CHIROCAINE Solution for injection Ref.[9273] Active ingredients: Levobupivacaine

All forms of local and regional anaesthesia with levobupivacaine should be performed in well-equipped facilities and administered by staff trained and experienced in the required anaesthetic techniques and able to diagnose and treat any unwanted adverse effects that may occur.

Levobupivacaine can cause acute allergic reactions, cardiovascular effects and neurological damage (see section 4.8).

Levobupivacaine should be used with caution for regional anaesthesia in patients with impaired cardiovascular function e.g. serious cardiac arrhythmias (see section 4.3).

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 levobupivacaine.

The introduction of local anaesthetics via either intrathecal or epidural administration into the central nervous system in patients with preexisting CNS diseases may potentially exacerbate some of these disease states. Therefore, clinical judgment should be exercised when contemplating epidural or intrathecal anaesthesia in such patients.

Epidural Anaesthesia

During epidural administration of levobupivacaine, concentrated solutions (0.5-0.75%) should be administered in incremental doses of 3 to 5 ml with sufficient time between doses to detect toxic manifestations of unintentional intravascular or intrathecal injection. Cases of severe bradycardia, hypotension and respiratory compromise with cardiac arrest (some of them fatal); have been reported in conjunction with local anaesthetics, including levobupivacaine. When a large dose is to be injected, e.g. in epidural block, a test dose of 3-5 ml lidocaine with adrenaline is recommended. An inadvertent intravascular injection may then be recognised by a temporary increase in heart rate and accidental intrathecal injection by signs of a spinal block.

Syringe aspirations should also be performed before and during each supplemental injection in continuous (intermittent) catheter techniques. An intravascular injection is still possible even if aspirations for blood are negative. During the administration of epidural anaesthesia, it is recommended that a test dose be administered initially and the effects monitored before the full dose is given.

Epidural anaesthesia with any local anaesthetic may cause hypotension and bradycardia. All patients must have intravenous access established. The availability of appropriate fluids, vasopressors, anaesthetics with anticonvulsant properties, myorelaxants, and atropine, resuscitation equipment and expertise must be ensured (see section 4.9).

Epidural Analgesia

There have been post-marketing reports of cauda equina syndrome and events indicative of neurotoxicity (see section 4.8) temporally associated with the use of levobupivacaine for 24 hours or more for epidural analgesia. These events were more severe and in some cases led to permanent sequelae when levobupivacaine was administered for more than 24 hours. Therefore, infusion of levobupivacaine for a period exceeding 24 hours should be considered carefully and only be used when benefit to the patient outweighs the risk.

It is essential that aspiration for blood or cerebrospinal fluid (where applicable) be done prior to injecting any local anaesthetic, both before the original dose and all subsequent doses, to avoid intravascular or intrathecal injection. However, a negative aspiration does not ensure against intravascular or intrathecal injection. Levobupivacaine should be used with caution in patients receiving other local anaesthetics or agents structurally related to amide-type local anaesthetics, since the toxic effects of these drugs are additive.

Major regional nerve blocks

The patient should have I.V. fluids running via an indwelling catheter to assure a functioning intravenous pathway. The lowest dosage of local anaesthetic that results in effective anaesthesia should be used to avoid high plasma levels and serious adverse effects. The rapid injection of a large volume of local anaesthetic solution should be avoided and fractional (incremental) doses should be used when feasible.

Use in Head and Neck Area

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. The injection procedures require the utmost care. Reactions may be due to intraarterial injection of the local anaesthetic with retrograde flow to the cerebral circulation. They may also be due to puncture of the dural sheath of the optic nerve during retrobulbar block with diffusion of any local anaesthetic along the subdural space to the midbrain. Patients receiving these blocks should have their circulation and respiration monitored and be constantly observed. Resuscitative equipment and personnel for treating adverse reactions should be immediately available.

Use in Ophthalmic Surgery

Clinicians who perform retrobulbar blocks should be aware that there have been reports of respiratory arrest following local anaesthetic injection. Prior to retrobulbar block, as with all other regional procedures, the immediate availability of equipment, drugs, and personnel to manage respiratory arrest or depression, convulsions, and cardiac stimulation or depression should be assured. As with other anaesthetic procedures, patients should be constantly monitored following ophthalmic blocks for signs of these adverse reactions.

Special populations

Debilitated, elderly or acutely ill patients: levobupivacaine should be used with caution in debilitated, elderly or acutely ill patients (see section 4.2).

Hepatic impairment: since levobupivacaine is metabolised in the liver, it should be used cautiously in patients with liver disease or with reduced liver blood flow e.g. alcoholics or cirrhotics (see section 5.2).

This medicinal product contains 3.5 mg/ml sodium in the bag or ampoule solution to be taken into consideration by patients on a controlled sodium diet.

In vitro studies indicate that the CYP3A4 isoform and CYP1A2 isoform mediate the metabolism of levobupivacaine. Although no clinical studies have been conducted, metabolism of levobupivacaine may be affected by CYP3A4 inhibitors e.g.: ketoconazole, and CYP1A2 inhibitors e.g.: methylxanthines.

Levobupivacaine should be used with caution in patients receiving anti-arrhythmic agents with local anaesthetic activity, e.g., mexiletine, or class III anti-arrhythmic agents since their toxic effects may be additive.

No clinical studies have been completed to assess levobupivacaine in combination with adrenaline.

Pregnancy

Levobupivacaine solutions are contraindicated for use in paracervical block in obstetrics. Based on experience with bupivacaine foetal bradycardia may occur following paracervical block (see section 4.3).

For levobupivacaine, there are no clinical data on first trimester-exposed pregnancies. Animal studies do not indicate teratogenic effects but have shown embryo-foetal toxicity at systemic exposure levels in the same range as those obtained in clinical use (see section 5.3). The potential risk for human is unknown. Levobupivacaine should therefore not be given during early pregnancy unless clearly necessary.

Nevertheless, to date, the clinical experience of bupivacaine for obstetrical surgery (at the term of pregnancy or for delivery) is extensive and has not shown a foetotoxic effect.

Lactation

It is unknown whether levobupivacaine and its metabolites are excreted in human breast milk.

As for bupivacaine, levobupivacaine is likely to be poorly transmitted in the breast milk. Thus, breastfeeding is possible after local anaesthesia.

Levobupivacaine can have a major influence on the ability to drive, or use machines. Patients should be warned not to drive, or operate machinery until all the effects of the anaesthesia and the immediate effects of surgery are passed.

The adverse drug reactions for levobupivacaine are consistent with those known for its respective class of medicinal products. The most commonly reported adverse drug reactions are hypotension, nausea, anaemia, vomiting, dizziness, headache, pyrexia, procedural pain, back pain and foetal distress syndrome in obstetric use (see table below).

Adverse reactions reported either spontaneously or observed in clinical trials are depicted in the following table. Within each system organ class, the adverse drug reactions are ranked under headings of frequency, using the following convention: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), not known (cannot be estimated from the available data).

Blood and lymphatic system disorders

Very Common: Anaemia

Immune system disorders

Not known: Allergic reactions (in serious cases anaphylactic shock), Hypersensitivity

Nervous system disorders

Not known: Dizziness, Headache

Not known: Convulsion, Loss of consciousness, Somnolence, Syncope, Paraesthesia, Paraplegia, Paralysis¹

Eye disorders

Not known: Vision blurred, Ptosis², Miosis², Enophthalmos²

Cardiac disorders

Not known: Atrioventricular block, Cardiac arrest, Ventricular tachyarrhythmia, Tachycardia, Bradycardia

Vascular disorders

Very common: Hypotension

Not known: Flushing²

Respiratory, thoracic and mediastinal disorders

Not known: Respiratory arrest, Laryngeal oedema, Apnoea, Sneezing

Gastrointestinal disorders

Very common: Nausea

Common: Vomiting

Not known: Hypoaesthesia oral, Loss of sphincter control¹

Skin and subcutaneous tissue disorders

Not known: Angioedema, Urticaria, Pruritus, Hyperhidrosis, Anhidrosis², Erythema

Musculoskeletal and connective tissue disorders

Common: Back pain

Not known: Muscle twitching, Muscular weakness

Renal and urinary disorders

Not known: Bladder dysfunction¹

Pregnancy, puerperium and perinatal conditions

Common: Foetal distress syndrome

Reproductive system and breast disorders

Not known: Priapism¹

General disorders and administration site conditions

Common: Pyrexia

Investigations

Not known: Cardiac output decreased, Electrocardiogram change

Injury, poisoning and procedural complications

Common: Procedural pain

¹ This may be a sign or symptom of cauda equina syndrome (see additional section 4.8 text below).
² This may be a sign or symptom of transient Horner’s syndrome (see additional section 4.8 text below).

Adverse reactions with local anaesthetics of the amide type are rare, but they may occur as a result of overdosage or unintentional intravascular injection and may be serious.

Cross-sensitivity among members of the amide-type local anaesthetic group has been reported (see section 4.3).

Accidental intrathecal injection of local anaesthetics can lead to very high spinal anaesthesia.

Cardiovascular effects are related to depression of the conduction system of the heart and a reduction in myocardial excitability and contractility. Usually these will be preceded by major CNS toxicity, i.e. convulsions, but in rare cases, cardiac arrest may occur without prodromal CNS effects.

Neurological damage is a rare but well recognised consequence of regional and particularly epidural and spinal anaesthesia. It may be due to direct injury to the spinal cord or spinal nerves, anterior spinal artery syndrome, injection of an irritant substance or an injection of a non-sterile solution. Rarely, these may be permanent.

There have been reports of prolonged weakness or sensory disturbance, some of which may have been permanent, in association with levobupivacaine therapy. It is difficult to determine whether the long-term effects where the result of medication toxicity or unrecognized trauma during surgery or other mechanical factors, such as catheter insertion and manipulation.

Reports have been received of cauda equina syndrome or signs and symptoms of potential injury to the base of the spinal cord or spinal nerve roots (including lower extremity paraesthesia, weakness or paralysis, loss of bowel control and/or bladder control and priapism) associated with levobupivacaine administration. These events were more severe and in some cases did not resolve when levobupivacaine was administered for more than 24 hours (see section 4.4).

However, it cannot be determined whether these events are due to an effect of levobupivacaine, mechanical trauma to the spinal cord or spinal nerve roots, or blood collection at the base of the spine.

There have also been reports of transient Horner’s syndrome (ptosis, miosis, enophthalmos, unilateral sweating and/or flushing) in association with use of regional anaesthetics, including levobupivacaine. This event resolves with discontinuation of therapy.

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.

Levobupivacaine may precipitate if diluted with alkaline solutions and should not be diluted or co-administered with sodium bicarbonate injections. This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.