SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Levobupivacaine 5 mg/ml solution for injection/ infusion

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml solution contains 5 mg of levobupivacaine as levobupivacaine hydrochloride.

Each ampoule of 10 ml contains 50 mg of levobupivacaine as levobupivacaine hydrochloride.

Excipient with known effect: 1 ml solution contains 3.6 mg of sodium, equivalent to 36 mg of sodium per ampoule of 10 ml.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Solution for injection/ infusion.

Clear colourless solution. pH 4.0 - 6.0

Osmolarity: 271 - 372 mOsmol/l

4    CLINICAL PARTICULARS

4.1 Therapeutic indications

Adults

Surgical anaesthesia

-    Major, e.g. epidural (including for caesarean section), intrathecal, perineural (peripheral nerve block).

-    Minor, e.g. infiltration

Pain management

-    Continuous epidural infusion, single or multiple bolus epidural administration for the management of pain especially post-operative pain or labour analgesia.

4.2 Posology and method of administration

Levobupivacaine should be administered only by, or under the supervision of, a clinician having the necessary training and experience.

Posology

The table below is a guide to dosage for the more commonly used blocks. For analgesia (e.g. epidural administration for pain management), the lower concentrations and doses are recommended. Where profound or prolonged anaesthesia is required with dense motor block (e.g. epidural), the higher concentrations may be used. Careful aspiration before and during injection is recommended to prevent intravascular injection.

There is limited safety experience with levobupivacaine therapy for periods exceeding 24 hours. In order to minimise the risk for severe neurological complications, the patient and the duration of administration of levbupivacaine should be closely monitored (see Section 4.4).

Maximum dose

The maximum dosage must be determined by evaluating the size and physical status of the patient, together with the concentration of the agent and the area and route of administration. Individual variation in onset and duration of block does occur. Experience from clinical studies shows onset of sensory block adequate for surgery in 10-15 minutes following epidural administration, with a time to regression in the range of 6-9 hours.

The recommended maximum single dose is 150 mg. Where sustained motor and sensory block are required for a prolonged procedure, additional doses may be required. The maximum recommended dose during a 24 hour period is 400 mg. For post-operative pain management, the dose should not exceed 18.75 mg/hour.

Special populations

Debilitated, elderly or acutely ill patients should be given reduced doses of levobupivacaine commensurate with their physical status.

In the management of post-operative pain, the dose given during surgery must be taken into account.

There are no relevant data in patients with hepatic impairment (see sections 4.4 and 5.2).

Table of Doses

Adults

	(mg/ml)1
Surgical Anaesthesia Epidural (slow) bolus for surgery - Adults	5.0-7.5	10-20 ml (50-150 mg)	Moderate to complete
Epidural slow injection3 for Caesarean Section	5.0	15-30 ml (75-150 mg)	Moderate to complete
Intrathecal	5.0	3 ml (15 mg)	Moderate to complete
Peripheral Nerve	2.5-5.0	1-40 ml (2.5-150 mg max.)	Moderate to complete
Local Infiltration - Adults	2.5	1-60 ml (2.5-150 mg max.)	Not applicable
Pain Management4 Labour Analgesia (epidural bolus5)	2.5	6-10 ml (15-25 mg)	Minimal to moderate
Labour Analgesia (epidural infusion)	1.256	4-10 ml/h (5-12.5 mg/h)	Minimal to moderate
Post-operative pain	1.256 2.5	10-15ml/h (12.5-18.75mg/h) 5-7.5ml/h (12.5-18.75mg/h)	Minimal to moderate

¹    Levobupivacaine solution for injection/infusion is available in 2.5, 5.0 and 7.5 mg/ml solutions.

²    Spread over 5 minutes (see also text).

³    Given over 15-20 minutes.

⁴    In cases where levobupivacaine is combined with other agents e.g. opioids in pain management, the levobupivacaine dose should be reduced and use of a lower concentration (e.g. 1.25 mg/ml) is preferable.

⁵    The minimum recommended interval between intermittent injections is 15 minutes.

⁶    For information on dilution, see section 6.6.

Method of administration

Levobupivacaine 2.5 mg/ml is indicated for epidural use, intrathecal use, perineural use (peripheral nerve blocks) and for infiltration (see table of doses above).

Aspiration should be repeated before and during administration of a bolus dose, which should be injected slowly and in incremental doses, at a rate of 7.5-30 mg/min, while closely observing the patient’s vital functions and maintaining verbal contact.

If toxic symptoms occur, the injection should be stopped immediately.

For instructions on dilution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

General contraindications related to regional anaesthesia, regardless of the local anaesthetic used, should be taken into account.

Levobupivacaine solutions are contraindicated in patients with a known hypersensitivity to levobupivacaine, local anaesthetics of the amide type or any of the excipients listed in section 6.1 (see section 4.8).

Levobupivacaine solutions are contraindicated for intravenous regional anaesthesia (Bier's block).

Levobupivacaine solutions are contraindicated in patients with severe hypotension such as cardiogenic or hypovolaemic shock.

Levobupivacaine solutions are contraindicated for use in paracervical block in obstetrics (see section 4.6).

4.4 Special warnings and precautions for use

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).

The introduction of local anesthetics 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 anesthesia 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 anesthetics, 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 anesthesia, 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 postmarketing 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 anesthetic, 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 anesthetic that results in effective anesthesia should be used to avoid high plasma levels and serious adverse effects. The rapid injection of a large volume of local anesthetic solution should be avoided and fractional (incremental) doses should be used when feasible.

Use in Head and Neck Area

Small doses of local anesthetics injected into the head and neck area, including 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 anesthetic with retrograde flow to the cerebral circulation. 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.

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 1.57 mmol (or 36 mg) sodium per ampoule of 10 ml solution. To be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

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 eg: ketoconazole, and CYP1A2 inhibitors eg: methylxanthines.

Levobupivacaine should be used with caution in patients receiving antiarrhythmic 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.

4.6 Fertility, pregnancy and lactation

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.

Breast-feeding

Levobupivacaine excretion in breast milk is unknown. However, levobupivacaine is likely to be poorly transmitted in the breast milk, as for bupivacaine. Thus breastfeeding is possible after local anaesthesia.

Fertility

There are no or only limited data available for Levobupivacaine to assess its impact on fertility.

4.7 Effects on ability to drive and use machines

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.

4.8 Undesirable effects

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 to <1/10)

Uncommon (>1/1,000 to <1/100)

Rare (>1/10,000 to <1/1,000)

Not known (cannot be estimated from the available data).

System Organ Class	Frequency	Adverse Reaction
Blood and lymphatic system disorders	Very Common	Anaemia
Immune system disorders	Not known Not known	Allergic reactions (in serious cases anaphylactic shock) Hypersensitivity

Nervous system disorders	Common Common Not known Not known Not known Not known Not known Not known Not known	Dizziness Headache Convulsion Loss of consciousness Somnolence Syncope Paraesthesia Paraplegia Paralysis1
Eye disorders	Not known	Vision blurred
	Not known	Ptosis2
	Not known	Miosis2
	Not known	Enophthalmos2
Cardiac disorders	Not known	Atrioventricular block
	Not known	Cardiac arrest
	Not known	Ventricular tachyarrhythmia
	Not known	Tachycardia
	Not known	Bradycardia
Vascular disorders	Very common	Hypotension
	Not known	Flushing2
Respiratory, thoracic and	Not known	Respiratory arrest
mediastinal disorders	Not known	Laryngeal oedema
	Not known	Apnoea
	Not known	Sneezing
Gastrointestinal disorders	Very	Nausea
	Common	Vomiting
	Common	Hypoaesthesia oral
	Not known Not known	Loss of sphincter control1
Skin and subcutaneous tissue	Not known	Angioedema
disorders	Not known	Urticaria
	Not known	Pruritus
	Not known	Hyperhidrosis
	Not known	Anhidrosis2
	Not known	Erythema
Musculoskeletal and	Common	Back pain
connective tissue disorders	Not known	Muscle twitching
	Not known	Muscular weakness
Renal and urinary disorders	Not known	Bladder dysfunction1
Pregnancy, puerperium and	Common	Foetal distress syndrome
perinatal conditions
Reproductive system and	Not known	Priapism1
breast disorders
General disorders and	Common	Pyrexia
administration site conditions
Investigations	Not known	Cardiac output decreased
	Not known	Electrocardiogram change
Injury, poisoning and	Common	Procedural pain
procedural complications

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 anesthetic group have 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 at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Accidental intravascular injection of local anaesthetics may cause immediate toxic reactions. In the event of overdose, peak plasma concentrations may not be reached until 2 hours after administration depending upon the injection site and, therefore, signs of toxicity may be delayed. The effects of the drug may be prolonged.

Systemic adverse reactions following overdose or accidental intravascular injection reported with long acting local anaesthetic agents involve both CNS and cardiovascular effects.

CNS Effects

Convulsions should be treated immediately with intravenous thiopentone or diazepam titrated as necessary. Thiopentone and diazepam also depress central nervous system, respiratory and cardiac function. Therefore their use may result in apnoea. Neuro-muscular blockers may be used only if the clinician is confident of maintaining a patent airway and managing a fully paralysed patient.

If not treated promptly, convulsions with subsequent hypoxia and hypercarbia plus myocardial depression from the effects of the local anaesthetic on the heart, may result in cardiac arrhythmias, ventricular fibrillation or cardiac arrest.

Cardiovascular Effects

Hypotension may be prevented or attenuated by pre-treatment with a fluid load and/or the use of vasopressors. If hypotension occurs it should be treated with intravenous crystalloids or colloids and/or incremental doses of a vasopressor such as ephedrine 5-10 mg. Any coexisting causes of hypotension should be rapidly treated.

If severe bradycardia occurs, treatment with atropine 0.3 - 1.0 mg will normally restore the heart rate to an acceptable level.

Cardiac arrhythmia should be treated as required and ventricular fibrillation should be treated by cardioversion.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Local anaesthetics, amide ATC Code: N01B B10

Levobupivacaine is a long acting local anaesthetic and analgesic. It blocks nerve conduction in sensory and motor nerves largely by interacting with voltage sensitive sodium channels on the cell membrane, but also potassium and calcium channels are blocked. In addition, levobupivacaine interferes with impulse transmission and conduction in other tissues where effects on the cardiovascular and central nervous systems are most important for the occurrence of clinical adverse reactions.

The dose of levobupivacaine is expressed as base, whereas, in the racemate bupivacaine the dose is expressed as hydrochloride salt. This gives rise to approximately 13% more active substance in levobupivacaine solutions compared to bupivacaine. In clinical studies at the same nominal concentrations levobupivacaine showed similar clinical effect to bupivacaine.

In a clinical pharmacology study using the ulnar nerve block model, levobupivacaine was equipotent with bupivacaine.

There is limited safety experience with levobupivacaine therapy for periods exceeding 24 hours.

5.2 Pharmacokinetic properties

Absorption

In human studies, the distribution kinetics of levobupivacaine following i.v. administration are essentially the same as bupivacaine. The plasma concentration of levobupivacaine following therapeutic administration depends on dose and, as absorption from the site of administration is affected by the vascularity of the tissue, on route of administration.

In a clinical pharmacology study where 40 mg levobupivacaine was given by intravenous administration, the mean half-life was approximately 80 + 22 minutes, C_max 14 + 0.2 pg/ml and AUC 70 + 27 pg^min/ml.

The mean C_max and AUC(0-24h) of levobupivacaine were approximately dose-proportional following epidural administration of 75 mg (0.5%) and 112.5 mg (0.75%) and following doses of 1 mg/kg (0.25%) and 2 mg/kg (0.5%) used for brachial plexus block. Following epidural administration of 112.5 mg (0.75%) the mean C_max and AUC values were 0.58 pg/ml and 3.56 pg^h/ml respectively.

Distribution

Plasma protein binding of levobupivacaine in man was evaluated in vitro and was found to be > 97% at concentrations between 0.1 and 1.0 pg/ml.

The volume of distribution after intravenous administration was 67 litres.

Biotransformation

There are no relevant data in patients with hepatic impairment (see section 4.4).

Levobupivacaine is extensively metabolised with no unchanged levobupivacaine detected in urine or faeces. 3-hydroxylevobupivacaine, a major metabolite of levobupivacaine, is excreted in the urine as glucuronic acid and sulphate ester conjugates. In vitro studies showed that CYP3A4 isoform and CYP1A2 isoform mediate the metabolism of levobupivacaine to desbutyl-levobupivacaine and 3-hydroxylevobupivacaine respectively. These studies indicate that the metabolism of levobupivacaine and bupivacaine are similar.

There is no evidence of in vivo racemisation of levobupivacaine.

Elimination

There are no data in patients with renal impairment. Levobupivacaine is extensively metabolised and unchanged levobupivacaine is not excreted in urine.

The mean total plasma clearance and terminal half-life of levobupivacaine after intravenous infusion were 39 litres/hour and 1.3 hours, respectively. Following intravenous administration, recovery of levobupivacaine was quantitative with a mean total of about 95% being recovered in urine (71%) and faeces (24%) in 48 hours.

5.3 Preclinical safety data

In an embryo-foetal toxicity study in rats, an increased incidence of dilated renal pelvis, dilated ureters, olfactory ventricle dilatation and extra thoracolumbar ribs was observed at systemic exposure levels in the same range as those obtained at clinical use. There were no treatment-related malformations.

Levobupivacaine was not genotoxic in a standard battery of assays for mutagenicity and clastogenicity. No carcinogenicity testing has been conducted.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium Chloride

Sodium Hydroxide (for pH adjustment) Hydrochloric acid (for pH adjustment) Water for Injections

Incompatibilities

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.

6.3    Shelf life

2 years.

After first opening: The product should be used immediately.

Shelf life after dilution:

Chemical and physical in-use stability has been demonstrated for Levobupivacaine diluted with sodium chloride 9 mg/ml (0.9%) to a final concentration of 0.625 mg/ml and 1.25 mg/ml, respectively, for 30 days either 2-8°C or 20°C - 25°C.

Chemical and physical in-use stability has been demonstrated for Levobupivacaine diluted with sodium chloride 9 mg/ml (0.9%) to a final concentration of 0.625 mg/ml and 1.25 mg/ml, respectively

-    With 8.4 pg/ml clonidine hydrochloride, 50 pg/ml morphine sulfate and 2-4 pg/ml fentanyl citrate for 30 days at either 2-8°C or 20°C-25°C .

-    With sufentanil added in the concentration of 0.4 pg/ml for 30 days at 28 °C or 7 days at 20 °C-25 °C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless the dilution and admix have taken place in controlled and validated aseptic conditions.

6.4    Special precautions for storage

This medicinal product does not require any special storage conditions.

For storage conditions of the diluted medicinal product, see section 6.3.

6.5    Nature and contents of container

10 ml polypropylene ampoules in sterile blister packs. It is supplied in packs of 5, 10 or 20 ampoules.

Not all pack sizes may be marketed.

Special precautions for disposal

For single use only. Discard any unused solution.

Do not use unless the container is undamaged.

The solution/dilution should be inspected visually prior to use. Only clear solutions without visible particles should be used.

A sterile blister container should be chosen when a sterile ampoule surface is required. Ampoule surface is not sterile if sterile blister is pierced.

Dilutions of levobupivacaine standard solutions should be made with sodium chloride 9 mg/ml (0.9%) solution for injection using aseptic techniques.

Clonidine 8.4 pg/ml, morphine 0.05 mg/ml, fentanyl 2-4 pg/ml and sufentanil 0.4 pg/ml have been shown to be compatible with levobupivacaine in sodium chloride 9 mg/ml (0.9%) solution for injection.

For the shelf-life of the diluted product see section 6.3.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7    MARKETING AUTHORISATION HOLDER

Fresenius Kabi Limited Cestrian Court, Eastgate Way,

Manor Park, Runcorn,

Cheshire, UK WA7 1NT

8    MARKETING AUTHORISATION NUMBER(S)

PL 08828/0251

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

22/05/2014

10    DATE OF REVISION OF THE TEXT

22/05/2014