Consumer medicine information

Bupivacaine Injection BP (Pfizer)

Bupivacaine hydrochloride

BRAND INFORMATION

Brand name

Pfizer (Australia) Bupivacaine Hydrochloride Injection BP

Active ingredient

Bupivacaine hydrochloride

Schedule

What is in this leaflet

This leaflet answers some common questions about Bupivacaine Injection BP.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of you taking Bupivacaine Injection BP against the benefits this medicine is expected to have for you.

This medicine is likely to be used while you are at the clinic or in hospital. If possible, please read this leaflet carefully before this medicine is given to you. In some cases this leaflet may be given to you after the medicine has been used.

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

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

What Bupivacaine Injection BP is used for

Bupivacaine is used to prevent or relieve pain, but it will not put you to sleep. Bupivacaine Injection BP is used during or after surgery to relieve pain. It can also be used to make childbirth less painful.

Bupivacaine Injection BP belongs to a group of medicines known as local anaesthetics. It is injected into the body where it will either totally stop pain or will cause partial loss of feeling (numbness), depending on the amount used.

Your doctor will have explained why you are being treated with Bupivacaine Injection BP and what dose you will be given.

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

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This product is available only on a doctor's prescription.

Before you are given Bupivacaine Injection BP

When you must not be given it:

Do not use Bupivacaine Injection BP if you have an allergy to:

any medicine containing bupivacaine or other local anaesthetics e.g. lidocaine (lignocaine)
any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

shortness of breath
wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body
rash, itching or hives on the skin.

You should not be given Bupivacaine Injection BP if:

you have an infection or swelling (redness) where the injection will be given
you have uncorrected low blood pressure.

If you are not sure whether any of these apply to you, check with your doctor.

Before you are given it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you are pregnant or intend to become pregnant. It is not known if it is safe for you to receive bupivacaine while you are pregnant. It may affect your baby if you receive it early in pregnancy or in the last weeks before your baby is due. However, bupivacaine may be used during childbirth. Your doctor will discuss with you the benefits and risks of being given it during pregnancy.

Tell your doctor if you are breastfeeding or plan to breast feed. Your baby can absorb bupivacaine in very small amounts from breast milk if you are breastfeeding. Your doctor will discuss with you the benefits and risks of being given it whilst you are breastfeeding.

Tell your doctor if you have or have had any medical conditions, especially the following:

problems with your blood pressure or circulation (especially low blood pressure)
problems with clotting of your blood
blood poisoning
acidosis, or too much acid in the blood
diseases of the brain, spine or nerves
muscle disease or weakness such as myasthenia gravis
kidney, liver, heart, or thyroid problems
epilepsy.

It may not be safe for you to be given Bupivacaine Injection BP if you have any of these conditions.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and bupivacaine may interfere with each other. These include:

medicines used to help control your heart beat, such as mexiletine
medicines to help prevent blood clots such as heparin
medicines for depression.

These medicines may affect the way bupivacaine works or be affected by bupivacaine. You may need different amounts of your medicine, or you may need to take a different medicine.

Your doctor will advise you about continuing to take other medicines while you are receiving Bupivacaine Injection BP.

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

How Bupivacaine Injection BP is given

How it is given

Bupivacaine Injection BP must only be given by a doctor or nurse.

It is given by injection into the skin, near a single nerve, or into an area which contains a large number of nerves (e.g. if you are given an epidural injection which is an injection around the spinal cord). This causes an area of numbness at 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 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.

Bupivacaine Injection BP should not be injected directly into the blood.

How much is given

Your doctor will decide what dose, how often and how long you will receive it. This depends on the type of pain relief required, your condition and other factors, such as your weight, age, how well your liver and kidneys are working, and whether or not other medicines are being given at the same time.

If you are given too much (overdose)

This rarely happens as Bupivacaine Injection BP is administered under the care of an experienced anaesthetist. Your condition will be carefully monitored following administration of bupivacaine.

However, if you are given too much bupivacaine, you may experience some of the effects listed under "Side Effects" below. Some side effects such as unconsciousness, low blood pressure and collapse will be monitored and detected by your doctor or nurse if it occurs.

Whenever you are given Bupivacaine Injection BP, equipment is available to treat you if you experience severe side effects.

If you think you have been given too much Bupivacaine Injection BP or if you experience severe side effects, tell your doctor or nurse immediately.

Side effects

Tell your doctor or nurse as soon as possible if you do not feel well while you are being treated with bupivacaine. Like other medicines, bupivacaine can cause some side effects. If they occur, most are likely to be minor or temporary. However, some may be serious and need medical attention.

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

Do not be alarmed by this list of possible side effects. You may not experience any of them.

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

nervousness, agitation
dizziness
ringing in the ears
blurred vision
numbness
disorientation (feeling strange)
nausea
vomiting
difficulty swallowing, slurred speech
shakes (tremor), tingling sensation (pins and needles).

These are usually mild side effects and should only last a short time.

After an epidural injection of bupivacaine you may develop a headache or backache which is not always related to the medicine used. This may last for some months after the injection was given, although this is rare.

Tell your doctor or nurse immediately if notice any of the following:

fits
difficulty breathing
severe dizziness with slow or irregular heart beat
joint pain, stiffness or loss of motion.

If Bupivacaine Injection BP is given wrongly, or you have a known sensitivity to it, it may cause the above side effects.

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

Other side effects not listed above, may occur in some patients. If you notice any other effects, check with your doctor. Some side effects may only be detected by your doctor.

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

After being given Bupivacaine Injection BP

Be careful driving or operating machinery after you have been given Bupivacaine Injection BP. You may be drowsy and feel light headed. Your reflexes may be made slower and you may feel nauseous.

Be careful when drinking alcohol following injection with bupivacaine. It may cause your blood pressure to drop and cause you to feel dizzy and faint.

Disposal

Any Bupivacaine Injection BP which is not used will be disposed of in a safe manner by your doctor or pharmacist.

Bupivacaine Injection BP is for single use only.

Product description

What it looks like

Bupivacaine Injection BP is a clear, colourless solution in either a 20 mL glass theatre vial or a plastic 10 mL Steriamp® or Steriluer® ampoule.

Ingredients

Bupivacaine Injection BP contains Bupivacaine Hydrochloride (as monohydrate) (0.25% or 0.5%).

It also contains:

Sodium Chloride
Hydrochloric acid
Sodium hydroxide
Water for Injections.

This medicine does not contain a preservative.

Supplier

Pfizer Australia Pty Ltd
Sydney, NSW
Toll Free number: 1800 675 229
www.pfizer.com.au

Australian registration numbers

Bupivacaine Injection BP 0.25% (sterile) 50 mg in 20 mL Theatre Vial: AUST R 11314

Bupivacaine Injection BP 0.5% (sterile) 100 mg in 20 mL Theatre Vial: AUST R 12725

Bupivacaine Injection BP 0.5% (sterile) 50 mg in 10 mL Steriluer® or Steriamp® Ampoule: AUST R 11312

Date of preparation

This leaflet was prepared in June 2022.

®= Registered Trademark

Published by MIMS July 2022

BRAND INFORMATION

Brand name

Pfizer (Australia) Bupivacaine Hydrochloride Injection BP

Active ingredient

Bupivacaine hydrochloride

Schedule

1 Name of Medicine

Bupivacaine hydrochloride monohydrate.

2 Qualitative and Quantitative Composition

Each vial of Bupivacaine Injection BP contains bupivacaine hydrochloride (as monohydrate) 50 mg or 100 mg.
Each ampoule of Bupivacaine Injection BP contains bupivacaine hydrochloride (as monohydrate) 50 mg.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection.
Bupivacaine Injection BP is a sterile, isotonic, preservative-free solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Bupivacaine Injection BP is 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 2 strengths, 0.25% and 0.5%, makes it possible to vary the degree of motor blockade.

4.2 Dose and Method of Administration

Dosage.

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 Bupivacaine Injection BP are intended for single use only. Any solution remaining from an opened container should be discarded.
Tables 1 and 2 are 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.
The normal recommended dose of plain bupivacaine injections for various anaesthetic procedures in the average, healthy 70 kg adult patient are as follows.

Notes.

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. 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.

Hypotension.

During thoracic, lumbar and caudal epidural anaesthesia, a marked fall in blood pressure and/or intercostal paralysis may occur, 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.

Method of administration.

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 bupivacaine is such that a single dose is sufficient.

Test dose.

For epidural anaesthesia, a 3 to 5 mL test dose of local anaesthetic solution, preferably containing up to 15 microgram adrenaline (epinephrine), should be administered. Verbal contact and repeated monitoring of the heart rate and blood pressure should be maintained for 5 minutes after the test dose after which, in the absence of signs of subarachnoid or intravascular injection, the main dose may be given.
Use of a test dose containing adrenaline (epinephrine) may have further advantages in that an intravascular injection of adrenaline (epinephrine) 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.
Before administration of the total dose, aspiration should be repeated. The main dose should be injected slowly at a rate of 25 to 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.

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.
Bupivacaine 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 vials should be discarded.

Dosage adjustment.

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.

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).

4.3 Contraindications

Allergy or hypersensitivity to local anaesthetics of the amide type. Detection of suspected hypersensitivity by skin testing is of limited value.
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.
Obstetrical paracervical block, intravenous regional anaesthesia (Bier's block) and all intravenous infusions.
Epidural and spinal anaesthesia in patients with uncorrected hypotension.
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

During administration of bupivacaine, it is mandatory to have emergency resuscitative equipment (including oxygen) and drugs immediately available to manage possible adverse reactions involving the cardiovascular, respiratory or central nervous systems (CNS).
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.
The safety and effectiveness of bupivacaine depend upon proper dosage, correct technique and adequate precautions. Standard textbooks should be consulted for specific techniques and precautions for various regional anaesthetic procedures.
Injections 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).
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.
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.
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.
Low molecular weight heparins and heparinoids (spinal/ epidural haematomas). When neuraxial anaesthesia (epidural/ spinal anaesthesia) is employed, patients anticoagulated or scheduled to be anticoagulated 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 nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors or other anticoagulants. Patients should be frequently monitored for signs and symptoms of neurological impairment.
The lowest dosage that results in effective anaesthesia should be used (see Section 4.2 Dose and Method of Administration). Repeated injection of Bupivacaine Injection BP 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.
Bupivacaine may cause acute toxicity effects 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.
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 antiarrhythmic drugs class III (e.g. amiodarone) should be under close surveillance and electrocardiogram (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.
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.
Patients with hyperthyroidism are also more susceptible to toxicity with bupivacaine.
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 the 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 should be used. Vasoconstrictors may aggravate tissue reaction and should be used only when indicated.
Fetal bradycardia/ tachycardia frequently follows paracervical block with some amide type local anaesthetics and may be associated with fetal acidosis and hypoxia. Added risk appears to be present in prematurity, toxaemia of pregnancy and fetal distress. Careful monitoring of the fetal heart rate is necessary (see Section 4.3 Contraindications).
Bupivacaine should be used with caution in patients with known drug sensitivities.
Hepatic dysfunction, with reversible increases of alanine aminotransferase (ALT), alkaline phosphates (ALP) and bilirubin, has been observed following repeated injections or long-term infusions of bupivacaine. Association between bupivacaine use and the development of drug-induced liver injury (DILI) has been reported in a small number of literature reports especially with prolonged use. While the pathophysiology of this reaction remains unclear, immediate withdrawal of bupivacaine has shown rapid clinical improvement. If signs of hepatic dysfunction are observed during administration with bupivacaine, the medicinal product should be discontinued.

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.

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

Antiarrhythmic 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 lidocaine (lignocaine), since potentiation of cardiac effects may occur. Specific interaction studies with bupivacaine and antiarrhythmic 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).

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.
Fetal adverse effects due to bupivacaine, such as fetal bradycardia, seem to be most apparent in paracervical block anaesthesia. Such effects may be due to high concentrations of anaesthetic reaching the fetus (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).
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 fetus, there are no adequate and well controlled studies in pregnant women of the effect of bupivacaine on the developing fetus. It is known that local anaesthetics cross the placenta rapidly. It 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 breastfeeding mother receiving parenteral bupivacaine is unlikely to lead to a significant accumulation of the parent drug in the breastfed 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 breastfed infant from bupivacaine remains to be determined.

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.

4.8 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 bupivacaine 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.

Central nervous system.

CNS manifestations are excitatory and/or depressant and may be characterised by lightheadedness, 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. If such a reaction occurs, it should be managed by conventional means.
The detection of sensitivity by skin testing is of doubtful value.

Musculoskeletal.

Although intra-articular continuous infusions of local anaesthetics following arthroscopic and other surgical procedures is an unapproved use, there have been postmarketing reports of chondrolysis in patients receiving such infusions. Symptoms include joint pain, stiffness and loss of motion.
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, bupivacaine should not be used for postoperative intra-articular continuous infusion.

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); Section 4.4 Special Warnings and Precautions for Use).
With accidental intravascular injections of local anaesthetics, the toxic effects will be obvious within 1 to 3 minutes. With overdosage, peak plasma concentrations may not be reached for 20 to 30 minutes, depending on the site of injection, and toxic signs will be delayed. Toxic reactions mainly involve the central nervous and cardiovascular systems.

Symptoms of acute toxicity.

Central nervous system toxicity is a graded response with symptoms and signs of escalating severity. The first symptoms are circumoral paraesthesia, numbness of the tongue, lightheadedness, hyperacusis and tinnitus. Visual disturbances and muscular tremors are more serious and precede the onset of generalised convulsions. These signs must not be mistaken for neurotic behaviour.
Unconsciousness and grand mal convulsions may follow. These may last from a few seconds to several minutes. Hypoxia and hypercapnia occur rapidly following convulsions due to increased muscular activity, together with the interference with normal respiration and loss of the airway. In severe cases, apnoea may occur. Acidosis, hyperkalaemia, hypocalcaemia and hypoxia increase and extend the toxic effects of local anaesthetics.
Recovery is due to redistribution of the local anaesthetic drug from the central nervous system and metabolism. Recovery may be rapid unless large amounts of the drug have been injected.
Signs of cardiovascular toxicity indicates a more severe situation. Hypotension, bradycardia, 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.
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 ultrashort 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.
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 is classed as a membrane stabilising agent and is a local anaesthetic of the amide type.
Bupivacaine, like other local anaesthetics, causes a reversible blockade of impulse propagation along nerve fibres by preventing the inward movement of sodium ions through the nerve membrane. Local anaesthetics of the amide type are thought to act within the sodium channels of the nerve membrane.
Local anaesthetic drugs may have similar effects on excitable membranes in the brain and myocardium. If excessive amounts of drug reach the systemic circulation rapidly, symptoms and signs of toxicity will appear, emanating mainly from the central nervous system and 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.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Bupivacaine is a long acting, amide type local anaesthetic chemically related to lignocaine and mepivacaine. Its potency and toxicity is approximately four times that of lignocaine.
In concentrations of 5 mg/mL it has a long duration of action, from 2 to 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 (epinephrine) may decrease the rate of absorption and prolong the duration of action.
Following injection of bupivacaine solutions for caudal, epidural or peripheral nerve block, peak plasma levels of bupivacaine are reached within 30 to 45 minutes and decline to insignificant concentrations 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 to 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 to 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 (epinephrine).
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.

Distribution.

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 (range 1.5 to 5.5 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 (range 8.1 to 14.0 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%.

Metabolism and excretion.

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 to 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 (epinephrine) in the solution and certain concomitant medication.

5.3 Preclinical Safety Data

Genotoxicity.

Mutagenic potential has not been determined.

Carcinogenicity.

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

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium chloride, hydrochloric acid, sodium hydroxide, water for injections.

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 bupivacaine 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.

6.4 Special Precautions for Storage

Store below 25°C. Single use only. Discard unused portion.

6.5 Nature and Contents of Container

Bupivacaine Injection BP 0.25% (sterile) 50 mg in 20 mL Glass Theatre Vial (5 vials).
Bupivacaine Injection BP 0.5% (sterile) 100 mg in 20 mL Glass Theatre Vial (5 vials).
Bupivacaine Injection BP 0.5% (sterile) 50 mg in 10 mL Steriamp Plastic Ampoule (50 ampoules).
Bupivacaine Injection BP 0.5% (sterile) 50 mg in 10 mL Steriluer Plastic Ampoule (50 ampoules).
Not all presentations are available.

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

Chemical structure.

It appears as a white, crystalline powder or colourless crystals. It is soluble in water, freely soluble in ethanol (96%), slightly soluble in chloroform and in ether. Bupivacaine has a pKa of 8.1 and is more lipid soluble than lignocaine.
The structural formula of bupivacaine hydrochloride monohydrate is represented below.

Chemical name: (2RS)-1-butyl-N-(2,6-dimethylphenyl) piperidine-2-carboxamide hydrochloride monohydrate.
Molecular Formula: C₁₈H₂₉ClN₂O.H₂O.
Molecular Weight: 342.9.

CAS number.

73360-54-0 (bupivacaine hydrochloride monohydrate).

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

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