BARTINEST 1:200 000, ARTIKENT 1:200 000, ISONEST 1:200 000, SEPTANEST 1:200 000 - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

SEPTANEST 1:200,000 / ARTIKENT 1:200,000 / BARTINEST 1:200,000 /

ISONEST 1:200,000

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Excipients with known effect: sodium metabisulfite (E223), sodium chloride.

Septanest/Arti­kent/Bartines­t/Isonest 1:200,000 contains 0.804 mg sodium per 1 ml of solution i.e. 1.37 mg/1.7 ml or 1.77 mg/2.2 ml.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Solution for injection.

Clear colourless solution.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Local and loco-regional anaesthesia in dental procedures.

Septanest/Arti­kent/Bartines­t/Isonest is indicated in adults, adolescents and children above 4 years of age (or from 20 kg (44 lbs) of body weight).

4.2 Posology and method of administration

For professional use by physicians or dentists only.

Posology

For all populations, the lowest dose leading to effective anaesthesia should be used. The necessary dosage must be determined on an individual basis.

For a routine procedure, the normal dose for adult patients is of 1 cartridge, but the contents of less of a cartridge may be sufficient for effective anaesthesia. At the discretion of the dentist, more cartridges may be required for more extensive procedures without exceeding the maximum recommended dose.

Septanest/Arti­kent/Bartines­t/Isonest 1:200,000 is indicated for use in most routine dental procedures.

Septanest/Arti­kent/Bartines­t/Isonest 1:100,000 is also available and is preferable for use in more complex procedures, such as requiring pronounced hemostasis.

Concomitant use of sedatives to reduce patient anxiety:

The maximum safe dose of local anaesthetics may be reduced in sedated patients due to an additive effect on central nervous system depression (see section 4.5).

Adults and adolescents (12 to 18 years of age)

In adults and adolescents, the maximum articaine dose is 7 mg/kg with an absolute maximum articaine dose of 500 mg. The maximum articaine dose of 500 mg corresponds to a healthy adult of more than 70 kg body weight.

The table below illustrates the maximum recommended dose:

Children (4 to 11 years of age)

The safety of Septanest/Arti­kent/Bartines­t/Isonest 1:200,000 in children aged 4 years and below has not been established. No data are available.

The quantity to be injected should be determined by the age and weight of the child and the magnitude of the operation. The average effective dose of articaine is 2 mg/kg and 4 mg/kg for simple and complex procedures, respectively. The lowest dose providing effective dental anaesthesia should be used. In children aged 4 years (or from 20 kg (44 lbs) of body weight) and above, the maximum dose of articaine is 7 mg/kg only with an absolute maximum dose of 385 mg articaine for a healthy child of 55 kg body weight.

The table below illustrates the maximum recommended dose:

(5.6 cartridges)

Special populations

Elderly and Patients with renal disorders:

Due to the lack of clinical data, particular precaution should be used in order to administer the lowest dose leading to effective anaesthesia in elderly patients and in patients with renal disorders (section 4.4 and 5.2).

Elevated product plasma levels may occur in these patients in particular after repeated use. In case of required reinjection, patient should be strictly monitored, to identity any sign of relative overdose (see section 4.9).

Patients with hepatic impairment

Particular precaution should be used in order to administer the lowest dose leading to efficient anaesthesia in patients with hepatic impairment, in particular after repeated use, although 90% of articaine is first inactivated by unspecific plasma esterases in the tissue and blood.

Patients with plasma cholinesterase deficiency

Elevated product plasma levels may occur in patients with cholinesterase deficiency or under acetylcholines­terase inhibitors treatment since the product is inactivated at 90% by plasmatic esterases, see section 4.4 and 5.2. Therefore, the lowest dose leading to effective anaesthesia should be used.

Method of Administration

Infiltration and perineural use in oral cavity.

Local anaesthetics should be injected with caution when there is inflammation and/or infection at the site of the injection. The rate of injection should be very slow (1 ml/min).

Precautions to be taken before handling or administering the medicinal product

This medicinal product should only be used by or under the supervision of physicians or dentists sufficiently trained and familiar with diagnosis and treatment of systemic toxicity. The availability of appropriate resuscitation equipment and medication should be ensured before induction of regional anaesthesia with local anaesthetics to enable prompt treatment of any respiratory and cardiovascular emergencies. The patient’s state of consciousness should be monitored after each local anaesthetic injection.

When using Septanest/Arti­kent/Bartines­t/Isonest 1:200,000 for infiltration or regional block anaesthesia, injection should always be made slowly and with prior aspiration.

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

4.3 Contraindications

– Hypersensitivity to articaine (or any local anaesthetic agent of the amide type), to adrenaline or to any of the excipients listed in section 6.1.

– Patients with epilepsy not controlled by treatment.

4.4 Special warnings and precautions for use

Before using this medicinal product, it is important:

– To make inquiries into the patient’s current therapies and history;

– To maintain verbal contact with the patient

– To have resuscitative equipment at hand (see section 4.9)

Special warnings

This medicinal product must be used with special caution in patients with the following disorders and postponement of dental surgery should be considered if the condition is severe and/or unstable.

Patients with cardiovascular disorders:

The lowest dose leading to efficient anaesthesia should be used in case of:

Cardiac impulse formation and conduction disturbances (e.g. 2nd or 3rd degree atrioventricular block, marked bradycardia)

Acute decompensated heart failure (acute congestive heart failure)

Hypotension

Patients with paroxysmal tachycardia or absolute arrhythmias with rapid heart rate

Patients with unstable angina or a history of recent (less than 6 months) myocardial infarction

Patients with recent (3 months) coronary artery bypass surgery

Patients taking non-cardioselective beta-blockers (e.g. propranolol) (risk of hypertensive crisis or severe bradycardia), (see section 4.5)

Patients with uncontrolled hypertension

Concomitant treatment with tricyclic antidepressants, as these active substances can intensify the cardiovascular effects of adrenaline. (see section 4.5)

This medicinal product must be used with caution in patients with the following disorders:

Patients with epileptic disease:

Because of their convulsive actions, all local anaesthetics should be used very cautiously.

Patients with plasma cholinesterase deficiency

A plasma cholinesterase deficiency can be suspected when clinical signs of overdose occurs with usual dosage of anesthesia and when a vascular injection has been excluded. In this case, caution shall be used for the next injection and reduced dose shall be applied.

Patients with renal disease:

The lowest dose leading to effective anaesthesia should be used.

Patients with severe hepatic disease:

This medicinal product should be used cautiously due to the presence of hepatic disease although 90% of articaine is first inactivated by unspecific plasma esterases in the tissue and blood.

Patients with myasthenia gravis treated by acetylcholines­terase inhibitors: The lowest dose leading to effective anaesthesia should be used.

Patients with porphyria

Septanest/Arti­kent/Bartines­t/Isonest should only be used in patients with acute porphyria when no safer alternative is available. Appropriate precautions should be taken in all patients with porphyria, as this medicinal product can trigger porphyria.

Patients with concomitant treatment with halogenated inhalation anaesthetics

The lowest dose of the medicinal product leading to effective anaesthesia should be used (see section 4.5).

Patients receiving treatment with antiplatelets / anticoagulants:

Septanest/Arti­kent/Bartines­t/Isonest should be administered with caution in patients, who are using antiplatelet/an­ticoagulant medicines or are suffering from coagulation disorder, because of higher risk of bleeding. The higher risk of bleeding is more associated with the procedure, rather than with the medicine.

Elderly patients:

Elevated product plasma levels may occur in elderly patients in particular after repeated use. In case of required reinjection, patient should be strictly monitored, to identity any sign of relative overdose (see section 4.9).

Therefore, the lowest dose leading to effective anaesthesia should be used.

The use of Septanest/Arti­kent/Bartines­t/Isonest 1:200,000 over

Septanest/Arti­kent/Bartines­t/Isonest 1:100,000 should be considered on account of its lower adrenaline content of 5 micrograms/ml in:

Patients with cardiovascular diseases (e.g. heart failure, coronary heart disease, history of myocardial infarction, cardiac arrhythmia, hypertension)

Patients with cerebral circulation disturbances, history of strokes

It is recommended that dental treatment with articaine/adre­naline be deferred for six months following a stroke due to the increased risk of recurrent strokes.

Patients with uncontrolled diabetes:

This medicinal product should be used cautiously due to hyperglycemic effect of adrenaline.

Patients with thyreotoxicosis:

This medicinal product should be used cautiously due to the presence of adrenaline.

Patients with pheochromocytoma:

This medicinal product should be used cautiously due to the presence of adrenaline.

Patients with susceptibility of acute angle-closure glaucoma:

This medicinal product should be used cautiously due to the presence of adrenaline.

The lowest dose leading to effective anaesthesia should be used.

This medicinal product must be used safely and effectively under appropriate conditions:

Adrenaline impairs the flow of blood in the gums, potentially causing local tissue necrosis.

Very rare cases of prolonged or irreversible nerve injury and gustatory loss have been reported after mandibular block analgesia.

The local anaesthetic effects may be reduced when this medicinal product is injected into an inflamed or infected area.

The dose must also be reduced in case of hypoxia, hyperkalaemia and metabolic acidosis.

Risk of biting trauma (lips, cheeks, mucosa, and tongue) exists, especially in children; the patient should be told to avoid chewing gum or eating until normal sensation is restored.

This medicinal product contains sodium metabisulfite, a sulfite that may rarely cause hypersensitivity reactions and bronchospasm.

This medicinal product contains less than 1 mmol sodium (23 mg) per cartridge, i.e. it is considered as essentially “sodium free”.

If there is any risk of an allergic reaction, choose a different medicine for anesthesia (see section 4.3).

Precautions for use

Risk associated with accidental intravascular injection:

Accidental intravascular injection may cause sudden high levels of adrenaline and articaine in the systemic circulation. This may be associated with severe adverse reactions, such as convulsions, followed by central nervous and cardiorespiratory depression and coma, progressing to respiratory and circulatory arrest.

Thus, to ensure that the needle does not penetrate a blood vessel during injection, aspiration should be performed before the local anaesthetic medicinal product is injected. However, the absence of blood in the syringe does not guarantee that intravascular injection has been avoided.

Risk associated with intraneural injection:

Accidental intraneural injection may lead the drug to move in retrograde manner along the nerve.

In order to avoid intraneural injection and to prevent nerve injuries in connection with nerve blockades, the needle should always be slightly withdrawn if electric shock sensation is felt by the patient during injection or if the injection is particularly painful. If needle nerve injuries occur, the neurotoxic effect could be aggravated by articaine potential chemical neurotoxicity and the presence of adrenaline as it may impair the perineural blood supply and prevent articaine local wash-out.

4.5 Interaction with other medicinal products and other forms of interaction

Interactions with articaine

Interactions requiring precautions for use:

Other local anaesthetics

Toxicity of local anaesthetics is additive.

The total dose of all local anaesthetics administered should not exceed the maximum recommended dose of the drugs used.

Sedatives (central nervous system depressants e.g. benzodiazepine, opioids): If sedatives are employed to reduce patient's appre­hension, reduced doses of anaesthetics should be used since local anaesthetic agents, like sedatives, are central nervous system depressants which in combination may have an additive effect (see section 4.2).

Interactions with adrenaline

Interactions requiring precautions for use:

Halogenated volatile anaesthetics (e.g., halothane):

Reduced doses of this medicinal product should be used due to sensitization of the heart to the arrhythmogenic effects of catecholamines: risk of severe ventricular arrhythmia.

Discussion with the anaesthetist before local anaesthetic administration during general anaesthesia is recommended.

Postganglionic adrenergic blocking agents (e.g., guanadrel, guanethidine, and rauwolfia alkaloids):

Reduced doses of this medicinal product should be used under strict medical supervision with careful aspiration due to possible increase response to adrenergic vasoconstrictors: risk of hypertension and other cardiovascular effects.

Non-selective beta-adrenergic blockers (e.g., propranolol, nadolol):

Reduced doses of this medicinal product should be used due to possible increase in blood pressure and an increased risk of bradycardia.

(TCAs) Tricyclic antidepressants (e.g., amitriptyline, desipramine, imipramine, nortriptyline, maprotiline and protriptyline):

Dose and rate of administration of this medicinal product should be reduced due to an increased risk of severe hypertension.

COMT inhibitors (Catechol-O-methyl transferase inhibitors) (e.g., entacapone, tolcapone):

Arrhythmias, increased heart rate and blood pressure variations may occur.

A reduced amount of adrenaline in dental anaesthesia should be given to patients on COMT inhibitors.

MAO inhibitors (both A-selective (e.g. moclobemide) and non-selective (e.g. phenelzine, tranylcypromine, linezolide) :

If the concurrent use of these agents cannot be avoided, the dose and rate of administration of this product should be reduced, and the product should be used under strict medical supervision due to possible potentiation of the effects of adrenaline leading to the risk of hypertensive crisis.”

Drugs causing arrhythmias (e.g., antiarrhythmics like digitalis, quinidine):

Dose of administration of this medicinal product should be reduced due to the increased risk of arrhythmia when both adrenaline and digital glucosides are administered concomitantly to patients. Careful aspiration prior to administration is recommended.

Ergot-type oxytocic drugs (e.g., methysergide, ergotamine, ergonovine): Use this medicinal product under strict medical supervision due to additive or synergistic increases in blood pressure and/or ischemic response.

Sympathomimetic vasopressors (e.g., mainly cocaine but also amphetamines, phenylephrine, pseudoephedrine, oxymetazoline):

There is a risk of adrenergic toxicity.

If any sympathomimetic vasopressor has been used within 24 hours, the planned dental treatment should be postponed.

Phenothiazines (and other neuroleptics):

Use with caution in patients taking phenothiazines considering the risk of hypotension due to possible inhibition of adrenaline effect.

4.6 Fertility, pregnancy and lactation

Pregnancy

Animal studies with articaine 40 mg/ml + adrenaline 10 micrograms/ml, as well as with articaine alone, have not shown adverse effects on pregnancy, embryonal/foetal development, birth or postnatal development (see section 5.3).

Animal studies have shown that adrenaline is toxic to reproduction at doses higher than maximal recommended dose (see section 5.3).

There is no experience of the use of articaine in pregnant women, except during childbirth. Adrenaline and articaine cross the placental barrier, although articaine does so to a lesser extent than other local anaesthetics. Serum concentrations of articaine measured in newborn infants were approx. 30% of maternal levels. In the event of inadvertent intravascular administration in the mother, adrenaline can reduce uterine perfusion.

During pregnancy, Septanest/Arti­kent/Bartines­t/Isonest 1:100,000 should only be used after a careful analysis of the benefit-to-risk ratio has been made.

On account of its lower adrenaline content, the use of Septanest/Artikent/ Bartinest/Isonest 1:200,000 over Septanest/Arti­kent/Bartines­t/Isonest 1:100,000 should be preferred.

Breastfeeding

As a result of the rapid drop in serum levels and rapid elimination, clinically relevant quantities of articaine are not found in breast milk. Adrenaline passes into breast milk but also has a short half-life.

It is not usually necessary to suspend breast-feeding for short-term use, starting from 5 hours following anesthesia.

Fertility

Animal studies with articaine 40 mg/ml + adrenaline 10 micrograms/ml have not shown effects on fertility (see section 5.3). At therapeutic doses, adverse effects on human fertility are not expected.

4.7 Effects on ability to drive and use machines

The combination articaine hydrochloride with adrenaline tartrate solution for injection may have a minor influence on the ability to drive and use machines. Dizziness (including vertigo, vision disorder and fatigue) may occur following administration of Septanest/Arti­kent/Bartines­t/Isonest (see Section 4.8 of SmPC). So, patients should not leave the dental office until they recover their abilities (generally within 30 minutes) following the dental procedure.

4.8 Undesirable effects

a) Summary of the safety profile

Adverse reactions following administration of articaine / adrenaline are similar to those observed with other local amide anaesthetics / vasoconstrictors. These adverse reactions are, in general, dose-related. They may also result from hypersensitivity, idiosyncrasy, or diminished tolerance by patient. Nervous system disorders, local injection site reaction, hypersensitivity, cardiac disorders and vascular disorders are the most frequently occurring adverse reactions.

Serious adverse reactions are generally systemic.

b) Tabulated list of adverse reactions

The reported adverse reactions come from spontaneous reporting, clinical studies and literature.

The frequencies classification follows the convention: Very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000), and very rare (<1/10,000)

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

c) Description of selected adverse reactions

1 Allergic reactions should not be mistaken with syncopal episodes (cardiac palpitations due to adrenaline).

2 A 2 week delay in the onset of facial paralysis has been described following administration of articaine combined with adrenaline, and the condition was unchanged 6 months later.

3 These neural pathologies may occur with various symptoms of abnormal sensations. Paresthesia can be defined as spontaneous abnormal usually non-painful sensation (e.g., burning, pricking, tingling or itching) well beyond the expected duration of anesthesia. Most cases of paresthesia reported following dental treatment are transient and resolve within days, weeks or months.

Persistent paresthesia, mostly following nerve blocks in the mandible, is characterized by slow, incomplete, or lack of recovery.

4 Several adverse events, like agitation, anxiety / nervousness, tremor, speech disorder may be warning signs before CNS depression. In attendance of these signs, patients should be requested to hyperventilate and surveillance should be instituted (see Section 4.9 of SmPC).

d) Paediatric population

The safety profile was similar in children and adolescents from 4 to 18 years old compared to adults. However, accidental soft tissue injury was observed more frequently, especially in 3 to 7 year old children, due to the prolonged soft tissue anaesthesia.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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 Store

4.9 Overdose

Types of overdose

Local anaesthetic overdose in the largest sense is often used to describe:

absolute overdose,

relative overdose such as:

– inadvertent injection into a blood vessel, or

– abnormal rapid absorption into the systemic circulation, or

– delayed metabolism and elimination of drug.

In case of relative overdose, patients generally present symptoms within the first minutes. Whereas in case of absolute overdose, signs of toxicity, depending on the injection site, appear later after the injection.

Symptoms

Due to an overdose (absolute or relative), since excitement may be transient or absent, the first manifestations may be drowsiness merging into unconsciousness and respiratory arrest.

Due to articaine:

The symptoms are dose-dependent and have progressive severity in the realm of neurological manifestations (presyncope, syncope, headache, restlessness, agitation, confusional state, disorientation, dizziness (lightheadedness), tremor, stupor, deep CNS depression, loss of consciousness, coma, convulsion (including tonic-clonic seizure), speech disorder (e.g., dysarthria, logorrhea), vertigo, balance disorder (disequilibrium)), eyes manifestations (mydriasis, vision blurred, accommodation disorder) followed by vascular (pallor (local, regional, general)), respiratory (apnoea (respiratory arrest), bradypnoea, tachypnoea, yawning, respiratory depression) and finally cardiac (cardiac arrest, myocardial depression) toxicity.

Acidosis exacerbates the toxic effects of local anaesthetics.

Due to adrenaline:

The symptoms are dose-dependent and have progressive severity in the realm of neurological manifestations (restlessness, agitation, presyncope, syncope) followed by vascular (pallor (local, regional, general)), respiratory (apnoea (respiratory arrest), bradypnoea, tachypnoea, respiratory depression) and finally cardiac (cardiac arrest, myocardial depression) toxicity.

Treatment of overdose

The availability of resuscitation equipment and medication should be ensured before administration of regional anaesthesia with local anaesthetics to enable prompt treatment of any respiratory and cardiovascular emergencies.

The seriousness of overdose symptoms should have physicians/dentists to implement protocols that foresee the necessity of timely securing the airway and providing assisted ventilation.

The patient’s state of consciousness should be monitored after each local anaesthetic injection.

systemic toxicity appear, injection of the local anaesthetic should be stoppedOxygen should rapidly be administered, if necessary by assisted ventilation. immediately. Change patient position to supine position if necessary.

CNS symptoms (convulsions, CNS depression) must promptly be treated with appropriate airway/respiratory support and the administration of anticonvulsant drugs. Optimal oxygenation and ventilation and circulatory support as well as treatment of acidosis may prevent cardiac arrest.

If cardiovascular depression occurs (hypotension, bradycardia), appropriate treatment with intravenous fluids, vasopressor, and/or inotropic agents should be considered. Children should be given doses commensurate with age and weight.

In case of cardiac arrest, immediate initiation of cardiopulmonary resuscitation should be performed.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Nervous System / Local Anaesthetics / Anaesthetics, local / Amides / Articaine, combinations

ATC code: N01BB58

Mechanism of action and pharmacodynamic effects:

Articaine, a local amide anaesthetic, reversibly blocks nerve conduction through a well-known mechanism commonly observed with other local amide anaesthetics. This consists in decreasing or preventing the large transient increase in the permeability of excitable membranes to sodium (Na+) that is normally produced by slight depolarisation of the membrane. These actions lead the anaesthetic action. As the anaesthetic action progressively develops in the nerve, the threshold for electrical excitability gradually increases, the rate of rise of the action potential declines and impulse conduction slows. The pKa of articaine has been estimated at 7.8.

Adrenaline, as vasoconstrictor, acts directly on both a- and P-adrenergic receptors; p— adrenergic effects predominate. Adrenaline prolongs the effect duration of the articaine, and reduces the risk of excessive uptake of articaine into the systemic circulation.

Clinical efficacy and safety: Septanest/Arti­kent/Bartines­t/Isonest has an onset of 1.5— 1.8 min for infiltration and 1.4—3.6 min for nerve block.

The anaesthetic duration of articaine 40 mg/mL with adrenaline 1: 100 000 is of 60 to 75 minutes for pulpal anaesthesia and 180 to 360 minutes for soft tissue anaesthesia. The anaesthetic duration of articaine 40 mg/mL with adrenaline 1: 200 000 is of 45 to 60 minutes for pulpal anaesthesia and 120 to 300 minutes for soft tissue anaesthesia.

No difference was observed in pharmacodynamic properties between the adult and the paediatric population.

5.2 Pharmacokinetic properties

Articaine

Absorption: In three published clinical studies describing the pharmacokinetic profile of the combination articaine hydrochloride 40 mg/ml with adrenaline 10 or 5 micrograms/ml, Tmax values were between 10 and 12 minutes, with Cmax values ranging from 400 to 2100 ng/ml.

In clinical trials performed in children, Cmax was 1382 ng/ml and Tmax 7.78 min following infiltration of a dose of 2 mg/kg body weight.

Distribution: High protein binding of articaine was observed with human serum albumin (68.5–80.8%), and ^/p-globulins (62.5–73.4%). Binding to Y-globulin (8.623.7%) was much lower. Adrenaline is a vasoconstrictor added to articaine to slow down absorption into the systemic circulation and thus prolong maintenance of active articaine tissue concentration.The volume of distribution in plasma was about 4 l/kg.

Biotransformation : Articaine is subject to hydrolysis of its carboxyl group by unspecific esterases in the tissue and in blood. Since this hydrolysis is very fast, about 90% of articaine is inactivated by this way. Articaine is additionally metabolised in the liver microsomes. Articainic acid is the major product of cytochrome P450-induced metabolism of articaine, further metabolised to form articainic acid glucuronide.

Elimination: Following dental injection, the elimination half-life of articaine was c.a. 20–40 min. In a clinical trial, plasma concentrations of articaine and articainic acid were shown to decrease rapidly following submucosal injection. Very little articaine was detected in plasma from 12 to 24 hours following injection. More than 50% of the dose was eliminated in the urine, 95% as articainic acid, within 8 hours of administration. Within 24 hours, approximately 57% (68 mg) and 53% (204 mg) of the dose was eliminated in the urine. Renal elimination of unchanged articaine accounted for only about 2% of total elimination.

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans at therapeutic doses, based on conventional studies of safety pharmacology, chronic toxicity, reproductive toxicity and genotoxicity.

At supratherapeutic doses, articaine has cardiodepressant properties and can exert vasodilatory effects.

Adrenaline exhibits sympathomimetic effects.

Subcutaneous injections of articaine combined with adrenaline induced adverse effects from 50 mg/kg/day in rats and 80 mg/kg/day in dogs after 4 weeks daily repeated administrations. However, these findings are of little relevance to its clinical use as acute administration.

In embryotoxicity studies with articaine, no increase in the foetal mortality rate or malformations were observed at daily i.v. doses of up to 20 mg/kg in rats and 12.5 mg/kg in rabbits.

Teratogenecity was observed in animals treated with adrenaline only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

Reproductive toxicity studies conducted with articaine 40 mg/ml + adrenaline 10 micrograms/ml administered by the subcutaneous route at doses up to 80 mg/kg/day revealed no adverse effects on fertility, embryonal/foetal development, or pre- and postnatal development.

No genotoxicity effect was observed during in-vitro and in-vivo studies conducted with articaine alone or in an in vivo study conducted with articaine in combination with adrenaline.

Contradictory findings were raised from in-vitro and in-vivo genotoxicity studies with adrenaline.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium chloride

Sodium metabisulphite (E223)

Sodium hydroxide solution

Water for injections

6.2 Incompatibilities

None reported

6.3 Shelf life

18 months.

6.4 Special precautions for storage

Store up to 25°C. Store in the original container protected from light. Do not freeze.

6.5 Nature and contents of container

Box containing 5 blister trays of 10 × 1.7 ml or 2.2 ml (glass) cartridges with rubber closure

6.6 Special precautions for disposal

To avoid risk of infection (e.g. hepatitis transmission), syringe and needles used to draw up the solution must always be fresh and sterile.

This medicinal product should not be used if the solution is cloudy or discoloured.

The cartridges are intended for single use. If only a portion of a cartridge is used, the remainder must be discarded.

Use immediately after the opening of the cartridge.

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

7 MARKETING AUTHORISATION HOLDER

Septodont UK Ltd.

Units R & S

Orchard Business Centre,

St Barnabas Close,

Allington, Maidstone

Kent ME16 0JZ

England

8 MARKETING AUTHORISATION NUMBER

PL 08313/0038

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

19/08/1998 / 28/01/2005