Consumer medicine information

Ubistesin 1:200,000 and Ubistesin Forte 1:100,000

Articaine hydrochloride + Adrenaline (epinephrine)

BRAND INFORMATION

Brand name

Ubistesin, Ubistesin Forte

Active ingredient

Articaine hydrochloride + Adrenaline (epinephrine)

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Ubistesin 1:200,000 and Ubistesin Forte 1:100,000.

WHAT IS IN THIS LEAFLET

Please read this leaflet carefully before you use UBISTESIN or UBISTESIN FORTE.

This leaflet answers some common questions about UBISTESIN or UBISTESIN FORTE. It does not contain all of the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Sometimes new risks are found even when a medicine has been used for many years. Your doctor has weighed the expected benefits of you taking UBISTESIN or UBISTESIN FORTE against the risks this medicine could have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

WHAT IS UBISTESIN and UBISTESIN FORTE USED FOR

UBISTESIN and UBISTESIN FORTE contain the active ingredients: Articaine hydrochloride, a local anaesthetic to prevent the pain, and adrenaline (epinephrine) hydrochloride, a vasoconstrictor, which makes it last longer (adrenaline (epinephrine) narrows the blood vessels at the site of injection, which keeps the anaesthetic where it's needed for a longer time) and controls bleeding during the surgery.

UBISTESIN and UBISTESIN FORTE belong to a group of medicines called local anaesthetics. UBISTESIN or UBISTESIN FORTE is injected into the mouth where it makes the nerves unable to pass messages to the brain.

Your dentist will have explained why you are being given UBISTESIN or UBISTESIN FORTE.

Follow all directions given to you by your dentist carefully. They may differ from the information contained in this leaflet. Ask your dentist if you want more information.

UBISTESIN and UBISTESIN FORTE are not addictive.

BEFORE YOU ARE GIVEN UBISTESIN OR UBISTESIN FORTE

When you must not be given UBISTESIN or UBISTESIN FORTE

  • You are allergic to adrenaline (epinephrine), articaine, or any local anaesthetic and any other ingredient included in the product.
  • You are asthmatic or have broncho-spasmic (difficulty in breathing) reactions to sulfites.
  • You lack a natural chemical substance called cholinesterase in your blood (plasma cholinesterase deficiency)
  • You have an overactive thyroid gland, whether or not treated for this.
  • You have a tumour called phaeochromocytoma (adrenal gland)
  • You suffer from severe heartbeat coordination problems (cardiac disorders, atrioventricular block)
  • Children under the age of 4 years old.

Before you are given UBISTESIN OR UBISTESIN FORTE:

You must tell your dentist if you have allergies to:

  • other local anaesthetics
  • any other medicines
  • any other substances such as foods, preservatives or dye
  • any other ingredients listed at the end of this leaflet

Tell your dentist if:

  • You have problems with your heart, blood vessels and heart rhythm.
  • You have epilepsy.
  • You have hepatic (liver) or renal (kidney) diseases.
  • You suffer from a disease called Myasthenia Gravis causing weakness in the muscles
  • You suffer from a condition called Porphyria which causes either neurological complications or skin problems
  • You have diabetes
  • You have cerebrovascular insufficiency (obstruction of one or more arteries that supply blood to the brain)
  • You suffer from a disease called angle-closure glaucoma which affects your eyes
  • You have inflammation or infection in the area to be injected
  • You are more than 70 years old
  • You are pregnant or breast-feeding. If UBISTESIN OR UBISTESIN FORTE is used when you are breast-feeding you should not breast-feed for at least 4 hours following use of UBISTESIN OR UBISTESIN FORTE.
  • You have any other medical conditions.

Taking other medicines

Tell your dentist if you are taking any other medicines including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Your dentist should take special attention if you are taking the following medicines:

  • Other local anaesthetics, medicines that cause reversible loss of sensation (including volatile anaesthetics such as halothane)
  • Sedatives (such as benzodiazepines, opioids)
  • Mono Amine Oxidase Inhibitors (MAOI) or tricyclic antidepressants (medicines used to treat depression), or have taken this type of medicine within the last two weeks.
  • COMT-inhibitors to treat Parkinson’s disease (such as entacapone) medicines used to treat irregular heartbeats (eg digitalis, quinidine)
  • Phenothiazines (medicines used to treat mental illnesses).
  • Cimetidine (medicine used to treat reflux and stomach or duodenal ulcers)
  • Thyroid hormone
  • Heart and blood pressure medicines
  • Medicine used to treat migraines (eg ergotamine or methysergide)
  • Medications to thin the blood and prevent blood clotting (eg antiplatelets, anticoagulants)
  • Sympathomimetic vasopressors* (eg oxymetazoline used to treat swelling or inflammation of the nose)

*If a sympathomimetic vasopressor such as cocaine, amphetamines, phenylephrine, pseudoephedrine, oxymetazoline has been used within the past 24 hours, the planned dental treatment must be postponed.

These medicines may be affected by UBISTESIN or UBISTESIN FORTE or may affect how well it works. Your dentist may need to adjust your dose.

HOW UBISTESIN AND UBISTESIB FORTE IS GIVEN?

UBISTESIN and UBISTESIN FORTE are given by injection to cause loss of feeling before and during dental procedures.

Your dentist will explain to you why you are being treated with UBISTESIN or UBISTESIN FORTE and what dose you will be administered.

Your dentist will inject UBISTESIN or UBISTESIN FORTE into your oral (mouth) cavity. This will result in an area of numbness at the site of the injection.

One cartridge is usually sufficient but your dentist may give you a greater quantity. He will adjust the dosage according to your age, your health, your weight and the dental work to be performed. If only a portion of a cartridge is used the remainder must be discarded.

Overdose

Your dentist will determine the amount of solution, which is needed to provide pain control during your treatment, and it is very unlikely that you would receive too much

However, some persons tolerate articaine and adrenaline (epinephrine) less well than others and the signs and symptoms of too much of these substances in your blood include: nervousness, dizziness, blurred vision, nausea, trembling, convulsions, slow or irregular heartbeat, troubled breathing.

Tell your dentist immediately if you experience any of these symptoms during or shortly after your treatment.

WHILE YOU ARE USING UBISTESIN OR UBISTESIN FORTE

Things you must not do:

Do not eat or drink anything until the feeling has returned to your mouth. You may burn or bite yourself.

Things to be careful of:

  • Be careful driving or operating machinery until you know how it affects you. You may be drowsy and your reflexes may be slow. This medicine may cause dizziness, light-headedness in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.
  • Do not drink alcohol immediately before or after you are given it.
  • If you drink alcohol while you are being given it, your blood pressure may drop making you feel dizzy and faint.
  • Please talk to your dentist or pharmacist about these possibilities if you think they may bother you.

SIDE EFFECTS

Tell your dentist as soon as possible if you do not feel well when using UBISTESIN or UBISTESIN FORTE.

All medicines may cause side effects in some patients. Although not all of these side effects may occur, if they do occur they may need medical attention. While you are in your dentist's office, your dentist will carefully follow the effects of UBISTESIN or UBISTESIN FORTE. However, some effects may not be noticed or appear later.

Tell your dentist if you notice any of the following serious side effects:

  • Swollen face, tongue or pharynx, difficulty swallowing or breathing, hives
  • Rash, itching, swelling of the throat and difficulty breathing (this could be symptoms of an allergic reaction)
  • Horner’s syndrome – a combination of drooping of the eyelid and constriction of the pupil

These serious side effects occur rarely (may affect up to 1 in 1,000 people).

Common side effects: may affect up to 1 in 10 people

  • you have a headache
  • your heart is beating slowly, rapidly or irregularly
  • your blood pressure is low
  • you are feeling dizzy, faint, look pale
  • you have facial swelling (tongue, lips, gums) or inflammation of gums, numbness of your tongue, mouth and/or lips
  • you have numbness or reduced sense of touch in and around mouth
  • your taste is disturbed or you have lost your taste function, metallic taste
  • you have neuropathic pain (pain due to nerve damage)
  • you have an increased sensitivity to heat

Uncommon side effects: may affect up to 1 in 100 people

  • High blood pressure
  • Burning sensation
  • Inflammation of the tongue or mouth
  • Nausea, vomiting, diarrhoea
  • Rash, itching
  • Pain in the neck or at the site of injection
  • Pain

Rare side effects: may affect up to 1 in 10,000 people

  • Wheezing, (bronchospasm), asthma, breathing difficulty
  • Fatigue, weakness
  • Anxiety, nervousness
  • Drowsiness
  • Facial nerve disorder (paralysis)
  • Involuntary eye movement
  • Muscle twitching, involuntary muscle contraction
  • Convulsions or fits
  • Double vision, temporary blindness
  • Balance disorder, vertigo
  • Loss of consciousness
  • Buzzing in the ears, sensitivity to hearing

If you are experiencing any of these, you may have had a serious (allergic) reaction to UBISTESIN OR UBISTESIN FORTE. You may need urgent medical attention or hospitalisation.

Tell your dentist if you notice anything else that is making you feel unwell. Some people may get other side effects while using UBISTESIN OR UBISTESIN FORTE.

You may be hypersensitive to sulfites and therefore show allergic symptoms to UBISTESIN or UBISTESIN FORTE such as breathing difficulties and/or skin reactions.

If you have problems with your blood vessels, circulation or have high blood pressure, you may react exaggeratedly to the vasoconstrictor contained in UBISTESIN OR UBISTESIN FORTE and develop a small injury at the site of injection.

AFTER USING UBISTESIN AND UBISTESIN FORTE

Storage

All medicines must be kept in a safe place out of the reach of children.

UBISTESIN and UBISTESIN FORTE will be stored by your dentist under recommended conditions.

The medicine should be stored below 25°C and protected from light.

PRODUCT DESCRIPTION

What it looks like

Solution is clear, not opalescent and colourless.

Active Ingredients

UBISTESIN contain Articaine hydrochloride 40 mg and Adrenaline (epinephrine) hydrochloride 0.006 mg

UBISTESIN FORTE contain Articaine hydrochloride 40 mg and Adrenaline (epinephrine) hydrochloride 0.012 mg

Other Ingredients

sodium sulphite, sodium chloride, hydrochloric acid, sodium hydroxide solution and water for injections

FURTHER INFORMATION

Only a dentist can administer this product. This leaflet provides only a summary of the information known about UBISTESIN and UBISTESIN FORTE. If you have any questions, want to know more about this medicine, or have some doubts, ask your dentist.

SPONSOR

3M Australia Pty Ltd
Building A, 1 Rivett Road
North Ryde NSW 2113

REGISTRATION NUMBERS

UBISTESIN – AUST R 165573

UBISTESIN FORTE – AUST R 165574

This leaflet was prepared in September 2017

Published by MIMS August 2018

BRAND INFORMATION

Brand name

Ubistesin, Ubistesin Forte

Active ingredient

Articaine hydrochloride + Adrenaline (epinephrine)

Schedule

S4

 

1 Name of Medicine

Articaine hydrochloride with adrenaline (epinephrine) (as hydrochloride).

6.7 Physicochemical Properties

Chemical structure.


Articaine hydrochloride.

MW 320.84 - Molecular formula C13H20N2O3S.HCl.
Chemical name: Methyl 4-methyl-3-[[(2RS)-2- (propylamino)propanoyl]amino] thiophene-2-carboxylate hydrochloride.
Articaine hydrochloride is a racemic mixture. It has a partition co-efficient in n-octanol/Soerensen buffer (pH:7.35) of 17 and a pKA of 7.8. White to almost white powder, odourless.

Adrenaline (epinephrine) (as hydrochloride).

MW: 183.2 - Molecular formula C9H13NO3.
Chemical name: 4-[(1R)-1-Hydroxy-2-(methylamino)ethyl]benzene-1,2-diol.
Adrenaline (epinephrine) is a white to greyish-white, crystalline powder, sparingly insoluble in water, practically insoluble in alcohol and ether.

CAS number.

Articaine: CAS No: 23964-58-1.
Adrenaline (epinephrine): CAS No: 51-43-4.

2 Qualitative and Quantitative Composition

Ubistesin.

Articaine hydrochloride 4% with adrenaline (epinephrine) 1:200,000 (as hydrochloride).

Ubistesin Forte.

Articaine hydrochloride 4% with adrenaline (epinephrine) 1:100,000 (as hydrochloride).
The active ingredients in Ubistesin and Ubistesin Forte are articaine hydrochloride and adrenaline (epinephrine) (as hydrochloride).
Articaine hydrochloride is a local anaesthetic.
Adrenaline (epinephrine) is a vasoconstrictor.
Amount per 1.7 mL cartridge. (See Table 1).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Dosage Form: Solution for injection.

Ubistesin.

Articaine hydrochloride 4% with adrenaline (epinephrine) 1:200,000 [i.e. articaine hydrochloride 40 mg/mL with adrenaline (epinephrine) 5 microgram/mL (as hydrochloride)]: clear, not opalescent, colourless solution, practically free from visible particles.

Ubistesin Forte.

Articaine hydrochloride 4% with adrenaline (epinephrine) 1:100,000 [i.e. articaine hydrochloride 40 mg/mL with adrenaline (epinephrine) 10 microgram/mL (as hydrochloride)]: clear, not opalescent, colourless solution, practically free from visible particles.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Articaine is a local anaesthetic of the amide type. Preclinical pharmacodynamic studies show that the mechanism of action of articaine is similar to that of other commonly used anaesthetics (lidocaine, procaine, prilocaine). Inhibition of the generation and the conduction of the action potential but no change in resting potential is shown.
Articaine blocks sodium channels and, with lower sensitivity, potassium channels at neutral pH. Inhibition of muscle activation after nerve stimulation and depression of cardiac electrophysiological measurements demonstrate that articaine has the same pharmacological activities as other local anaesthetics. When injected close to sensitive nerve filaments, articaine has the reversible effect of blocking the conduction of painful sensations.
Adrenaline (epinephrine) added to the solution reduces bleeding during surgery, slows down the passage of articaine into the general circulation and thus ensures the prolonged maintenance of an active tissue concentration.
Adrenaline (epinephrine) acts on both adrenergic receptors of tissue innervated by sympathetic nerves, except for the sweat glands and arteries of the face. It is the most important alpha-receptor activator. Adrenaline (epinephrine) stimulates the heart to increase output, raises the systolic blood pressure, lowers the diastolic blood pressure, relaxes bronchial spasm and mobilises liver glycogen, resulting in hyperglycaemia and possibly glycosuria.
The mean time to onset of anaesthesia after administration of articaine 4% with adrenaline (epinephrine) 1:100,000 is about 3.5 minutes with a range of one to six minutes, and the mean duration of anaesthesia is about 68 minutes with a range of 20 to 175 minutes. The pulpal analgesia lasts 75 minutes and the bleeding during surgery is significantly reduced.

Clinical trials.

Three randomised, double blind, active controlled studies were designed to evaluate effectiveness of articaine and adrenaline (epinephrine) 1:100,000 injection as a dental anaesthetic. A total of 882 patients received injection. Of these, 7% were between 4 and 16 years old, 87% were between 17 and 65 years old, and 6% were at least 65 years old. In addition, 53% of patients were female and 47% were male, with a racial/ ethnic distribution of 73% White, 11% Hispanic, 8% Black, 5% Asian and 3% 'other' races/ ethnicities. These patients underwent simple dental procedures, single apical resections and single crown procedures, and complex dental procedures such as multiple extractions, multiple crowns and/or bridge procedures, multiple apical resections, alveolectomies, mucogingival operations and other surgical procedures on the bone.
Articaine and adrenaline (epinephrine) 1:100,000 injection was administered as submucosal infiltration and/or nerve block. Efficacy was measured immediately following the procedure by having the patient and investigator rate the patient's procedural pain using a 10 cm visual analogue scale (VAS), in which a score of zero represented no pain, and a score of ten represented the worst pain imaginable. Mean patient and investigator VAS pain scores were 0.3 to 0.4 cm for simple procedures and 0.5 to 0.6 cm for complex procedures. These values are summarised in Table 5.
In clinical trials, 61 paediatric patients between the ages of 4 and 16 years received articaine and adrenaline (epinephrine) 1:100,000 injection. Among these paediatric patients, doses from 0.76 to 5.65 mg/kg (0.9 to 5.1 mL) were administered safely to 51 patients for simple procedures and doses between 0.37 and 7.48 mg/kg (0.7 to 3.9 mL) were administered safely to ten patients for complex procedures. However, there was insufficient exposure to articaine and adrenaline (epinephrine) 1:100,000 injection at doses greater than 7.00 mg/kg in order to assess its safety in paediatric patients. No unusual adverse events were noted in these patients. Approximately 13% of these paediatric patients required additional injections of anaesthetic for complete anaesthesia.
In the clinical trials 54 patients between the ages of 65 and 75 years and eleven patients 75 years and over received articaine and adrenaline (epinephrine) 1:100,000 injection. Among all patients between 65 and 75 years, doses from 0.43 to 4.76 mg/kg (0.9 to 11.9 mL) were administered safely to 35 patients for simple procedures and doses from 1.05 to 4.27 mg/kg (1.3 to 6.8 mL) were administered safely to 19 patients for complex procedures. Among the eleven patients greater than or equal to 75 years old, doses from 0.78 to 4.76 mg/kg (1.3 to 11.9 mL) were administered safely to seven patients for simple procedures and doses of 1.12 to 2.17 mg/kg (1.3 to 5.1 mL) were administered to four patients for complex procedures.

5.2 Pharmacokinetic Properties

Absorption.

Following dental injection by the submucosal route of an articaine 4% solution containing adrenaline (epinephrine) 1:200,000, articaine reaches peak blood concentration about 25 minutes after a single dose injection and 48 minutes after three doses. Peak plasma levels of articaine achieved after 68 minutes and 204 mg doses are 385 and 900 nanogram/mL, respectively.

Distribution.

Approximately 60 to 80% of articaine hydrochloride is bound to human serum albumin and gamma-globulins at 37°C in vitro.

Metabolism.

Articaine hydrochloride is rapidly metabolised by plasma carboxyesterase to its primary metabolite, articainic acid, which is inactive. Articainic acid concentration reaches its peak about 30 to 60 minutes following the peak in articaine concentration. In vitro studies show that the human liver microsome P450 isoenzyme system metabolises approximately 5 to 10% of the available articaine with nearly quantitative conversion to articainic acid.

Excretion.

The elimination half-life of articaine is about 1.8 hours and that of articainic acid is about 1.5 hours. Articaine is excreted primarily through urine with 53 to 57% of the administered dose eliminated in the first 24 hours following submucosal administration. Articainic acid is the primary metabolite in urine. A minor metabolite, articainic acid glucuronide, is also excreted in urine. Articaine constitutes only 2% of the total dose in excreted urine.

Special populations.

Effect of age.

No pharmacokinetic data are available in the following populations: elderly, children.

Race.

No pharmacokinetic data are available for different racial groups.

Renal and hepatic impairment.

No pharmacokinetic data are available for patients with hepatic or renal impairment.

5.3 Preclinical Safety Data

Genotoxicity.

Articaine was negative in bacterial and mammalian assays for gene mutation and a chromosomal aberration test in Chinese hamster ovary cells. In vivo clastogenecity (mouse micronucleous) assays with articaine alone and with adrenaline were negative at a low subcutaneous dose (same as the maximal recommended clinical dose on a mg/m2 basis).

Carcinogenicity.

Studies to evaluate the carcinogenic potential of articaine hydrochloride in animals have not been conducted.

4 Clinical Particulars

4.1 Therapeutic Indications

Ubistesin is used for local anaesthesia (infiltration and nerve-block anaesthesia) in dentistry during minor procedures in adults, adolescents and children 4 years of age and older.
Ubistesin Forte is used for local and regional anaesthesia (infiltration and nerve-block anaesthesia) in dentistry during minor and complicated procedures in adults, adolescents and children 4 years of age and older.

4.3 Contraindications

Hypersensitivity to articaine (or any local anaesthetic agent of the amide type) or to adrenaline (epinephrine) or to any of the excipients (see Section 6.1 List of Excipients).
Phaeochromocytoma.
Uncontrolled hyperthyroidism.
Plasma cholinesterase deficiency.
Complete heart block not compensated by a pacemaker.
This product contains sodium sulfite, which may cause allergic reactions, including anaphylactic reactions and asthmatic episodes, in susceptible people (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).

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.
When any local anaesthetic agent is used, resuscitative equipment and resuscitative drugs, including oxygen, should be immediately available in order to manage possible adverse reactions involving the cardiovascular, respiratory or central nervous systems.
Injection should always be made slowly with frequent aspirations to avoid inadvertent intravascular injection, which can produce cerebral symptoms even at low doses. (See Section 4.2 Dose and Method of Administration.)

Special warnings.

This product must be 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; do not use in complete heart block (grade III) not compensated by a pacemaker;
Peripheral vascular disease;
Heart failure;
Hypotension.
For all patients with cardiovascular disorders, the lowest dose leading to efficient anaesthesia should be used. For patients with severe uncontrolled hypertension, unstable angina, recent myocardial infarction (< 3 months), or severe/refractory arrhythmias, elective dental treatment should be postponed. Stress and anxiety reduction is crucial in the management of patients with cardiovascular disorders.

Patients with epileptic disease.

Because of their convulsive actions, all local anaesthetics should be used very cautiously, particularly in those patients with poorly-controlled disease. Stress reduction procedures should be employed to minimize the risk of a seizure developing during treatment.

Patients with plasma cholinesterase deficiency.

A plasma cholinesterase deficiency can be suspected when clinical signs of overdose occurs with the usual dosage of anaesthesia and when a vascular injection has been excluded. In this case the subsequent use of products containing articaine should be avoided (see Section 4.3 Contraindications).

Use in hepatic impairment.

The lowest dose leading to efficient anaesthesia should be used (see Section 4.2 Dose and Method of Administration).

Use in renal impairment.

The lowest dose leading to efficient anaesthesia should be used (see Section 4.2 Dose and Method of Administration).

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 in patients taking anticoagulants.

Patients receiving treatment with monoamine oxidase inhibitors (MAOIs).

This product must be used with caution in patients receiving concomitant treatment with MAOI.

Patients with porphyria.

This product should be used cautiously.

Patients with diabetes.

The use of this product in those with uncontrolled diabetes mellitus is not advised due to the hyperglycaemic effect of adrenaline. This product should be used with caution in those patients with diabetes mellitus which is well-controlled by diet or oral hypoglycaemic agents. Patients treated with insulin may be at greater risk of complications following the administration of adrenaline (epinephrine).

Patients with susceptibility of acute angle-closure glaucoma.

This product should be used cautiously due to the presence of adrenaline (epinephrine), which may precipitate acute angle closure.

Use in the elderly.

In patients over 70 years old, the lowest dose leading to efficient anaesthesia should be used (see Section 4.2 Dose and Method of Administration).

Patients with cerebrovascular insufficiency.

Due to the presence of adrenaline, vasoconstriction may occur in patients with cerebrovascular insufficiency, leading to a risk of transient cerebral ischaemia. Reduced doses should be used to minimise the risk of transient cerebral ischaemia.

Paediatric use.

Ubistesin and Ubistesin Forte should not be used in children younger than 4 years of age as safety and effectiveness have not been established in this age group (see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 4.2 Dose and Method of Administration).

Effects on laboratory tests.

No data available.

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, atrioventricular block or ventricular arrhythmias followed by central nervous system and cardiorespiratory depression and coma, progressing to respiratory and cardiac arrest. Thus, to ensure that the needle does not penetrate a blood vessel during injection, aspiration should be performed before the local anaesthetic product is injected. However, the absence of blood in the syringe does not guarantee that intravascular injection has been avoided.
Careful and constant monitoring of cardiovascular and respiratory vital signs and the patient's state of consciousness should be accomplished after each local anaesthetic injection. It should be kept in mind that restlessness, anxiety, tinnitus, dizziness, blurred vision, tremors or drowsiness may be early warning signs of central nervous system toxicity (see Section 4.9 Overdose).

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 the potential chemical neurotoxicity of articaine and the presence of adrenaline as it may impair the perineural blood supply and prevent articaine local wash-out. The risk of nerve damage is likely to be greater if repeated injections are given into a previously anaesthetised site or if higher concentration local anaesthetic solutions are administered.
Concomitant use of other medicinal products may require more thorough monitoring (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
This product must be used safely and effectively under appropriate conditions.
Adrenaline (epinephrine) 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 and the risk of systemic adverse effects increased 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.
This product contains less than 1 mmol sodium (23 mg) per cartridge, i.e. it is considered essentially "sodium free".

4.5 Interactions with Other Medicines and Other Forms of Interactions

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.

Cimetidine.

Increased serum levels of amide anaesthetics have been reported after concomitant administration of cimetidine. Cimetidine may increase the cardiac and neurological effects of local anaesthetics.

Sedatives (central nervous system depressants e.g. benzodiazepine, opioids).

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

Due to the presence of adrenaline.

Interactions requiring precautions for use.

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

Reduced doses of this product should be used due to sensitisation of the heart to the arrhythmogenic effects of catecholamines, leading to the risk of severe ventricular arrhythmia.
Discussion with the anaesthetist before the local anaesthetic administration during general anaesthesia is recommended.

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

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

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

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

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

If the concurrent use of these agents cannot be avoided, the dose and rate of administration of this product should be reduced due to an increased risk of severe hypertension and dysrhythmia.

MAO inhibitors [both A-selective (e.g. moclobemide) and non-selective (e.g. phenelzine, tranylcypromine, linezolid)].

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.

COMT inhibitors (catechol-O-methyl transferase inhibitors) (e.g. entacapone).

Arrhythmias, increased heart rate and blood pressure variations may occur. A reduced amount of adrenaline (epinephrine) in dental anaesthesia should be given to patients taking COMT inhibitors.

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

A reduced dose of this product should be used due to the increased risk of arrhythmia when both adrenaline (epinephrine) and digital glucosides are administered concomitantly to patients.
Careful aspiration prior to administration is recommended.

Thyroid hormones.

When administered concomitantly with the product, thyroid hormones can increase the adrenaline (epinephrine) concentration, leading to tachycardia, dysrhythmia, pulse alterations or myocardial ischemia.

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

Use this product under strict medical supervision due to additive or synergistic increases in blood pressure.

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 the vasoconstricting effect of adrenaline (epinephrine).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No effects on male or female fertility were observed in rats given articaine hydrochloride with adrenaline (epinephrine) subcutaneously from prior to mating until mating (males) or early gestation (females) at doses up to 80 mg/kg/day (approximately twice the maximum recommended human dose on a mg/m2 basis).
(Category B3)
Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans.
No clinical experience of the use of articaine and adrenaline (epinephrine) injections in pregnant women is available.
Safe use of local anaesthetics during pregnancy has not been established with respect to adverse effects on fetal development. The product should only be used in pregnancy when the benefits are considered to outweigh the risks.
No effects on embryofetal development were observed when articaine hydrochloride with adrenaline (epinephrine) was administered subcutaneously throughout organogenesis at doses up to 40 mg/kg/day in rabbits and 80 mg/kg/day in rats (approximately 2 times the maximum recommended human dose on a mg/m2 basis). In rabbits, fetal death and increased fetal skeletal variations were observed at the maternotoxic dose of 80 mg/kg (approximately 4 times the maximum recommended human dose on a mg/m2 basis).
When articaine hydrochloride alone was administered subcutaneously to rats throughout gestation and lactation, 80 mg/kg/day (approximately 2 times the maximum recommended human dose on a mg/m2 basis) increased the number of stillbirths, delayed eye opening, and adversely affected passive avoidance, a measure of learning, in pups, along with maternal toxicity were observed. A dose of 40 mg/kg/day (approximately the maximum recommended human dose on a mg/m2 basis) did not produce these effects. A similar study using articaine hydrochloride with adrenaline produced maternal toxicity, but no effects on the offspring.
 It is unknown whether articaine or adrenaline (epinephrine) is excreted in human breast milk. The excretion of articaine or adrenaline (epinephrine) in milk has not been studied in animals. A decision on whether to continue/ discontinue breast-feeding or to continue/ discontinue therapy with articaine and adrenaline (epinephrine) injections should be made taking into account the benefit of breast-feeding to the child and the benefit of articaine and adrenaline (epinephrine) injections therapy to the woman. Nursing mothers are advised to express and discard breast milk for approximately 4 hours after administration of articaine.

4.8 Adverse Effects (Undesirable Effects)

a) Summary of the safety profile.

Adverse reactions following the administration of articaine/ adrenaline (epinephrine) 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, diminished tolerance by the patient or unintentional intravascular injection. Nervous system disorders, local injection site reactions, hypersensitivity, cardiac disorders and vascular disorders are the most frequently occurring adverse reactions.
Serious adverse reactions are generally systemic. Early symptoms and signs of CNS toxicity include metallic taste, tinnitus, lightheadedness and confusion, followed by tremors and shivering. Seizures and cardiorespiratory arrest may ultimately occur (see Section 4.9 Overdose).

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" indicates the frequency cannot be estimated from the available data. (See Table 4).

c) Description of selected adverse reactions.

1 Allergic reactions should not be mistaken with syncopal episodes.
2 A 2 week delay in the onset of facial paralysis has been described following administration of articaine combined with adrenaline (epinephrine), and the condition was unchanged 6 months later.
3 These neural pathologies may occur with various symptoms of abnormal sensations. Paraesthesia can be defined as spontaneous abnormal usually non painful sensations (e.g. burning, pricking, tingling or itching) well beyond the expected duration of anaesthesia. Most cases of paraesthesia reported following dental treatment are transient and resolve within days, weeks or months.
Persistent paraesthesia, mostly following nerve blocks in the mandible, is characterized by slow, incomplete, or lack of recovery. The risk of nerve damage is likely to be greater if repeated injections are given into a previously anaesthetized site or if higher concentration local anaesthetic solutions are administered.
Symptoms and signs of depressed cardiovascular function may result from a vasovagal reaction, particularly if the patient is in upright position.

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 suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Ubistesin and Ubistesin Forte are exclusively recommended for use in dentistry.
As for any cartridge, the diaphragm should be disinfected just prior to use. It should be carefully swabbed: either with ethyl alcohol 70%; or with pure isopropyl alcohol 90% for pharmaceutical use.
The cartridges should under no circumstances be dipped into any solution whatsoever. The solution for injection should not be mixed with any other product into the same syringe. No opened cartridge of anaesthetic solution should be reused.

Dosage.

The smallest possible volume of solution which will lead to an effective anaesthesia should be used.

Use in adults.

Table 2 summarises the recommended volumes and concentrations of Ubistesin and Ubistesin Forte for various types of anaesthetic procedures. For most common operations, one infiltration with Ubistesin and Ubistesin Forte 1.7 mL is sufficient. In all cases, the injection must be done slowly (about 1 mL/minute). For an infiltration in the interdental septum, a quantity of 0.3 to 0.5 mL is generally sufficient. Higher volumes should rarely be required.
Maximum recommended dose for normal healthy adults of articaine hydrochloride administered by submucosal infiltration and/or nerve block should not exceed 7 mg/kg of bodyweight. This corresponds, for a subject weighing 60 kg, to six standard 1.7 mL cartridges (doses of 7 mg/kg were not exceeded in clinical trials). Anaesthesia is obtained rapidly (one to six minutes).
The suggested volumes (see Table 2) serve only as a guide for normal healthy adults. Other volumes may be used provided that the total maximum recommended dose is not exceeded.
The duration of the anaesthesia during which an operation can be performed is about one hour (pulpal analgesia) depending on the technique used, and on the procedure.

Use in children.

Safety and effectiveness in paediatric patients below the age of 4 years have not been established. Dosages in paediatric patients (over 4 years) should be reduced, commensurate with age, bodyweight and physical condition. See Table 3.
Use of Ubistesin and Ubistesin Forte in children under 4 years of age is not recommended due to the absence of safety and efficacy data. Maximum recommended dose for normal healthy children must not exceed 7 mg/kg of bodyweight.

Special populations.

Elderly population.

Increased plasma levels of Ubistesin can occur in older patients due to diminished metabolic processes and reduced distribution volume. The risk of accumulation of Ubistesin is particularly increased after repeated administration; (see Section 4.4 Special Warnings and Precautions for Use).

Patients with hepatic impairment.

Articaine is also metabolised by the liver. Lower doses of articaine may be required in patients with hepatic dysfunction due to prolonged effects and systemic accumulation.
Dosages should be reduced from adult recommendations, taking into consideration any cardiac or liver disease; (see Section 4.4 Special Warnings and Precautions for Use).

Patients with renal impairment.

Articaine and its metabolites are mainly eliminated in the urine. Lower doses of articaine may be required in patients with severe renal dysfunction due to prolonged effects and systemic accumulation (see Section 4.4 Special Warnings and Precautions for Use).

Patients with particular genotype.

In patients who are known to have an inborn or acquired deficiency in plasma cholinesterase activity the use of Ubistesin is contraindicated (see Section 4.3 Contraindications).

Other relevant special populations.

The dose has to be likewise reduced in patients with certain pre-existing diseases (angina pectoris, arteriosclerosis; see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Dose recommendation for special populations.

A lower dosage range is thus recommended in all such cases (i.e. minimum volume of Ubistesin for sufficient anaesthetic effect).

Method of administration.

Injection should always be made slowly with frequent aspirations to avoid inadvertent intravascular injection, which can produce cerebral symptoms even at low doses (see Section 4.4 Special Warnings and Precautions for Use).
One or more cartridges should be used on a single patient on one occasion only during each session of treatment. If only a portion of a cartridge is used, the remainder must be discarded.
For single patient use only. Contains no antimicrobial agent. Discard unused contents after use (see Section 6.6 Special Precautions for Disposal).

4.7 Effects on Ability to Drive and Use Machines

The combination articaine hydrochloride with adrenaline (epinephrine) 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 the combination of articaine hydrochloride with adrenaline (epinephrine). Patients experiencing these symptoms should not drive or use machinery until any such symptoms have completely resolved.

4.9 Overdose

The most serious effects of articaine intoxication are on the CNS and cardiovascular system. The type of toxic reaction is unpredictable and depends on such factors as dosage, rate of absorption, unintended intravascular injection and clinical status of the patient. To minimise the risk, the patient's cardiovascular and respiratory vital signs and state of consciousness should be monitored after each injection.
Two types of reactions that effect stimulation and/or depression of the central cortex and medulla may result from systemic absorption.
Slow onset symptoms following overdose include stimulation leading to restlessness, nervousness, dizziness, apprehension, light headedness, paraesthesias, euphoria, logorrhoea, sweating, headache, blurred vision, tinnitus, nausea, vomiting, muscle twitching and tremors, nystagmus, tachypnoea, difficulty in swallowing, metallic taste, slurred speech and convulsions. Excitatory manifestations may not occur at all or may be transient, followed by depression with drowsiness, peripheral vasodilatation, hypotension, bradycardia, bradypnoea, cardiorespiratory arrest and coma.
Rapid onset symptoms following overdose include cardiorespiratory depression, leading primarily to respiratory arrest, cardiovascular collapse and cardiac arrest. Since cardiac arrest symptoms may occur rapidly and with little warning, treatment should be readily available.

Treatment.

For all symptoms.

If acute toxicity occurs the injection should be stopped immediately. The patient should be placed in a recumbent position. Supportive treatment should be given; for circulatory depression this may require the administration of intravenous fluids and resuscitative drugs as directed by the clinical situation. A patent airway should be established and maintained, oxygen should be administered, and assisted or controlled ventilation should be provided as required.

Circulatory collapse.

Immediately resuscitate with oxygen and commence cardiovascular resuscitation procedures as appropriate.

Convulsions.

Appropriate medication for the management of convulsions should be used. Supportive treatment should be given; standard cardiopulmonary resuscitative therapy, including respiratory support may be required to counter adverse effects on the cardiovascular and/or respiratory symptoms and to control convulsions. There is no specific antidote.
If not treated immediately, both convulsions and cardiovascular depression may result in hypoxia, acidosis, bradycardia, arrhythmia and cardiac arrest.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Hydrochloric acid 14% (for pH adjustment), sodium chloride, sodium hydroxide solution 9% (for pH adjustment), sodium sulfite, water for injections.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

2 years.

6.4 Special Precautions for Storage

Store below 25°C. Protect from light. Do not freeze.

6.5 Nature and Contents of Container

One tin contains 50 cartridges of 1.7 mL each.
Cartridge made of colourless neutral glass I.
Stopper and rubber disc are made of butyl rubber.
Aluminium cap made of aluminium-iron-silicon-alloy.

6.6 Special Precautions for Disposal

For single patient use only. Contains no antimicrobial agent. Discard unused contents after use.
In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

Summary Table of Changes