LIGNOSPAN SPECIAL, UTILYCAINE, LIGNOKENT, EUROCAINE 2%, REXOCAINE - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

LIGNOSPAN SPECIAL 20 mg/ml + 12.5 micrograms/ml, solution for injection

UTILYCAINE – LIGNOKENT – EUROCAINE – REXOCAINE

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml of solution for injection contains:

Lidocaine hydrochloride 20 mg

Adrenaline 12.5 micrograms (as tartrate) (1:80,000).

One cartridge of 1.8 ml of solution for injection contains 36 mg of lidocaine hydrochloride and 22.5 micrograms of adrenaline (as tartrate).

One cartridge of 2.2 ml of solution for injection contains 44 mg of lidocaine hydrochloride and 27.5 micrograms of adrenaline (as tartrate).

Excipient(s) with known effect:

This medicinal product contains 1.20 mg/ml potassium metabisulfite (E224) (equivalent to 0.422 mg/ml potassium (0.0108 mmol/ml)), and 2.602 mg/ml sodium (0.11 mmol/ml).

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Solution for injection.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

4.3 Contraindications

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

Due to lidocaine:

Severe conduction disturbances (e.g., severe bradycardia, 2nd / 3rd degree AV blocks)

Acute intermittent porphyria;

Due to adrenaline:

Uncontrolled /severe hypertension,

Persistent / refractory tachyarrhythmia

Pheochromocytoma.

4.4 Special warnings and precautions for use

Before using this medicinal product, it is important:

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

To maintain verbal contact with the patient;

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

Special warnings

This product must be used with caution in:

Patients with cardiovascular disorders:

– Peripheral vascular disease.

– Arrhythmias particularly of ventricular origin;

– Heart failure;

– Hypotension.

The product should be administered with caution in patients with impaired cardiac function since they may be less able to compensate changes due to the prolongation of atrio-ventricular conduction.

Patients with myasthenia gravis:

The lowest dose leading to effective anaesthesia should be used as these patients are particularly sensible to the effect of local anaesthetics.

Patients with epileptic disease:

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

Patients with hepatic disease:

The lowest dose leading to efficient anaesthesia should be use, see section 4.2.

Patients with renal disease:

The lowest dose leading to effective anaesthesia should be used.

Patients with thyrotoxicosis:

The lowest dose leading to effective anaesthesia should be used.

Patients with coronary artery disease and valvular cardiac disease:

The lowest dose leading to effective anaesthesia should be used.

Patients receiving treatment with antiplatelets / anticoagulants:

The increased risk of severe bleeding after accidental vessel puncture and during oro-maxillo-facial surgery should be considered. INR monitoring should be increased in patients under anticoagulants.

Patients with uncontrolled diabetes:

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

Patients with susceptibility of acute angle-closure glaucoma:

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

Patients under the influence of illicit drug:

The efficacy of this product may be decreased in these patients.

Elderly patients:

Dosages should be reduced in elderly patients over 70 years old (lack of clinical data).

The product must be used safely and effectively under appropriate conditions:

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

The local anaesthetic effects may be reduced if the product is injected into an inflamed or infected area.

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 sensation is restored.

Precautions for use

Risk associated with an accidental intravascular injection:

Accidental intravascular injection (e.g.: inadvertent intravenous injection into the systemic circulation, inadvertent intravenous or intra-arterial injection in the head area and neck area) may be associated with severe adverse reactions, e.g., convulsions, followed by central nervous system or cardiorespiratory depression and coma, progressing ultimately to respiratory arrest, due to the sudden high level of adrenaline and / or lidocaine in the systemic circulation.

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 lidocaine’s po­tential chemical neurotoxicity and the presence of adrenaline as it may impair the perineural blood supply and prevent lidocaine local wash-out.

Risk of Takotsubo cardiomyopathy or stress-induced cardiomyopathy:

Stress cardiomyopathy induced by injected catecholamines has been reported.

Because of the presence of adrenaline, precautions and monitoring should be enhanced in the following situations: patients stressed prior to dental procedure or conditions of use which may contribute to induce a systemic passage of adrenaline e.g. an administered dose higher than recommended or in case of an accidental intravascular injection.

Any previous knowledge of such underlying conditions in patients requiring dental anaesthesia should be minded and a minimal dose of local anaesthetic with vasoconstrictor u­sed.

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

The medicinal product contains potassium, less than 1 mmol (39 mg) for a maximal dose of 16 ml, i.e. essentially ‘potassium-free’.

The medicinal product contains 0.1132 mmol/ml (2.602 mg/ml) sodium (main component of cooking/table salt). This is equivalent to approximately 0.665% of the recommended maximum daily dietary intake of sodium for an adult. The maximum recommended dose of this medicinal product (16 ml) contains 1.8112 mmol (41.632 mg) sodium, which is equivalent to 10.65% of the recommended maximum daily intake of sodium for an adult.

Concomitant use of the other medicinal products may require thorough monitoring (See section 4.5).

4.5 Interaction with other medicinal products and other forms of interaction Interactions that are not recommended

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

Reduced dose of this product should be used under strict medical supervision followed by careful aspiration due to possible increased response to adrenergic vasoconstrictors: risk of hypertension and other cardiovascular effects.

Interactions requiring precautions for use

Additive interactions with other local anaesthetics

Toxicity of local anaesthetics is additive.

This point is considered as not relevant with regard to dental anaesthesia doses and blood levels in adults, but it is a concern in children.

The total dose of administered lidocaine should not exceed the maximum recommended dose.

Opioid sedatives (central nervous system depressants)

Reduced doses of this product should be used due to potential additive CNS effects of lidocaine and sedatives.

Inhibitors of metabolism (e.g. cimetidine)

Increased serum levels of amide anaesthetics have been reported after concomitant administration of cimetidine.

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

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

The patient's hemo­dynamic status should be closely monitored.

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

Reduced doses of this product should be used due to possible-increase in blood pressure.

Close cardiovascular monitoring is recommended.

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

Dose and rate of administration of this product should be reduced due to strengthening of adrenaline activity.

Close cardiovascular monitoring is recommended.

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

Use under strict medical supervision due to possible potentialization of the effects of adrenaline.

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

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

Cardiovascular monitoring is recommended.

Drugs with combination of adrenergic-serotoninergic effect (e.g., venlafaxine, milnacipran, sertraline):

Dose and rate of administration of this product should be reduced due to additive or synergistic effects on blood pressure and heart rate.

Cardiovascular monitoring (preferably by ECG) is recommended.

Drugs causing arrhythmias in combination with adrenaline (e.g., antiarrhythmics like digitalis, quinidine):

Dose of administration of this product should be reduced due to additive or synergistic effects on heart rate.

Careful aspiration prior to administration and cardiovascular monitoring (ECG) are recommended.

Ergot-type oxytocic drugs (e.g., methysergide, ergotamine, ergonovine):

Use this 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) and other sympathomimetics (e.g., isoproterenol, levothyroxine, methyldopa, antihistamines (such as chloropheniramine, diphenhydramine):

Risk of adrenergic toxicity. Reduced doses of this product should be used.

If cocaine has been used within 24 hours, the planned dental treatment should be postponed

Phenothiazines and other neuroleptics:

Use under strict medical supervision and cardiovascular monitoring in case of patients with hypotension due to possible inhibition of adrenaline effect.

4.6 Fertility, pregnancy and lactation

Pregnancy

No effects during pregnancy are anticipated, since systemic exposure to lidocaine and adrenaline is negligible. This product can be used during pregnancy. Refer to section 5.3

Breastfeeding

Lidocaine/meta­bolites are excreted in human milk, but at therapeutic doses of this product no effects on the breastfed newborns/infants are anticipated.

Fertility

No adverse effects on fertility were observed in preclinical studies.

4.7 Effects on ability to drive and use machines

Lidocaine in combination with adrenaline solution may have minor influence on the ability to drive and use machines. Dizziness (including vertigo, vision disorder and fatigue) may occur following administration of this product (see section 4.8). Patients should not leave the dental office within 30 minutes following the dental procedure.

4.8 Undesirable effectsa) Summary of the safety profile

Adverse reactions following administration of the product are similar to those observed with other amide local anaesthetics combined with vasoconstrictors. These adverse reactions are, in general, dose-related and may result from high plasma levels caused by overdose, rapid absorption or unintended intravascular injection. They may also result from hypersensitivity, idiosyncrasy, or diminished tolerance by the specific patient. Nervous system disorders, cardiac disorders and vascular disorders are the most frequently occurring adverse reactions.

Serious adverse reactions are generally systemic. The presence of adrenaline increases the product’s safety profile due to its sympathomimetic effects.

b) Tabulated list of adverse reactions

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

By convention, frequency of initial signs of CNS or CVS toxicity is considered as rare.

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), Very Rare (<1/10,000) and “Not known (cannot be estimated from the available data)”.

1 Hypersensitivity (anaphylactic or anaphylactoid reactions) may characteristically occur with various symptoms of rash (eruption), urticarial, pruritus, bronchospasm/as­thma, wheezing, and angiodema. Angioedema include oedema of face / tongue / lip / throat / larynx / periorbital oedema. Laryngo-pharyngeal oedema may characteristically occur with hoarseness and / or dysphagia. Bronchospasm (bronchoconstric­tion) may characteristically occur with dyspnoea;

2

2 These neural pathologies may occur with the various symptoms of abnormal sensations of the lips, tongue, and oral tissues.

3 Respiratory depression may characteristically occur with various symptoms such as apnoea (respiratory arrest);

4 These neurally mediated effects are due to the presence of local anaesthetic / vasoconstrictor at excessive concentrations regionally or in the systemic circulation;

5 This mostly occurs in patients with underlying cardiac disease or those receiving certain drugs (section 4.5)

6 Necrosis is due to excessive local effect of the vasoconstrictor and mostly occurs in patients with underlying ischemic diseases;

7

7 This may be the sign of an injury to the lingual nerve

8

8 Procedural pain, post procedural pain and contusion are symptoms that may be associated to injection site reaction

Because of the presence of adrenaline, precautions and monitoring should be enhanced in the following situations: patients stressed prior dental procedure.

Any previous knowledge of such underlying conditions in patients requiring dental anaesthesia should be minded and a minimal dose of local anaesthetic with vasoconstrictor u­sed.

The safety profile was similar in children and adolescents from 4 to 18 years old compared to adults.

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

4.9 Overdose

Types of overdose

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

o Absolute overdose

o Relative overdose

– inadvertent injection into a blood vessel, or

– abnormal rapid absorption into the systemic circulation, or

– delayed metabolism and elimination of the product.

Symptomatology

o Due to lidocaine:

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

o Due to adrenaline:

Overdose of adrenaline may cause cardiovascular effects.

Treatment of overdose

The availability of resuscitation equipment should be ensured before the onset of dental anaesthesia with local anaesthetics.

If signs of acute toxicity are suspected, the injection of this product must immediately be stopped.

Oxygen should rapidly be administered, if necessary by assisted ventilation. Change patient position to supine position if necessary.

In case of cardiac arrest, immediate initiation of cardiopulmonary resuscitation is necessary.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

ATC Code: N01BB52

Mechanism of action:

Lidocaine stabilizes the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of nerve impulses, thereby effecting local anaesthetic action.

Since lidocaine, as most agents currently used for local anaesthesia, is not a vasoconstrictor, adrenaline is included in the solution with the anaesthetic:

■ by localizing the solution at the site of the injection, this vasoconstrictor intensifies and prolongs the anaesthetic effect and decreases the rate at which the anaesthetic drug enters the systemic circulation,

■ the presence of a vasoconstrictor also decreases surgical haemorrhage in the immediate area of injection.

Onset duration of anaesthesia:

with adrenaline at doses much higher than those recommended for dental treatments in humans.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium chloride, potassium metabisulfite (E224), disodium edetate, sodium hydroxide (for pH-adjustment) and water for injections.

6.2 Incompatibilities

None stated.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

Store below 25°C.

Keep the cartridges in the outer carton tightly closed, in order to protect from light.

Do not freeze.

6.5 Nature and contents of container

– Glass cartridges with rubber closures.

– 50 dental cartridges of 1.8 ml or 2.2 ml in blister packs grouped in a cardboard box.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

One cartridge can only be used for one single patient during one single session.

No opened cartridge of anaesthetic solution should be reused. If only a part is used, the remainder must be discarded.

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