Ultracaine® d-s

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ULTRACAINE® D-S (ULTRACAINE®D-S)

Composition:

Active substances: articaine hydrochloride, epinephrine (adrenaline) hydrochloride;

1 ml of solution contains 40 mg of articaine hydrochloride and 0.006 mg of epinephrine (adrenaline) hydrochloride;

Excipients: sodium metabisulfite (E 223), sodium chloride, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless solution, practically free from visible particles.

Pharmacotherapeutic group. Local anesthetics. Amides. Articaine, combinations.

ATC code N01B B58.

Pharmacological Properties

Pharmacodynamics. Ultracaine® D-S is an amide-type local anesthetic used in dentistry for infiltration and conduction anesthesia. The drug has a rapid onset of action (latent period – 1–3 minutes) and provides strong analgesic effect. The duration of effective anesthesia is approximately 45 minutes.

The mechanism of action of articaine is believed to involve reduced impulse conduction along nerve fibers through blockade of voltage-dependent sodium channels in cell membranes.

Clinical studies involving up to 210 patients demonstrated that the use of Ultracaine® D-S in doses up to 5 mg/kg of articaine and Ultracaine® D-S forte in doses up to 7 mg/kg of articaine in children aged 3.5 to 16 years provided reliable local analgesia when administered via infiltration anesthesia (for the mandible) and conduction anesthesia (for the maxilla). The duration of anesthesia was similar across all age groups and depended on the amount of anesthetic administered.

Pharmacokinetics. Articaine is 95% bound to plasma proteins. After injection into the oral mucosa, the elimination half-life is 25.3 ± 3.3 minutes. Approximately 10% of articaine is metabolized in the liver, primarily by esterases present in blood plasma and tissues. Articaine is excreted predominantly by the kidneys in the form of articaine acid.

In children, total exposure following infiltration anesthesia from the vestibular side was similar to that in adults; however, maximum serum concentrations were reached more rapidly.

Preclinical Safety Data.

Results of standard preclinical studies on safety pharmacology, chronic toxicity, reproductive toxicity, and genotoxicity indicate no special hazard for humans when therapeutic doses are used. At doses exceeding therapeutic levels, articaine exerts cardiodepressant effects and may produce vasodilatory action. Epinephrine counteracts the effects of sympathomimetics.

In embryotoxicity studies, no increase in fetal mortality or occurrence of developmental malformations was observed with daily intravenous administration of articaine at doses up to 20 mg/kg (rats) and 12.5 mg/kg (rabbits). Epinephrine demonstrated toxic effects on reproductive function in animals at doses ranging from 0.1 to 5 mg/kg (several times higher than the maximum dose of epinephrine entering the body when using Ultracaine® D-S), manifested by the development of congenital malformations and impairment of uteroplacental blood flow.

In studies on embryofetotoxicity of articaine and epinephrine, no increased incidence of developmental abnormalities was observed with daily subcutaneous administration of articaine at doses up to 80 mg/kg (rats) and 40 mg/kg (rabbits).

In studies assessing the effects of the drug on fertility and early embryofetal development in rats, no negative effects on fertility in males or females were observed at doses causing toxic manifestations in parent animals.

Clinical characteristics.

Indications. Routine procedures such as uncomplicated single or multiple tooth extractions, caries cavity preparation, tooth preparation for crown placement.

Contraindications. Ultracaine® D-S must not be used in cases of hypersensitivity to the active ingredients – epinephrine and articaine, as well as to sulfites (metabisulfite (E 223)) or to any of the excipients of the drug.

Due to the presence of articaine in Ultracaine® D-S, it must not be used in cases of:

• hypersensitivity to other amide-type local anesthetics;
• severe disturbances of cardiac impulse generation or conduction disorders (II–III degree atrioventricular block, pronounced bradycardia);
• acute decompensated heart failure (acute congestive heart failure);
• severe arterial hypotension.

Due to the presence of epinephrine in Ultracaine® D-S, it must not be used:

• in patients with closed-angle glaucoma;
• in patients with hyperthyroidism;
• in patients with paroxysmal tachycardia or atrial fibrillation with tachycardia;
• in patients who have recently (within 3 to 6 months) suffered myocardial infarction;
• in patients who have recently (within 3 months) undergone coronary artery bypass surgery;
• in patients taking non-selective beta-blockers, such as propranolol (due to the risk of hypertensive crisis or severe bradycardia);
• in patients with pheochromocytoma;
• in patients with severe arterial hypertension;
• during concomitant treatment with tricyclic antidepressants or monoamine oxidase inhibitors (MAOIs), as their active substances may potentiate cardiovascular effects of epinephrine. This phenomenon may persist for up to 14 days after discontinuation of MAO inhibitors.

Intravenous administration of the drug is contraindicated.

Due to the presence of epinephrine in Ultracaine® D-S, it should not be used for anesthesia of extremities (e.g., fingers), as there is a risk of ischemia.

Ultracaine® D-S must not be used in patients with bronchial asthma and hypersensitivity to sulfites. In such patients, administration of Ultracaine® D-S may provoke an acute allergic reaction with anaphylactic symptoms, such as bronchospasm.

Interaction with other medicinal products and other forms of interaction.

Combinations of different anesthetics have additive effects and may produce more pronounced effects on the cardiovascular system and CNS.

Hypertensive effects of sympathomimetic vasoconstrictors (e.g., epinephrine) may be enhanced by tricyclic antidepressants or MAO inhibitors. Therefore, such combinations are contraindicated (see section "Contraindications").

Ultracaine® D-S is prohibited for use in patients taking non-selective beta-blockers, such as propranolol (see section "Contraindications").

Epinephrine may inhibit insulin release from the pancreas, thereby reducing the effectiveness of oral antidiabetic agents.

Some inhalational anesthetics, such as halothane, may increase myocardial sensitivity to catecholamines, potentially causing ventricular arrhythmias after administration of Ultracaine® D-S.

It should be noted that in patients receiving antithrombotic therapy (e.g., heparin, acetylsalicylic acid), accidental puncture of a blood vessel during local anesthesia may lead to serious bleeding. Such patients generally have an increased tendency to bleeding.

Special precautions for use.

Ultracaine® D-S should be administered to patients with cholinesterase deficiency only when absolutely indicated, as in such cases there is a higher probability of prolonged drug action and sometimes of undesirable intensification of its effects.

Ultracaine® D-S should be used with caution in the following conditions:

• Coagulation disorders;
• Severe renal or hepatic impairment;
• Concomitant use of halogen-containing inhalational anesthetics (see section "Interaction with other medicinal products and other forms of interaction");
• History of epilepsy (see section "Adverse reactions").

Ultracaine® D-S should also be used with particular caution in the following cases. In addition, Ultracaine® D-S contains less epinephrine than Ultracaine® D-S forte, making it more suitable for patients with:

• Cardiovascular diseases (e.g. heart failure, ischemic heart disease, angina pectoris, history of myocardial infarction, cardiac arrhythmia, arterial hypertension);
• Atherosclerosis;
• Cerebrovascular disorders, history of stroke;
• Chronic bronchitis, pulmonary emphysema;
• Diabetes mellitus;
• Marked anxiety.

Injections must not be administered into inflamed (infected) areas (this increases absorption of Ultracaine® D-S, leading to reduced efficacy).

Before administering this medicinal product, the patient should be interviewed, a medical history taken, information obtained about concomitant medications, and verbal contact with the patient maintained throughout administration. A test injection with 5 to 10% of the intended dose should be performed if there is a risk of allergic reaction.

To avoid adverse effects, the following measures are necessary:

• Use the lowest possible dose;
• Perform a two-step aspiration test before injection (to avoid intravascular administration).

Patients are advised to eat only after full sensation has returned.

Ultracaine® D-S contains sodium, but the amount does not exceed 1 mmol (23 mg) per 1 ml.

Use in children.

Caregivers of young children should be warned about the possible risk of soft tissue injury due to biting, resulting from prolonged soft tissue numbness after anesthesia.

Sodium metabisulfite may rarely cause hypersensitivity reactions and bronchospasm.

The product contains less than 1 mmol/dose of sodium, i.e. it is practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy. There is no clinical experience with the use of articaine in pregnant women, except during labor. Animal studies have shown no evidence of any direct or indirect adverse effects of articaine on pregnancy, embryofetal development, labor, or postnatal development. Animal studies have demonstrated that epinephrine, at doses higher than the maximum recommended, has a toxic effect on reproductive function (see section "Non-clinical safety data"). Epinephrine and articaine cross the placental barrier, although articaine crosses to a significantly lesser extent compared to other local anesthetics. Articaine concentrations in newborn serum are approximately 30% of maternal serum concentrations. Accidental intravascular administration of epinephrine to the mother may reduce uterine blood flow. Use of Ultracaine® D-S during pregnancy is possible only after careful benefit-risk assessment.

Ultracaine® D-S should be preferred, as it contains less epinephrine (1:200,000) than Ultracaine® D-S forte.

Breastfeeding. Due to rapid decline in plasma concentrations and fast elimination, articaine is not present in breast milk in clinically significant amounts. Epinephrine passes into breast milk but also rapidly degrades. There is no need to interrupt breastfeeding after short-term use of the medicinal product.

Fertility.

Animal studies with articaine 40 mg/mL + epinephrine 0.01 mg/mL showed no negative effect on fertility (see section "Pharmacological properties"). When used at therapeutic doses, a negative effect of the medicinal product on human fertility is not expected.

Ability to affect reaction speed when driving or operating machinery.

Only the dentist should determine when, after administration of Ultracaine® D-S, the patient can resume driving or operating machinery. Fear related to anticipated dental procedures and associated stress may impair the ability to act effectively. However, appropriate studies have shown that local anesthesia with articaine does not cause any noticeable deterioration in the ability to drive a vehicle.

Method of Administration and Dosage.

In the case of uncomplicated forceps removal of an upper jaw tooth, in the absence of inflammation, it is sufficient to inject 1.7 mL of the preparation into the vestibular fold on the vestibular side for each tooth. Occasionally, to achieve complete anesthesia, an additional vestibular injection of 1–1.7 mL of the preparation may be required. In most cases, there is no need to perform a painful palatal injection.

If an incision on the palate or suturing of the palate is required, 0.1 mL of the preparation injected on the palatal side is sufficient to create an anesthetic depot.

In cases of multiple extractions of adjacent teeth, the number of vestibular depot injections can usually be reduced.

In uncomplicated forceps removal of lower premolars, in the absence of inflammation, mandibular anesthesia may be omitted, as infiltration anesthesia achieved by injecting 1.7 mL of the preparation per tooth is usually sufficient. If this does not provide complete analgesia, an additional vestibular injection of 1–1.7 mL should first be performed. Only if this also fails to achieve complete anesthesia is standard inferior alveolar nerve block indicated.

For caries cavity preparation or tooth preparation for a crown, except for lower molars, an injection of Ultracaine**®** D-S from the vestibular side at a dose of 0.5–1.7 mL per tooth is indicated; the dose depends on the extent and duration of treatment.

Any residue remaining after opening ampoules or using cartridges must be discarded.

For surgical procedures, the dosage of Ultracaine**®** D-S should be selected according to the severity and duration of the surgery.

During one treatment course, adults may receive up to 7 mg of ultracaine (articaine) per 1 kg of body weight. Doses up to 500 mg (equivalent to 12.5 mL of injection solution), following a prior aspiration test, have been well tolerated.

Children.

The medicinal product Ultracaine**®** D-S should be administered to children in the minimal amount required to achieve adequate analgesia; the amount administered should be individually adjusted according to the child's age and body weight. The maximum dose of 7 mg of articaine per 1 kg of body weight must not be exceeded.

The use of this preparation in children under 1 year of age has not been studied.

Elderly patients and patients with severe hepatic and renal dysfunction.

In elderly patients and in patients with severe hepatic and renal dysfunction, increased plasma concentrations of articaine are possible. Particular caution should be exercised in such patients, and the minimum dose necessary to achieve adequate depth of anesthesia should be used.

Method and duration of administration.

Ultracaine**®** D-S is intended for submucosal administration into the oral cavity.

To avoid intravascular injection, an aspiration test should always be performed before injection. The aspiration test should be conducted in two stages, i.e., by rotating the needle 90°, or preferably 180°. When using cartridges, the "Unidjet® K" or "Unidjet® K vario" syringes are most suitable for performing this test.

Serious systemic reactions resulting from accidental intravascular injection can mostly be avoided by using the following injection technique: slowly inject 0.1–0.2 mL, then, not earlier than 20–30 seconds later, slowly administer the remainder of the preparation. The injection pressure should correspond to tissue sensitivity.

The use of appropriate syringes (for infiltration anesthesia ─ "Unidjet® K" or "Unidjet® K vario"; for intraligamentary anesthesia ─ "Ultrajet®") ensures maximum protection against cartridge glass damage and guarantees smooth administration. Damaged cartridges must not be used for injections.

To prevent infection (e.g., transmission of hepatitis virus), new sterile needles and syringes should always be used when drawing up the solution.

This medicinal product must not be used if it is cloudy or has changed color.

Children.

The medicinal product Ultracaine**®** D-S should be administered to children in the minimal amount required to achieve adequate analgesia; the amount administered should be individually adjusted according to the child's age and body weight. The maximum dose of 7 mg of articaine per 1 kg of body weight must not be exceeded.

The use of this preparation in children under 1 year of age has not been studied.

Overdose.

Symptoms of overdose.

Signs of central nervous system (CNS) excitation: restlessness, anxiety, confusion, rapid breathing, tachycardia, elevated blood pressure accompanied by facial flushing, nausea, vomiting, tremor, involuntary muscle contractions, tonic-clonic seizures.

Signs of CNS depression: dizziness, hearing loss, inability to speak, stupor, loss of consciousness, muscular atony, vasomotor paralysis (weakness, pallor of the skin), dyspnea, fatal outcome due to respiratory center paralysis.

Signs of cardiovascular depression: bradycardia, arrhythmia, ventricular fibrillation, decreased blood pressure, cyanosis, cardiac arrest.

Emergency measures and antidotes.

At the first signs of an adverse reaction or toxic effect (e.g., dizziness, motor excitation, or stupor), the injection should be stopped and the patient placed in a horizontal position. Airway patency should be ensured, and pulse and blood pressure monitored.

Even if intoxication symptoms do not appear severe, it is recommended to insert an intravenous catheter to ensure immediate intravenous access if needed.

Depending on the severity of respiratory disturbances, oxygen should be administered, and if necessary, ─ artificial ventilation. If required, tracheal intubation combined with controlled lung ventilation should be performed.

Involuntary muscle contractions or generalized seizures should be controlled by intravenous administration of short-acting spasmolytic agents (e.g., succinylcholine chloride, diazepam). Artificial ventilation (oxygen) is also recommended.

Hypotension, tachycardia, or bradycardia can be managed by placing the patient in a horizontal position with elevated lower limbs.

In severe circulatory disturbances and shock, regardless of the cause, the following emergency measures should be taken immediately after stopping the injection:

• Place the patient in a horizontal position with elevated lower limbs, and ensure airway patency (oxygen insufflation);
• Initiate intravenous infusion of a balanced electrolyte solution;
• Administer intravenous glucocorticoids (e.g., 250–1000 mg of prednisolone or equivalent amount of its derivative, e.g., methylprednisolone);
• Restore circulating blood volume (plasma substitutes or human albumin may be additionally used if necessary).

In case of impending circulatory collapse and progressive bradycardia, immediate intravenous injection of epinephrine (adrenaline) is required. For this purpose, 1 mL of epinephrine solution 1:1000 should be diluted to 10 mL (alternatively, epinephrine solution 1:10,000 may be used), and 0.25–1 mL of this solution (containing 0.025–0.1 mg epinephrine) should be slowly administered, with continuous monitoring of pulse rate and blood pressure (caution: cardiac arrhythmia may occur). Do not administer more than 1 mL of this solution (0.1 mg epinephrine) during a single intravenous injection. If this amount of epinephrine is insufficient, it is recommended to add it to the infusion solution (infusion rate adjusted according to pulse rate and blood pressure).

Severe forms of tachycardia and tachyarrhythmia can be managed with antiarrhythmic drugs (but not non-selective beta-blockers such as propranolol) (see section "Contraindications"). In such cases, oxygen administration and circulatory monitoring are essential.

In hypertensive patients with elevated blood pressure, if necessary, peripheral vasodilators should be administered.

Adverse Reactions

The following categories are used to classify the frequency of adverse reactions: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from the available data).

Immune system disorders.

Frequency not known: hypersensitivity reactions (allergic and pseudoallergic) may occur. These may manifest as swelling and/or inflammation at the injection site, or independently of the injection site as skin redness, itching, conjunctivitis, rhinitis, facial swelling resembling angioedema, including swelling of the upper and/or lower lip and/or cheeks, swelling of the vocal cords causing a sensation of a lump in the throat and difficulty swallowing, urticaria, and breathing difficulties which may progress to anaphylactic shock.

Nervous system disorders.

Common: paraesthesia, hypoesthesia, headache (mainly due to the presence of epinephrine).

Uncommon: dizziness.

Frequency not known:

• Dose-dependent central nervous system reactions may occur when excessively high doses are administered or in case of accidental intravascular injection: restlessness, nervousness, stupor (which may sometimes progress to loss of consciousness), coma, respiratory depression which may sometimes progress to respiratory arrest, muscle tremors, involuntary muscle contractions which may sometimes progress to generalized seizures.
• Theoretical possibility of nerve injury exists during any dental procedure due to improper injection technique or anatomical peculiarities of the injection site. In such cases, injury to the facial nerve and development of facial nerve palsy may occur. This may lead to reduced taste sensitivity.

Eye disorders.

Frequency not known: during injection of local anaesthetic (or shortly after) in the head area, visual disturbances (blurred vision, diplopia, mydriasis, blindness) may also occur, which are usually temporary.

Cardiovascular system disorders.

Uncommon: tachycardia.

Frequency not known: cardiac arrhythmias, increased blood pressure, arterial hypotension, bradycardia, heart failure, and shock (which may be life-threatening).

Gastrointestinal disorders.

Common: nausea, vomiting.

General disorders and administration site conditions.

Frequency not known: in case of unintentional intravascular injection, ischemic areas may appear at the injection site, which may sometimes progress to tissue necrosis (see section "Dosage and administration").

Special warnings.

In isolated cases, particularly in patients with bronchial asthma, the drug may cause hypersensitivity reactions due to the presence of sodium metabisulfite in its composition. These reactions may clinically manifest as vomiting, diarrhea, stridor, acute asthma attack, disturbances of consciousness, or shock.

Pediatric population

According to published study results, the safety profile in children aged 4 to 18 years was similar to that in adults. However, accidental soft tissue injuries due to prolonged soft tissue anaesthesia were observed more frequently (up to 16% of children), especially in children aged 3 to 7 years. In a retrospective study involving 211 children aged 1 to 4 years, dental treatment was performed using up to 4.2 mL of Ultracaine**®** D-S or Ultracaine**®** D-S forte, with no reports of adverse effects.

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.

Shelf life. Ampoules – 3 years, cartridges – 2.5 years.

Storage conditions. Keep out of the reach of children. Store at a temperature not exceeding +25 °C in the original packaging to protect from light.

Incompatibilities. The medicinal product should not be mixed with other medicinal products.

Packaging.

For manufacturer Sanofi-Aventis Deutschland GmbH, Germany.

Ampoules: No. 100 (10×10): 2 mL in an ampoule; 10 ampoules in a cardboard blister pack; 1 cardboard blister pack in a cardboard box; 10 cardboard boxes wrapped in cellophane film.

Cartridges: No. 100 (10×10): 1.7 mL in a cartridge; 10 cartridges in a cardboard blister pack; 10 cardboard blister packs in a cardboard box.

For manufacturer DELPHARM DIJON, France.

Ampoules: No. 100 (5×2×10): 2 mL in an ampoule; 5 ampoules in a polystyrene pack; 2 polystyrene packs in a cardboard box; 10 cardboard boxes wrapped in cellophane film.

Prescription category. Prescription only.

Manufacturer.

Ampoules: No. 100 (10×10) and cartridges: No. 100 ( 10×10):

Sanofi-Aventis Deutschland GmbH, Germany.

Ampoules: No. 100 (5×2×10):

DELPHARM DIJON, France.

Manufacturer addresses.

Bruningstrasse 50, Industriepark Hoechst, 65926 Frankfurt am Main, Germany.

6 Boulevard de l’Europe, QUETIGNY, 21800, France.

Marketing authorization holder.

LLC "Sanofi-Aventis Ukraine", Ukraine.