Levobupivacaine

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.

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.

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.

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.

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

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

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. 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.

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.

Adverse reactions reported either spontaneously or observed in clinical trials are depicted in the following list. 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
² This may be a sign or symptom of transient Horner’s syndrome

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.

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.

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.