BETOLINA® is used for the production of prolonged local anaesthesia by percutaneous
infiltration, Peripheral nerve block(s) and central neural block (caudal or epidural), Bupivacaine Hydrochloride is also indicated for the relief of labour pain.
BETOLINA® is indicated for:
• Surgical anaesthesia in adults and children above 12 years of age.
• Acute pain management in adults, infants and children above 1 year of age.

Adults and children above 12 years of age
The following table is a guide to dosage for the more commonly used techniques 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.
N.B. 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.
The clinician's experience and knowledge of the patient's physical status is important in calculating the required dose.
The lowest dose required for adequate anaesthesia should be used. Individual variations in onset and duration occur

 

Dosage recommendations for adults

Remarks
I) Dose includes test dose -
2) The dose or a major nerve block must be adjusted according to site of administration and patient status. Interscalene and supraclavicular brachial plexus blocks may be associated with a higher frequency of serious adverse reactions, regardless of the local anaesthetic used (see section Special Warnings and precautions for use).
3) In total <400 mg/24 h.
4) This solution is often used for epidural administration in combination with a suitable opioid for pain management. In total <400 mg/24h.
5) If additional bupivacaine is used by any other techniques in the same patient, an overall dose limit of 150 mg should not be exceeded.
6) There have been post-marketing reports of chondrolysis in patients receiving post-operative intraarticular continuous infusion of local anaesthetics. Bupivacaine solution for injection is not approved for this indication (See section 4.4).
7) Bupivacaine without adrenaline.

In general, surgical anaesthesia (e.g. epidural administration) requires the use of higher
concentrations and doses.

When a less intense block is required (e.g. in the relief of labour pain), the use of a lower concentration is indicated.

The volume of drug used will affect the extent of spread of anaesthesia.

In order to avoid intravascular injection, aspiration should be repeated prior to and during administration of the main dose, which should be injected slowly or in incremental doses, at a rate of 25-50 mg/min, while closely observing the patient's vital functions and maintaining verbal contact.
An inadvertent intravascular injection may be recognised by a temporary increase in heart rate and an accidental intrathecal injection by signs of a spinal block. If toxic symptoms occur, the injection should be stopped immediately (See section 4.8.1).
Experience to date indicates that 400 mg administered over 24 hours is well tolerated in the average adult.

Paediatric patients 1 to 12 years of age
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 paediatrics. Individual variations occur. In children with a high body weight a gradual reduction of the dosage is often necessary and should be based on the ideal body weight. Standard textbooks should be consulted for factors affecting specific block techniques and for individual patient requirements.
The lowest dose required for adequate analgesia should be used.

Dosage recommendations for children 1 to 12 years of agea) The onset and duration of peripheral nerve blocks depend on the type of block and the dose
administered.
b) Thoracic epidural blocks need to be given by incremental dosage until the desired level of anaesthesia is achieved.
In children, the dosage should be calculated on a weight basis up to 2 mg/kg.
In order to avoid intravascular injection, aspiration should be repeated prior to and during administration of the maindose. This should be injected slowly in incremental doses, particularly in the lumbar and thoracic epidural routes, constantly and closely observing the patient's vital functions.

Peritonsillar infiltration has been performed in children above 2 years of age with bupivacaine 2.5 mg/ml at a dose of 7.5-12.5mg per tonsil.
Ilioinguinal-iliohypogastric blocks have been performed in children aged 1 year or older with bupivacaine 2.5 mg/ml at a dose of 0.1-0.5 ml/kg equivalent to 0.25-1.25 mg/kg. Children aged 5 years or older have received bupivacaine 5 mg/ml at a dose of 1.25-2 mg/kg.

For penile blocks bupivacaine 5 mg/ml has been used at total doses of 0.2-0.5 ml/kg equivalent to 1-
2.5 mg/kg.
The safety and efficacy of bupivacaine with and without adrenaline in children < 1 year of age have not been established. Only limited data are available. Safety and efficacy of intermittent epidural bolus injection or continuous infusion have not been established. Only limited data is available.

- Hypersensitivity to the active substance or to local anaesthetic medicinal products of the amide type or to any of the excipients listed in section 6.1. - Intravenous regional anaesthesia (Bier's-block) - Obstetrical paracervical block. - injection of adrenaline containing bupivacaine in areas of end arteries (e.g. penile block, Oberst block) may cause ischemic tissue necrosis Epidural anaesthesia, regardless of the local anaesthetic used, has its own contra-indications which include: - active diseases of the Central Nervous System such as meningitis, poliomyelitis and intracranic hemorrhage, subacute 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 treatment.

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. 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 section 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 section 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 medicinal products class III (e.g. amiodarone) should be under close surveillance and ECG monitoring, since cardiac effects may be additive.
Patients allergic to ester-type local anaesthetic medicinal products (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 medicinal products.
• 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.
• 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 intraarticular 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 solution for injection.
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 anaesthesia with any local anaesthetic 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 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.

Pediatric population:
The safety and efficacy of Bupivacaine hydrochloride in children < 1 year of age have not been established. Only limited data are available.
The use of bupivacaine for intra-articular block in children 1 to 12 years of age has not been documented.
The use of bupivacaine for major nerve block in children 1 to 12 years of age has not been documented

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.

Each ml of Bupivacaine 5 mg/ml solution for injection contains approximately 0.14 mmol (3.19 mg) of sodium. To be taken into consideration by patients on a controlled sodium diet.

 

Bupivacaine should be used with caution in patients receiving other local anaesthetfcs or agents structurally related to amide-type local anaesthetics, e.g. certain anti-arrhythmics, such as lidocaine and mexiletin since the systemic toxic effects are additive. Specific interaction studies with bupivacaine and anti-arrhythmic drugs class Ill (e.g. amiodarone) have not been performed, but caution should be advised.

 

Pregnancy:
There are limited amount of data from the use of bupivacaine in human pregnancy. Animal studies have shown decreased pup survival and embryotoxic effects (see section 5.3). Bupivacaine injection should therefore not be given in pregnancy unless the benefits are considered to outweigh the risks.
Bupivacaine solutions are contraindicated for use in paracervical block in obstetrics, because foetal bradycardia may occur following paracervical block (see section 4.3).

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

Bupivacaine 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 coordination even in the absence of overt CNS toxicity, and may temporarily impair locomotion and alertness.

 

General
The adverse reaction profile for Betolina 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 the needle puncture.

Table of Adverse Drug Reactions
Very Common (>1/10):
Vascular disorders: hypotension
Gastrointestinal disorders: nausea
Common (> 1/100<1/10):
Nervous system disorders: paraesthesia, dizziness
Cardiac disorders: bradycardia
Vascular disorders: hypertension
Gastrointestinal disorders: vomiting
Renal and urinary disorders: urinary retention
Uncommon (>1/1,000<1/100):
Nervous system disorders: Signs and symptoms of CNS toxicity (convulsions, paraesthesia circumoral, numbness of the tongue, hyperacusis, visual disturbances, loss of consciousness, tremor light headedness, tinnitus, dysarthria)
Rare (<1/1,000):
Immune system disorders: Allergic reactions, anaphylactic reaction/shock
Nervous system disorders: Neuropathy, peripheral nerve injury, arachnoiditis, paresis and paraplegia Eye
disorders: Diplopia
Cardiac disorders: Cardiac arrest, cardiac arrhythmias
Respiratory disorders: Respiratory depression

To reports any side effect(s):

The National Pharmacovigilance and Drug Safety Centre (NPC) :
• Fax: +966-11-205-7662
• Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
• Toll free phone: 8002490000
• E-mail: npc.drug@sfda.gov.sa
 Website: www.sfda.gov.sa/npc

 

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.

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).

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, circumoral paraesthesia, numbness of the tongue, light-headedness, 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.

In children, early signs of local anaesthetic toxicity may be difficult to detect in cases where the block is given during general anaesthesia.

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). If convulsions occur, they must be treated promptly by intravenous injection of thiopental 100-200 mg or diazepam 5-10 mg.

Prolonged convulsions may jeopardise the patient's ventilation and oxygenation. If so, injection of a muscle relaxant (e.g. succinylcholine 1 mg/kg bw) will facilitate ventilation, and oxygenation can be controlled. Early endotracheal intubation must be considered in such situations.

Once convulsions have been controlled and adequate ventilation of the lungs ensured, no other treatment is generally required. If hypotension is present, however, a vasopressor, preferably one with inotropic activity, e.g. ephedrine 15-30 mg, should be given intravenously.

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.
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.

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

 

ATC code: N01BB01

Mechanism of action
Bupivacaine is a long acting, amide-type local anaesthetic with both anaesthetic and analgesic effects. At high doses it produces surgical anaesthesia, while at lower doses it produces sensory block (analgesia) with less pronounced motor block. Onset and duration of the local anaesthetic effect of bupivacaine depend on the dose and site of administration.
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 cell membrane of the nerve fibres. The sodium channel of the nerve membrane is considered a receptor for local anaesthetic molecules.
Local anaesthetics may have similar effects on other excitable membranes e.g. in the brain and myocardium. It excessive amounts of drug reach the systemic circulation, symptoms and signs of toxicity may appear, emanating from the central nervous and cardiovascular systems.
Central nervous system toxicity usually precedes the cardiovascular effects as central nervous system toxicity 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 (hypotension, bradycardia) may occur after epidural administration depending on the extent of the concomitant sympathetic block.

Absorption
Bupivacaine has a pKa of 8.2 and a partition coefficient of 346 (25°C n-octanol/ phosphate buffer pH
7.4). The metabolites have a pharmacological activity that is less than that of bupivacaine.
The plasma concentration of bupivacaine depends upon the dose, the route of administration and the
vascularity of the injection site.
Bupivacaine shows complete and biphasic absorption from the epidural space with half-lives in the
order of 7 min and 6 h respectively. The slow absorption is rate-limiting in the elimination of
bupivacaine, which explains why the
apparent half-life after epidural administration is longer than that after intravenous administration.
Distribution and Elimination Bupivacaine has a total plasma clearance of 0.58 l/min, a volume of
distribution at steady state of 73 l, a terminal half-life of 2.7 h and an intermediate hepatic extraction
ratio of 0.38 after IV administration. It is mainly bound to alpha-lacid glycoprotein with plasma
binding of 96%. Clearance of bupivacaine is almost entirely due to liver metabolism and
more sensitive to changes in intrinsic hepatic enzyme function that to liver perfusion.
Pediatric population
In children the pharmacokinetics are similar to that in adults.

An increase in total plasma concentration has been observed during continuous epidural infusion.
This is related to a postoperative increase in alpha 1-acid glycoprotein. The unbound, i.e.
pharmacologically active, concentration is similar before and after surgery.
Bupivacaine readily crosses the placenta and equilibrium with regard to the unbound concentration is
rapidly reached.
The degree of plasma protein binding in the foetus is less than in the mother, which results in lower
total plasma concentrations in the foetus.
Bupivacaine is extensively metabolised in the liver, predominately by aromatic hydroxylation to 4-
hydroxy-bupivacaine and N-dealkylation to PPX, both mediated by cytochrome P4503A4. About 1%
of bupivacaine is excreted in the urine as unchanged drug in 24 h and approximately 5% as PPX. The
plasma concentrations of PPX and 4-hydroxybupivacaine during and after continuous administration
of bupivacaine are low as compared to the parent drug

Based on conventional studies of safety pharmacology, acute and subchronic toxicity, non-clinical
data reveal no special hazard other than those already reported elsewhere in this document.
The mutagenic and carcinogenic potential of bupivacaine has not been determined.
Bupivacaine crosses the placenta. In reproduction toxicity studies, decreased survival of the offspring
of rats and embryolethality in rabbits was observed at bupivacaine doses which were five- or ninefold
the maximum recommended daily dose in humans. A study in rhesus monkeys suggested altered
postnatal behaviour following exposition to bupivacaine at birth.

 

 

Sodium chloride, Sodium hydroxide, Water for injections.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

2 years

Do not store above 30°C. Do not freeze & avoid excessive heat.

Vial 20ml with Rubber stopper 20 mm

For single use only.
Only clear solutions practically free from particles should be used. Any unused solution should be discarded.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.