Local anesthetic for dental use.

Administration:
Infiltration or nerve block injection.

Adults:
Use 1 to a maximum of 3 cartridges.

Pediatric population:
Children from 4 years of age (ca. 20kg body weight) and older (see 4.3)

Recommended therapeutic dose:

The quantity to be injected should be determined by the age and weight of the child and the magnitude of the operation.

The average dosage is 0.75mg/kg=0.025ml of mepivacaine solution per kg body weight.

Maximum recommended dosage:

Do not exceed the equivalent of 3mg mepivacaine/kg (0.1ml mepivacaine/kg) of body weight.

Children below 4 years of age (ca. 20 kg body weight), Hypersensitivity to the active ingredient or to amide type anaesthetics, Porphyria. Patient with severe disorders of the atrioventricular conduction not compensated by pace-maker, Epilepsy not controlled by any treatment,

Warnings

Risk of anaesthesiophagia: various biting trauma (lips, cheeks, mucosa, tongue); tell the patient to avoid chewing gumor foodstuffs as long as there is no sensitivity. In children under 4 years of age, the product is not recommended, due to anaesthetic procedure not suitable under thisage. Athletes should be warned that this medicinal product contains an active substance likely to induce a positive reactionto tests undertaken in anti-doping controls.

Precautions for use

Practitioners who use local anaesthetic agents should be well versed in diagnosis and management of emergencieswhich may arise from their use. Resuscitation equipment, oxygen and other resuscitation drugs should be available for immediate use.

Mepivacaine use requires:
- Consultation to assess medical history and ongoing concomitant medication.
- Aspiration before the local anaesthetic solution is injected, so as to minimize the risk of intravascular injection.
- Slow injection while talking to the patient.

The lowest dosage that results in effective anaesthesia should be used to avoid high plasma levels and serious adverseeffects. Repeated doses of mepivacaine may cause significant increases in blood levels with each repeat dose due toslow accumulation of the drug or its metabolites. Tolerance to elevated blood levels varies with the status of the patient. Debilitated, elderly patients, acutely ill patients, and children should be given reduced doses commensurate with theirage and physical condition. Cardiovascular and respiratory (adequacy of ventilation) vital signs and the patient’s state of consciousness should bemonitored after each local anaesthetic injection. Restlessness, anxiety, tinnitus, dizziness, blurred vision, tremors, depression or drowsiness should alert the practitionerto the possibility of central nervous system toxicity. Signs and symptoms of depressed cardiovascular function may commonly result from a vasovagal reaction, particularlyif the patient is in an upright position. Dose should be minimised for patients suffering from hepatic (due to hepatic metabolisation) or renal disease. Use with caution when there is inflammation and/or sepsis in the area of the proposed injection site. Injection intohighly vascular areas especially if these are inflamed or traumatised, may result in reduced effect and increasedabsorption. Monitoring should be increased in patients under anti-coagulants (monitoring of the INR). Mepivacaine should be used cautiously (reduce the dose) in case of hypoxia, hyperkalemia and acidosis. Due to its cardiotoxicity effect, mepivacaine should be used with caution in patients with repolarisation disorder suchas QT prolongation; the indication and Posology must be discussed to prevent increased plasmatic concentration, whichmight cause severe ventricular arrhythmia. In common with other local anaesthetics, Mepivacaine should be used cautiously in patients with epilepsy, impairedcardiac conduction, or impaired respiratory function.

The product is for single use on one patient during one treatment only. Any remaining contents should be discarded.

Increased serum levels of amide anaesthetics have been reported after concurrent administration of cimetidine. If sedatives are employed to reduce patient apprehension, reduced doses of anaesthetic solution should be used sincelocal anaesthetic agents, like sedatives, are central nervous system depressants which in combination may have anadditive effect

Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with this solution. On the basis of long usage, anaesthetics of the mepivacaine type are considered to be reasonably safe for use onpregnant women.

Retrospective studies of pregnant women receiving local anaesthetics for emergency surgery early in pregnancy havenot shown that local anaesthetics cause birth defects. However, no controlled studies have been carried out in pregnant women. Moreover, no reproduction studies have been performed with the product. Therefore, caution should be taken before administering this anaesthetic during early pregnancy.

Breast-feeding

It is not known whether local anaesthetics are excreted in human milk. Because many drugs are excreted in humanmilk, caution should be exercised when mepivacaine is administered to a nursing woman

Mepivacaine hydrochloride may have a minor influence on the ability to drive and use machines. Dizziness (includingvertigo, vision disorder and fatigue) may occur following administration of mepivacaine hydrochloride (see section4.8).

Patients experiencing these symptoms should not drive or use machinery until any such symptoms havecompletely resolved.

The reported adverse effects come from spontaneous reporting and literature. The frequency classification follows the convention: Very common ( 1/10), Common (1/100 to <1/10), Uncommon ((1/1000 to <1/100), Rare ((1/10,000 to <1/1000) and Very rare (<1/10,000). Frequency “not known”: cannot be estimated from the available data. The seriousness of adverse reactions is classified from 1 (most serious) to 3 (less serious) in the following table:

¹ Laryngo-pharyngeal oedemamay characteristically occur with hoarseness and / or dysphagia.
²Bronchospasm(bronchoconstriction) may characteristically occur  with dyspnoea.
³These neuralpathologies may occur with the various symptoms of abnormal sensations (i.e.,paresthesia,hypoesthesia,dysesthesia, hyperesthesia,etc)of the lips, tongueandoral tissues. These data originated in post-marketings reports, mostly following nerve blocks in mandible, involving various branches of the trigeminal nerve.
⁴This mostly occurs in patients with underlying cardiac disease or in patients receiving certain drugs.
⁵This occurs in predisposed patients or inpatients with risk factors of ischemic heart disease.
⁶Hypoxia and hypercapnia are secondary to respiratory depression and/or to seizures and sustained muscular exertion.
⁷This occurs by accidental biting or chewing of the lips or tongue while the anaesthesia persists.

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 Saudi vigilance system.

• SaudiArabia:
The National Pharmacovigilance and Drug Safety Centre (NPC)
o Fax: +966-11-205-7662
o Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
o Toll free phone: 8002490000
o E-mail: npc.drug@sfda.gov.sa
o Website: www.sfda.gov.sa/npc

• Other GCC states:
Please contact the relevant competent authority.

Acute emergencies from local anaesthetics are generally related to high plasma levels encountered during therapeutic use of excessive dosages of local anaesthetics or to unintended intravascular injections of local anaesthetic solution.

Symptomatology

The symptoms are dose-dependent and have progressive severity in the realm of neurological manifestations, followedby vascular, respiratory and finally cardiac toxicity (detailed in section 4.8).

Central Nervous System toxicity is typical of the entire class of local anaesthetics. Symptoms may include lightheadedness, dizziness, restlessness, auditory and visual disturbances, drowsiness, disorientation, slurred speech, shivering, muscle twitching, tremors of the face, fingers and toes, generalized seizures and respiratory arrest. Hypoxia and hypercapnia occur rapidly following convulsions due to increased muscular activity, together with the interference with normal respiration. In severe cases, apnoea may occur. Acidosis increases the toxic effects of local anaesthetics. Effects on the cardiovascular system may be seen in the severe cases. Hypotension, bradycardia, arrhythmia and cardiac arrest may occur as a result of high systemic concentrations, with potentially fatal outcome. Recovery occurs as a consequence of redistribution of the local anaesthetic drug from the central nervous system and metabolism and may be rapid unless large amounts of the drug have been injected.

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 and 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 or a benzodiazepine may be administered intravenously. The clinician should be familiar, prior to use of local anaesthetics, with these anticonvulsant drugs. Supportive treatment of circulation 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, arrhythmias and cardiac arrest. If cardiac arrest should occur, standard cardio-pulmonary 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 mepivacaine.

 

Pharmacotherapeutic group: Local anaesthetics for dental use

ATC Code: N01BB03.

Mepivacaine is a local anaesthetic of amide type, acting rapidly and causing a long duration reversible block of the motor and sensorial nervous fibres and of the heart stimulation. Vasoconstriction reactions have been noted only in the case of intradermic administration.

Mepivacaine decreases the permeability of the membrane to the cations, more particularly sodium and potassium, when concentrations are high. The nervous fibres excitability decreases according to the concentrations, as the sudden increase of the permeability to sodium necessary to the formation of an action potential lowers. The neutral base comes through the myelinic tube more rapidly than the cation. The exact effect of the local anaesthetic effect has not yet been explained. The models developed until now are still hypothetical. After having taken the axon internal pH, the cation is likely to induce the nerve block, as present active form of the local anaesthetic.

The activity of the membrane is modified, as well as regards cations as the local anaesthetic molecules which are not charged.

The absorption of the local anaesthetic depends on the physico-chemical properties (as lipid solubility), on the pharmacological properties (as vasodilator effect) and on the vascularization and the irrigation of the injection area of the product.

The mepivacaine effect appears within 2 or 4 minutes in case of peripheric nerve blocks. The effect duration is determined by the progress from the tissues and by the diffusion in the blood vessels. The distribution ratio is 0.8. The plasma half-life is lengthened in patients suffering from liver disease or uraemia. The link of plasma proteins is 60-78 % for mepivacaine, mainly with -glycoprotein acid. The mepivacainepKa is 7.6.

The blood half-life lasts between 2 and 3 hours after the administration of 600 mg of mepivacaine for a spineanaesthesia. The clearance of the amides depends strongly on the liver irrigation.

The metabolism of mepivacaine occurs mainly through an oxidising process in the liver, following a N-demethylation pathway leading to 2’-6’-pipecoloxylidide (PPX) and an aromatic hydroxylation pathway leading to PPX-4’- hydroxymethyl and PPX-3’-hydroxymethyl. The hydroxylated metabolites are eliminated mainly by the bile and are glucuronized at 99 %. The metabolites are then reabsorbed by the intestines and eliminated in the urines.
In adults, only 5 % of mepivacaine are eliminated under the unchanged form, through the kidneys. The elimination of the unchanged form can be increased by urine acidification.

The remaining part of the administered dose is eliminated in the urines under the form of PPX and glucuronized PPX hydroxylated metabolites. Only a small part of the metabolites are found in the faeces. In the new-borns, 71 % of the administered dose is excreted under unchanged mepivacaine.

In adults and neonates, 90% of the administered dose is excreted in the urines within 24 hours.

The DL⁵⁰ is 39.9 mg/kg in the mouse and 27.8 mg/kg in the rat in the case of intravenous injection. The toxic dose (TD⁵⁰) is 7.2 mg/kg in the dog in case of intravenous administration. The mepivacaine toxic threshold in the man ranges between 5 and 10 μg/ml. The relative toxicity is 0.81, compared to lidocaine and 1, compared to procaine.

Sodium Chloride

Water for Injections

In the absence of compatibility studies, Medicaine 3% must not be mixed with any other medicinal products.

36 months.

Do not store above 25°C.

In order to protect from light, keep the cartridge in the outer carton tightly closed.

Do not freeze.

Cartridges of 1.8 ml.

Box containing 50 cartridges.

One cartridge should be used on one patient during one session of treatment only. If only part is used, the remainder must be discarded.