Articaine-Binergia with epinephrine (Solution) Instructions for Use

Marketing Authorization Holder

Binergia JSC (Russia)

Manufactured By

Armavir Biopharmaceutical Plant, FSE (Russia)

ATC Code

N01BB58 (Articaine in combination with other drugs)

Active Substances

Articaine (Rec.INN registered by WHO)

Epinephrine (Rec.INN registered by WHO)

Dosage Form

Articaine-Binergia with epinephrine

Injection solution 20 mg+0.005 mg/1 ml: amp. 2 ml 10 pcs. or 5 ml 5 pcs.; cartridges 1.7 ml 10 pcs.

Dosage Form, Packaging, and Composition

Solution for injection transparent, colorless or with a yellowish tint.

Excipients : sodium disulfite – 0.5 mg, sodium chloride – 5.2 mg, disodium edetate – 0.25 mg, 1M sodium hydroxide solution – to pH 5.0, water for injection – to 1 ml.

2 ml – ampoules of colorless glass (5) – plastic contour packs (2) – cardboard boxes.
5 ml – ampoules of colorless glass (5) – plastic contour packs (1) – cardboard boxes.
1.7 ml – cartridges of colorless glass (10) – plastic contour packs (1) – cardboard boxes^×.

^× two protective labels with the company logo (first opening control) are affixed to the box.

Clinical-Pharmacological Group

Local anesthetic with a vasoconstrictor component

Pharmacotherapeutic Group

Local anesthetic agent + alpha- and beta-adrenomimetic

Pharmacological Action

Articaine-Binergia with epinephrine is a combined preparation, which contains articaine (a local anesthetic of the amide type) and epinephrine (a vasoconstrictor), which is added to the preparation to prolong anesthesia.

Articaine exerts a local anesthetic effect by blocking voltage-gated sodium channels in the neuronal cell membrane, which leads to reversible inhibition of impulse conduction along the nerve fiber and reversible loss of sensation.

With all methods of administration, articaine has a rapid (latent period – from 1 to 11 min) and strong anesthetic effect and has good tissue tolerance.

The duration of anesthesia for solutions with the addition of epinephrine is from 120 to 420 min. For superficial anesthesia, articaine has a very slight anesthetic effect.

Pharmacokinetics

Absorption, distribution, metabolism

After intramuscular administration, the C_max of articaine in the blood is reached after 20-40 min. The binding of articaine to plasma proteins is approximately 95%. Articaine is rapidly and almost immediately after administration metabolized (by hydrolysis) by non-specific plasma esterases in tissues and blood (90%); the remaining 10% of the articaine dose is metabolized by hepatic microsomal enzymes.

Excretion

T_1/2 is 39.8±3.1 min.

Articaine is excreted by the kidneys, mainly in the form of articainic acid.

Indications

• For local and regional blockade of nerve endings.

ICD codes

Dosage Regimen

Articaine-Binergia with epinephrine is used for epidural and targeted local anesthesia.

The minimum dose with which the desired sufficient anesthesia is achieved should be administered.

Dosage should be individualized according to the characteristics of each specific case.

Dose selection is necessary for children and elderly patients.

The recommended maximum dose for adults is 5-6 mg/kg body weight (not more than 600 mg). The approximate doses are presented below, which must be adjusted depending on the depth of anesthesia and the patient’s condition

To avoid accidental intravascular injection, an aspiration test should always be performed before administering the drug and during the administration of the main dose. The injection pressure should correspond to the sensitivity of the tissues.

Adverse Reactions

The frequency of adverse effects is presented in accordance with the classification recommended by WHO: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), including isolated reports; frequency unknown (cannot be estimated from the available data).

Nervous system disorders: common – paresthesia, hypesthesia, headache (due to the presence of epinephrine in the preparation); uncommon – dizziness; frequency unknown – dose-dependent reactions from the CNS (especially when too high a dose is administered or in case of accidental intravascular injection), including feeling of anxiety, nervousness, stupor, confusion up to loss of consciousness, coma, respiratory disorders, sometimes progressing to respiratory arrest, muscle tremor, muscle twitching, sometimes progressing to generalized convulsions.

Eye disorders: frequency unknown – visual disturbances (blurred vision, mydriasis, blindness, double vision), usually reversible and occurring during or shortly after the injection of the local anesthetic.

Gastrointestinal disorders: common – nausea, vomiting.

Cardiac and vascular disorders: uncommon – tachycardia; frequency unknown – palpitations, arrhythmia, signs of angina pectoris, increased blood pressure, arterial hypotension, bradycardia, heart failure and shock (under certain circumstances with life-threatening potential).

During obstetric anesthesia, in particular with paracervical block, fetal bradycardia may occur. It is recommended to carefully monitor fetal heart tones.

Immune system disorders: frequency unknown – allergic or allergy-like reactions. At the injection site, they may manifest as swelling and/or inflammation. Manifestations not associated with the injection site may include skin redness, itching, conjunctivitis, rhinitis, angioedema of the face. Angioedema may manifest as swelling of the upper lip and/or lower lip, cheeks, swelling of the vocal cords with a feeling of a “lump in the throat” and difficulty swallowing, urticaria and difficulty breathing up to anaphylactic shock.

Other due to the presence of sodium disulfite (sodium metabisulfite) in the preparation, allergic reactions in the form of vomiting, diarrhea, difficult breathing, acute asthma attack, confusion or shock may very rarely occur, particularly in patients suffering from bronchial asthma.

Contraindications

Hypersensitivity to articaine, epinephrine, sulfites (in particular, in patients suffering from bronchial asthma with hypersensitivity to sulfites, because acute allergic reactions with symptoms of anaphylactic shock, such as bronchospasm, are possible), or to any other of the excipients of the drug.

Contraindications related to articaine

• Hypersensitivity to other local anesthetics of the amide type;
• Severe sinus node dysfunction or severe conduction disorders (such as severe bradycardia, AV block II or III degree);
• Acute decompensated heart failure (acute impairment of heart functional status);
• Severe arterial hypotension, shock;
• Children under 4 years of age (lack of sufficient clinical experience).

Contraindications related to epinephrine

• Anesthesia of the terminal phalanges of fingers and toes (risk of ischemia);
• Paroxysmal tachycardia, tachyarrhythmia;
• Recent (3-6 months ago) myocardial infarction;
• Recently performed (3 months ago) coronary artery bypass grafting;
• Concomitant use of non-selective beta-blockers, for example, propranolol (risk of hypertensive crisis and severe bradycardia);
• Closed-angle glaucoma;
• Hyperthyroidism;
• Pheochromocytoma;
• Severe arterial hypertension;
• Concomitant use of tricyclic antidepressants or MAO inhibitors, because these active substances may enhance the effect of epinephrine on the cardiovascular system. This applies to the period of time up to 14 days after the end of treatment with MAO inhibitors.

Intravenous injections are contraindicated.

With caution

• In patients with blood clotting disorders;
• In patients with severe liver dysfunction;
• In patients with severe renal dysfunction;
• With simultaneous use with halogen-containing agents during inhalation anesthesia (see section “Drug Interactions”);
• In patients with a history of epilepsy;
• In patients with chronic heart failure, coronary artery disease, angina pectoris, history of myocardial infarction, cardiac arrhythmias, arterial hypertension;
• In patients with atherosclerosis;
• In patients with cerebrovascular disorders, history of stroke;
• In patients with chronic bronchitis, pulmonary emphysema;
• In patients with diabetes mellitus;
• In patients with severe forms of anxiety neurosis.

Use in Pregnancy and Lactation

Pregnancy

There is no experience with the use of articaine in pregnant women, except for its use during childbirth.

Experimental studies in animals have not revealed any signs of direct or indirect negative effects of articaine on pregnancy, embryonic/fetal development, childbirth or postnatal development. The results of the animal study demonstrated that epinephrine has toxicity to reproductive function in animals at doses exceeding the maximum recommended dose.

Articaine and epinephrine cross the placental barrier to a lesser extent compared to other local anesthetics.

The concentration of articaine in the serum of newborns (after administration of the drug to the mother) is approximately 30% of the concentration of articaine in the mother’s serum.

In case of accidental intravascular administration, epinephrine may reduce uterine blood supply.

The decision to use Articaine-Binergia with epinephrine can only be made by a doctor if the potential benefit of its use for the mother justifies the potential risk to the fetus.

No negative effect of articaine on newborns when used for obstetric anesthesia has been identified.

Lactation period

Due to the short half-life of epinephrine, as well as the very rapid drop in serum concentration and rapid elimination of articaine from the body, clinically significant concentrations of articaine and epinephrine are not detected in breast milk. Therefore, with short-term use of the drug during breastfeeding, it is generally not necessary to interrupt breastfeeding.

Fertility

Experimental studies of the use of articaine 40 mg/ml + epinephrine 0.01 mg/ml in animals (which is several times higher than in Articaine-Binergia with epinephrine) did not show an effect on fertility. When used in therapeutic doses, the drug has no negative effect on human fertility.

Use in Hepatic Impairment

Use with caution in patients with severe liver dysfunction.

Use in Renal Impairment

Use with caution in patients with severe renal dysfunction.

Pediatric Use

Contraindicated in children under 4 years of age (lack of sufficient clinical experience).

Dose selection is necessary for children.

Geriatric Use

Dose selection is necessary for elderly patients.

Special Precautions

Regional and local anesthesia should be performed by experienced specialists in an appropriately equipped room with readily available equipment and drugs necessary for monitoring cardiac activity and resuscitation. The personnel performing anesthesia must be qualified and trained in anesthesia techniques, must be familiar with the diagnosis and treatment of systemic toxic reactions, adverse events and reactions and other complications.

Intravenous injections are contraindicated!

Articaine-Binergia with epinephrine should not be injected into inflamed (infected) tissue areas (increased absorption of articaine with reduced effectiveness).

To avoid the risk of adverse reactions, the following conditions must be observed

• In patients at risk and when using higher doses (more than 25% of the maximum single dose), venous access should be freed so that, if necessary, it is possible to immediately make an intravenous injection;
• Use the minimum effective doses of the drug;
• Before administering the drug, perform a two-stage aspiration test in two planes (to avoid accidental intravascular injection);
• Regularly monitor vital signs (monitoring of the cardiovascular system and consciousness).

To prevent infection (including viral hepatitis), care must be taken to ensure that new sterile syringes and needles are always used when withdrawing the drug from ampoules and vials.

Opened ampoules and vials must not be reused.

The medicinal product should not be used if the solution has changed its color or become cloudy.

Articaine-Binergia with epinephrine contains sodium disulfite, therefore its use is contraindicated in patients with bronchial asthma with hypersensitivity to sulfites, because the development of acute allergic reactions, such as bronchospasm, is possible (see section “Contraindications”).

1 ml of Articaine-Binergia with epinephrine solution for injection (10 mg + 0.005 mg)/ml contains 0.127 mmol (2.9 mg) of sodium.

1 ml of Articaine-Binergia with epinephrine solution for injection (20 mg + 0.005 mg)/ml contains 0.096 mmol (2.2 mg) of sodium.

These data should be taken into account when using Articaine-Binergia with epinephrine in patients controlling sodium intake (low-salt diet).

Effect on ability to drive vehicles and operate machinery

The decision on when the patient can return to driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions should be made by the doctor.

Anticipatory neurosis and postoperative stress can lead to a change in the ability to drive vehicles or other activities, despite the fact that local anesthesia with articaine, according to the results of appropriate tests, did not show detectable deviations from the usual ability to drive vehicles.

Overdose

Symptoms

From the CNS: CNS excitation – feeling of anxiety, fear, confusion, hyperpnea, tachycardia, increased blood pressure with facial flushing, nausea, vomiting, tremor, twitching, tonic-clonic convulsions;

CNS depression – dizziness, hearing impairment, loss of speech ability, stupor, unconsciousness, atony, paralysis of vasomotor nerves (weakness, pallor), shortness of breath, death from paralysis of respiratory muscles.

From the cardiovascular system: bradycardia, arrhythmia, ventricular fibrillation, drop in blood pressure, cyanosis, cardiac arrest.

Treatment

At the first manifestations of intoxication or side effects of the drug, such as dizziness, motor agitation or stupor during the administration of the drug, its administration should be stopped and the patient should be placed in a horizontal position with elevated lower limbs. It is necessary to ensure airway patency and monitor hemodynamic parameters (heart rate and blood pressure).

It is recommended to free venous access (even if the symptoms do not seem serious) in order to be able, if necessary, to immediately administer the necessary drugs intravenously.

In case of respiratory disorders, depending on their severity, oxygen supply is recommended, if necessary – artificial respiration, and under certain circumstances – endotracheal intubation and controlled mechanical ventilation.

Muscle twitching and generalized convulsions can be controlled by intravenous administration of fast-acting agents with muscle relaxant and anticonvulsant action (e.g., suxamethonium chloride, diazepam). Mechanical ventilation (oxygen supply) is also recommended.

A sharp decrease in blood pressure, bradycardia or tachycardia can be eliminated by simply placing the patient in a horizontal position with elevated lower limbs.

In case of severe circulatory disorders and shock of any origin, the administration of the drug must be discontinued. The patient should be placed in a horizontal position with elevated lower limbs and the airways should be freed (oxygen insufflation). Intravenous administration of balanced electrolyte solutions, corticosteroids (e.g., 250-1000 mg prednisolone or an equivalent amount of its derivative, e.g., methylprednisolone), replacement infusion therapy (if necessary, additionally, plasma substitute, including human albumin) should be carried out.

In case of development of circulatory collapse and increasing bradycardia, epinephrine (adrenaline) is administered intravenously immediately. After diluting 1 ml of 0.1% epinephrine solution (1:1000) to 10 ml or using 0.01% epinephrine solution (1:10000), slow intravenous administration is performed first 0.25-1 ml (0.025-0.1 mg epinephrine), monitoring heart rate and blood pressure (caution: cardiac arrhythmias are possible!).

Do not exceed the single intravenous dose of 1 ml (0.1 mg of epinephrine). If it is necessary to administer doses exceeding the single intravenous dose of 0.1 mg of epinephrine, epinephrine should be administered with an infusion solution, adjusting the drip rate according to the heart rate and blood pressure.

Severe tachycardia and tachyarrhythmia can be controlled with antiarrhythmic agents, excluding non-selective beta-blockers, such as, for example, propranolol. In such cases, oxygen supply and circulation monitoring are necessary.

An increase in blood pressure in patients with arterial hypertension, if necessary, is controlled with peripheral vasodilators.

Drug Interactions

Combinations of different local anesthetics cause additional effects on the cardiovascular system and CNS.

Contraindicated Combinations

With non-selective beta-blockers, for example, propranolol

Risk of hypertensive crisis and severe bradycardia.

With tricyclic antidepressants or MAO inhibitors

Potentiation of the hypertensive effect of epinephrine is possible (for up to 14 days after discontinuation of MAO inhibitor therapy).

Interaction to be taken into account

With oral hypoglycemic agents

Epinephrine may inhibit insulin release from pancreatic β-cells and reduce the effects of oral hypoglycemic agents.

With some agents for inhalation anesthesia (halothane)

Halothane may increase myocardial sensitivity to catecholamines and increase the risk of cardiac arrhythmias following injections of Articaine-Binergia with epinephrine.

With anticoagulants and other drugs that reduce blood clotting

When administering injections of Articaine-Binergia with epinephrine to patients receiving, for example, heparin or acetylsalicylic acid, serious bleeding may develop in case of unintentional vessel perforation, as such patients have a higher tendency to bleed.

Storage Conditions

The drug should be stored out of the reach of children, in a light-protected place at a temperature not exceeding 25°C (77°F). Do not freeze.

Shelf Life

Shelf life is 3 years. Do not use after the expiration date stated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.