1. Name Of The Medicinal Product
Chirocaine 0.625 mg/ml solution for infusion
Chirocaine 1.25 mg/ml solution for infusion
2. Qualitative And Quantitative Composition
Levobupivacaine hydrochloride corresponding to 0.625 mg/ml or 1.25mg/ml Levobupivacaine.
Excipients: 3.6mg/ml of sodium per bag.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Solution for infusion
Clear solution
4. Clinical Particulars
4.1 Therapeutic Indications
Adults
Pain management
Continuous epidural infusion, for the management of post operative pain and 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.
Chirocaine Solution for Infusion is for epidural use only. It must not be used for intravenous administration.
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Careful aspiration before infusion is recommended to prevent intravascular injection. 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. 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, however the accumulated dose for a 24 hour period should not exceed 400 mg. For labour analgesia by epidural infusion, the dose should not exceed 12.5 mg/ hour.
Children
The safety and efficacy of levobupivacaine in children for pain management has 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).
4.3 Contraindications
General contra-indications related to regional anaesthesia, regardless of the local anaesthetic used, should be taken into account.
Levobupivacaine solutions are contra-indicated in patients with a known hypersensitivity to levobupivacaine, local anaesthetics of the amide type or any of the excipients (see section 4.8)
Levobupivacaine solutions are contra-indicated for intravenous regional anaesthesia (Bier's block).
Levobupivacaine solutions are contra-indicated in patients with severe hypotension such as cardiogenic or hypovolaemic shock.
Levobupivacaine solutions are contra-indicated 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
The introduction of local anesthetics 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 anesthesia in such patients.
This medicinal product contains 3.6 mg/mL sodium in the bag or ampoule solution to be taken into consideration by patients on a controlled sodium diet.
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. 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).
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).
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 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.
Lactation
Levobupivacaine excretion in breast milk is unknown. However, levobupivacaine is likely to be poorly transmitted in the breast milk, as for bupivacaine. Thus breast feeding is possible after local anaesthesia.
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 Chirocaine 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 (
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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.
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.
5.2 Pharmacokinetic Properties
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.
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.
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.
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.
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.
The mean total plasma clearance and terminal half-life of levobupivacaine after intravenous infusion were 39 litres/hour and 1.3 hours, respectively. The volume of distribution after intravenous administration was 67 litres.
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.
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.
There is no evidence of in vivo racemisation of levobupivacaine.
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.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Sodium Chloride
Sodium Hydroxide
Hydrochloric acid
Water for Injections
6.2 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 6.3.
6.3 Shelf Life
Shelf life as packaged for sale: 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 has been demonstrated for both levobupivacaine 0.625 mg/ml and 1.25 mg/ml with 8.3-8,4 μg/ml clonidine, 50 μg /ml morphine and 2 μg /ml fentanyl, respectively, stored for 30 days at either 2-8ºC or 20–22°C. Chemical and physical in-use stability has been demonstrated for both levobupivacaine 0.625 mg/ml and 1.25 mg/ml with sufentanil added in the concentration of 0.4 μg /ml and stored for 30 days at 2-8ºC or 7 days at 20–22°C.
From a microbiological point of view, the product should be used immediately after opening. 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 2-8ºC, unless the admix has been prepared 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 reconstituted medicinal product, see section 6.3.
6.5 Nature And Contents Of Container
Chirocaine is available in two presentations;
• 100 ml solution in a 100 ml flexible polyester bag with an aluminium foil overpouch.
• 200 ml solution in a 250 ml flexible polyester bag with an aluminium foil overpouch.
Each polyester bag contains one PVC admixture port and one PVC administration port.
Pack sizes: 5 bags of the 100 ml solution.
5 bags of the 200 ml solution.
24 bags of the 100 ml solution.
12 bags of the 200 ml solution.
60 bags of the 100 ml solution.
32 bags of the 200 ml solution.
Not all pack sizes may be marketed.
6.6 Special Precautions For Disposal And Other Handling
For single epidural use only. Do not use unless the solution is clear and container is undamaged. Discard any unused solution.
The solution/dilution should be inspected visually prior to use. Only clear solutions without visible particles should be used.
7. Marketing Authorisation Holder
Abbott Laboratories Ltd
Abbott House
Vanwall Business Park
Vanwall Road
Maidenhead
Berkshire
SL6 4XE
United Kingdom
8. Marketing Authorisation Number(S)
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9. Date Of First Authorisation/Renewal Of The Authorisation
Date of first authorisation: 20th August 2003
Date of last renewal: 18th December 2008
10. Date Of Revision Of The Text
02nd July 2010
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