Document: Septocaine Forte solution for injection ENG SmPC change

• Septocaine Forte 40 mg per ml_10 microgram per ml solution for injection SmPC
• Septocaine Forte solution for injection ENG SmPC

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SUMMARY OF THE PRODUCT CHARACTERISTICS

Septocaine forte, 40 mg/ml + 10 micrograms/ml, solution for injection

1 ml contains articaine hydrochloride 40 mg and adrenaline 10 micrograms as adrenaline tartrate.

Septocaine Forte contains 84.74 mg sodium per 100 ml of solution i.e. 1.44 mg/1.7 ml.

Excipients with known effect: Septocaine Forte contains sodium metabisulfite (E223), sodium chloride, disodium edetate, sodium hydroxide.

For thefull list of excipients, see section 6.1.

Solution for injection.

Clear colourless solution.

Local and loco-regional anaesthesia in dental procedures of longer duration and when there is a risk of significant bleeding into the operative field in adults, adolescents and children above 4 years of age (or from 20 kg (44 lbs) of body weight).

For professional useby dentists and stomatologists only.

Posology

The lowest dose leading to efficientanaesthesia should be used. The necessary dosage must be determined on an individual basis.

● Adults and adolescents (12 to 18 years of age)

In adults and adolescents, the maximum dose is 7 mg/kg with an absolute maximum dose of 500 mg for an healthy adult of 70 kg body weight.

● Children (4 to 11 years of age)

Due to lack of clinical data, this product should not be used in children under 4 years of age. In children aged 4 years (or from 20 kg (44 lbs) of body weight) and above, the maximum dose is 5 mg/kg only with an absolute maximum dose of 275 mg articaine for a healthy child of 55 kg body weight.

● Special populations

Due to the lack of clinical data, particular precaution should be used in order to administer the lowest dose leading to efficient anaesthesia in elderly patients over 70 years old and in patients with renal or hepatic impairment.

Method of Administration

Infiltration and perineural use in oral cavity.

Before injection, aspiration is always recommended to avoid intravascular injection.

The rate of injection should not exceed 1 ml of solution per minute.

For information relevant to the handling of the product see section 6.6.

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 product mustbe used with caution in:

Patients with cardiovascular disorders:

- Uncontrolled/severe hypertension

- Severe ischemic heart disease

- Recent myocardial infarction

- Recent coronary artery bypass surgery

- Persistent/refractory tachyarrhythmia

- Atrioventricular block grade I, II and III

- Peripheral vascular disease

- Heart failure

- Hypotension.

The lowest dose leading to efficient anaesthesia should be used.

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 thyreotoxicosis

The lowest dose leading to efficient anaesthesia should be used.

Patients with pheochromocytoma

The lowest dose leading to efficient anaesthesia should be used.

Patients with hepatic disease:

The lowest dose leading to efficient anaesthesia should be used.

Patients with renal disease:

The lowest dose leading to efficient anaesthesia should be used.

Patients with myasthenia gravis:

The lowest dose leading to efficient 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 inpatients taking anticoagulants.

Patients with porphyria:

This productshould be used cautiously.

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.

Elderlypatients:

In patients over 70 years old, the lowest dose leading to efficient anaesthesia should be used.

This 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 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 normal sensation is restored.

Thisproduct contains sodium metabisulfite, a sulfite that may rarely cause hypersensitivityreactionsand bronchospasm.

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

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. Thismay 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 notpenetrate a blood vessel during injection, aspiration should be performed before the local anaesthetic product is injected. However, the absence of blood in the syringedoes not guarantee that intravascular injection has been avoided.

Risk associated with intraneuralinjection:

Accidental intraneural injection may leadthe drugtomove in retrograde manneralong the nerve.

In order toavoid intraneuralinjection and to prevent nerve injuries in connection with nerve blockades,the needleshould always be slightly withdrawnif electric shock sensationis felt by the patientduringinjection or ifthe injectionis particularly painful. If needlenerve injuries occur, the neurotoxic effect could be aggravated by articaine potential chemical neurotoxicity andthe presenceof adrenaline as itmay impair the perineural blood supply and prevent articaine local wash-out.

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

Due to the presence of 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):

In children receiving benzodiazepines or opioids, reduced doses of this productshould be used due to additive effects.

Due to the presence of adrenaline

Interactions requiring precautions for use:

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.

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 product should be used under strict medical supervision followed by 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 product should be used due to possible increase in blood pressure and an increased risk of bradycardia.

(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 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.

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

Dose of administration of this 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 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.

Pregnancy

No clinical experience of the use of Septocaine Fortein pregnant women is available. Animal studies with articaine do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development.

Studies in rats with adrenaline have shown reproductive toxicity.The risk for humans is unknown. Caution should be exercised when prescribing to pregnant women.

Breastfeeding

It is unknown whether articaine or adrenaline is excreted in human breast milk. The excretion of articaine or adrenaline in milk has not been studied in animals. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Septocaine Forte should be made taking into account the benefit of breast-feeding to the child and the benefit of Septocaine Forte therapy to the woman. Nursing mothers are advised to express and discard the first milk after administration of articaine.

The combination articaine hydrochloride with adrenaline tartrate solution for injection may have minor influence on the ability to drive and use machines. Dizziness (including vertigo, vision disorder and fatigue) may occur following administration of the combination articaine hydrochloride with adrenaline tartrate (see section 4.8). Patients experiencing these symptoms should not drive or use machinery until any such symptoms have completely resolved.

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)”.

MedDRA Sytem Organ Class	Frequency	Adverse Reactions
Immune system disorders	Rare	Angioedema (face / tongue / lip / throat / larynx / periorbital oedema) Bronchospasm/ asthma Allergic1, anaphylactic / anaphylactoid reactions Urticaria
Psychiatric disorders	Rare	Nervousness / anxiety
	Not known	Euphoric mood
Nervous system disorders	Common	Neuropathy: Neuralgia (neuropathic pain) Hypoesthesia / numbness (oral and perioral) Hyperesthesia Dysesthesia (oral and perioral), including Dysgeusia (e.g., taste metallic, taste disturbance) Ageusia Allodynia Thermohyperesthesia
	Uncommon	Burning sensation
	Rare	Facial nerve disorder2 (palsy, paralysis and paresis) Somnolence (Drowsiness) Nystagmus
	Very rare	Paresthesia3 (persistent hypoesthesia and gustatory loss) after mandibular or inferior alveolar nerve blocks
Eye disorders	Rare	Horner’s syndrome (eyelid ptosis, enophthalmos, miosis). Diplopia (paralysis of oculomotor muscles) Visual impairment (temporary blindness) Ptosis Miosis Enophthalmos
Ear and labyrinth disorders	Rare	Hyperacusis Tinnitus
Cardiac disorders	Common	Bradycardia (also named bradyarrhythmia) Tachycardia
	Rare	Palpitations
	Not known	Conduction disorders (atrioventricular block)
Vascular disorders	Common	Hypotension (with possible circulatory collapse)
	Uncommon	Hypertension
	Rare	Hot flush
	Not known	Vasodilatation Vasoconstriction
Respiratory, thoracic and mediastinal disorders	Rare	Dyspnoea2
	Not known	Dysphonia (Hoarseness)1
Gastrointestinal disorders	Common	Gingivitis Swelling of tongue, lip, gums
	Uncommon	Stomatitis, glossitis Nausea, vomiting, diarrhoea
	Rare	Gingival / oral mucosal exfoliation (sloughing) / ulceration
	Not known	Dysphagia
Skin and subcutaneous tissue disorders	Uncommon	Rash (eruption) Pruritus
	Not known	Erythema
Musculoskeletal and connective tissue disorders	Uncommon	Neck pain
	Rare	Muscle twitching Chills (shivering)
	Not known	Aggravation of the neuromuscular manifestations in Kearns-Sayre syndrome
General disorders and administration site conditions	Uncommon	Injection site pain
	Rare	Injection site exfoliation / necrosis Fatigue, asthenia (weakness)
	Not known	Local swelling Hyperhidrosis, Feeling hot, Feeling cold

c) Description of selected adverse reactions

¹Allergic 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.

³These neural pathologies may occur with various symptoms of abnormal sensations. paresthesia can be defined as spontaneous abnormal usually nonpainful 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.

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 listed in Appendix V.

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.

Symptomatology

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, 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.

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 should be ensured before the onset of dental anaesthesia with local anaesthetics.

If signs of acute toxicity are suspected, the injection of Septocaine Fortemust immediately be stopped.

Oxygen should rapidly be administered, if necessary by assisted ventilation.

Change patient position to supine position if necessary.

If seizures do not stop spontaneously within 15 – 20 seconds an anticonvulsant drug must be administered. Muscle relaxing agents may be necessary but requires tracheal intubation.

Hypotension and/or bradycardia may be treated with ephedrine.

In case of cardiac arrest, immediate initiation of cardiopulmonary resuscitation should be performed with the combination of epinephrineand atropine.

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

ATC-code: N01BB58

Mechanism of action: 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.

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

Onset of action: Septocaine Forte has an onset of 1.5-1.8 min for infiltration and 1.4-3.6 min for nerve block.

Analgesia duration: Pulpal analgesia lasts from 45 to 75 min, and soft-tissue analgesia lasts from 120 to 360 min depending on administered dose.

Paediatric population: No difference was obtained in pharmacodynamic properties.

Absorption: In three published clinical studies describing the pharmacokinetic profile of the combination articaine hydrochloride 40 mg/ml with adrenaline 0.010 or 0.005 mg/ml, T_maxvalues were between 10 and 12 minutes, with C_maxvalues ranging from 400 to 2100 ng/mL.

In clinical trials performed in children, C_max was 1382 ng/ml and T_max7.78 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 /-globulins (62.5-73.4%). Binding to -globulin (8.6-23.7%) 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.

Metabolism: 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.

Excretion: Following dental injection, the plasmatic half-life of articaine was shown c.a. 20 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.

There are no preclinical data considered relevant to clinical safety beyond data included in other sections of the SPC.

Sodium chloride,

Disodiumedetate,

Sodium metabisulfite(E223),

Sodium hydroxide (for pH-adjustment),

Water for injections.

Not applicable.

2 years.

Store below 25°C.

Do not refrigerate or freeze.

Keep the cartridge in the outer carton inorder to protect from light and moisture.

Cylindrical class I glass cartridge sealed at its base by a mobile rubber plunger and at the top by a rubber seal kept in place by a metal cap.

Box containing glass cartridges 50 x 1.7 ml.

Box containing glass cartridges, selfaspirating 50 x 1.7 ml.

Pack of 4 boxes containing glass cartridges 50 x 1.7 ml.

Pack of 8 boxes containing glass cartridges 50 x 1.7 ml.

Not all pack sizes may be marketed.

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

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

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

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

Specialites Septodont.

58, rue du Pont de Créteil

94100 Saint-Maur-des-Fossés

FRANCE

14251

[To be completed nationally]

2014-11-19