Marcain Heavy 0.5% solution for injection – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Bupivacaine 0.5% w/v with Glucose solution for injection.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Bupivacaine Hydrochloride BP 5.28 mg/ml equivalent to 5 mg/ml bupivacaine hydrochloride anhydrous.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Solution for injection.

Clear, colourless solution.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Bupivacaine 0.5% w/v with glucose solution for injection is indicated in adults and children of all ages for intrathecal (subarachnoid) spinal anaesthesia for surgery (urological and lower limb surgery lasting 2–3 hours, abdominal surgery lasting 45–60 minutes).

Bupivacaine is a long-acting anaesthetic agent of the amide type. Bupivacaine injection has a rapid onset of action and long duration. The duration of analgesia in the T₁₀–T₁₂ segments is 2–3 hours.

Bupivacaine injection produces a moderate muscular relaxation of the lower extremities lasting 2–2.5 hours. The motor blockade of the abdominal muscles makes the solution suitable for performance of abdominal surgery lasting 45–60 minutes. The duration of the motor blockade does not exceed the duration of analgesia. The cardiovascular effects of Bupivacaine injection are similar or less than those seen with other spinal agents. Bupivacaine 5 mg/ml with glucose 80 mg/ml is exceptionally well tolerated by all tissues with which it comes in contact.

4.2 Posology and method of administration

Adults and children above 12 years of age

The doses recommended below should be regarded as a guide for use in the average adult.

The figures reflect the expected average dose range needed. Standard textbooks should be consulted for factors affecting specific block techniques and for individual patient requirements.

The clinician’s experience and knowledge of the patient’s physical status are of importance in calculating the required dose. The lowest dose required for adequate anaesthesia should be used. Individual variations in onset and duration occur, and the extent of the spread of anaesthesia may be difficult to predict, but will be affected by the volume of the drug used, especially with the isobaric (plain) solution.

Dosage recommendations

Intrathecal anaesthesia for surgery:

2-4 ml (10-20 mg bupivacaine hydrochloride).

The dose should be reduced in the elderly and in patients in the late stages of pregnancy, see Section 4.4.

Neonates, infants and children up to 40 kg

Bupivacaine injection may be used in children.

One of the differences between small children and adults is a relatively high CSF volume in infants and neonates, requiring a relatively larger dose/kg to produce the same level of block as compared to adults.

Paediatric regional anaesthesia procedures should be performed by qualified clinicians who are familiar with this population and the techniques.

The doses in the table should be regarded as guidelines for use in paediatric patients. Individual variations occur. Standard textbooks should be consulted for factors affecting specific block technique and for individual patient requirements. The lowest dose required for adequate anaesthesia should be used.

Dosage recommendations in neonates, infants and children

The spread of anaesthesia obtained with Bupivacaine injection depends on several factors including the volume of solution and the position of the patient during and following the injection.

When injected at the L3–L4 intervertebral space, with the patient in the sitting position, 3 ml of Bupivacaine injection spreads to the T7–T10 spinal segments. With the patient receiving the injection in the horizontal position and then turned supine, the blockade spreads to T4–T7 spinal segments. It should be understood that the level of spinal anaesthesia achieved with any local anaesthetic can be unpredictable in a given patient.

The recommended site of injection is below L3.

The effects of injections of Bupivacaine injection exceeding 4 ml have not yet been studied and such volumes can therefore not be recommended.

Method of administration

Route of administration: For intrathecal injection.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Hypersensitivity to local anaesthetics of the amide type.

Intrathecal anaesthesia, regardless of the local anaesthetic used, has its own contraindications, which include:

• Active disease of the central nervous system such as meningitis, poliomyelitis, intracranial haemorrhage, sub-acute combined degeneration of the cord due to pernicious anaemia and cerebral and spinal tumours.
• Spinal stenosis and active disease (e.g. spondylitis, tuberculosis, tumour) or recent trauma (e.g. fracture) in the vertebral column.
• Septicaemia.
• Pyogenic infection of the skin at or adjacent to the site of lumbar puncture.
• Cardiogenic or hypovolaemic shock.
• Coagulation disorders or ongoing anticoagulation treatment.

4.4 Special warnings and precautions for use

Intrathecal anaesthesia should only be undertaken by clinicians with the necessary knowledge and experience.

Regional anaesthetic procedures should always be performed in a properly equipped and staffed area. Resuscitative equipment and drugs should be immediately available and the anaesthetist should remain in constant attendance.

Intravenous access, e.g. an i.v. infusion, should be in place before starting the intrathecal anaesthesia. The clinician responsible should take the necessary precautions to avoid intravascular injection and be appropriately trained and familiar with the diagnosis and treatment of side effects, systemic toxicity and other complications. If signs of acute systemic toxicity or total spinal block appear, injection of the local anaesthetic should be stopped immediately, see sections 4.8 & 4.9.

Like all local anaesthetic drugs, 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 or injection into highly vascular areas.

Ventricular arrhythmia, ventricular fibrillation, sudden cardiovascular collapse and death have been reported in connection with high systemic concentrations of bupivacaine. Should cardiac arrest occur, a successful outcome may require prolonged resuscitative efforts. High systemic concentrations are not expected with doses normally used for intrathecal anaesthesia.

There is an increased risk of high or total spinal blockade, resulting in cardiovascular and respiratory depression, in the elderly and in patients in the late stages of pregnancy. The dose should therefore be reduced in these patients.

Intrathecal anaesthesia can cause hypotension and bradycardia. The risk of such effects can be reduced, e.g., by injecting a vasopressor. If hypotension develops it should be treated promptly with a sympathomimetic intravenously, repeated as necessary. Severe hypotension may result from hypovolaemia due to haemorrhage or dehydration, or aorto-caval occlusion in patients with massive ascites, large abdominal tumours or late pregnancy. Marked hypotension should be avoided in patients with cardiac decompensation.

Patients with hypovolaemia due to any cause can develop sudden and severe hypotension during intrathecal anaesthesia.

Intrathecal anaesthesia can cause intercostal paralysis and patients with pleural effusions may suffer respiratory embarrassment. Septicaemia can increase the risk of intraspinal abscess formation in the postoperative period.

Neurological injury is a rare consequence of intrathecal anaesthesia and may result in paraesthesia, anaesthesia, motor weakness and paralysis. Occasionally these are permanent.

Before treatment is instituted, consideration should be taken if the benefits outweigh the possible risks for the patient.

Patients in poor general condition due to ageing or other compromising factors such as partial or complete heart conduction block, advanced liver or renal dysfunction require special attention, although regional anaesthesia may be the optimal choice for surgery in these patients.

Patients treated with anti-arrhythmic drugs class III (e.g. amiodarone) should be kept under close surveillance and ECG monitoring considered, since cardiac effects may be additive. (See section 4.5)

4.5 Interaction with other medicinal products and other forms of interaction

Bupivacaine should be used with caution in patients receiving other local anaesthetics or agents structurally related to amide-type local anaesthetics, e.g. certain anti-arrhythmics, such as lidocaine and mexiletine, since the systemic toxic effects are additive.

Specific interaction studies with bupivacaine and anti-arrhythmic drugs class III (e.g. amiodarone) have not been performed, but caution is advised (see also section 4.4).

4.6 Fertility, pregnancy and lactation

Pregnancy

There is no evidence of untoward effects in human pregnancy. In large doses, there is evidence of decreased pup survival in rats and an embryological effect in rabbits if bupivacaine is administered in pregnancy. Bupivacaine should not therefore be given in early pregnancy unless the benefits are considered to outweigh the risks.

It should be noted that the dose should be reduced in patients in the late stages of pregnancy, see section 4.4.

Breast-feeding

Bupivacaine enters the mother’s milk, but in such small quantities that there is generally no risk of affecting the child at therapeutic dose levels.

4.7 Effects on ability to drive and use machines

Bupivacaine injection has minor influence on the ability to drive and use machines. Besides the direct anaesthetic effect, local anaesthetics may have a very mild effect on mental function and co-ordination even in the absence of overt CNS toxicity and may temporarily impair locomotion and alertness.

4.8 Undesirable effects

Tabulated list of adverse reactions

The adverse reaction profile for Bupivacaine injection is similar to those for other long acting local anaesthetics used for intrathecal anaesthesia.

Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to<1/1,000), very rare (<1/10,000) or not known (cannot be estimated from the available data). Table of Adverse Drug Reactions

System Organ

Class

Frequency

Classification

Adverse Drug Reaction

Immune system

disorders

Rare Allergic reactions, anaphylactic shock

Nervous system

disorders

Common Postdural puncture headache

Uncommon Paraesthesia, paresis, dysaesthesia

Rare Total unintentional spinal block, paraplegia, paralysis, neuropathy, arachnoiditis Cardiac disorders Very Common Hypotension, bradycardia

Rare Cardiac arrest

Respiratory,

thoracic and

mediastinal

disorders

Rare Respiratory depression

Gastrointestinal

disorders

Very Common Nausea

Common Vomiting

Musculoskeletal

and connective

tissue disorders

Uncommon Muscle weakness, back pain

Renal and

urinary disorders

Common Urinary retention, urinary incontinence

Adverse reactions caused by the drug per se are difficult to distinguish from the physiological effects of the nerve block (e.g. decrease in blood pressure, bradycardia, temporary urinary retention), events caused directly (e.g. spinal haematoma) or indirectly (e.g. meningitis, epidural abcess) by needle puncture or events associated to cerebrospinal leakage (e.g. postdural puncture headache).

4.8.2 Acute systemic toxicity

Bupivacaine injection, used as recommended, is not likely to cause blood levels high enough to cause systemic toxicity. However, if other local anaesthetics are concomitantly administered, toxic effects are additive and may cause systemic toxic reactions.

Systemic toxicity is rarely associated with spinal anaesthesia but might occur after accidental intravascular injection. Systemic adverse reactions are characterised by numbness of the tongue, light-headedness, dizziness and tremors, followed by convulsions and cardiovascular disorders.

4.8.3 Treatment of acute systemic toxicity

No treatment is required for milder symptoms of systemic toxicity but if convulsions occur then it is important to ensure adequate oxygenation and to arrest the convulsions if they last more than 15–30 seconds. Oxygen should be given by face mask and the respiration assisted or controlled if necessary. Convulsions can be arrested by injection of thiopental 100–150 mg intravenously or with diazepam 5–10 mg intravenously. Alternatively, succinylcholine 50–100 mg intravenously may be given but only if the clinician has the ability to perform endotracheal intubation and to manage a totally paralysed patient.

High or total spinal blockade causing respiratory paralysis should be treated by ensuring and maintaining a patent airway and giving oxygen by assisted or controlled ventilation.

Hypotension should be treated by the use of vasopressors, e.g. ephedrine 10–15 mg intravenously and repeated until the desired level of arterial pressure is reached. Intravenous fluids, both electrolytes and colloids, given rapidly can also reverse hypotension.

Paediatric population

Adverse drug reactions in children are similar to those in adults, however, in children, early signs of local anaesthetic toxicity may be difficult to detect in cases where the block is given during sedation or general anaesthesia.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme. Website:

www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Bupivacaine injection, used as recommended, is not likely to cause blood levels high enough to cause systemic toxicity. However, if other local anaesthetics are concomitantly administered, toxic effects are additive and may cause systemic toxic reactions. (See section 4.8.2 and 4.8.3).

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group (ATC code): N01B B01

Bupivacaine is a long acting local anaesthetic agent of the amide type.

Moderate muscular relaxation of lower extremities.

Motor blockade of the abdominal muscles.

Bupivacaine injection is hyperbaric and its initial spread in the intrathecal space is affected by gravity.

5.2 Pharmacokinetic properties

Rapid onset of action and long duration i.e. T10–T12 segments – duration 2–3 hours.

Muscular relaxation of lower extremities lasts 2–2.5 hours.

Blockade of the abdominal muscles lasts 45–60 minutes. The duration of motor blockade does not exceed duration of analgesia.

In children the pharmacokinetics are similar to that in adults.

5.3 Preclinical safety data

Bupivacaine hydrochloride is a well established active ingredient.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Glucose anhydrous and/or glucose monohydrate

Sodium hydroxide

Water for injection

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Do not store above 25ºC.

6.5 Nature and contents of container

4 ml sterile wrapped glass ampoules or One Point Cut ampoules. Not all pack sizes may be marketed.

6.6 Special precautions for disposal

The solution should be used immediately after opening of the ampoule. Any remaining solution should be discarded. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Aspen Pharma Trading Limited,

3016 Lake Drive,

Citywest Business Campus,

Dublin 24, Ireland

8 MARKETING AUTHORISATION NUMBER(S)

PL 39699/0077

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

20/09/2004

10 DATE OF REVISION OF THE TEXT

30/08/2022