Botulinum toxin type A - hemagglutinin complex - instructions for use, doses, side effects, contraindications

The drug is a muscle relaxant. A botulinum toxin type A molecule consists of two chains: heavy (with a molecular weight of 100,000 daltons) and light (with a molecular weight of 50,000 daltons) connected by a disulfide bond.

The heavy chain has a high affinity for specific receptors localized on the surface of target neurons. The light chain is characterized by Zn²⁺dependent protease activity. It is specific for the cytoplasmic regions of the synaptosomal-linked protein with a molecular weight of 25,000 daltons (SNAP-25), which takes part in the processes of exocytosis.

The first stage the action of botulinum toxin type A is the specific binding of the molecule to the presynaptic membrane.

The second stage - penetration of the bound toxin into the cytoplasm of neurons by endocytosis. Inside the cell, the light chain exhibits Zn²⁺-dependent protease activity, selectively destroying SNAP-25, which the third stage leads to a blockade of the release of acetylcholine from the presynaptic endings of the cholinergic neurons.

The end result is a prolonged chemodenervation.

Clinically, there is marked relaxation of the muscles in which the injection was made. In the deinervated muscles, the process of reinnervation occurs due to the formation of lateral processes of nerve endings 12 weeks after the injection, which leads to the restoration of muscle contractions. However, the shoots are partially effective and subsequently regress, while the primary neuromuscular transmission is activated.

Pharmacokinetics:

Pharmacological effect of the drug develops at the injection site. It is proved that presynaptic seizure and retrograde axonal transport of the drug from the injection site is insignificant.

In therapeutic doses, the drug does not penetrate the blood-brain barrier.

Antibodies to botulinum toxin type A can be formed after repeated injections in 1-5% of cases. The production of antibodies contributes to the administration of large doses of the drug, as well as repeated administration in small doses at short intervals (less than 14 days). When forming antibodies to botulinum toxin type A, the effect of its further use can be reduced.

Indications:

Blepharospasm; hemifacial spasm; cervical dystonia (spasmodic torticollis); focal spasticity of the wrist and hand in patients who had a stroke; paralytic strabismus (strabismus); local muscular spasm in children's cerebral palsy in children aged 2 years and older; Correction of facial wrinkles.

ICD-10

VI.G20-G26.G24.3 Spasmodic torticollis

VI.G20-G26.G24.5 Blepharospasm

VI.G80-G83.G80 Cerebral palsy

VII.H49-H52.H50 Other forms of strabismus

XVIII.R25-R29.R25.2 Cramp and spasm

Contraindications:

Are common: proven hypersensitivity to any component of the drug; inflammatory process at the site of the proposed injection (injection); acute phase of infectious diseases; pregnancy; lactation.

For blepharospasm and correction of facial muscles: pronounced gravitational ptosis of facial tissues; expressed "hernia" in the upper and lower eyelids.

Pregnancy and lactation:

The drug is contraindicated for use in pregnancy and lactation.

Dosing and Administration:

Correction of facial wrinkles

It is not recommended to use the drug for correcting vertical interbrow mimic wrinkles in patients under 18 and over 65 years of age.

The drug solution (100 U / 2.5 ml) was injected with a 30G needle.

At 4 units, enter into 5 points for injection: in the musculus corrugator - 2 points on each side, in the musculus procerus - 1 point. The total dose is 20 units.

Before the injection, the thumb and index finger should be pressed firmly against the skin below the edge of the orbit to prevent the drug from spreading below this level. When injecting, the needle should be directed upward and medially. To reduce the risk of developing ptosis, it is necessary to avoid the administration of the drug near the muscle that lifts the upper eyelid, especially in patients with a well expressed muscle that lowers the upper eyelid. When the drug is injected into the musculus corrugator, the injection should be performed in the central part of the muscle, retreating no less than 1 cm above the arch of the eyebrow.

Smoothing of vertical facial wrinkles occurs usually within a week after the procedure. The effect lasts up to 4 months.

The interval between the procedures should be at least 3 months. In the absence of effect from the introduction of the drug or a decrease in its severity after repeated injections, other methods of treatment should be recommended.

For all indications for use

If the first procedure is ineffective, that is, there is no significant clinical improvement, compared to the baseline condition, 1 month after drug administration, it is necessary:

- clinical confirmation of the effect of toxin on the injected muscle (muscle), which may include electromyographic research carried out by an experienced specialist in a specialized department;

- analysis of the reasons for the ineffectiveness of the procedure, for example, inadequate selection of injection points, insufficient dose, incorrect injection technique, signs of fixed contracture, weakness of antagonist muscles, formation of neutralizing antibody toxins;

- reassessment of the feasibility of treatment with botulinum toxin type A;

- In the absence of any undesirable effects associated with the first administration of the drug, the following conditions must be observed in the repeated procedure: correction of the dose, taking into account the reasons for the ineffectiveness of the previous procedure; electromyographic control; the interval between the procedures should be at least 3 months.

In the absence of effect from the introduction of the drug or a decrease in its severity after repeated injections, other methods of treatment should be recommended.

Treatment of cervical dystonia (spasmodic torticollis)

The solution of the drug is injected with a needle measuring 25-30G / 0.5-0.3 mm.

When treatment of spasmodic torticollis the drug solution is injected into the most strained muscles of the neck in a dose of no more than 50 units per point.

In the sternocleidomastoid muscle injected no more than 100 units of the drug.

The total dose of the drug during the first procedure should not exceed 200 units.

In the treatment of spastic torticollis, the drug is injected into the sternocleidomastoid muscle on the side opposite the rotation, and into the ribbon muscle on the side of rotation.

In cases accompanied by lifting of the shoulder, the drug should be injected additionally into the trapezius muscle and the muscle that lifts the scapula, on the side of the lesion.

When the head is tilted back, the drug is injected into the belt and trapezius muscles from both sides.

When the head is tilted forward, the drug is injected into the sternocleidomastoid muscles from both sides.

With the subsequent administration of the dose of the drug can be adjusted depending on the previous clinical outcome and the observed side effects.

Clinical improvement manifests itself within the first two weeks after the injection of the drug. The most pronounced clinical effect is achieved approximately 6 weeks after the injection. The duration of the clinical effect on average reaches 12 weeks, after which, if necessary, treatment can be repeated. Intervals between treatment sessions of less than 10 weeks are not recommended.

When complex forms of torticollis or a weak effect of treatment should be carried out electromyography muscles of the neck for a more accurate establishment of the localization of stressed muscles.

Safety and effectiveness of the drug in the treatment of spasmodic torticollis in children under 12 years of age not demonstrated.

Treatment of local muscular spasm in children's cerebral palsy

The drug solution is injected with a needle of size 23-26 G / 0.6-0.45 mm.

In the treatment of spasticity and equino-varus deformities of the foot in children with infantile cerebral palsy, the drug solution is injected into 2 points of each head of the gastrocnemius muscle (medial and lateral). With hemiplegia, the drug can be injected into the flexor muscles of the forearm, when crossing the hips - in addition to the adductor muscles of the thigh. The total dose of the drug per procedure is determined from the calculation of 4-6 units per kg of body weight and distributed evenly between all the muscles into which the injections are performed. The total dose should not exceed 200 units.

Clinical improvement manifests itself in the first 7-14 days after the injection. The drug is re-introduced with a decrease in the severity of the clinical effect by half, but not earlier than 3 months after the previous procedure. The dose of the drug is selected in such a way as to achieve a minimum of 6-month interval between the procedures. Improve the clinical effect of injections of the drug can contribute to orthopedic correction, muscle stretching and physiotherapy.

Treatment of focal spasticity of the wrist and hand in patients who have suffered a stroke

The drug solution is injected with a 25G, 27G or 30G needle into the superficial muscles and a longer needle into the deeply located muscles.

To establish the localization of muscles involved in the pathological process, you can use electromyographic control or methods of stimulation of nerve fibers. The introduction of the drug at several points can contribute to a more even distribution of it in the muscle, which is especially justified when the drug is injected into large muscles.

Selection of the exact dose of the drug and the number of points for injection must be carried out individually in accordance with the size, number and location of the muscles involved in the pathological process, the severity of spasticity, the presence of local muscle weakness and the nature of the patient's response to the preceding treatment.

Side effects:

Correction of facial wrinkles

From the nervous system: headaches, paresthesia.

From the side of the eyes: ptosis.

From the gastrointestinal tract: nausea.

From the skin: erythema, tightness of the skin.

From the musculoskeletal system: muscle weakness.

General reactions and the reaction at the site of administration: pain in the face, swelling of the injection site, ecchymosis, pain at the injection site, irritation of the skin at the injection site.

From the nervous system: dizziness, paresis of facial muscles, paralysis of mimic muscles.

From the side of the eyes: ptosis, punctate keratitis, lagophthalmus, dry eyes, photophobia, increased lacrimation, difficulty of closing the eyelids, keratitis, ectropion (eyelid eversion), diplopia, entropion (eyelid twist), acuity reduction and other visual impairment, the formation of erosions on the cornea.

Skin: rash / dermatitis; general reactions and reactions at the site of administration; irritation and swelling of the facial skin; fatigue.

Overdose:

Symptoms Overdose manifests after a while after the injection. If the drug is accidentally injected or swallowed, the patient should be under medical supervision for several days to identify the clinical manifestations and symptoms of general weakness or paralysis of the muscles.

Patients with symptoms of poisoning with botulinum toxin A (general weakness, ptosis, diplopia, difficulty swallowing and speech disorders or paresis of respiratory muscles) should be hospitalized.A case of severe generalized muscle paralysis is described in case of drug overdose.

When paralysis of the respiratory musculature requires intubation and transfer to artificial ventilation of the lungs to improve the patient's condition.

Interaction:

With the simultaneous use of the action of the drug potentiates the antibiotics of the aminoglycoside group, erythromycin, tetracycline, polymyxins, drugs that reduce neuromuscular transmission (especially curare-like muscle relaxants).

Studies on drug interactions were not conducted. Clinically significant cases of drug interaction are not described.

Special instructions:

A drug is released, stored and used in specialized medical institutions. The drug is stored in a separate closed labeled box in the refrigerator.

Immediately after the injection, the drug solution remaining in the vial or syringe must be inactivated with a solution of sodium hypochlorite (0.5%). Alternatively, the contents of unused bottles should be restored with a small amount of water, and then autoclaved.All auxiliary materials in contact with the preparation must be disposed of in accordance with the rules for the destruction of biological waste. Spilled solution of the drug should be wiped with an absorbent cloth impregnated with 1% sodium hypochlorite solution.

In cases of prior surgical intervention in the face, the time interval between surgery and administration should be at least 3 months.

As with any method of treatment that gives previously immobilized patients the opportunity to return to physical activity, the patient should be warned about the importance of restoring activity gradually.

A drug should be used with caution in severe weakness or atrophy in the muscle to which the action of the drug is directed. The drug should be used with caution in the treatment of patients with peripheral motor neuropathic diseases (eg, amyotrophic lateral sclerosis or motor neuropathy).

The drug should be used with extreme caution and under constant monitoring in patients with subclinical or clinical signs of a violation of neuromuscular transmission,for example, with myasthenia gravis or Lambert-Eaton syndrome; this group of patients has increased sensitivity to this drug, which can lead to the development of severe muscle weakness. Patients with neuromuscular diseases may be at a risk of developing clinically pronounced systemic effects, including severe dysphagia and breathing disorders, by administering conventional doses of the drug. Treatment of such patients should be conducted with caution.

Blepharospasm

A rare blinking associated with the administration of botulinum toxin to the circular muscle of the eye can lead to pathological changes in the cornea. One should carefully study the sensitivity of the cornea of the eye, which were previously operated on, avoid the introduction of the drug in the lower eyelid to prevent the development of eyelid eversion, and actively treat any defects in the epithelial cover. For this, drops with protective properties, ointments, therapeutic soft contact lenses, eye closure with a bandage or other means may be used.

In the soft tissues of the eyelids, ecchymoses easily arise. To reduce the incidence of their occurrence, it is necessary to easily push into the injection site immediately after the administration of the drug.

Since botulinum toxin has anticholinergic activity, it should be used with caution in patients with closed-angle glaucoma.

Cervical dystonia (spasmodic torticollis)

Patients with spastic torticollis should be informed of the possibility of developing dysphagia of varying severity: from mild to severe. Dysphagia may persist for 2 to 3 weeks after the administration of the drug, it was reported that the case of dysphagia persists for up to 5 months. Dysphagia can be a potential cause of aspiration, dyspnoea, requiring intubation. In rare cases, it is possible to develop aspiration pneumonia with a lethal outcome.

The frequency of dysphagia can be reduced by reducing the dose of the drug, injected into the sternocleidomastoid muscle, to 100 units or less. It was shown that the group of increased risk of dysphagia consists of patients with a reduced mass of neck muscles, as well as patients who are injected into the sternocleidomastoid muscles from both sides. The development of dysphagia is associated with the penetration of toxin into the muscular layer of the esophageal wall. The introduction of the drug into the muscle that lifts the scapula may be associated with an increased risk of developing upper respiratory tract infections and dysphagia.

Dysphagia can contribute to limiting the intake of food and water, which leads to loss of body weight and dehydration. The group of increased risk of dysphagia after the administration of the drug is the patients with subclinical dysphagia.

Paralytic strabismus (strabismus)

The drug is not effective in chronic paralytic strabismus. In combination with surgical treatment, it causes only a reduction in the contraction of the muscles of the antagonists. The effectiveness of the drug in the treatment of strabismus more than 50 prismatic diopters, restrictive strabismus, Duane syndrome with weakness of the lateral rectus muscle, secondary strabismus caused by excessive surgical resection of the antagonist muscle, is questionable. To increase the effectiveness of treatment can over time to resort to repeated administration of the drug.

During the introduction of the drug, it is possible to penetrate the needle into the orbit with the development of retrobulbar hemorrhages, which can worsen the blood supply to the retina, therefore it is recommended that tools be available during the procedure to decompress the orbit.

The state of paralysis of one or more muscles of the eyeball can lead to loss of orientation in space, double vision. The severity of symptoms can be reduced by closing the affected eye.

Correction of facial wrinkles

A rare blinking associated with the introduction of the drug into the circular muscle of the eye can create conditions for frequent corneal contact with environmental factors, the appearance of epithelial defects and corneal erosions, especially in patients with lesions of the VII pair of cranial nerves.

The drug should be used with caution in the following cases:

- with a pronounced asymmetry of the face;

- with ptosis, dermatochalasis, deep scars;

- in patients with dense skin or in the absence of significant smoothing of vertical mimic interbrow wrinkles during mechanical stretching of the skin.

Impact on the ability to drive vehicles and manage mechanisms

A drug can lead to asthenia, muscle weakness, dizziness and visual disturbances. If such symptoms develop, there may be a danger in driving or working with moving machinery.

Instructions

Botulinum toxin type A - hemagglutinin complex (Botulinum toxin type A - hemagglutinin complex)