Levobupivacaine 7.5 mg/ml solution for injection/infusion

Martindale Pharma, an Ethypharm Group Company🇬🇧 Electronic Medicines Compendium

Approval Date: N/A
Approval ID: dc2a04f8b2781c1e
Company: Martindale Pharma, an Ethypharm Group Company
Type: Standard

Approval Details

Approval Id: dc2a04f8b2781c1e
Drug Approval Emc Name: Levobupivacaine 7.5 mg/ml solution for injection/infusion
Drug Name: Levobupivacaine 7.5 mg/ml solution for injection/infusion
Company Name: Martindale Pharma, an Ethypharm Group Company
Company Address: Jupiter House, Mercury Park, Wooburn Green, High Wycombe, Buckinghamshire, HP10 0HH, UK
Company Website: http://ethypharm.co.uk/
Company Telephone: +44 (0) 1277 266 600
Company Medical Info Email: medinfo@ethypharm.com
Atc Code: N01BB10
Legal Category: Prescription only medicine
Authorisation Holder: Altan Pharmaceuticals, S.A. C/ Cólquide N° 6, Portal 2, 1ª Planta, Oficina F. Edificio Prisma Las Rozas, 28230 Madrid, Spain
Authorisation Number: PL 51338/0004
Authorisation Date: 13/04/2023
Instruction Authorisation Holder: Altan Pharmaceuticals, S.A. C/ Cólquide N° 6, Portal 2, 1ª Planta, Oficina F. Edificio Prisma Las Rozas, 28230 Madrid, Spain
Instruction Authorisation Number: PL 51338/0004
Instruction Authorisation Date: 13/04/2023
Instruction Composition: One ml contains 7.5 mg levobupivacaine (as hydrochloride). Each 10 ml ampoule contains 75 mg levobupivacaine (as hydrochloride). Excipients: 3.5 mg/ml of sodium per ampoule. For the full list of excipients, see Section 6.1.
Instruction Dosage Form: Solution for injection/infusion. Clear colourless solution. pH: 4.0 – 6.5 Osmolality: 288 – 352 mOsmol/Kg
Instruction Clinical Particulars: 4.1 Therapeutic indications Adults \*Surgical anaesthesia\* - Major e.g. epidural intrathecal, peripheral nerve block. - Minor e.g. local infiltration, peribulbar block in ophthalmologic surgery. \*Pain management\* - Continuous epidural infusion, single or multiple bolus epidural administration for the management of pain, especially post-operative pain Paediatric population Analgesia (ilioinguinal / iliohypogastric blocks) No data are available in paediatric population less than 6 months of age.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. The table below is a guide for dosage of more commonly used blocks. For analgesia (e.g epidural administration for the treatment of pain) the lowest doses and contentrations are recommended. Whenever deep or longer anaesthesia with complete motor block is required (i.e. epidural or peribulbar block) the highest concentrations can be used. Careful aspiration should be repeated before and during injection so as 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 levobupivacaine should be closely monitored (see section 4.4). Aspiration should be repeated before and during administration of bolus dose, that should be slowly injected increasing at a speed of 7.5-30 mg/min, while monitoring closely vital functions and verbal contact is kept with the patient. If toxic symptoms occur, the injection should be stopped immediately. Maximum dose The maximum dosage must be determined by evaluating the size and physical status of the patient together with the concentration of the medicine, the administration site and route. There is an individual variation at the beginning and block duration. Experience gathered in clinical studies show the adequate sensitive block is produced within 10-15 minutes after epidural administration with a regression time range of 6-9 hours. The maximum recommended single dose is 150 mg. Additional doses may be necessary whenever continuous motor and sensitive blockage is required for extended procedures. The maximum recommended dose for a 24- hour period is 400 mg. For treatment of post-surgical pain, dose should not exceed 18.75 mg/hour. Obstetrics For caesarean section, higher concentrations than the 5.0 mg/ml solution should not be used (see section 4.3). The maximum recommended dose is 150 mg. For labour analgesia by epidural infusion, the dose should not exceed 12.5 mg/hour. Paediatric population In children the maximum recommended dose for analgesia (ilioinguinal/iliohypogastric block) is 1.25 mg/kg/each side. The maximum dosage must be determined by evaluating the size, body constitution and physical status of the patient/ child. The safety and efficacy of levobupivacaine in children for other indications have not been established. 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). \*\*Dosage Table\*\* | | | | | | --- | --- | --- | --- | | | \*\*Concentration\*\* \*\*(mg/ml)1\*\* | \*\*Dose\*\* | \*\*Motor Block\*\* | | \*\*Surgical Anaesthesia\*\* \*\*Epidural Bolus2 (slow) for surgery\*\* \*\*-Adults\*\* | 5-7.5 | 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\*\* \*\*Iloinguinal/Iliohypogastric blocks in children <12 years4\*\* | 2.5-5.0 2.5 5.0 | 1-40 ml (2.5-150 mg max.) 0.5 ml/kg/side (1.25 mg/kg/side) 0.25 ml/kg/side (1.25 mg/kg/side) | Moderate to complete Not applicable | | \*\*Ophtalmic (peribulbar block)\*\* | 7.5 | 5-15 ml (37.5-112.5 mg) | Moderate to complete | | \*\*Local Infiltration\*\* \*\*-Adults\*\* | 2.5 | 1-60 ml (2.5-150 mg max.) | Not aplicable | | \*\*Pain Management5\*\* \*\*Labour Analgesia (epidural bolus)\*\* | 2.5 | 6-10 ml (15-25 mg) | Minimal to moderate | | \*\*Labour Analgesia (epidural infusion)\*\* | 1.257 | 4-10 ml/h (5-12.5 mg/h) | Minimal to moderate | | \*\*Post-operative pain\*\* | 1.257 2.5 | 10-15 ml/h (12.5-18.75 mg/h) 5-7.5 ml/h (12.5-18.75 mg/h) | Minimal to moderate | 1 Levobupivacaine solution for injection/infusion is available in solutions of 2.5.0-5-7.5 mg/ml 2 Diffuse for 5 minutes (See also the text) 3 Administered for 15-20 minutes. 4 No data are available in paediatric population < 6 months of age 5 In cases where levobupivacaine is combined with other medicines, e.g. opioids in pain management, the dose of levobupivacaine should be reduced and preferably use a lower concentration (e.g. 1.25 mg/ml) 6 Minimal recommended interval between intermittent injections is 15 minutes. 7 Further information on dilution, see Section 6.64.3 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 active substance, 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. Based on the experience with bupivacaine, the 7.5 mg/ml solution is contraindicated for obstetric use due to an enhaced risk for cardiotoxic events (see section 4.6). 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 neuro-muscle damage (see section 4.8). Levobupivacaine should be carefully used for regional anaesthesia in patients with cardiovascular impairment, e.g. severe cardiac arrhythmia (see seccion 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 either intrathecal or via 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 recognized 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 anaesthesia 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 at least for 24 hours 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 anaesthesia, 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 IV constant fluid perfusion through permanent catheter so as to ensure intravenous functioning. The lowest efficient dose of local anaesthesia should be used to prevent high plasma levels and severe adverse reactions. Fast injection of large volume of local anaesthesia solution should be avoided. Fractioned (increasing) doses should be used whenever it is possible. Use in Head and Neck areas Lower doses of local anaesthetics injected in the areas of the head and the neck, including retrobulbar, dental and cervix- thoracic ganglions may provoke adverse reactions similar to systemic toxicity observed with accidental IV injections with greater doses. Injecting procedures require extreme care. Reactions could be caused by an intraarterial anaesthesia local injection with retrograde flow to brain circulation. Also, they could be caused by a dura mater puncture of the optical nerve during a retrobulbar block with perfusion of any local anaesthesia through the subdural space to the mid-brain. Patients undergoing such blocks, should be monitored constantly verifying circulation and breathing. Immediate reanimation equipment should be available as well as personnel to treat such adverse reactions. Use in Ophthalmic surgery Doctors practicing retrobulbar blocks should be conscious of the notifications of breathing arrest after local anaesthesia. Before retrobulbar blocks, as well as for any other regional procedure, immediate reanimation equipment should be granted as well as the personnel necessary to control a breathing arrest or depression, convulsions, and cardiac stimulation or depression. As with other anaesthetic procedures, patients should be constantly monitored after an ophthalmic block so as to be able to observe signs indicating such 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 1.5mmol (3.5 mg/ml) sodium per ampoule 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 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.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). The 7.5 mg/ml solution is contraindicated for obstetric use due to enhanced risk for cardiotoxic events based on experience with bupivacaine (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. Lactation It is unknown whether levobupivacaine or 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. Fertility No data or limited data is available on the use of levobupivacaine and its relation with fertility.4.7 Effects on ability to drive and use machines Levobupivacaine may have major influence on the ability to drive or use machines. Patients should be warned not to drive or operate machinery until the effects of anaesthesia have ended as well the immediate effects of the surgery.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 organ or system, the adverse drug reactions are decreasingly 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). | | | | | --- | --- | --- | | \*\*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 | Comon 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 Not known Not known Not known | Vision blurred Ptosis2 Miosis2 Enophthalmos2 | | Cardiac disorders | Not known Not known Not known Not known Not known | Atrioventricular block Cardiac arrest Ventricular tachyarrhythmia Tachycardia Bradycardia | | Vascular disorders | Very common Not known | Hypotension Flushing2 | | Respiratory, thoracic and mediastinal disorders | Not known Not known Not known Not known | Respiratory arrest Laryngeal oedema Apnoea Sneezing | | Gastrointestinal disorders | Very Common Common Not known Not known | Nausea Vomiting Hypoaesthesia oral Loss of sphincter control1 | | Skin and subcutaneous tissue disorders | Not known Not known Not known Not known Not known Not known | Angioedema Urticaria Pruritus Hyperhidrosis Anhidrosis2 Erythema | | Musculoskeletal and connective tissue disorders | Common Not known Not known | Back pain 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 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 ection 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 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 recognized 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 national reporting system Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store4.9 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 paralyzed patient. If not treated promptly, convulsions with subsequent hypoxia and hypercarbia plus myocardial depression from the effects of the local anaesthesia 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.
Instruction Pharmacology: 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 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. 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. Distribution In human studies, the distribution kinetics of levobupivacaine following i.v. administration are essentially the same as bupivacaine. 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 μg/ml. The volume of distribution after intravenous administration was 67 litres. Biotransformation 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 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. The mean total plasma clearance and terminal half-life of levobupivacaine after intravenous infusion were 39 litres/hour and 1.3 hours, respectively. In a clinical pharmacology study where 40 mg levobupivacaine was given by intravenous administration, the mean half-life was approximately 80 + 22 minutes, Cmax 1.4 + 0.2 μg/ml and AUC 70 + 27 μg•min/ml. Linearity The mean Cmax 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 Cmax and AUC values were 0.58 µg/ml and 3.56µg•h/ml respectively. Hepatic and renal impairment There are no relevant data in patients with hepatic impairment (see section 4.4). There are no data in patients with renal impairment. Levobupivacaine is extensively metabolised and unchanged levobupivacaine is not excreted in urine.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 thoraco-lumbar 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.
Instruction Pharmaceutical Particulars: 6.1 List of excipients Sodium Chloride Sodium Hydroxide Hydrochloric acid Water for Injections6.2 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 Shelf life packaged, unopened: 3 years. Shelf life after first opening: The product should be used immediately. Shelf life after dilution in sodium chloride solution 0.9%: Chemical and physical in-use stability for 7 days at 20-22°C. Chemical and physical in-use stability together with clonidine, morphine and fentanyl has been demonstrated for 40 hours at 20-22°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.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 ampoule, glass type I in packages of 5 and 10 ampoules. Not all pack sizes may be marketed6.6 Special precautions for disposal and other handling For single use. Discard any unused solution. The solution/dilution should be inspected visually prior to use. Only clear solutions without visible particles should be used. Dilutions of standard solutions of levobupivacaine should be carried out with 9 mg/ml (0.9%) sodium chloride solution for injection using aseptic techniques. Clonidine 8.4 μg/ml, morphine 0.05 mg/ml and fentanyl 4 μg/ml have demonstrated to be compatible with con levobupivacaine in 9 mg/ml (0.9%) sodium chloride solution for injection. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Instruction Content: ## Composition One ml contains 7.5 mg levobupivacaine (as hydrochloride). Each 10 ml ampoule contains 75 mg levobupivacaine (as hydrochloride). Excipients: 3.5 mg/ml of sodium per ampoule. For the full list of excipients, see Section 6.1. ## Pharmaceutical Form Solution for injection/infusion. Clear colourless solution. pH: 4.0 – 6.5 Osmolality: 288 – 352 mOsmol/Kg ## Clinical Particulars 4.1 Therapeutic indications Adults \*Surgical anaesthesia\* - Major e.g. epidural intrathecal, peripheral nerve block. - Minor e.g. local infiltration, peribulbar block in ophthalmologic surgery. \*Pain management\* - Continuous epidural infusion, single or multiple bolus epidural administration for the management of pain, especially post-operative pain Paediatric population Analgesia (ilioinguinal / iliohypogastric blocks) No data are available in paediatric population less than 6 months of age.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. The table below is a guide for dosage of more commonly used blocks. For analgesia (e.g epidural administration for the treatment of pain) the lowest doses and contentrations are recommended. Whenever deep or longer anaesthesia with complete motor block is required (i.e. epidural or peribulbar block) the highest concentrations can be used. Careful aspiration should be repeated before and during injection so as 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 levobupivacaine should be closely monitored (see section 4.4). Aspiration should be repeated before and during administration of bolus dose, that should be slowly injected increasing at a speed of 7.5-30 mg/min, while monitoring closely vital functions and verbal contact is kept with the patient. If toxic symptoms occur, the injection should be stopped immediately. Maximum dose The maximum dosage must be determined by evaluating the size and physical status of the patient together with the concentration of the medicine, the administration site and route. There is an individual variation at the beginning and block duration. Experience gathered in clinical studies show the adequate sensitive block is produced within 10-15 minutes after epidural administration with a regression time range of 6-9 hours. The maximum recommended single dose is 150 mg. Additional doses may be necessary whenever continuous motor and sensitive blockage is required for extended procedures. The maximum recommended dose for a 24- hour period is 400 mg. For treatment of post-surgical pain, dose should not exceed 18.75 mg/hour. Obstetrics For caesarean section, higher concentrations than the 5.0 mg/ml solution should not be used (see section 4.3). The maximum recommended dose is 150 mg. For labour analgesia by epidural infusion, the dose should not exceed 12.5 mg/hour. Paediatric population In children the maximum recommended dose for analgesia (ilioinguinal/iliohypogastric block) is 1.25 mg/kg/each side. The maximum dosage must be determined by evaluating the size, body constitution and physical status of the patient/ child. The safety and efficacy of levobupivacaine in children for other indications have not been established. 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). \*\*Dosage Table\*\* | | | | | | --- | --- | --- | --- | | | \*\*Concentration\*\* \*\*(mg/ml)1\*\* | \*\*Dose\*\* | \*\*Motor Block\*\* | | \*\*Surgical Anaesthesia\*\* \*\*Epidural Bolus2 (slow) for surgery\*\* \*\*-Adults\*\* | 5-7.5 | 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\*\* \*\*Iloinguinal/Iliohypogastric blocks in children <12 years4\*\* | 2.5-5.0 2.5 5.0 | 1-40 ml (2.5-150 mg max.) 0.5 ml/kg/side (1.25 mg/kg/side) 0.25 ml/kg/side (1.25 mg/kg/side) | Moderate to complete Not applicable | | \*\*Ophtalmic (peribulbar block)\*\* | 7.5 | 5-15 ml (37.5-112.5 mg) | Moderate to complete | | \*\*Local Infiltration\*\* \*\*-Adults\*\* | 2.5 | 1-60 ml (2.5-150 mg max.) | Not aplicable | | \*\*Pain Management5\*\* \*\*Labour Analgesia (epidural bolus)\*\* | 2.5 | 6-10 ml (15-25 mg) | Minimal to moderate | | \*\*Labour Analgesia (epidural infusion)\*\* | 1.257 | 4-10 ml/h (5-12.5 mg/h) | Minimal to moderate | | \*\*Post-operative pain\*\* | 1.257 2.5 | 10-15 ml/h (12.5-18.75 mg/h) 5-7.5 ml/h (12.5-18.75 mg/h) | Minimal to moderate | 1 Levobupivacaine solution for injection/infusion is available in solutions of 2.5.0-5-7.5 mg/ml 2 Diffuse for 5 minutes (See also the text) 3 Administered for 15-20 minutes. 4 No data are available in paediatric population < 6 months of age 5 In cases where levobupivacaine is combined with other medicines, e.g. opioids in pain management, the dose of levobupivacaine should be reduced and preferably use a lower concentration (e.g. 1.25 mg/ml) 6 Minimal recommended interval between intermittent injections is 15 minutes. 7 Further information on dilution, see Section 6.64.3 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 active substance, 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. Based on the experience with bupivacaine, the 7.5 mg/ml solution is contraindicated for obstetric use due to an enhaced risk for cardiotoxic events (see section 4.6). 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 neuro-muscle damage (see section 4.8). Levobupivacaine should be carefully used for regional anaesthesia in patients with cardiovascular impairment, e.g. severe cardiac arrhythmia (see seccion 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 either intrathecal or via 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 recognized 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 anaesthesia 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 at least for 24 hours 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 anaesthesia, 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 IV constant fluid perfusion through permanent catheter so as to ensure intravenous functioning. The lowest efficient dose of local anaesthesia should be used to prevent high plasma levels and severe adverse reactions. Fast injection of large volume of local anaesthesia solution should be avoided. Fractioned (increasing) doses should be used whenever it is possible. Use in Head and Neck areas Lower doses of local anaesthetics injected in the areas of the head and the neck, including retrobulbar, dental and cervix- thoracic ganglions may provoke adverse reactions similar to systemic toxicity observed with accidental IV injections with greater doses. Injecting procedures require extreme care. Reactions could be caused by an intraarterial anaesthesia local injection with retrograde flow to brain circulation. Also, they could be caused by a dura mater puncture of the optical nerve during a retrobulbar block with perfusion of any local anaesthesia through the subdural space to the mid-brain. Patients undergoing such blocks, should be monitored constantly verifying circulation and breathing. Immediate reanimation equipment should be available as well as personnel to treat such adverse reactions. Use in Ophthalmic surgery Doctors practicing retrobulbar blocks should be conscious of the notifications of breathing arrest after local anaesthesia. Before retrobulbar blocks, as well as for any other regional procedure, immediate reanimation equipment should be granted as well as the personnel necessary to control a breathing arrest or depression, convulsions, and cardiac stimulation or depression. As with other anaesthetic procedures, patients should be constantly monitored after an ophthalmic block so as to be able to observe signs indicating such 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 1.5mmol (3.5 mg/ml) sodium per ampoule 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 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.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). The 7.5 mg/ml solution is contraindicated for obstetric use due to enhanced risk for cardiotoxic events based on experience with bupivacaine (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. Lactation It is unknown whether levobupivacaine or 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. Fertility No data or limited data is available on the use of levobupivacaine and its relation with fertility.4.7 Effects on ability to drive and use machines Levobupivacaine may have major influence on the ability to drive or use machines. Patients should be warned not to drive or operate machinery until the effects of anaesthesia have ended as well the immediate effects of the surgery.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 organ or system, the adverse drug reactions are decreasingly 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). | | | | | --- | --- | --- | | \*\*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 | Comon 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 Not known Not known Not known | Vision blurred Ptosis2 Miosis2 Enophthalmos2 | | Cardiac disorders | Not known Not known Not known Not known Not known | Atrioventricular block Cardiac arrest Ventricular tachyarrhythmia Tachycardia Bradycardia | | Vascular disorders | Very common Not known | Hypotension Flushing2 | | Respiratory, thoracic and mediastinal disorders | Not known Not known Not known Not known | Respiratory arrest Laryngeal oedema Apnoea Sneezing | | Gastrointestinal disorders | Very Common Common Not known Not known | Nausea Vomiting Hypoaesthesia oral Loss of sphincter control1 | | Skin and subcutaneous tissue disorders | Not known Not known Not known Not known Not known Not known | Angioedema Urticaria Pruritus Hyperhidrosis Anhidrosis2 Erythema | | Musculoskeletal and connective tissue disorders | Common Not known Not known | Back pain 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 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 ection 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 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 recognized 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 national reporting system Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store4.9 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 paralyzed patient. If not treated promptly, convulsions with subsequent hypoxia and hypercarbia plus myocardial depression from the effects of the local anaesthesia 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. ## 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 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. 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. Distribution In human studies, the distribution kinetics of levobupivacaine following i.v. administration are essentially the same as bupivacaine. 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 μg/ml. The volume of distribution after intravenous administration was 67 litres. Biotransformation 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 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. The mean total plasma clearance and terminal half-life of levobupivacaine after intravenous infusion were 39 litres/hour and 1.3 hours, respectively. In a clinical pharmacology study where 40 mg levobupivacaine was given by intravenous administration, the mean half-life was approximately 80 + 22 minutes, Cmax 1.4 + 0.2 μg/ml and AUC 70 + 27 μg•min/ml. Linearity The mean Cmax 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 Cmax and AUC values were 0.58 µg/ml and 3.56µg•h/ml respectively. Hepatic and renal impairment There are no relevant data in patients with hepatic impairment (see section 4.4). There are no data in patients with renal impairment. Levobupivacaine is extensively metabolised and unchanged levobupivacaine is not excreted in urine.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 thoraco-lumbar 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. ## Pharmaceutical Particulars 6.1 List of excipients Sodium Chloride Sodium Hydroxide Hydrochloric acid Water for Injections6.2 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 Shelf life packaged, unopened: 3 years. Shelf life after first opening: The product should be used immediately. Shelf life after dilution in sodium chloride solution 0.9%: Chemical and physical in-use stability for 7 days at 20-22°C. Chemical and physical in-use stability together with clonidine, morphine and fentanyl has been demonstrated for 40 hours at 20-22°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.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 ampoule, glass type I in packages of 5 and 10 ampoules. Not all pack sizes may be marketed6.6 Special precautions for disposal and other handling For single use. Discard any unused solution. The solution/dilution should be inspected visually prior to use. Only clear solutions without visible particles should be used. Dilutions of standard solutions of levobupivacaine should be carried out with 9 mg/ml (0.9%) sodium chloride solution for injection using aseptic techniques. Clonidine 8.4 μg/ml, morphine 0.05 mg/ml and fentanyl 4 μg/ml have demonstrated to be compatible with con levobupivacaine in 9 mg/ml (0.9%) sodium chloride solution for injection. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

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