrillation and death. Pulmonary oedema may also lead to death because of the peripheral constriction and cardiac stimulation produced.
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.

Treatment of overdosage.

If signs of acute systemic toxicity appear, injection of the local anaesthetic should be immediately stopped.
If convulsions occur then immediate attention is required for the maintenance of patent airway and assisted or controlled ventilation with oxygen, via a positive airway pressure delivery system mask. Adequacy of the circulation should then be evaluated, bearing in mind that drugs used to treat convulsions depress the circulation when administered intravenously.
Should convulsions persist despite adequate respiratory support, and if the status of the circulation permits, appropriate anticonvulsant medication such as an ultra-short acting barbiturate (e.g. thiopentone) or a benzodiazepine (e.g. diazepam) may be administered IV. The clinician should be familiar with these anticonvulsant drugs prior to use of local anaesthetics.
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.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Marcain contains sodium chloride, sodium hydroxide and/or hydrochloric acid and water for injection.
Marcain with Adrenaline contains sodium chloride, sodium metabisulphite, sodium hydroxide and/or hydrochloric acid and water for injection.

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 or Marcain with Adrenaline solutions 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.
Marcain solutions contain no antimicrobial agent and should be used only once and any residue discarded.
Solutions showing discolouration and unused portions of solutions from ampoules and single dose vials should be discarded.
Polyamps and solutions with adrenaline should not be reautoclaved. Surface sterilisation using pure, undiluted isopropyl alcohol (91%) or 70% ethanol maybe carried out if desired. Soaking of any Marcain presentation is not recommended.

6.4 Special Precautions for Storage

Marcain or Marcain with Adrenaline presentations in glass ampoules, Polyamp DuoFit, or Polybag should be stored below 30°C.
Marcain or Marcain with Adrenaline in single dose vials should be stored below 25°C.
Solutions with adrenaline should be protected from light.

6.5 Nature and Contents of Container

Marcain 0.125% epidural infusion.

100 mL and 200 mL Polybag in Sterile AstraZeneca Theatre Pack.

Marcain 0.25%.

20 mL Polyamp DuoFit ampoules in Sterile AstraZeneca Theatre Pack.
100 mL Polybag in Sterile AstraZeneca Theatre Pack.

Marcain 0.25% with adrenaline 1:400,000.

10 mL^ and 20 mL single dose vials in Sterile AstraZeneca Theatre Pack.

Marcain 0.375%.

20 mL Polyamp DuoFit ampoules^ in Sterile AstraZeneca Theatre Pack.

Marcain 0.5%.

5 x 10 mL and 5 x 20 mL Polyamp DuoFit ampoules in Sterile AstraZeneca Theatre Pack, 50 x 10 mL Polyamp DuoFit ampoules, 10 mL Top Hat vials^.

Marcain 0.5% with adrenaline 1:200,000.

10 mL^ and 20 mL single dose vials in Sterile AstraZeneca Theatre Pack.
^Registered but not marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes