SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Hyperbaric Bupivacaine Hydrochloride Injection 0.5% W/V.

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml contains bupivacaine hydrochloride 5.28mg equivalent to anhydrous bupivacaine hydrochloride 5mg.

3. PHARMACEUTICAL FORM

Solution for Injection.

4.1    Therapeutic indications

Spinal anaesthesia in adults and children of all ages. Spinal anaesthesia for surgery (urological and lower limb surgery lasting 2-3 hours and abdominal surgery lasting 45-60 minutes).

4.2    Posology and method of administration

Route of administration: for injection into the spinal subarachnoid space.

The following recommended doses should be regarded as a guide for use in the average adult:

Spinal anaesthesia for surgery:

Adults only: 2 - 4ml (10 - 20mg bupivacaine hydrochloride anhydrous). Pregnant women: 2 - 2.5 ml (10 - 12.5mg bupivacaine hydrochloride anhydrous).

The spread of anaesthesia obtained with hyperbaric bupivacaine solution 0.5% w/v depends on several factors, including the volume administered and the position of the patient during and after the injection. When injected at the L3 -L4 intervertebral space with the patient in the sitting position, a dose of 3ml spreads to the T7 - T10 spinal segments. If the patient receives the injection in the horizontal position and is then turned supine, the blockade spreads to the T4 - T7 spinal segments. It should be noted that the level of spinal anaesthesia achieved with any local anaesthetic can be unpredictable in a given patient.

The effects of injecting volumes in excess of 4ml have not been studied and such volumes cannot, therefore, be recommended.

Paediatric population:

Neonates, infants and children up to 40kg

Hyperbaric Bupivacaine Hydrochloride Injection 0.5% W/V 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 anaesthetic procedures should be performed by qualified clinicians who are familiar with this population and the technique.

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.

Table: Dosage recommendations in neonates, infants and children

Body weight (kg)	Dose (mg/kg)
<5	0.40-0.50 mg/kg
5 to 15	0.30-0.40 mg/kg
15 to 40	0.26-0.30 mg/kg

4.3 Contraindications

Known hypersensitivity to local anaesthetics of the amide type.

Injection into inflamed or infected areas.

Spinal anaesthesia, regardless of the local anaesthetic used, has its

Own contra-indications 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.

•    Tuberculosis of the spine.

•    Pyogenic infection of the skin at or adjacent to the site of lumbar puncture.

•    Cardiogenic or hypovolaemic shock.

•    Coagulation disorders or ongoing anticoagulation therapy.

4.4 Special warnings and precautions for use

There have been reports of cardiac arrest during the use of bupivacaine for epidural anaesthesia or peripheral nerve blockade where resuscitative efforts have been difficult, and were required to be prolonged before the patient responded. However, in some instances resuscitation has proven impossible despite apparently adequate preparation and appropriate management.

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.

Adequate resuscitation equipment should be available whenever local or general anaesthesia is administered. The clinician responsible should take the necessary precautions to avoid intravascular injection (see 4.2).

Before any nerve block is attempted, intravenous access for resuscitation purposes should be established. Clinicians 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 4.9 & 4.8).

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 bupivacaine hydrochloride may cause significant increases in blood levels with each repeated dose due to slow accumulation of the drug. Tolerance varies with the status of the patient.

Although regional anaesthesia is frequently the optimal anaesthetic technique, some patients require special attention in order to reduce the risk of dangerous side effects:

•    The elderly and patients in poor general condition should be given reduced doses 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

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

Only in rare cases have amide local anaesthetics been associated with allergic reactions (with anaphylactic shock developing in most severe instances).

Patients allergic to ester-type local anaesthetics drugs ( procaine , tetracaine, benzocaine, etc) have not shown cross-sensitivity to agents of the amide-type such as bupivacaine.

Certain local anaesthetic procedures may be associated with serious adverse reactions, regardless of the local anaesthetic drug used.

•    Local anaesthetics 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 A-V conduction produced by these drugs.

•    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 very rarely reach the cranial subarachnoid space causing temporary blindness, cardiovascular collapse, apnoea, convulsions etc.

•    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.

•    Paracervical block may have a greater adverse effect on the foetus, than other nerve blocks used in obstetrics. Due to the systemic toxicity of bupivacaine, special care should be taken when using bupivacaine for paracervical block.

•    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 Bupivacaine.

Local anaesthetics should be used with caution for epidural or spinal anaesthesia in the following situations: marked obesity, senility, cerebral atheroma, myocardial degeneration and toxaemia.

Epidural and spinal anaesthesia with any local anaesthetic can cause hypotension and bradycardia which should be anticipated and appropriate precautions taken. These may include preloading the circulation with crystalloid or colloid solution. If hypotension develops it should be treated with a vasopressor such as ephedrine 10-15mg 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.

Epidural 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.

When bupivacaine is administered as intra-articular injection, caution is advised when recent major intra-articular trauma is suspected or extensive raw surfaces within the joint have been created by the surgical procedure, as that may accelerate absorption and result in higher plasma concentrations.

Epidural and spinal anaesthesia, properly performed, is generally well tolerated by obese patients and by those with obstructive lung disease. However, patients with a splinted diaphragm which interferes with breathing, such as those with hydramnios, large ovarian or uterine tumours, pregnancy, ascites or omental obesity are at risk from hypoxia due to respiratory inadequacy and aortocaval compression due to tumour mass. Lateral tilt, oxygen and mechanical ventilation should be used when indicated. Dosage should be reduced in such patients.

Paediatric population:

For Epidural anaesthesia children should be given incremental doses commensurate with their age and weight as especially epidural anaesthesia at a thoracic level may result in severe hypotension and respiratory impairment.

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 should be advised (see also section 4.4).

4.6 Pregnancy and lactation

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.

Foetal adverse effects due to local anaesthetics, such as foetal bradycardia, seem to be most apparent in paracervical block anaesthesia. Such effects may be due to high concentrations of anaesthetic reaching the foetus (see also Section 4.4).

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

4.7 Effects on ability to drive and use machines

Following spinal anaesthesia, sufficient time should be allowed for the return of full functions before driving or using machines

Depending on dosage, 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

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

The adverse reaction profile for Bupivacaine hydrochloride is similar to those for other long acting local anaesthetics. 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), events caused directly (e.g., nerve trauma) or indirectly (e.g., epidural abscess) by needle puncture.

Neurological damage is a rare but well recognised consequence of regional and particularly epidural and spinal anaesthesia. It may be due to several causes, e.g. direct injury to the spinal cord or spinal nerves, anterior spinal artery syndrome, injection of an irritant substance, or an injection of a nonsterile solution. These may result in localised areas of paraesthesia or anaesthesia, motor weakness, loss of sphincter control and paraplegia. Occasionally these are permanent.

The adverse reactions considered at least possibly related to treatment with Bupivacaine hydrochloride from clinical trials with related products and postmarketing experience are listed below by body system organ class and absolute frequency. Frequencies are defined as very common ( 1/10), common ( 1/100, < 1/10), uncommon ( 1/1,000, < 1/100), rare ( 1/10,000, < 1/1,000) or not known (identified through post-marketing safety surveillance and the frequency cannot be estimated from the available data).

Table of Adverse Drug Reactions (ADR)

System Organ Class	Frequency Classification	Adverse Drug Reaction
Immune system disorders	Rare	Allergic reactions, anaphylactic reaction/shock (see section 4.4)
Nervous system disorders	Common	paraesthesia, dizziness Following epidural injection of some local anaesthetic agents including bupivacaine, high sympathetic blockade may occasionally result in ocular and other symptoms similar to those seen in Horner’s syndrome. These effects are encountered more commonly in pregnant women.
	Uncommon	Signs and symptoms of CNS toxicity (convulsions, circumoral paraesthesia, numbness of the tongue, hyperacusis, visual disturbances, loss of consciousness, tremor, light headedness, tinnitus, dysarthria, muscle twitching)
	Rare	Neuropathy, peripheral nerve injury, arachnoiditis, paresis and paraplegia
Eye disorders	Rare	Diplopia
Cardiac disorders	Common	Bradycardia (see section 4.4)
	Rare	Cardiac arrest (see section 4.4), cardiac arrhythmias
Vascular disorders	Very Common	Hypotension (see section 4.4)

System Organ Class	Frequency Classification	Adverse Drug Reaction
	Common	Hypertension (see section 4.5)
Respiratory disorders	Rare	Respiratory depression
Gastrointestinal disorders	Very Common	Nausea
	Common	Vomiting
Renal and Urinary	Common	Urinary retention

Hepatic dysfunction, with reversible increases of SGOT, SGPT, alkaline phosphates and bilirubin, has been observed following repeated injections or long-term infusions of bupivacaine. If signs of hepatic dysfunction are observed during treatment with bupivacaine, the drug should be discontinued.

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.

4.8.1 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 drug, both quantitatively and qualitatively.

Central nervous system toxicity is a graded response with symptoms and signs of escalating severity. The first symptoms are usually light-headedness, circumoral paraesthesia, numbness of the tongue, 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 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 subsequent metabolism and excretion. Recovery may be rapid unless large amounts of the drug 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, arrhythmia 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.

4.8.2 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 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.

If cardiovascular depression occurs (hypotension, bradycardia) appropriate treatment with intravenous fluids, vasopressor, and or inotropic agents should be considered. Children should be given doses commensurate with age and weight.

4.9 Overdose

Accidental intravascular injections of local anaesthetics may cause immediate (within seconds to a few minutes) systemic toxic reactions. In the event of overdose, systemic toxicity appears later (15-60 minutes after injection) due to the slower increase in local anaesthetic blood concentration. (See sections 4.8.1 & 4.8.2).

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group (ATC code): N01B B51

Bupivacaine is a long-acting local anaesthetic of the amide type. As with other local anaesthetic agents, bupivacaine acts by preventing the generation and conduction of nerve impulses.

Hyperbaric bupivacaine solution 0.5% w/v produces a moderate muscular relaxation of the lower extremities lasting 2 - 2.5 hours. The motor blockade of abdominal muscles makes the solution suitable for performance of abdominal surgery lasting 45 - 60 minutes. The duration of motor blockade does not exceed the duration of analgesia.

At high doses it produces surgical anaesthesia, while at lower doses it produces sensory block (analgesia) with less pronounced motor block. Cardiovascular effects of bupivacaine 5mg/ml with dextrose 80mg/ml are similar or less than those seen with other spinal agents and the solution has been shown to be well tolerated by all tissues with which it comes in contact.

Following absorption, bupivacaine may cause stimulation of the C.N.S followed by depression and, in the cardiovascular system; it acts primarily on the myocardium where it may decrease electrical excitability, conduction rate, force of contraction and eventually cardiac arrest.

5.2    Pharmacokinetic properties

Like other local anaesthetics, the rate of systemic absorption of bupivacaine is dependent upon the total dose and concentration of drug administered, the route of administration and vascularity of the tissue locally. Hyperbaric bupivacaine solution 0.5% w/v has a rapid onset of action and long duration. In the T10 - T12 segments, the duration of analgesia is 2-3 hours.

Following absorption, bupivacaine is distributed to some extent to all body tissues, with higher concentrations found in highly perfused organs such as the liver, lungs, heart and brain. The drug is about 95% bound to plasma proteins. Only the free, unbound drug is available for placental transfer and foetal concentrations of bupivacaine are lower than maternal concentrations. In children the pharmacokinetics is similar to that in adults.

Bupivacaine is metabolised in the liver and is excreted in the urine principally as metabolites with only 5 to 6% as unchanged drug.

In adults, the terminal half-life of Bupivacaine is 2.7 hours. The maximum blood concentration varies with the site of injection

5.3    Preclinical safety data

No further relevant information other than that which is included in other parts of the summary of product characteristics.

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Dextrose monohydrate Sodium hydroxide Water for injections

6.2 Incompatibilities

Hyperbaric bupivacaine hydrochloride injection should not be mixed with other drugs. The solution must not be stored in contact with metals e.g. needles or metal parts of syringes as dissolved metals ions cause swelling at the site of injection.

6.3 Shelf life

3 Years.

6.4 Special precautions for storage

Do not store above 25°C.

Keep the container in the outer carton.

6.5 Nature and contents of container

Translucent plastic ampoules made from polypropylene Ph.Eur packed in cardboard cartons to contain 5, 10 or 20 ampoules. Translucent plastic ampoules made from polypropylene Ph.Eur packed in individual thermoformed sterile polypropylene lidded trays, which are then packed in cardboard cartons to contain 5 or 10 ampoules.

6.6 Instructions for use/handling

Use as directed by the physician.

Keep out of reach of children.

If only part used, discard the remaining solution.

MARKETING AUTHORISATION HOLDER

Mercury Pharma International Ltd 4045, Kingswood Road,

City West Business Park,

Co Dublin, Ireland

8. MARKETING AUTHORISATION NUMBER

PL 02848/0201.

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

07/04/2005

10 DATE OF REVISION OF THE TEXT

27/02/2014