BUPICAN Solution for injection Ref.[50440] Active ingredients: Bupivacaine

DURING LOCAL ANAESTHESIA RESUSCITATIVE MEDICINES AND EQUIPMENT MUST BE PRESENT AT ALL TIMES.

Before any nerve block is attempted, intravenous access for resuscitation purposes should be established. Medical practitioners should have received adequate and appropriate training in the procedure to be performed and should be familiar with the diagnosis and treatment of side effects, systemic toxicity or other complications (see section 4.9).

Paracervical block with amide-type local anaesthetics, such as BUPICAN, during labour often precedes fetal bradycardia and may be associated with fetal acidosis. The risk increases with premature birth, toxaemia of pregnancy, and fetal l distress. Paracervical block using BUPICAN is not recommended.

There have been reports of cardiac arrest during the use of bupivacaine, as in BUPICAN, for epidural anaesthesia or peripheral nerve blockade where resuscitative efforts have been difficult, and were required to be prolonged before the patient responded.

BUPICAN may cause acute toxicity effects on the central nervous and cardiovascular systems if utilised for local anaesthetic procedures resulting in high blood concentrations of bupivacaine. This is especially the case after unintentional intravascular administration. Ventricular dysrhythmia, ventricular fibrillation, sudden cardiovascular collapse and death have been reported in connection with high systemic concentrations of bupivacaine.

Major peripheral nerve blocks may require the administration of a large volume of local anaesthetic in areas of high vascularity, often close to large vessels where there is an increased risk of intravascular injection and/or systemic absorption. This may lead to high plasma concentrations.

Overdosage or accidental intravenous injection may give rise to toxic reactions.

Injection of repeated doses of BUPICAN may cause significant increases in blood levels with each repeated dose due to accumulation of bupivacaine. Tolerance varies with the status of the patient.

Patients at risk and risks associated with certain anaesthesia techniques:

• Debilitated, elderly or acutely ill patients should be given reduced doses to commensurate with their physical status.
• Patients with partial or complete heart block – due to the fact that local anaesthetics may depress myocardial conduction.
• Patients with advanced liver disease or severe renal dysfunction.
• Patients in the late stages of pregnancy.
• Caution is advised for co-administration of BUPICAN and anti-dysrhythmic medicines class III, e.g. amiodarone (see section 4.5).
• Patients allergic to ester-type local anaesthetic medicines (procaine, tetracaine, benzocaine, etc.) have not shown cross-sensitivity to agents of the amide-type such as bupivacaine.
• Local anaesthetics such as BUPICAN should be used with caution for epidural anaesthesia in patients with impaired cardiovascular function since they may be less able to compensate for functional changes associated with the prolongation of AV conduction produced by these medicines.
• The physiological effects generated by a central neural blockade are more pronounced in the presence of hypotension. Patients with hypovolaemia due to any cause can develop sudden and severe hypotension during epidural anaesthesia. Epidural anaesthesia should therefore be avoided or used with caution in patients with untreated hypovolaemia or significantly impaired venous return.
• Retrobulbar injections may reach the cranial subarachnoid space causing serious/severe reactions, including temporary blindness, cardiovascular collapse, apnoea and convulsions.
• 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 and/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.
• Small doses of local anaesthetics injected into the head and neck, including retrobulbar, dental and stellate ganglion blocks, may produce systemic toxicity due to inadvertent intra-arterial injection.
• There have been post-marketing reports of chondrolysis in patients receiving post-operative intra-articular continuous infusion of local anaesthetics. The majority of reported cases of chondrolysis have involved the shoulder joint. Due to multiple contributing factors and inconsistency in the scientific literature regarding mechanism of action, causality has not been established. Intra-articular continuous infusion is not an approved indication for BUPICAN.

Epidural anaesthesia can cause intercostal paralysis and patients with pleural effusions may suffer respiratory distress.

Epidural anaesthesia with BUPICAN can cause hypotension and bradycardia which should be anticipated and appropriate precautions taken. These may include pre-loading the circulation with crystalloid or colloid solution. If hypotension develops it should be treated with a suitable vasopressor intravenously. 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 epidural anaesthesia.

The physiological effects generated by a central neural blockade are more pronounced in the presence of hypotension. Patients with hypovolaemia due to any cause can develop sudden and severe hypotension during epidural anaesthesia. Epidural anaesthesia should therefore be avoided or used with caution in patients with untreated hypovolaemia or significantly impaired venous return.

When administering repeat doses of BUPICAN, precaution should be taken with patients with severe liver disease (see section 5.2). If signs of hepatic dysfunction are observed during the treatment with BUPICAN, the medicine should be discontinued.

Septicaemia can increase the risk of intraspinal abscess formation in the post-operative period (see section 4.3).

Information on excipients of BUPICAN

BUPICAN contains 31,5 mg sodium per vial, equivalent to 1,6 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

BUPICAN should be used with caution in patients receiving other local anaesthetics or medicines structurally related to amide-type local anaesthetics, e.g. certain antidysrhythmics, such as lidocaine (lignocaine), since systemic toxic effects are additive (see section 4.2).

Specific interaction studies with bupivacaine and antidysrhythmic medicines class III (e.g. amiodarone) have not been performed, but caution should be advised (see also section 4.4).

Propranolol may reduce the clearance of BUPICAN. There is a risk of increased bupivacaine toxicity when these medicines are used concomitantly.

There is a possible risk that the adverse effects of BUPICAN on the heart may be enhanced in patients taking calcium-channel blockers.

Interactions between BUPICAN and histamine H₂-antagonists, such as cimetidine and ranitidine, resulted in a decreased clearance of bupivacaine and an increased plasma concentration, respectively, but had no significant clinical effects.

Safe use in pregnancy and lactation, other than for use in labour, has not yet been established (see section 4.5).

Bupivacaine, the active ingredient of BUPICAN, is distributed into breast milk.

Besides the direct anaesthetic effect on sensory and motive functioning, BUPICAN may have an effect on mental function and co-ordination even in the absence of overt CNS toxicity, and may temporarily impair locomotion and alertness.

Immune system disorders

Less frequent: Allergic reactions, anaphylactic reaction/shock.

Psychiatric disorders

Less frequent: Excitation, depression, nervousness.

Nervous system disorders

Frequent: Paraesthesia, dizziness.

Less frequent: Convulsions, circumoral paraesthesia, numbness of the tongue, hyperacusis, visual disturbances, loss of consciousness, tremors, light-headedness, dysarthria, muscle twitching, chills, fever, drowsiness, neurological damage, neuropathy, peripheral nerve injury, arachnoiditis, paresis and paraplegia.

Eye disorders

Less frequent: Constriction of the pupils, diplopia, blurred vision.

Ear and labyrinth disorders

Less frequent: Tinnitus.

Cardiac disorders

Frequent: Bradycardia.

Less frequent:Myocardial depression, cardiac arrest, oedema, ventricular dysrhythmias.

Vascular disorders

Frequent: Changes in blood pressure (usually hypotension), hypertension.

Respiratory, thoracic and mediastinal disorders

Less frequent:Respiratory depression.

Gastrointestinal disorders

Frequent: Nausea, vomiting.

Hepato-biliary disorders

Less frequent: Hepatic dysfunction, with reversible increase of liver enzymes and bilirubin.

Skin and subcutaneous tissue disorders

Less frequent:Pruritus, urticaria, skin rash.

Renal and urinary disorders

Frequent: Urinary retention.

General disorders and administration site conditions

Less frequent:Skin or intravenous reaction may occur at the site of injection if the patient shows sensitivity to BUPICAN.

Accidental sub-arachnoid injection can lead to very high spinal anaesthesia possibly with apnoea and severe hypotension.

Acute systemic toxicity

Systemic toxic reactions primarily involve the central nervous system (CNS) and the cardiovascular system. Such reactions are caused by high blood concentrations of a local anaesthetic, which may appear due to (accidental) intravascular injection, overdose or exceptionally rapid absorption from highly vascularised areas (see section 4.4). CNS reactions are similar for all amide local anaesthetics, while cardiac reactions are more dependent on the medicinal product, both quantitatively and qualitatively.

Central nervous system toxicity is a graded response with symptoms and signs of escalating severity. The first symptoms are usually circumoral paraesthesia, numbness of the tongue, lightheadedness, hyperacusis, tinnitus and visual disturbances. Dysarthria, muscular twitching or 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, which may last from a few seconds to several minutes. Hypoxia and hypercarbia occur rapidly following convulsions due to the increased muscular activity, together with the interference with respiration and possible loss of functional airways. 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 medicinal product from the central nervous system and subsequent metabolism and excretion. Recovery may be rapid unless large amounts of the medicinal product have been injected.

Cardiovascular system toxicity may be seen in severe cases and is generally preceded by signs of toxicity in the central nervous system. In patients under heavy sedation or receiving a general anaesthetic, prodromal CNS symptoms may be absent. Hypotension, bradycardia, dysrhythmia and even cardiac arrest may occur as a result of high systemic concentrations of local anaesthetics, but in rare cases cardiac arrest has occurred without prodromal CNS effects.

Treatment of acute toxicity

If signs of acute systemic toxicity appear, injection of the local anaesthetic should be immediately stopped.

Treatment of a patient with systemic toxicity consists of arresting convulsions and ensuring adequate ventilation with oxygen, if necessary by assisted or controlled ventilation (respiration).

Once convulsions have been controlled and adequate ventilation of the lungs ensured, no other treatment is generally required.

If cardiovascular depression occurs (hypotension, bradycardia) appropriate treatment with intravenous fluids, vasopressor, inotropic agents and/or lipid emulsion should be considered. If circulatory arrest should occur, immediate cardiopulmonary resuscitation should be instituted. Optimal oxygenation and ventilation and circulatory support as well as treatment of acidosis are of vital importance.

Cardiac arrest due to bupivacaine can be resistant to electrical defibrillation and resuscitation must be continued energetically for a prolonged period.

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of BUPICAN is important. It allows continued monitoring of the benefit/risk balance of BUPICAN. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the “Adverse Drug Reactions Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8.

BUPICAN should not be mixed with other medicines.