SUMMARY OF PRODUCT CHARACTERISTICS

Transcription

1 PART II SUMMARY OF PRODUCT CHARACTERISTICS 1. NAME OF THE MEDICINAL PRODUCT Lignospan Special (20 mg/12.5 microgram per ml) Solution for injection 2.2 ml 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Lidocaine hydrochloride, anhydrous 20 mg/ml (as lidocaine hydrochloride). Adrenaline (epinephrine) 12.5 micrograms/ml (as adrenaline tartrate (epinephrine bitartrate)). Each cartridge containing 2.2 ml of solution contains 44 mg of Lidocaine hydrochloride anhydrous (as lidocaine hydrochloride) and 27.5 micrograms of adrenaline (epinephrine) (as adrenaline tartrate (epinephrine bitartrate)). The solution contains 1.2 mg/ml of potassium metabisulphite (E224). For a full list of excipients, see section PHARMACEUTICAL FORM Solution for injection. Clear, colourless, sterile injection solution. 4. CLINICAL PARTICULARS 4.1 Therapeutic Indications Local anaesthesia for dental procedures by infiltration or nerve block injections. 4.2 Posology and Method of Administration LIGNOSPAN SPECIAL is restricted to adults and children aged 4 and over. This kind of anesthesia is not appropriate for children below Posology Adults The amount of LIGNOSPAN 2% SPECIAL to be administered depends on the extent of the procedure. For most common operations, one cartridge is sufficient; for more extensive procedures, 2 to 3 cartridges may be used. Whatever the procedure is, the dose of 300 mg (# 6 mg/kg) of lidocaine hydrochloride should not be exceeded in one sitting. Paediatric patients The amount of LIGNOSPAN 2% SPECIAL to be injected should be determined according to the child s age and body weight and to the procedure to be performed. The average dose of lidocaine hydrochloride is 20 to 30 mg per sitting. According to the child's body weight, the average recommended dose per sitting is: - 10 to 20 kg: 0.45 to 0.90 ml - 20 to 30 kg: 0.70 to 1.4 ml - 30 to 40 kg: 0.90 to 1.8 ml

2 The maximal dose of lidocaine hydrochloride (mg) to be given per sitting may be calculated as follows: body weight (kg) x The dose of 2.2 mg/kg should not be exceeded in one sitting. Elderly The dose of LIGNOSPAN 2% SPECIAL should be half of that recommended in adults for a similar procedure. Lidocaine is metabolized by the liver. Reduced doses should be administered in patients with severe hepatic failure The dose should be reduced in case of hypoxia, hyperkalemia or metabolic acidosis Method of administration The injection must be local or regional, intra-buccal and submucosal. Toxic reactions may be associated with accidental intravascular injection. Therefore the dentist must verify that there is no risk of inadvertent intravascular injection by repeated aspirations during the injection to ensure that the point of the needle is not in the lumen of a vessel, particularly in case of locoregional anesthesia (trunkular anesthesia). The speed of injection should not exceed 1ml /minute. LIGNOSPAN 2% SPECIAL must not be mixed with any other preparation for injection 4.3 Contraindications LIGNOSPAN SPECIAL is contra-indicated in the following situations: Hypersensitivity to lidocaine or to any local anesthetic agents of the amide type. Patients with known hypersensitivity to potassium bisulfite Severe and not equipped atrio-venticular conduction disorders Uncontrolled epilepsy Severe uncontrolled hypertension or evolutive coronary disease Acute intermittent porphyria Patients receiving guanethidine and guanethidine related drugs 4.4 Special Warnings and Special Precautions for Use Warnings This product contains an adrenergic direct agonist: adrenaline. This medicinal product contains a sulphite which may rarely cause severe hypersensitivity reaction and bronchspasm. This medicinal product contains less than 1 mmol sodium (23mg) and less than 1 mmol potassium (39mg) per cartridge i.e essentially sodium-free and potassium-free There is a risk of local necrosis in patients with diabetes mellitus or hypertension The injection into an inflamed or infected tissue should be avoided (risk of reduction of anesthetic efficacy).

3 There is a risk of anesthesiophagia leading to bites (lips, jaws, tongue); patients should be advised to avoid chewing chewing-gum or any type of food as long as the anesthesia persists. It is recommended that the patient does not take any food before he has recovered sensitivity. There is a possibility of positive results on doping tests performed on sportsmen. Precautions for use The use of LIGNOSPAN SPECIAL absolutely requires: - careful patient's interview prior to the injection in order to be informed of his general condition, his current concomitant medications and his history, - to inject first a test dose (5 to 10% of the dose required for the procedure) when there is a risk of known allergy, - to inject the product slowly (see mode of administration) with repeated aspirations to ensure that the point of the needle is not in a vessel; this monitoring should be even more extensive in patients receiving anticoagulants, - to keep talking with the patient during the injection to monitor his condition. Due to the presence of adrenaline, LIGNOSPAN SPECIAL must be used with particular caution in patients with arrhythmia (except bradycardia) particularly of ventricular origin, repolarisation disturbances with QT segment prolongation, coronary disease and hypertension, obstructive cardiomyopathy and uncontrolled hyperthyroidism. 4.5 Interaction with other medicinal products and other forms of interaction Due to the presence of adrenaline, the following drug interactions may occur. Contra-indicated associations: Guanethidine and related drugs (adrenergic antiglaucoma preparations) : risk of severe hypertension. If the use of LIGNOSPAN SPECIAL cannot be avoided, the products should be used with special care and in reduced doses. Clinically significant interactions requiring precautions for use: - volatile halogenated anesthetics: risk of severe ventricular arrhythmias; in this case the dose of vasoconstrictors should be reduced; do not exceed 0.1 mg of vasoconstrictors within 10 minutes or 0.3 mg within one hour in adults, - imipramin related tricyclic antidepressants: risk of paroxystic hypertension with possible arrhythmias; do not exceed 0.1 mg of vasoconstrictors within 10 minutes or 0.3 mg within one hour in adults, - serotoninergic and noradrenergic antidepressants (has been described for minalcipran and venlafaxine): risk of paroxystic hypertension with possible arrhythmias; do not exceed 0.1 mg of vasoconstrictors within 10 minutes or 0.3 mg within one hour in adults, - non-selective (iproniazid) and selective (moclobemide, toloxatone) mono-amine-oxydase inhibitors: risk of increase of the vasoconstrictive properties of adrenaline and noradrenaline; concomitant administration with LIGNOSPAN SPECIAL should be done only under strict medical supervision. 4.6 Pregnancy and Lactation Use in pregnancy In experimental studies, no lidocaine induced teratogenic or embryotoxic effects have been observed. The frequency of congenital abnormalities (major malformations, minor malformations and major classes of congenital abnormalities) did not increase among the children of 293 women treated with lidocaine as a local anesthetic during the first 4 lunar months of pregnancy in the Collaborative

4 Perinatal Project. Similarly, the frequency of congenital abnormalities was not higher than expected among children born from 947 women treated any time during pregnancy with lidocaine as a local anesthetic. These data suggest that the risk of congenital anomalies in children of women given lidocaine as a local anesthetic during pregnancy is probably not substantially greater than the risk in the general population. It is recognized that in humans lidocaine crosses the blood-placenta barrier and that only prospective epidemiological studies could rule out the risk of teratogenicity; however due to the small quantity of drug administered during dental anesthesia and the reassuring clinical and experimental data mentioned above, lidocaine may be administered during pregnancy, if requested by the patient's condition. Use during lactation It is established that very low amounts of lidocaine is excreted in human milk. Due to the small quantity of drug administered during dental anesthesia that would result in a minor non significant exposure of the infants, lidocaine may be administered during pregnancy, if requested by the patient's condition. 4.7 Effects on ability to Drive and Use Machines 4.8 Undesirable Effects ADR are rare (< 1/1,000,000). Adverse experiences following the administration of lidocaine are similar in nature to these observed with other amide local anaesthetic agents. These adverse experiences are, in general, dose-related and may result from high plasma levels caused by excessive dosage, rapid absorption or unintended intravascular injection or may result from a hypersensitivity, idiosyncrasy or diminished tolerance on the part of the patient. The incidence and nature of adverse events following the administration of 2% lidocaine/epinephrine in dental practice was evaluated in a randomized, double-blind, clinical trials (refs. 1, 2, 3). The following adverse reactions may occur:

5 FREQUENCY OF ADVERSE EVENTS Very common (> 0.1%) 1 Body as a Whole Injection site pain, headache, face oedema, infection, gingivitis, hypoaesthesia, paraesthesia, dizziness, chest pain, vomiting, neuralgia. Skin and subcutaneous tissue disorder: pruritus, rash,, sweating Musculoskeletal disorder: arthralgia, myalgia Rare (> and < 0.001%) 1,2,3 Immune system disorders Allergic reactions are characterised by skin lesion, urticaria, oedema or anaphylactoid reactions. Allergic reactions as a result of sensitivity to lidocaine are extremely rare and, if they occur, should be managed by conventional means. The detection of sensitivity by skin testing is of doubtful value. Not known Psychiatric disorders Nervousness, euphoric mood, and anxiety Nervous system disorders CNS manifestations are excitatory and/or depressant and may be characterised by agitation, (light headedness), logorrhea, tinnitus, nystagmus, somnolence, confusional state (drowsiness), tremor, convulsion. The excitatory manifestations may be very brief or may not occur at all, in which case the first manifestation of toxicity may be drowsiness merging into disturbances in consciousness and respiratory arrest. Drowsiness following the administration of lidocaine is usually an early sign of a high blood level of the drug and may occur as a consequence of rapid absorption. Eye disorders Diplopia, vision blurred Cardiac disorders Cardiovascular manifestations are usually depressant and rare characterized by bradycardia, cardiovascular depression with arterial hypotension and possible cardiovascular collapse. Others: tachycardia, arrhythmia (cardiac ventricular disorder, ventricular fibrillation), conduction disorder (atrioventricular block) and finally possible risk of cardiac arrest. Signs and symptoms of depressed cardiovascular function may commonly result from a vasovagal reaction, particularly if the patient is in an upright position. Less commonly, they may result from a direct effect of the drug. Failure to recognise the premonitory signs such as sweating, a feeling of faintness, changes in pulse or sensorium may result in progressive cerebral hypoxia and seizure or serious cardiovascular catastrophe. Vascular disorders Hypotension, cardiovascular insufficiency (cardiovascular depression), circulatory collapse. Respiratory, thoracic and mediastinal disorders Breathing abnormalities like tachypnea, bradypnea, respiratory depression which could lead to respiratory arrest. Gastrointestinal disorders: Nausea General disorders and administration site conditions: Malaise, feeling hot (sensation of heat), feeling cold, oedema (Injection site oedema).

6 This product contains sulphites that may induce or worsen anaphylactic reactions (risk of severe bronchoconstriction). 4.9 Overdose a - Overdosage - Symptoms Acute emergencies from local anaesthetics are generally related to high plasma levels encountered during therapeutic use of excessive dosage of local anaesthetics, or to unintended intra-vascular injection of local anaesthetic solution (See Undesirable Effects - Special Warnings and Special Precautions for Use). b - Management of local anaesthetic emergencies The first consideration is prevention, best accomplished by careful and constant monitoring of cardiovascular and respiratory vital signs and the patient's state of consciousness after each local anaesthetic injection. At the first sign of change, oxygen should be administered. The first step in the management of convulsions consists of immediate attention to the maintenance of a patent airway, assisted or controlled ventilation with oxygen and a delivery system capable of permitting immediate positive airway pressure by mask. Immediately after the institution of these ventilatory measures, the adequacy of the circulation should be evaluated, keeping in mind that drugs used to treat convulsions sometimes depress the circulation when administered intravenously. Should convulsions persist despite adequate respiratory support and if the status of the circulation permits, small increments of an ultra-short acting barbiturate (such as thiopental or thiamylal) or a benzodiazepine (such as diazepam) may be administered intravenously. The clinician should be familiar, prior to use of local anaesthetics, with these anticonvulsant drugs. Supportive treatment of circulatory depression may require administration of intravenous fluids and, when appropriate, a vasopressor as directed by the clinical situation (e.g., ephedrine). If not treated immediately, both convulsions and cardiovascular depression can result in hypoxia, acidosis, bradycardia, arrhythmia and cardiac arrest. If cardiac arrest should occur, standard cardiopulmonary resuscitative measures should be instituted. Endotracheal intubation, employing drugs and techniques familiar to the clinician, may be indicated, after initial administration of oxygen by mask, if difficulty is encountered in the maintenance of a patent airway or if prolonged ventilatory support (assisted or controlled) is indicated. Dialysis is of negligible value in the treatment of acute overdosage with lidocaine. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic Properties ATC code N01 BB 52 Lidocaine hydrochloride is the anaesthetic agent in the formula. It stabilizes the neuronal membrane and prevents the initiation and transmission of nerve impulses, thereby effecting anaesthesia. The presence of adrenaline tartrate, a vasoconstrictor in Lignospan Special, has the effect of retaining the anaesthetic at the site of injection; this reduces the rate of elimination, through absorption, of lidocaine hydrochloride, thus prolonging the duration of the local anaesthetic action.

7 5.2 Pharmacokinetic Properties Information derived from diverse formulations, concentrations and usages reveals that lidocaine is completely absorbed following parenteral administration. Its rate of absorption depending, for example, upon various factors such as the site of administration and the presence or absence of a vasoconstrictor agent. The plasma binding of lidocaine is dependent on drug concentration and the fraction bound decreases with increasing concentration; at concentration of 1 to 4 micrograms of free base per ml, 60 to 80% of lidocaine is protein bound. Binding is also dependent on the plasma concentration of the alpha-1-acid glycoprotein. Lidocaine crosses the blood brain and placental barriers presumably by passive diffusion. Lidocaine is metabolised rapidly by the liver, and metabolites and unchanged drug are excreted by the kidneys. Biotransformation includes oxidative N-dealkylation, ring hydroxylation, cleavage of the amide linkage and conjugation. N-dealkylation, a major pathway of biotransformation, yields the metabolites monoethylglycinexylidide and glycinexylidide. The pharmacological and toxicological actions of these metabolites are similar to, but less potent than, those of lidocaine. Approximately 90% of lidocaine administered is excreted in the form of various metabolites and less than 10% is excreted unchanged. The primary metabolite in urine is a conjugate of 4-hydroxy-2,6-dimethylaniline. Because of the rapid rate at which lidocaine is metabolised, any condition that affects liver function may alter lidocaine kinetics. The half-life may be prolonged two-fold or more in patients with liver dysfunction. Renal dysfunction does not affect lidocaine kinetics but may increase the accumulation of metabolites. Factors such as acidosis and the use of CNS stimulants and depressants affect the CNS levels of lidocaine required to produce overt systemic effects. Objective adverse manifestations become increasingly apparent with increasing venous plasma levels above 6 micrograms free base per ml. In the rhesus monkey, arterial blood levels of 18 to 21 micrograms/ml have been shown to be threshold for convulsive activity. Absorption of adrenaline from subcutaneous tissues occurs slowly because of local vasoconstriction. Adrenaline is rapidly inactivated in the body despite its stability in the blood. The liver, which is rich in both of the enzymes responsible for the destruction of circulating adrenaline (COMT and MAO), is an important tissue in the degradation process. The greater part of a dose of adrenaline injected into man is excreted as metabolites in the urine (GOODMAN and GILMAN'S). Adrenaline tartrate has the effect of prolonging the localisation of the anaesthetic at the site of the injection. From the information quoted beforehand, it can be concluded that in Lignospan Special solution, the presence of the vasoconstrictor slows down the absorption, and therefore the metabolism of lidocaine.

8 5.3 Preclinical Safety Data Acute and subacute toxicity studies Lidocaine The LD50 of IV lidocaine is 20-46, 20 and mg/kg in mouse, rat and rabbit respectively. Acute toxicity is highly reduced when the drug is injected subcutaneously (LD50 in mouse and rat : and 335 mg/kg respectively). The cause of death is respiratory arrest that is preceded by convulsions. In rats, concomitant IV administration of adrenaline was found to decrease the LD 50 of lidocaine by a 1.8 fold extent (11.4 versus 20.1 mg/kg). Subacute toxicity studies in the rat and monkey with 2% solutions of lidocaine in a dose range of mg/kg revealed no signs of toxicity. Adrenaline The LD 50 of adrenaline by subcutaneous administration is 5 mg/kg in rat and dog. When administered intravenously, the LD 50 is 0.1 mg/kg in dog. Effect on reproduction and teratogenicity studies The studies one may conclude that lidocaine is devoid of teratogenic effect and of deleterious effect on reproduction, in rats. Mutagenicity and carcinogenicity studies The mutagenic potential of lidocaine has not been determined. Long-term studies with local anesthetics (including lidocaine) have not been conducted to evaluate the carcinogenic potential due to short term administration in humans. 6. PHARMACEUTICAL PARTICULARS 6.1 List of Excipients Sodium chloride, Potassium metabisulphite (E224), Disodium edetate, Sodium hydroxide solution (for ph-adjustment), Water for injections. 6.2 Incompatibilities None applicable. 6.3 Shelf Life Two years. 6.4 Special Precautions for Storage Do not store above 25 C. Store in the original package in order to protect from light. Do not freeze.

9 6.5 Nature and Contents of Container Dental clear type I glass cartridges sealed with a rubber stopper and aluminium ring at one end and a rubber plunger at the other. Each box contains 50 cartridges of 2.2 ml. 6.6 Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product Use on one patient during one session of treatment only. If only part is used the remainder must be discarded in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Septodont 58, rue du Pont de Créteil Saint-Maur-des-Fossés France 8. MARKETING AUTHORISATION NUMBER PA 196/13/2 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 16 February 1988 Date of last renewal: 16 February DATE OF REVISION OF THE TEXT