Artinibs with epinephrine 1:100.000

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ARTINIBSA WITH EPINEPHRINE 1:100,000 (ARTINIBSA WITH EPINEPHRINE 1:100,000)

Composition:

Active substances: articaine, adrenaline;

1 ml of solution contains 40 mg of articaine hydrochloride, 0.01 mg of adrenaline tartrate calculated as adrenaline;

1 cartridge (1.8 ml) contains 72 mg of articaine hydrochloride, 0.018 mg of adrenaline tartrate calculated as adrenaline;

Excipients: sodium chloride; sodium metabisulfite (E 223); citric acid monohydrate; hydrochloric acid (for pH adjustment); sodium hydroxide (for pH adjustment); water for injections.

Pharmaceutical form. Injection solution.

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

Pharmacotherapeutic group.

Local anesthetics. Amides. Articaine, combinations. ATC code N01BB58.

Pharmacological Properties

Pharmacodynamics

The drug contains articaine, an amide-type local anesthetic used in dentistry. It causes reversible blockade of autonomic, sensory, and motor nerve fibers. The mechanism of action of articaine is believed to be blockade of voltage-dependent sodium channels in the nerve fiber membrane.

It is characterized by rapid onset of anesthesia (onset time: 1 to 3 minutes), reliable and strong analgesic effect, and good local tolerance.

Adrenaline (epinephrine) (diluted to 1/100,000), added to the articaine solution, slows the entry of articaine into systemic circulation, thereby maintaining a longer-lasting effective concentration in tissues. This, in turn, provides a surgical field with reduced bleeding.

The duration of action is at least 45 minutes for pulpal anesthesia and from 120 to 240 minutes for soft tissue anesthesia.

Pharmacokinetics

The drug is rapidly and almost completely absorbed.

The maximum plasma concentration of articaine after intraoral injection is reached within approximately 10–15 minutes. The volume of distribution is 1.67 L/kg, and the elimination half-life is approximately 20 minutes.

Protein binding of articaine in plasma is up to 95%. It is rapidly hydrolyzed by plasma cholinesterases into its primary metabolites, articainic acid, which are further metabolized into glucuronic acid conjugates of articainic acid. Articaine and its metabolites are primarily excreted via the kidneys. Adrenaline is rapidly metabolized in the liver and other tissues. Both adrenaline and its metabolites are excreted by the kidneys.

Clinical characteristics.

Indications.

Local (infiltration and conduction) anesthesia in dentistry for performing complex procedures requiring deep analgesia.

Contraindications.

• Hypersensitivity to articaine or to other amide-type local anesthetics, epinephrine (adrenaline), sulfites, or to any of the excipients of the medicinal product;
• Paroxysmal tachycardia and other tachyarrhythmias;
• Acute heart failure, unstable angina, recent myocardial infarction (within 3 to 6 months), recent coronary artery bypass surgery (within 3 months), refractory arrhythmia and paroxysmal tachycardia, or high-frequency prolonged arrhythmia, untreated or uncontrolled congestive heart failure, cardiac conduction disorders (second- to third-degree atrioventricular block, documented bradycardia), severe (untreated or uncontrolled) arterial hypertension, severe arterial hypotension;
• Severe bronchial asthma and hypersensitivity to sulfites;
• Angle-closure glaucoma;
• Concurrent use of non-selective β-adrenoblockers;
• Severe hepatic insufficiency (porphyria);
• Hemorrhagic diatheses (increased risk of bleeding), especially when conduction anesthesia is used;
• History of abnormal plasma cholinesterase activity (including drug-induced forms);
• Hyperthyroidism;
• Pheochromocytoma;
• Methemoglobinemia, hypoxia, sulfonamide intolerance (especially in patients with bronchial asthma);
• Severe diabetes mellitus;
• Concurrent terminal anesthesia;
  • Pharmacologically uncontrolled epilepsy;
• Injection into inflamed areas (reduces the effectiveness of local anesthesia);
• Concurrent treatment with tricyclic antidepressants or monoamine oxidase inhibitors (MAOIs), and within 14 days after discontinuation of MAOI therapy;
• Age under 4 years (body weight below 20 kg).

The medicinal product must not be used in acral parts of the limbs.

Intravenous administration of the medicinal product is contraindicated!

Special safety precautions.

Prior to injection, a skin test for hypersensitivity to the medicinal product should be performed. There is no international consensus regarding the procedure for performing and interpreting skin tests with this medicinal product. Multicenter studies to determine the appropriate concentration of the medicinal product, testing protocol, and to establish specificity, sensitivity, and safety have not been conducted. Validated testing procedures for diagnosing hypersensitivity to the medicinal product, including test concentrations, are not available.

Before administering Artinibs with epinephrine 1:100,000, the following must be done:

• Inquire about the patient’s history of allergies and current medications;
• Perform a test injection in cases of possible allergy risk by administering 5–10% of the intended dose;
• Maintain verbal contact with the patient;
• Keep resuscitation equipment readily available.

Risk associated with accidental intravascular injection

Accidental intravascular injection (e.g., unintentional intravenous injection into systemic circulation, unintentional intravenous or intra-arterial injection in the head or neck region) may be associated with serious adverse reactions, such as seizures followed by central nervous system or cardiorespiratory depression, and coma, progressing to respiratory arrest due to a sudden high level of adrenaline and articaine in systemic circulation.

An aspiration test should be performed to ensure that the needle has not entered a blood vessel, especially during nerve block.

The injection should be administered slowly, with aspiration testing performed in at least two planes (needle rotation – 180º C) to avoid intravascular injection.

However, the absence of blood in the syringe does not guarantee prevention of intravascular injection.

Risk associated with intraneural injection

Accidental intraneural injection may result in the drug moving retrogradely along the nerve.

If the patient experiences an electric shock sensation or if the injection is particularly painful, the needle should be slightly withdrawn to prevent intraneural injection and avoid nerve injury related to nerve block.

If the nerve is injured by the needle, the neurotoxic effect may be enhanced by the potential chemical neurotoxicity of articaine. This may impair perineural blood supply and prevent the elimination of the drug from the injection site.

Concomitant use of other medicinal products requires careful monitoring.

Skin testing with local anesthetics should be performed in individuals with confirmed reactions to these agents. Particular attention should be paid when testing local anesthetics containing adrenaline due to an increased frequency of false-negative reactions. Provocation tests are recommended if skin tests yield negative results. Testing of patients with confirmed allergic reactions to local anesthetics should only be performed by allergologists experienced in the field of local anesthesia.

Verbal contact with the patient must be maintained.

After anesthesia is achieved, there is a risk of unintentional trauma due to biting the mucosa of the lip, cheek, or tongue. The patient should be warned not to chew during the anesthetic effect.

Injections into infected or inflamed tissues should be avoided (reduces the effectiveness of local anesthesia).

Interaction with other medicinal products and other types of interactions.

Postganglionic adrenergic blockers (e.g., guanadrel, guanethidine, and rauwolfia alkaloids). If this combination cannot be avoided, the dose of the medicinal product should be reduced. Caution is required due to the possible increased response to adrenergic vasoconstrictors: risk of arterial hypertension and other cardiovascular effects (hyperreactivity associated with reduced sympathetic tone and/or slowed uptake of adrenaline into sympathetic fibers).

Non-selective β-adrenoblockers (propranolol, nadolol). The medicinal product is contraindicated during treatment with non-selective β-adrenoblockers, as this increases the risk of hypertensive crisis and pronounced bradycardia (see section "Contraindications").

Tricyclic (imipramine-type) antidepressants (amitriptyline, desipramine, imipramine, nortriptyline, maprotiline, and protriptyline) and monoamine oxidase inhibitors (MAOIs), both selective (brofaromine, moclobemide, toloxatone) and non-selective (phenelzine, tranylcypromine, linezolid). The hypertensive effects of sympathomimetic vasoconstrictors (e.g., epinephrine) may be enhanced by tricyclic antidepressants or MAOIs. Therefore, such combinations are contraindicated (see section "Contraindications").

Anesthetics. Combinations of different anesthetics have an additive effect and exhibit a more pronounced impact on the cardiovascular and central nervous systems.

Halogenated inhalational anesthetics (e.g., halothane). The dose of the medicinal product should be reduced due to increased myocardial sensitivity to catecholamines, which predisposes to arrhythmias (increased cardiac excitability): risk of severe ventricular extrasystoles or serious ventricular arrhythmias.

Hemodynamic parameters should be carefully monitored, and administration of the anesthetic should be limited, e.g., less than 0.1 mg of adrenaline within 10 minutes or 0.3 mg within 1 hour in adults.

Catechol-O-methyltransferase (COMT) inhibitors (entacapone, tolcapone). Possible increase in heart rate and changes in blood pressure.

Monitoring of the cardiovascular system is recommended.

Serotonergic and noradrenergic antidepressants (serotonin-norepinephrine reuptake inhibitors – venlafaxine, milnacipran, sertraline). The dose and rate of administration of the medicinal product should be reduced due to cumulative or synergistic effects on blood pressure and heart rate. Paroxysmal hypertension with arrhythmias is possible (inhibition of adrenaline uptake into sympathetic fibers). Administration of the anesthetic should be limited, e.g., less than 0.1 mg of adrenaline within 10 minutes or 0.3 mg within 1 hour in adults. The local anesthetic effect of articaine is enhanced and prolonged by vasoconstrictive agents.

Monitoring of the cardiovascular system (ECG) is recommended.

Agents causing arrhythmias (antiarrhythmics such as digitalis, quinidine). The dose of the medicinal product should be reduced due to cumulative or synergistic effects on heart rate.

Careful aspiration before injection and monitoring of the cardiovascular system (ECG) are recommended.

Oxytocin. The medicinal product should be used under strict medical supervision due to possible cumulative or synergistic increase in blood pressure and/or ischemic reactions.

Sympathomimetic vasopressors (primarily cocaine, as well as amphetamine, phenylephrine, pseudoephedrine, oxymetazoline). There is a risk of adrenergic toxicity. If cocaine has been used within the past 24 hours, planned dental treatment should be postponed.

Other sympathomimetics (e.g., isoprenaline, levothyroxine, methyldopa, antihistamines such as chlorpheniramine, diphenhydramine). The lowest possible doses of the medicinal product should be used.

Phenothiazines (and other neuroleptics). Phenothiazines may reduce or neutralize the pressor effect of adrenaline. In patients with arterial hypotension, due to the possible inhibition of adrenaline's effect, the medicinal product should be used under strict medical supervision with careful monitoring of the cardiovascular system.

Oral antidiabetic agents. Adrenaline may inhibit insulin secretion by the pancreas, thereby reducing the effectiveness of oral antidiabetic agents.

Antithrombotic agents. Concurrent use of antithrombotic agents (heparin, acetylsalicylic acid) increases the risk of bleeding. Accidental puncture of a blood vessel during local anesthesia may lead to severe hemorrhage.

The medicinal product should be used with caution when combined with hypoglycemic agents, antiarrhythmics (procainamide, mexiletine, disopyramide, quinidine, amiodarone), antiepileptic drugs, cardiac glycosides, and thyroid hormones.

Caution is recommended when using articaine with epinephrine concomitantly with other local anesthetics. Toxic effects of local anesthetics are additive.

Concomitant use of these medicinal products should be avoided. In situations where concomitant use is necessary, careful monitoring of the patient is required.

Special precautions for use.

Artinibs with epinephrine 1:100,000 should be used with special caution in the following cases:

• severe impairment of renal and hepatic function;
• angina pectoris (see sections "Contraindications" and "Method of administration and dosage");
• atherosclerosis;
• significant impairment of blood coagulation; treatment with anticoagulants (e.g., warfarin) or platelet aggregation inhibitors (e.g., heparin or acetylsalicylic acid). The overall risk of bleeding is increased (see section "Interaction with other medicinal products and other forms of interaction");
• diabetes mellitus;
• lung diseases, especially allergic asthma;
• cardiovascular dysfunction due to reduced ability to compensate for prolonged atrioventricular conduction.

Since amide-type local anesthetics are also metabolized in the liver, the drug should be used cautiously in patients with liver disease. Patients with acute liver disease have an increased risk of developing toxic plasma concentrations of articaine.

Patients with kidney disease should receive the smallest dose that produces effective anesthesia.

Accidental intravascular injection or unintentional overdose may cause seizures and central nervous system (CNS) depression or cardiopulmonary failure. Resuscitation equipment, oxygen, and emergency medications must be available for immediate use.

The drug should be used cautiously in patients with cardiovascular diseases (e.g., heart failure, ischemic heart disease, history of myocardial infarction, cardiac arrhythmia, arterial hypertension), as they have a reduced ability to compensate for functional changes associated with prolonged arteriovenous conduction caused by these drugs.

The drug should be used cautiously in patients with a history of epilepsy; particularly, high doses should be avoided, as well as use in cases of marked anxiety, cerebral circulation disorders, or history of stroke.

Dental treatment is recommended to be postponed for six months after a stroke due to an increased risk of recurrent stroke.

Plasma cholinesterase deficiency may be suspected when clinical signs of overdose occur at normal anesthetic doses and vascular injection has been excluded. In such cases, patients with plasma cholinesterase deficiency should be cautious during subsequent injections and receive reduced doses.

Patients with myasthenia who are receiving acetylcholinesterase inhibitors should receive the smallest dose that produces effective anesthesia.

The drug should be administered to patients with acute porphyria only when no safer alternatives are available. All patients with porphyria should take appropriate preventive measures, as this medicinal product may trigger porphyria.

Patients undergoing concomitant treatment with halogenated inhalational anesthetics should receive the smallest dose of the drug that produces effective anesthesia (see section "Interaction with other medicinal products and other forms of interaction").

Dosage should also be reduced in cases of hypoxia, hyperkalemia, and metabolic acidosis.

It should be noted that during treatment with anticoagulants (such as heparin or aspirin), accidental vascular puncture during local anesthetic injection may lead to severe bleeding and overall increased risk of bleeding (see section "Interaction with other medicinal products and other forms of interaction").

Accidental intravascular injection must be avoided (see section "Method of administration and dosage", subsection "Method of administration").

Patients should be advised to exercise caution to avoid accidental trauma to the lips, tongue, cheek mucosa, or soft palate while these areas remain anesthetized. Therefore, patients should avoid eating until the anesthetic effect has worn off.

When preparing a tooth cavity or preparing a tooth for a crown, it should be considered that due to the presence of adrenaline in the preparation, blood flow in pulp tissues is reduced, thus creating a risk of failing to detect an accidentally exposed pulp.

Precautionary measures

Therapeutic drugs/procedures listed below must be available every time a local anesthetic is used:

• anticonvulsants (drugs for treating seizures, e.g., benzodiazepines or barbiturates), glucocorticoids, muscle relaxants (drugs that reduce tension in voluntarily contracting muscles), atropine, vasoconstrictors (drugs for treating low blood pressure), electrolyte solutions, or adrenaline in case of acute allergic or anaphylactic reactions;
• resuscitation equipment (especially oxygen sources) for artificial ventilation if necessary;
• careful and continuous monitoring of cardiovascular and respiratory parameters and the patient’s level of consciousness after each local anesthetic injection. Restlessness, anxiety, tinnitus, dizziness, blurred vision, tremor, depression, or drowsiness are the first signs of toxic effects on the CNS (see section "Overdose").

Artinibs with epinephrine 1:100,000 should be used with special caution in patients taking phenothiazines or cardioselective β-adrenoblockers (see section "Interaction with other medicinal products and other forms of interaction"). Concurrent use of these drugs should be avoided. In situations where concomitant therapy is necessary, careful monitoring of the patient is required.

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, stridorous breathing, acute bronchospasm, disturbances of consciousness, or shock.

Methyl-4-hydroxybenzoate may cause allergic reactions (possibly delayed-type), and in isolated cases, bronchospasm.

1 mL of the drug contains 0.71 mg of sodium. This may be harmful to patients on a low-sodium diet.

Anesthesia should be administered with caution to elderly patients and children.

Elderly patients

Elevated plasma levels of the drug may occur in elderly patients, especially after repeated administration. If repeated injection is necessary, the patient should be closely monitored for any signs of relative overdose (see section "Overdose").

Use in children

Caregivers of young children should be warned about the potential for soft tissue injury due to biting as a result of prolonged soft tissue numbness after anesthesia.

Use in athletes

It should be noted that this drug contains articaine and adrenaline, which may result in a positive finding in doping control tests.

Use during pregnancy or breastfeeding

Fertility

No adverse effects on fertility were observed in animal studies.

Pregnancy

Animal studies have shown reproductive toxicity.

There is no experience with the use of articaine in pregnant women, except for its use during labor. Adrenaline 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 blood concentrations. Accidental intravascular injection of adrenaline in a pregnant woman may reduce uterine blood flow.

The safety of local anesthetics during pregnancy with regard to effects on fetal development has not been established.

The potential risk to humans is unknown.

Therefore, as a precautionary measure, it is advisable to avoid using the drug during pregnancy.

Breastfeeding

No clinical studies have been conducted in breastfeeding women.

It is unknown whether articaine and its metabolites pass into breast milk. However, preclinical safety data suggest that articaine concentrations in breast milk do not reach clinically significant levels. Adrenaline passes into breast milk but is rapidly degraded.

Therefore, women during lactation are advised to express and discard the first milk and refrain from breastfeeding for 10 hours after anesthesia.

Ability to affect reaction speed when driving or operating machinery.

The drug may have a minor effect on the ability to drive or operate machinery. Dizziness, visual disturbances, and fatigue may occur after administration. Therefore, after injection, the patient should remain in the dentist's office for at least 30 minutes.

Method of Administration and Dosage.

FOR DENTAL ANALGESIA ONLY.

Artinibs with epinephrine 1:100,000 is intended for use in adults and children aged 4 years and older.

Dosage Recommendations

To ensure effective anesthesia, the minimum necessary amount of solution should be used.

For the extraction of upper teeth, 1.8 mL of the preparation per tooth is usually sufficient, and painful palatal injections are not required. When extracting adjacent teeth sequentially, the injection dose may be reduced.

If a palatal incision or suturing is required, palatal anesthesia should be administered with approximately 0.1 mL per injection.

For uncomplicated extraction of lower premolars under infiltration anesthesia, 1.8 mL of the preparation per tooth is usually sufficient. In individual cases, an additional injection of 1 to 1.8 mL into the buccal area may be needed. Rarely, an injection into the mandibular foramen may be indicated.

Vestibular injections of 0.5 to 1.8 mL of the preparation per tooth allow for treatment of dental stumps prior to restorations and prosthetic constructions.

Conduction anesthesia may be used for treatment of lower premolars.

Dosage for surgical procedures should be individually calculated depending on the duration of the procedure and the patient’s general condition.

Children

Generally, a dose of 0.25–1 mL is sufficient for children weighing 20–30 kg; for children weighing 30–45 kg, the dose is 0.5 to 2 mL.

The preparation must not be used in children under 4 years of age.

Dosage in Elderly Patients and Patients with Underlying Diseases

In elderly patients, plasma levels of the drug may be increased due to impaired metabolism and reduced volume of distribution. The risk of drug accumulation is especially elevated after repeated injections. Such patients require special caution, and the minimum dose necessary to achieve adequate depth of anesthesia should be used.

A similar effect may occur in patients with poor general health, as well as in those with impaired cardiac, hepatic, or renal function. In such cases, dosage reduction is recommended (the minimum amount required for adequate analgesia).

Dosage should also be reduced in patients with certain conditions (e.g., angina pectoris, arteriosclerosis).

Maximum Recommended Dose

Adults

The maximum dose for healthy adults is 7 mg of articaine/kg body weight (500 mg for a 70 kg patient), equivalent to 12.5 mL of the preparation.

The maximum dose is 0.175 mL of solution/kg body weight.

Children aged 4 years and older

The amount of Artinibs with epinephrine 1:100,000 administered should be determined based on the child’s age, body weight, and duration of the procedure. Do not exceed the equivalent of 7 mg of articaine/kg body weight (0.175 mL of preparation/kg body weight).

Body weight (kg) (each age group according to ± limits of the growth chart)	Maximum recommended dose (equivalent to 7 mg/kg body weight)
	Articaine (mg)	Artinibs with epinephrine 1:100,000 (ml)
20–˂ 30	140	3.5
30–˂ 40	210	5.25
40–˂ 45	280	7.0
45–˂ 50	315	7.9
50–˂ 60	350	8.7
60–˂ 70	420	10.5
70–˂ 80	490	12.2

Method of Administration

For injection into the oral mucosa.

FOR DENTAL ANESTHESIA ONLY.

To avoid intravascular injections, careful aspiration testing should always be performed in at least two planes (needle rotation – 180º), although a negative aspiration result does not exclude inadvertent and undetected intravascular injection.

The injection rate should not exceed 0.5 mL per 15 seconds, i.e., one cartridge per minute.

Most systemic reactions resulting from accidental intravascular injection can be avoided by proper injection technique: after aspiration, slowly inject 0.1–0.2 mL, then slowly administer the remainder no sooner than 20–30 seconds later.

Cartridges containing residual solution must not be used for other patients. Cartridges with remaining solution must be destroyed after completion of the dental procedure.

Children.

Artinibs with epinephrine 1:100,000 may only be used in children aged 4 years and older (body weight greater than 20 kg), as the efficacy and safety of the drug in children under 4 years of age have not been established.

Artinibs with epinephrine 1:100,000 should be administered to children in the minimal amount required to achieve adequate anesthesia; the dose should be individually adjusted according to the child's age and body weight. The maximum dose of 5 mg of articaine per kg of body weight must not be exceeded.

The safety profile in children aged 4 to 18 years was similar to that in adults. However, accidental soft tissue injuries occur more frequently, especially in children under 7 years of age, due to prolonged soft tissue anesthesia.

Overdose.

Cases of overdose with local anesthetics most commonly described include:

• absolute overdose;
• relative overdose, such as accidental intravascular injection, abnormally rapid absorption into systemic circulation, or delayed metabolism and elimination of the drug.

The most serious manifestation of articaine intoxication involves effects on the central nervous and cardiovascular systems.

Symptoms that may be caused by articaine

Cardiovascular system: arterial hypertension, arterial hypotension, facial flushing, agitation, palpitations, angina pectoris, generalized vasoconstriction, conduction disturbances, arrhythmia, bradycardia, vasomotor paralysis, cyanosis, cardiovascular collapse, cardiac arrest.

Central nervous system: headache, nervousness, anxiety, restlessness, motor agitation, stupor, loss of speech, muscular atonia, coma, confusion, dizziness, hearing loss, tinnitus, taste disturbances, nausea, vomiting, tremor, involuntary muscle contractions, dyspnea, tachypnea, restlessness, drowsiness, loss of consciousness, tonic-clonic seizures, respiratory arrest.

The most dangerous symptoms are: arterial hypotension, cardiac arrest, conduction disturbances, tonic-clonic epileptic seizures, respiratory paralysis, and drowsiness/coma.

Symptoms that may be caused by epinephrine

Circulatory disorders: increased systolic blood pressure, increased diastolic blood pressure, increased venous pressure, increased pulmonary artery pressure, arterial hypotension.

Cardiac disorders: bradycardia, tachycardia, arrhythmia (e.g., atrial tachycardia, atrioventricular block, ventricular tachycardia, ventricular extrasystoles, ventricular fibrillation).

These symptoms, as well as pulmonary edema, cardiac arrest, renal failure, and metabolic acidosis, may lead to life-threatening consequences. Fatal outcome may result from paralysis of the respiratory center.

Treatment.

Resuscitation equipment must be available before initiating dental anesthesia with local anesthetics.

If early signs of adverse or toxic reactions occur during injection, administration should be stopped immediately and the patient placed in a supine position. Airway patency should be ensured, and pulse and blood pressure monitored. Intravenous infusion of symptomatic agents is recommended, even if symptoms do not appear severe, to ensure reliable intravenous access. In case of respiratory impairment, oxygen should be administered according to the severity of the condition; if necessary, artificial respiration (mouth-to-nose) or endotracheal intubation combined with controlled ventilation should be applied. In case of cardiac arrest, immediate cardiopulmonary resuscitation measures must be initiated.

Central-acting analeptics are contraindicated.

Involuntary muscle contractions or generalized muscle seizures require intravenous administration of short-acting anticonvulsants (e.g., succinylcholine chloride, diazepam) or short- or ultra-short-acting barbiturates.

Barbiturates should be administered slowly, depending on the observed effect, while continuing oxygen administration and cardiac monitoring to avoid the risk of circulatory disturbances and respiratory depression. Barbiturate administration should be accompanied by infusion of fluids through a previously established cannula. Tachycardia and hypotension may often be counteracted simply by placing the patient in a supine position with legs slightly elevated above the head.

In case of bradycardia, atropine may be administered intravenously.

In severe circulatory disturbances and shock, regardless of cause, the following measures should be taken after stopping the injection: place the patient in a supine position with slightly elevated lower limbs, ensure airway patency, and administer oxygen by insufflation. Additionally, establish intravenous infusion of balanced electrolyte solution; administer glucocorticoids intravenously (e.g., 250–1000 mg methylprednisolone), and provide fluid replacement (if necessary, also plasma substitutes and human albumin). In case of life-threatening circulatory collapse and progressive bradycardia, immediate intravenous injection of epinephrine is required. For this purpose, 1 mL of epinephrine 1:1000 solution should be diluted to 10 mL, and initially 0.25–1 mL of this solution (0.025–0.1 mg epinephrine) should be slowly administered. Pulse rate and blood pressure should be monitored. Do not administer more than 1 mL of this solution (0.1 mg epinephrine) at once. If this dose is insufficient, epinephrine should be added to the infusion solution (infusion rate adjusted according to pulse rate and blood pressure).

Severe forms of tachycardia or tachyarrhythmia may also be treated with antiarrhythmic agents (except non-selective β-blockers).

Oxygen administration and monitoring of circulatory parameters are mandatory in these cases. In patients with arterial hypertension and elevated blood pressure, peripheral vasodilators should be used. The upper part of the patient’s body should be elevated in the supine position; if necessary, sublingual nifedipine may be administered.

In case of cardiac arrest, immediate cardiopulmonary resuscitation is required.

Adverse Reactions

Adverse reactions following administration of the drug are similar to those observed with other amide-type local anesthetics combined with vasoconstrictors.

Overall, the use of the medicinal product is considered highly safe. It is difficult to assess causality (exact differentiation is not possible), as adverse reactions may be related not only to the drug itself, but also to the underlying dental condition, dental intervention, or the use of local anesthesia.

These adverse effects are dose-dependent and may occur due to elevated plasma levels of the drug resulting from overdose, rapid absorption, or accidental intravascular injection. They may also arise due to allergy, idiosyncrasy, or reduced patient tolerance to medicinal agents. Most commonly, adverse reactions affect the nervous and cardiovascular systems.

In general, adverse reactions are systemic in nature.

The presence of adrenaline enhances the drug's safety profile due to its sympathomimetic effect.

The most frequently observed adverse reactions include: nervous disturbances, pain, procedural pain, sensitivity, headache, swelling, sensory disturbances (e.g., hypoesthesia, paresthesia, taste disturbances). In case of suspected hypersensitivity reactions, appropriate allergy testing is recommended.

The drug is generally well tolerated by patients; however, the following adverse reactions may occur.

Adverse reactions listed below are categorized according to frequency of occurrence: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (< 1/10,000), and not known (cannot be estimated based on available data). All adverse events categorized as "not known" have been observed during post-marketing surveillance.

Immune system disorders: not known – allergic reactions, severe cases including anaphylactic shock, angioedema of varying severity (including swelling of the upper and/or lower lip and/or neck, laryngeal edema with swallowing difficulty, urticaria, respiratory distress).

Psychiatric disorders: not known – restlessness, anxiety.

Nervous system disorders: common – headache; uncommon – paresthesia, hypoesthesia and dysesthesia, dizziness; rare – taste disturbances, peripheral neuropathies, somnolence, altered consciousness; not known – metallic taste in mouth, tinnitus, yawning, syncope, tremor, nervousness, excitement, insomnia, disorientation, clouding of consciousness, loss of consciousness, loss of taste, nystagmus, logorrhea, hypergeusia, facial hypoesthesia, decreased muscle tone, sixth cranial nerve paralysis, facial nerve paralysis, presyncope, muscle twitching, tonic-clonic seizures, coma, respiratory paralysis, sensory disturbances.

Respiratory, thoracic and mediastinal disorders: rare – nasal congestion; not known – dysphonia, dyspnea, laryngeal edema, pharyngeal edema, pulmonary edema, bronchospasm, rhinitis, tachypnea, bradypnea, which may progress to apnea.

Cardiac disorders: rare – palpitations, tachycardia, bleeding, pallor; not known – hypotension, hypertension, bradycardia, cardiovascular depression with arterial hypotension potentially leading to collapse, cardiac arrhythmias (ventricular extrasystoles and ventricular fibrillation), conduction disturbances (atrioventricular block). These manifestations may lead to cardiac arrest.

Eye disorders: rare – blepharospasm; not known – mydriasis, ptosis, miosis, enophthalmos, blurred vision, transient blindness, decreased visual acuity, diplopia, conjunctivitis.

Ear and labyrinth disorders: uncommon – vertigo, ear pain; not known – tinnitus.

Skin and subcutaneous tissue disorders: uncommon – pruritus, hyperhidrosis, rash; not known – skin erythema, urticaria, angioedema.

Musculoskeletal and connective tissue disorders: rare – back pain, muscle tension, trismus; not known – osteonecrosis.

Gastrointestinal disorders: uncommon – gingivitis, nausea, vomiting; rare – diarrhea, abdominal pain, cheilitis, constipation, dry mouth, dyspepsia, oral mucosal ulcers, nausea/vomiting, tooth loss, hypersalivation, increased tooth sensitivity, stomatitis; not known – oral hypoesthesia, oral swelling, oral paresthesias.

General disorders and administration site conditions: common – pain, weakness, swelling; uncommon – facial swelling, injection site swelling, injection site pain, hematoma at injection site; rare – asthenia, chills, fatigue, malaise, thirst; not known – tenderness on pressure, necrosis at injection site, mucosal inflammation, mucosal swelling, fever, nerve injury (up to paralysis) due to incorrect injection technique.

Extremely rarely, accidental intravascular injection may lead to ischemic areas at the injection site, which may occasionally progress to tissue necrosis.

Investigations: uncommon – hypotension, increased heart rate, hypertension; rare – signs of myocardial ischemia (on ECG), vital function disturbances, positive allergy test; not known – inability to measure blood pressure, decreased heart rate.

Injury, poisoning and procedural complications: common – procedural pain; rare – oral injuries, incorrect injection route, nerve damage; not known – gingival injuries, wound complications, injury to the 5th cranial nerve.

Post-marketing surveillance data indicate that the risk of adverse reactions associated with dental local anesthesia using Artinibs with epinephrine 1:100,000 is very low.

Description of selected adverse reactions

Two types of adverse reactions have particular clinical significance, although they are not the most frequently reported. The description is primarily based on post-marketing surveillance data.

Nerve function disorders

Nerve function disorders in dentistry may arise from various causes, including the underlying dental disease, dental treatment, or direct adverse reactions related to the use of local anesthetics. Considering the frequency of adverse reactions, the risk of such disorders is low. Discussion focuses on serious adverse reactions, as their clinical significance lies in the risk of irreversible damage. Most of these adverse effects are reversible.

Hypersensitivity reactions

Hypersensitivity reactions have been rarely observed in post-marketing studies. Most reactions were not severe, but life-threatening reactions cannot be completely ruled out.

In case of suspected hypersensitivity reactions, appropriate allergy testing is recommended, including testing for individual components of the drug.

Children

Studies have not revealed any differences in safety profile between children and adults.

In children, accidental soft tissue injuries due to prolonged soft tissue anesthesia are more frequently observed.

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.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions following administration of the medicinal product is of great importance. It enables continuous monitoring of the benefit-risk balance of the drug. Healthcare professionals are requested to report any adverse reactions.

Shelf life: 30 months.

Storage conditions

Store at temperatures not exceeding 30 °C in the original packaging.

Do not freeze.

Keep out of reach and sight of children.

Incompatibilities

Due to lack of compatibility studies, the drug must not be mixed with other medicinal products.

Packaging

1.8 mL colorless glass cartridges, sealed at one end with a rubber stopper and aluminum cap, and with a rubber plunger at the other end. Pack of 50 cartridges in a cardboard box.

Prescription status: Prescription only.

Manufacturer:

LABORATORIOS INIBSA, S.A.

Manufacturer's address and place of business:

Ctra. Sabadell a Granollers, 14.5 km, 08185, Les Franqueses del Vallès (Barcelona), Spain.