Ultracaine® d-s forte

INSTRUCTIONS FOR MEDICAL USE OF ULTRACAIN® D-S FORTE (Ultracain® D-S Forte)

Composition:

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

1 ml of solution contains 40 mg of articaine hydrochloride and 0.012 mg of epinephrine (adrenaline) hydrochloride;

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

Pharmaceutical form. Injection solution.

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

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

ATC code N01B B58.

Pharmacological Properties.

Pharmacodynamics. Ultracaine® D-S forte 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 produces a strong analgesic effect. The duration of effective anesthesia is approximately 75 minutes.

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

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

Pharmacokinetics. The plasma protein binding of articaine is 95%. 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 articainic acid.

In children, total exposure after administration of infiltration anesthesia from the vestibular side was similar to that in adults, although 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 to humans when therapeutic doses are used. At doses exceeding therapeutic levels, articaine exerts cardiodepressant effects and may produce vasodilatory effects. Epinephrine counteracts the effects of sympathomimetics.

In embryotoxicity studies, no increase in fetal mortality or incidence 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 received when using Ultracaine® D-S forte), manifested by the occurrence of congenital malformations and impairment of uteroplacental blood flow.

In studies of 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 effects in parent animals.

Clinical characteristics.

Indications. Surgical procedures on the mucous membranes and bones requiring more intense ischemia; surgical procedures on dental pulp (amputation and extirpation); removal of periodontal or broken teeth (osteotomy); prolonged surgical procedures; transcutaneous osteosynthesis; removal of cysts; surgical procedures on gingival mucosa; apical resection.

Contraindications. Ultracaine**®** D-S forte must not be used in cases of hypersensitivity to the active substances—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 forte, it must not be used in cases of:

• hypersensitivity to other amide-type local anesthetics;
• severe disturbances in 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 forte, 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 the past 3 to 6 months) suffered myocardial infarction;
• in patients who have recently (within the past 3 months) undergone aortocoronary bypass surgery;
• in patients taking non-selective beta-blockers, such as propranolol (there is a risk of hypertensive crisis or severe bradycardia);
• in patients with pheochromocytoma;
• in patients with severe arterial hypertension;
• during concomitant treatment with tricyclic antidepressants or MAO inhibitors, as their active substances may potentiate cardiovascular effects of epinephrine. This phenomenon may occur within 14 days after discontinuation of MAO inhibitor therapy.

Intravenous administration of the drug is contraindicated.

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

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

Interaction with other medicinal products and other types of interactions.

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 forte must not be used 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 drugs.

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

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 forte should be administered to patients with cholinesterase deficiency only when absolutely indicated, as in such cases there is a higher probability of prolonged duration of action and sometimes of undesirable potentiation of its effects.

Ultracaine® D-S forte should be used with caution in:

• 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 forte should be used with particular caution in patients with:

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

In addition, Ultracaine® D-S contains less epinephrine than Ultracaine® D-S forte; therefore, in the above-mentioned conditions, Ultracaine® D-S is preferable.

Injections must not be administered into areas of inflammation (infection) (absorption of Ultracaine® D-S forte is enhanced, leading to reduced efficacy).

Before administering this medicinal product, the patient must be interviewed, a medical history taken, information collected regarding concomitant medications, and verbal contact with the patient must be maintained continuously during 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 should be observed:

• Use the lowest possible dose;
• Perform an aspiration test in two stages before injection (to avoid intravascular administration).

It is recommended that the patient eat only after full sensation has returned.

Ultracaine® D-S forte 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 following 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 not revealed any evidence of direct or indirect harmful effects of articaine on pregnancy, embryofetal development, labor, or postnatal development. Animal studies have demonstrated that epinephrine (adrenaline), at doses higher than the maximum recommended, has toxic effects on reproductive function (see section "Preclinical safety data"). Epinephrine and articaine cross the placental barrier, although articaine crosses to a much lesser extent compared to other local anesthetics. Articaine concentrations in newborn serum are approximately 30% of maternal serum concentrations. Accidental intravascular injection of epinephrine (adrenaline) in the mother may reduce uterine blood flow. Use of Ultracaine® D-S forte during pregnancy is possible only after careful assessment of the benefit-risk ratio.

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 rapid elimination of articaine from the body, it is not present in breast milk in clinically significant amounts. Epinephrine passes into breast milk but is also rapidly metabolized. With short-term use of the medicinal product, there is no need to discontinue breastfeeding.

Fertility.

Animal studies with articaine 40 mg/ml + epinephrine 0.01 mg/ml did not reveal any 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 decide when, after administration of Ultracaine® D-S forte, the patient may resume driving or operating machinery. Fear related to anticipation of dental procedures and the associated stress may impair the ability to act effectively; however, relevant studies have shown that local anesthesia with articaine does not cause any noticeable impairment in the ability to drive a vehicle.

Administration and Dosage

In uncomplicated forceps extraction of maxillary teeth, in the absence of inflammation, it is sufficient to administer 1.7 mL of the preparation into the vestibular fold on the vestibular side for each tooth. Occasionally, an additional vestibular injection of 1–1.7 mL of the preparation may be required to achieve complete anesthesia. In most cases, painful palatinal injection is not necessary.

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

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

In uncomplicated forceps extraction of mandibular 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 complete analgesia is not achieved, an additional vestibular injection of 1–1.7 mL should first be administered. Only if this also fails to provide complete anesthesia is standard inferior alveolar nerve block indicated.

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

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

During a single treatment course, adults may receive up to 7 mg of Ultracaine (articaine) per 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.

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

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

Elderly patients and patients with severe hepatic or renal dysfunction.

In elderly patients and in patients with severe impairment of liver or kidney function, increased plasma concentrations of articaine may occur. Extreme caution should be exercised in such patients, and the minimum effective dose required to achieve adequate depth of anesthesia should be used.

Route of administration and duration of use.

Ultracaine® D-S forte is intended for submucosal administration in the oral cavity.

To avoid intravascular injection, aspiration should always be performed prior to injection. The aspiration test should be performed in two stages, i.e., by rotating the needle 90°, or preferably 180°. When cartridges are used, Unijet® K or Unijet® K Vario syringes are best suited for performing this test.

Serious systemic reactions due to accidental intravascular injection can mostly be avoided by using the following injection technique: after aspiration, slowly inject 0.1–0.2 mL, then wait at least 20–30 seconds before slowly injecting the remainder of the solution. Injection pressure should be adapted to tissue sensitivity.

Using appropriate syringes (for infiltration anesthesia — Unijet® K or Unijet® K Vario; for intraligamentary anesthesia — Ultrajet®) ensures maximum protection against cartridge glass breakage and guarantees smooth delivery. Damaged cartridges must not be used for injections.

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

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

Children.

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

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

Overdose.

Symptoms of overdose.

Signs of 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), respiratory distress, and 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 adverse reaction or toxic effects (e.g., dizziness, motor agitation, or stupor), the injection should be stopped immediately and the patient placed in a supine position. Airway patency must 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 and, if necessary, artificial ventilation should be administered. Endotracheal intubation combined with controlled ventilation may be required if needed.

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 may be managed by placing the patient in a supine position with elevated lower limbs.

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

• Place the patient in a supine 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 dose of its derivative, such as methylprednisolone);
• Restore circulating blood volume (plasma substitutes or human albumin may be additionally used if necessary).

In case of impending circulatory collapse and increasing bradycardia, immediate intravenous injection of epinephrine (adrenaline) is required. Dilute 1 mL of 1:1000 epinephrine solution to 10 mL (alternatively, use 1:10,000 epinephrine solution) and slowly inject 0.25–1 mL of this solution (containing 0.025–0.1 mg epinephrine), monitoring pulse rate and blood pressure (caution: arrhythmias may occur). Do not administer more than 1 mL (0.1 mg epinephrine) in a single intravenous injection. If this dose is insufficient, epinephrine should be added to the infusion solution (infusion rate adjusted according to pulse rate and blood pressure).

Severe tachycardia and tachyarrhythmias may be managed with antiarrhythmic agents (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, peripheral vasodilators may be used if necessary.

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:

• Central nervous system dose-dependent reactions may occur following administration of excessively high doses or 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 risk of nerve injury exists with any dental procedure due to incorrect injection technique or anatomical peculiarities of the injection site. In such cases, injury to the facial nerve and facial nerve paresis may occur. This may lead to reduced taste sensitivity.

Eye disorders.

Frequency not known: injection of a local anesthetic (or shortly after) in the head area may also lead to visual disturbances (blurred vision, diplopia, mydriasis, blindness), 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: following 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 product may cause hypersensitivity reactions due to the presence of sodium metabisulfite in its composition. These reactions may clinically manifest as vomiting, diarrhea, stridorous breathing, 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 injury due to prolonged soft tissue anesthesia was 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 of suspected adverse reactions after marketing authorization is an important procedure. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested 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 reach of children. Store at temperatures not exceeding +25 °C in the original packaging to protect from light.

Incompatibilities. The 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 blister pack; 1 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 blister pack; 10 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 locations and addresses of places of business.

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 / Sanofi-Aventis Ukraine LLC, Ukraine.