SUMMARY CMI

Bupivacaine with Adrenaline Phebra Injection

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why is Bupivacaine with Adrenaline Injection being used?

Bupivacaine with Adrenaline Injection contains the active ingredients bupivacaine hydrochloride and adrenaline (epinephrine) (as acid tartrate). Bupivacaine with Adrenaline Injection is used to prevent or relieve pain, but it will not put you to sleep. It is also used after surgery to relieve pain and to make childbirth less painful.

For more information, see Section 1. Why is Bupivacaine with Adrenaline Injection being used? in the full CMI.

2. What should I know before Bupivacaine with Adrenaline Injection is used?

Do not use if you have ever had an allergic reaction to Bupivacaine with Adrenaline Injection or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before Bupivacaine with Adrenaline Injection is used? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Bupivacaine with Adrenaline Injection and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How is Bupivacaine with Adrenaline Injection used?

Bupivacaine with Adrenaline Injection will be injected by your doctor into the skin, near a single nerve, or into an area that contains a large number of nerves.

More instructions can be found in Section 4. How is Bupivacaine with Adrenaline Injection used? in the full CMI.

5. What should I know while Bupivacaine with Adrenaline Injection is being used?

For more information, see Section 5. What should I know while Bupivacaine with Adrenaline Injection is being used? in the full CMI.

6. Are there any side effects?

Bupivacaine with Adrenaline Injection may cause nervousness, dizziness, blurred vision, a tingling feeling (pins and needles), ringing in the ears, numbness, feeling strange (disoriented), nausea (feeling sick), vomiting, seizure, unconsciousness, breathing problems, low blood pressure, slow heartbeat and collapse.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

FULL CMI

Bupivacaine with Adrenaline Phebra Injection

Active ingredients: bupivacaine hydrochloride and adrenaline (epinephrine) (as acid tartrate)

Consumer Medicine Information (CMI)

This leaflet provides important information about using Bupivacaine with Adrenaline Injection. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about Bupivacaine with Adrenaline Injection being used.

Where to find information in this leaflet:

1. Why is Bupivacaine with Adrenaline Injection being used?
2. What should I know before Bupivacaine with Adrenaline Injection is used?
3. What if I am taking other medicines?
4. How is Bupivacaine with Adrenaline Injection used?
5. What should I know while Bupivacaine with Adrenaline Injection is being used?
6. Are there any side effects?
7. Product details

1. Why is Bupivacaine with Adrenaline Injection being used?

Bupivacaine with Adrenaline Injection contains the active ingredients bupivacaine hydrochloride (as monohydrate) and adrenaline (epinephrine) (as acid tartrate).
Bupivacaine with Adrenaline Injection belongs to a group of medicines known as local anaesthetics.

Bupivacaine with Adrenaline Injection is used to prevent or relieve pain, but it will not put you to sleep. It is also used after surgery to relieve pain and to make childbirth less painful.

Depending on the amount used, Bupivacaine with Adrenaline Injection will either totally stop pain or will cause a partial loss of feeling. When injected it makes the nerves nearby unable to pass messages to the brain and will therefore prevent or relieve pain.

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

Follow all the directions and advice given to you by your doctor carefully.

Your doctor may have prescribed Bupivacaine with Adrenaline Injection for uses other than those listed above.

2. What should I know before Bupivacaine with Adrenaline Injection is used?

Warnings

Do not use Bupivacaine with Adrenaline Injection if:

• you are allergic to bupivacaine or adrenaline (epinephrine), other local anaesthetics [e.g. lidocaine (lignocaine)] or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.

Check with your doctor if you have or have had:

• 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
• a disease of the brain or spine
• thyrotoxicosis
• diabetes
• muscle disease or weakness (e.g. myasthenia gravis).
• hyperkalaemia (too much potassium in your blood)
• hypocalcaemia (low calcium levels in your blood)

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Ask your doctor about the risks and benefits of being given Bupivacaine with Adrenaline Injection while you are pregnant or breastfeeding.

Check with your doctor if you are pregnant or intend to become pregnant.

It is not known if it is safe for you to be given Bupivacaine with Adrenaline Injection while you are pregnant. It may affect your baby if you are given early in pregnancy or in the last weeks before your baby is due. However, Bupivacaine with Adrenaline Injection can be used during childbirth.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

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

If you have not told your doctor about any of the above, tell him/her before you are given Bupivacaine with Adrenaline Injection.

3. What if I am taking other medicines?

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

Some medicines may interfere with Bupivacaine with Adrenaline Injection and affect how it works.

Such medicines may include:

• medicines that control your heartbeat, including beta blockers
• medicines used to thin the blood, including aspirin
• low molecular weight heparin or other medicines used to prevent blood clots
• medicines for depression
• medicines for allergies
• medicines used to help thyroid function
• inhaled anasthetics
• quinidine used to treat malaria
• oxytocic drugs of ergot type
• medicines that you buy at the chemist, supermarket or health food shop

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Bupivacaine with Adrenaline Injection.

4. How is Bupivacaine with Adrenaline Injection used?

How much to use

• The dosage you will be given will depend on your body size, age and the type of pain relief required. Your doctor will determine the best dose for you.

If you use too much Bupivacaine with Adrenaline Injection

Bupivacaine with Adrenaline Injection will be given to you by a doctor and so it is unlikely that you will be given an overdose.

However, if you are particularly sensitive to Bupivacaine with Adrenaline Injection, 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. If you experience any of these it's important to tell your doctor or nurse.

Whenever you are given Bupivacaine with Adrenaline Injection, your doctor will have suitable equipment and procedures in place if you experience signs of being given too much.

Symptoms of an overdose may include the side effects listed in Section 6. Are there any side effects? But are usually of a more severe nature.

5. What should I know while Bupivacaine with Adrenaline Injection is being used?

Driving or using machines

Be careful driving or operating machinery after you have been given Bupivacaine with Adrenaline Injection.

Bupivacaine with Adrenaline Injection may cause dizziness, light-headedness or weakness in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else dangerous.

Drinking alcohol

Tell your doctor if you drink alcohol.

Do not drink alcohol if your doctor plans to administer Bupivacaine with Adrenaline Injection.

If you drink alcohol while you are being given Bupivacaine with Adrenaline Injection your blood pressure may drop, making you feel dizzy and faint.

Looking after your medicine

• Bupivacaine with Adrenaline Injection will be stored by your doctor or pharmacist under the recommended conditions, out of the reach of children.
• Bupivacaine with Adrenaline Injection should be kept in a cool dry place where the temperature stays below 25°C.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Serious side effects

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

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

7. Product details

Bupivicaine with Adrenaline Injection is a prescription medicine and is only administered under a doctor's supervision.

What Bupivacaine with Adrenaline Injection contains

Do not take this medicine if you are allergic to any of these ingredients.

Bupivacaine with Adrenaline Injection does not contain lactose, sucrose, gluten, tartrazine, alcohol, dyes or any preservatives.

What Bupivacaine with Adrenaline Injection looks like

Bupivacaine with Adrenaline Injection is a colourless or almost colourless solution in a clear glass vial sealed with a grey rubber stopper and with a flip off tear off seal. It is packaged in a sterile theatre pack.

Bupivacaine with Adrenaline Injection is available in two strengths:

• BUPIVACAINE 0.5% WITH ADRENALINE 1:200,000 PHEBRA solution for injection vial - AUST R 373819
• BUPIVACAINE 0.25% WITH ADRENALINE 1:400,000 PHEBRA solution for injection vial - AUST R 408186

Who distributes Bupivacaine with Adrenaline Injection

Bupivacaine with Adrenaline Injection is manufactured and supplied in Australia by:

Phebra Pty Ltd
19 Orion Road, Lane Cove West,
NSW 2066, Australia.
Telephone: 1800 720 020

This leaflet was prepared in January 2024.

Phebra and the Phi symbol are trademarks of Phebra Pty Ltd, 19 Orion Road, Lane Cove West, NSW 2066, Australia.

Published by MIMS April 2024

1 Name of Medicine

Bupivacaine hydrochloride monohydrate.
Adrenaline (epinephrine) acid tartrate.

2 Qualitative and Quantitative Composition

Bupivacaine with Adrenaline Phebra solution for injection is available in two strengths:
Bupivacaine 0.25% with Adrenaline 1:400,000 Phebra solution for injection contains bupivacaine hydrochloride 50 mg/20 mL with adrenaline (epinephrine) (as acid tartrate) 50 microgram/20 mL.
Bupivacaine 0.5% with Adrenaline 1:200,000 Phebra solution for injection contains bupivacaine hydrochloride 100 mg/20 mL with adrenaline (epinephrine) (as acid tartrate) 100 microgram/20 mL.
The pH of the solution is between 3.0 - 5.5.

Excipient with known effect.

3 Pharmaceutical Form

Clear, colourless, or almost colourless isotonic aqueous solution for injection or infusion.

4 Clinical Particulars

4.1 Therapeutic Indications

Bupivacaine with Adrenaline Phebra solution is indicated for the production of local or regional anaesthesia and analgesia in individuals as follows:

Surgical anaesthesia.

Analgesia.

4.2 Dose and Method of Administration

Bupivacaine 0.125%, 0.25%, 0.375% and 0.5% solutions for injection, are unavailable in this brand, however are available in other brands.
Where correct dosing requires a bupivacaine solution without adrenaline (epinephrine) products from other suppliers should be used.
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.
Bupivacaine with Adrenaline Phebra is for single use only. Use in one patient on one occasion only and discard. Contains no antimicrobial preservative.
The following tables are a guide to dosage. The clinician's experience and knowledge of the patient's physical status are of importance in deciding the dose. Studies to date indicate that 400 mg administered over 24 hours is well tolerated in average adults.
Bupivacaine with Adrenaline Phebra 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 (epinephrine) have not been shown to outweigh the risks.

Dosage recommendations for bupivacaine solutions for injection, with or without adrenaline (epinephrine), for various anaesthetic procedures in an average, healthy 70 kg adult patient.

Note.

1. Recommended doses.

2. Injection.

3. Hypotension.

4. Test dose.

5. Prolonged blocks.

Use in children.

Use in pregnancy.

Use in debilitated or elderly patients.

4.3 Contraindications

1. Allergy or hypersensitivity to amide type local anaesthetics or sodium metabisulfite in adrenaline (epinephrine) 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 (epinephrine):
6. Adrenaline (epinephrine) 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 (epinephrine) 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 (epinephrine) should not be used in patients with a known sensitivity to sympathomimetic amines.
9. Solutions with adrenaline (epinephrine) 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 glenohumeral chondrolysis have been described in paediatric and adult patients following intra-articular continuous infusions of local anaesthetics with and without adrenaline (epinephrine) 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, Bupivacaine with Adrenaline Phebra 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 bupivacaine depends 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 bupivacaine 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 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.
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. 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.)
15. Bupivacaine should be used with caution in patients with known drug sensitivities.
16. Solutions containing adrenaline (epinephrine) 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 (epinephrine) 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 (epinephrine) (see Section 4.3 Contraindications). Adrenaline (epinephrine) may induce anginal pain in patients suffering from ischaemic heart disease.
18. Solutions containing adrenaline (epinephrine) 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; Section 4.8 Adverse Effects (Undesirable Effects)).
19. Hepatic dysfunction, with reversible increases of alanine aminotransferase (ALT), alkaline phosphates (AlkP) 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.

Use in renal impairment.

Use in the elderly.

Paediatric use.

Effects on laboratory tests.

4.5 Interactions with Other Medicines and Other Forms of Interactions

1. Antiarrhythmic drugs.

2. CNS acting drugs.

3. Oxytocic drugs of the ergot type.

4. Adrenergic neuron blocking agents.

5. Beta blockers.

6. Inhalation anaesthetics.

7. Cardiac glycosides.

8. Quinidine.

9. Hypoglycaemia.

10. Alkaline solutions.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

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.
Adverse reactions to adrenaline (epinephrine) are similar to those observed with other sympathomimetics. These may include dizziness, unusual anxiety, nervousness, restlessness, headache, hypertension and tachycardia.

Central nervous system.

Cardiovascular.

Haemodynamic.

Neurologic.

Allergic.

Reporting suspected adverse effects.

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; 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.

Treatment of overdosage.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Clinical trials.

5.2 Pharmacokinetic Properties

Bupivacaine 0.125%, 0.25%, 0.375% and 0.5% solutions for injection, without adrenaline (epinephrine), are available in other brands. Pharmacokinetic information obtained using bupivacaine 0.125%, 0.25%, 0.375% and 0.5% solutions for injection, with or without adrenaline (epinephrine), are also included in the following sub-sections for prescriber information.
Bupivacaine is a long acting, amide-type local anaesthetic chemically related to lidocaine (lignocaine) and mepivacaine. It is approximately four times as potent as lidocaine (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 lidocaine (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. After injection of bupivacaine 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 (epinephrine).
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 (epinephrine) in the solution and certain concomitant medication.

5.3 Preclinical Safety Data

Genotoxicity.

Carcinogenicity.

6 Pharmaceutical Particulars

6.1 List of Excipients

Bupivacaine with Adrenaline Phebra contains sodium chloride, sodium metabisulfite, hydrochloric acid (for pH adjustment) and 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 with Adrenaline Phebra 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)¹. The expiry date can be found on the packaging.
Bupivacaine with Adrenaline Phebra contains no antimicrobial agent and should be used only once and any residue discarded.
Solutions showing discolouration and unused portions of solutions from single dose vials should be discarded.
Bupivacaine with Adrenaline Phebra should not be reautoclaved. Surface sterilisation using pure, undiluted isopropyl alcohol (91%) or 70% ethanol maybe carried out if desired. Soaking of any Bupivacaine with Adrenaline Phebra presentation is not recommended.
¹ AUST R 373819, AUST R 408186.

6.4 Special Precautions for Storage

Bupivacaine with Adrenaline Phebra should be stored below 25°C and protected from light.

6.5 Nature and Contents of Container

Bupivacaine 0.5% with Adrenaline 1:200,000 Phebra is supplied in a sterile theatre pack which contains one type 1 clear glass 20 mL single dose vial with a grey chlorobutyl rubber stopper, and an aluminium seal with a green plastic flip-off cap. Each carton contains 5 sterile theatre packs, each containing 1 x 20 mL single dose vial.
Bupivacaine 0.25% with Adrenaline 1:400,000 Phebra is supplied in a sterile theatre pack which contains one type 1 clear glass 20 mL single dose vial with a grey chlorobutyl rubber stopper and an aluminium seal with an orange plastic flip-off cap. Each carton contains 5 sterile theatre packs, each containing 1 x 20 mL single dose vial.

6.6 Special Precautions for Disposal

Single use only. Discard any unused content.
In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Bupivacaine hydrochloride is a white or almost white, crystalline powder or colourless crystals. It is soluble in water and freely soluble in ethanol (96%). Bupivacaine has a pKa of 8.09 and is more lipid soluble than lidocaine (lignocaine).
The chemical name for bupivacaine hydrochloride (as monohydrate) is (2RS)-1-Butyl-N-(2,6- dimethylphenyl) piperidine-2-carboxamide hydrochloride monohydrate.
Bupivacaine hydrochloride (as monohydrate) has the chemical formula C₁₈H₂₉ClN₂O.H₂O and molecular weight value 342.9.
Adrenaline (epinephrine) acid tartrate appears as a white to greyish-white, crystalline powder that is freely soluble in water and slightly soluble in ethanol (96%) and methanol.
The chemical name for adrenaline (epinephrine) is (1R)-1-(3,4-Dihydroxyphenyl)-2-(methylamino) ethanol hydrogen (2R,3R)-2,3-dihydroxybutanedioate.
Adrenaline (epinephrine) acid tartrate has the chemical formula C₁₃H₁₉NO₉ and a molecular weight of 333.3.

Chemical structure.

CAS number.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

Summary Table of Changes