Botox - instructions for use, dose, side effects, contraindications

The 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 exocytosis processes.

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 in the third stage results in 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 denervated 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:

The pharmacological effect of Botox® 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, Botox® 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:

associated with dynamic deformation of the foot as a "horse foot" due to spasticity in patients 2 years and older with infantile cerebral palsy who are on an outpatient basis,
wrist and hand in adult patients who had a stroke,
ankle in adult patients who had a stroke;

- strabismus (strabismus);

- dysfunction of the bladder:

idiopathic urinary bladder hyperactivity with urinary incontinence, mandatory urges to urinate and frequent urination in adults in the case of inadequate efficacy or intolerance to anticholinergic therapy,
urinary incontinence in patients with neurogenic hyperactivity detrusor (neurogenic bladder) as a result of chronic subcervical spinal cord injury or multiple sclerosis;

- relief of migraine symptoms that meet the criteria for chronic migraine (headaches are present for 15 days a month or more, of which at least 8 days are migraines) with an inadequate response to the use of prophylactic antimigraine drugs or their intolerance,

- temporary correction of appearance of the wrinkles of the upper third of the face (interbrown, frontal wrinkles and periorbital wrinkles such as "crow's feet") in adults.

Contraindications:

Are common:

- a history of hypersensitivity to any component of the drug;

- inflammatory process at the site of the proposed injection (injection);

- acute phase of infectious diseases;

- pregnancy and breastfeeding.

Blepharospasm and correction of wrinkles of the upper third of the face:

- pronounced gravitational ptosis of facial tissues;

- expressed "hernia" in the upper and lower eyelids.

Correction of wrinkles of the upper third of the face:

- Myasthenia gravis or Lambert-Eaton syndrome.

Bladder dysfunction:

- urinary tract infection at the time of treatment;

- acute urinary retention at the time of treatment in the absence of standard catheterization;

- refusal / inability of the patient to undergo, if necessary, catheterization of the bladder after treatment.

Dosing and Administration:

Rules for the preparation and storage of injection solutions

Preparation of solution for injection and a set of solution in a syringe should be carried out on a work surface covered with a paper towel on a polyethylene lining, which will make it possible to quickly remove the spilled drug. Restoration of the preparation Botox® produces only 0.9% solution of sodium chloride for injection. The injection solution is prepared by piercing the stopper with a sterile needle and injecting the necessary amount of the solvent into the vial. If the solvent is not drawn into the vial under the action of a vacuum, the vial is destroyed. Before puncturing, the central part of the rubber plug must be treated with alcohol.To puncture the corks use a sterile needle size 23-25 G.

Instructions for content dilution vials Botox® for treatment hyperactivity of the bladder:

1. Dissolve the contents of the vial containing 100 units of Botox® in 10 ml of 0.9% saline without preservatives and gently mix.

2. Collect 10 ml of the resulting solution from the vial into a 10 ml syringe.

As a result, you will receive one 10 ml syringe containing 100 units of diluted Botox® preparation. Use immediately after reconstitution in a syringe. Dispose of unused saline.

Instructions for content dilution Botox® vials for the treatment of urinary incontinence, aboutbucolic neurogenic hyperactivity detrozora:

1. Prepare two bottles of Botox® 100 ED.

2. The contents of the vials are restored by injecting in each 6 ml of a 0.9% solution of sodium chloride for injection and gently stir.

3. Collect 4 ml of the resulting solution from each vial into each of two 10 ml syringes.

4. Collect 2 ml, remaining in each of the vials, in a third syringe with a capacity of 10 ml.

5. For the final dilution, add another 6 ml of 0.9% sodium chloride solution for injection into each of the three 10 ml syringes and mix gently.

As a result, you will receive three 10 ml syringes containing together 200 units of diluted Botox® preparation.

Use immediately after reconstitution in a syringe. Dispose of unused saline.

Table 1. Breeding of Botox® for use in other indications:

Final dose (ED in 0.1 ml)	The amount of solutionpitela (0.9% solution of sodium chloride for injection), added to the vial (ml)
20	0,5
10	1
5	2
4	2,5
2,6	4
1,25	8

Carefully insert the solvent into the vial (see table above), with light rotational movements of the vial, mixing the powder with the solvent. Active vortexing of the vial and the formation of foam can lead to denaturation of the drug.

The prepared solution is a clear, colorless or slightly yellowish liquid without foreign impurities; slight opalescence can be observed.

The recovered Botox® can be stored in the refrigerator at a temperature of 2-8 ° C for 24 hours in the original bottle. On the label it is necessary to record the date and time of breeding. After dilution, the product should be used within 24 hours provided it is properly stored. The unused solution must be disposed of (see page 5).section Special instructions).

Units of action of botulinum toxin at different preparations are not interchangeable. The recommended doses, expressed in terms of the action for Botox®, differ from those of other botulinum toxin preparations.

Application in elderly patients

In general, except for the use of the drug in the treatment of bladder hyperactivity, adequate studies of dosages in the geriatric population have not been conducted. It is recommended to use the lowest effective dose at the largest clinically acceptable interval between administrations. Care should be taken when treating elderly patients with a history of medical history and concomitant therapy.

Use in children

The safety and efficacy of Botox® for treatment of each of the indications for use has not been studied in children and adolescents less than that indicated below for this indication:

Cerebral Palsy -	2 years
Blepharospasm, hemifacial spasm -	12 years
Cervical dystonia -	12 years
Spasticity of upper and lower extremity after stroke -	18 years
Chronic migraine -	18 years
Idiopathic hyperactivity of the bladder and detrusor neurogenic hyperactivity -	18 years

Botox injection should be carried out by a qualified doctor who has undergone a special training course and obtained the permission of the manufacturer.

It is allowed to perform outpatient injections in a procedural room.

The dose of Botox® and the injection points are determined individually for each patient in accordance with the severity and localization of muscular hyperactivity. In some cases, electromyography (EMG) is used to more accurately establish the localization of the pathological process.

Treatment of blepharospasm and hemifacial spasm

Solution Botox® is injected with a needle size of 27-30G/ 0.40-0.30 mm. For the treatment of bilateral blepharospasm, the drug is injected superficially into the upper eyelid into the medial and lateral parts of the circular eye muscle and in the lower eyelid to the lateral section of the circular eye muscle. Other points for injection: the protarzal part of the circular eye muscle, the eyebrow area and the forehead area (with the effect of the spasm arising in it on the eyesight).

To prevent the occurrence of ptosis as a complication of the procedure, it is necessary to avoid the administration of the drug near the muscle that lifts the upper eyelid.

For the prevention of diplopia, as complications of the procedure, it is necessary to avoid the introduction of the drug into the medial part of the lower eyelid.

The initial dose is 1.25-2.5 units of ED at each injection site. The total initial dose should not exceed 25 units per side. The effect of the drug appears during the first three days after the procedure and reaches its maximum extent 1-2 weeks after it. The duration of the effect from the action of the drug reaches 3 months, after which the procedure can be repeated.

If the effect of the initial treatment is regarded as insufficient, with repeated administration of the drug, the dose can be increased no more than twice. However, the administration of more than 5 units of the drug at each injection site is not accompanied by a significant improvement in the clinical effect.

In the treatment of blepharospasm, the total dose of Botox® in 12 weeks should not exceed 100 units.

Treatment patients with hemifacial spasm is carried out in the same way as with unilateral blepharospasm, if necessary, injections of the drug are also performed in other affected muscles of the face. The total dose of Botox® in the treatment of hemifacial spasm should be the same as with blepharospasm.

The safety and efficacy of Botox® in the treatment of blepharospasm and hemifacial spasm in children (under 12 years of age) have not been demonstrated.

Treatment of cervical dystonia (spasmodic torticollis)

Solution Botox® is injected with a 25-30 needleG/ 0,50-0,30mm. In clinical studies conducted to establish the safety and efficacy of the drug in cervical dystonia, the dose of diluted Botox ® was varied from 140 to 280 units. There are also data on the use of doses from 95 to 360 units (average dose of about 240 units).

As with any drug treatment, for patients not previously treated with botulinum toxin, the minimum effective dose should be used as the initial dose. The dose given to each point should not exceed 50 units. The sternocleidomastoid muscle is injected with no more than 100 units of the drug. To reduce the risk of dysphagia is not recommended bilateral introduction of the drug in the sternocleidomastoid muscle. The total dose of the drug during the first procedure should not exceed 200 units, in subsequent courses the dose is adjusted taking into account the response to the initial treatment.For any one-time administration, the total dose of 300 U should not be exceeded. The optimal number of points for injection depends on the size of the muscle.

In the treatment of spastic torticollis, the drug is injected into the sternocleidomastoid muscle on the side opposite to 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 lifting the shoulder blade on the side of the lesion.

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

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

Clinical improvement manifests itself during the first two pellets after 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 EMG neck muscles for more accurate establishment of localization of stressed muscles.

The safety and efficacy of Botox® in the treatment of spasmodic torticollis in children (under 12 years of age) have not been demonstrated.

Treatment of focal spasticity in children with cerebral palsy

Solution Botox injected with a needle size 23-260 / 0,60-0,45 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 muscles of the flexor of the forearm, with the crossing of the hips - in addition to the adductor muscles of the thigh. In hemiplegia, the initial recommended total dose is 4 U / kg of body weight in the affected limb. In diplegia, the initial recommended total dose is 6 U / kg of body weight per both affected limbs. 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.Improving the clinical effect of injections of Botox® can be facilitated by orthopedic correction, muscle stretching and physiotherapy.

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

Solution Botox® is injected with a 25-gauge needleG, 27G or 30G. The length of the needle should be selected based on the depth of the localization of the muscle.

To establish the localization of muscles involved in the pathological process, you can use EMG 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.

The choice of the exact dose of the drug and the number of injection points 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.

Table 2. Doses of Botox® when administered to the muscles of the hand

Muscle	Total dose; Number of points for injection
Deep flexor of fingers	15-50 units; 1-2 points
Superficial flexor of fingers	15-50 units; 1-2 points
Radial wrist flexor	15-60 units; 1-2 points
The ulnar flexor of the wrist	10-50 units; 1-2 points
The muscle that leads the thumb of the hand	20 units; 1-2 points
The long flexor of the thumb of the hand	20 units; 1-2 points

In clinical trials, doses of 200 to 240 U distributed between the selected muscles were used for one course of treatment. In controlled clinical trials, patients were observed for 12 weeks after one course of treatment. Improvement of muscle tone was noted for 2 weeks, the maximum effect was usually observed within 4-6 weeks. In an open, uncontrolled follow-up study, most patients underwent repeatinjectionsrez 12-16 weeks after the initial administration, when the effect of the drug on muscle tone decreased. The maximum total dose for such patients who received 4 courses of injection for 54 weeks was 960 units.

The change in the degree and nature of muscle spasticity before repeated administration of the drug may require adjustment of the dose of Botox® and the determination of new points for injection. The minimum effective dose should be used.

In patients with focal spasticity, Botox® is used in combination with a standard treatment regimen. The drug is not intended to be used as a substitute for these therapies.

Treatment of focal spasticity of the ankle in patients who underwent a stroke

Solution Botox® is injected with a 25-gauge needleG, 27G or 30G. The length of the needle should be selected based on the depth of the localization of the muscle.

The figure shows the injection points for injection with spasticity of the lower limb (see Figure 2).

The recommended therapeutic dose for spasticity of the lower extremity affecting the ankle is 300 units, distributed on three muscles.

Table 3. Doses of Botox® on each muscle in the treatment of spasticity of the lower limb:

Muscle	Total dose; Number of points for injection
Calf:
Medial head	75 units; 3 injection points
Lateral head	75 units; 3 injection points
Flounder	75 units; 3 injection points
Posterior tibial	75 units; 3 injection points

Provided that the doctor deems it advisable, a repeat procedure should be performed when the clinical effect of the previous injection decreases, but not earlier than 12 weeks after it.

Treatment of strabismus (strabismus)

Solution Botox® is injected with a needle size 27G.

Botox® is introduced into the muscles of the eyeball under EMG control. To prepare the eye for injection of Botox it is recommended to instill several drops of local anesthetic and decongestant into the conjunctival sac a few minutes before the procedure.

For small deviations of the eyeball, the minimum doses of the drug are used, in the treatment of a more pronounced deviation, the dose is increased.

Initial doses:

- PWhen introduced into the muscles that perform vertical movements of the eyeball (upper and lower rectus muscles) and with horizontal strabismus, less than 20 prismatic diopters: from 1.25 to 2.5 units for any muscle.

- With horizontal strabismus from 20 to 50 prismatic diopters: from 2.5 to 5 units for any muscle.

- With paralysis of the abducent nerve (VI nerve), which persists for 1 month or more: from 1.25 to 2.5 units in the medial rectus muscle.

The initial effect is noted 1-2 days after the procedure, increases during the first week, persists for 2-6 weeks and gradually decreases in the same time period. Rare cases of the effect persistence for more than 6 months are described.

Approximately half of the patients after the first injection of the drug require its reintroduction due to an inadequate clinical response of the muscles to the first procedure or due to mechanical factors: significant deviation or restriction of mobility of the eyeballs, and also when it is impossible to stabilize the position of the eyes due to the motor component of binocular fusion, .

It is recommended to examine the patients 7-14 days after each injection to assess the effect of the procedure.

Patients who had adequate relaxation of the target muscle during the initial course of therapy, the dose of the drug upon repeated administration is left unchanged.

In patients with incomplete relaxation of the target muscle with subsequent administration, the dose of the drug can be increased to a maximum of two times the original dose.Repeated administration of the drug ns should be carried out until the clinical effect of the previous procedure fades, which is expressed in the stable restoration of the function of injected and located near them muscles.

The maximum recommended dose for single administration to any muscle in the treatment of strabismus is 25 units.

Dysfunction of the bladder

At the time of treatment, urinary tract infection should be avoided. Prophylactic antibacterial therapy is prescribed for 1-3 days before treatment, on treatment day and for 1-3 days after treatment. It is recommended to stop taking disaggregant drugs at least 3 days before the injection. Patients receiving anticoagulants need appropriate measures to reduce the risk of bleeding.

The introduction of Botox® for the treatment of urinary incontinence should only be performed by physicians with experience in diagnosis and treatment dysfunction of urinary bubble(for example, urologists or urogynecologists).

Bladder hyperactivity:

Before the administration of the drug, it is possible to perform an intravesical instillation of a dilute solution of a local anesthetic with a sedative effect or not having this effect.When carrying out an intravesical instillation of a local anesthetic before the procedure, it is necessary to empty and rinse the bladder with a sterile physiological solution.

The recommended dose of the drug Botox® is 100 units in the form of 0.5 ml (5 units) of injection into 20 points of the dutrusor.

Diluted Botox® (100 U / 10 ml) is injected into the detrusor muscle with a rigid or flexible cystoscope, avoiding the zone of the urinary bladder and the bottom of the bladder. The bladder should be sufficiently filled with physiological saline to achieve proper imaging of injections, however, excessive bladder stretching should be avoided.

Before the injection, the needle for injection should be filled (rinsed) with approximately 1 ml of the solution (depending on the length of the needle) to remove air.

The needle should be injected approximately 2 mm deep into the detrusor, producing 20 injections but 0.5 ml (total volume 10 ml) at a distance of about 1 cm from each other (see the figure below). As the last injection, approximately 1 ml of sterile saline is injected so that the total dose is fully administered. After completion of the injections, a saline solution is injected, filling the bladder for better visualization.The patient should be monitored for at least 30 minutes after the injection and until the moment of spontaneous urination.

Usually clinical improvement is noted within 2 weeks. Consideration should be given to the possibility of repeated injections after a decrease in the effect of the previous injection (the average duration of the effect in clinical trials of the 3 phase was 166 days (approximately 24 weeks)), but not earlier than 3 months after previous injections into the bladder.

Treatment of urinary incontinence due to neurogenic hyperactivity detrusor

Before injection, according to the approach adopted in the clinic, use intravesical administration of a diluted anesthetic (in combination with or without sedatives) or general anesthesia. In the case of local administration of an anesthetic into the bladder, bladder catheterization and washing with a sterile saline solution are necessary before the next stages of Botox® injection.

The recommended dose of Botox^®is 200 units, with the introduction of 1 ml (about 6.7 units) at 30 detrusor points. Divorced Botox® (200 U / 30 ml) is injected into detrusor muscle using a rigid or flexible cystoscope, avoiding the zone of the urinary bladder and the bottom of the bladder.The bladder should be filled with a sufficient amount of saline to adequately visualize the injection points; however, overextension of the bladder should be avoided.

Before the injection, the needle for injection should be filled (rinsed) with approximately 1 ml of the solution (depending on the length of the needle) to remove air.

The needle should be injected approximately 2 mm deep into the detrusor, making 30 injections of 1 ml (total volume 30 ml) at points approximately 1 cm apart (see the figure). As the last injection, approximately 1 ml of sterile saline is administered until the full dose is reached. After completion of the injections, a saline solution is injected, filling the bladder for better visualization. The patient should be monitored for at least 30 minutes after the injection. Usually clinical improvement is noted within 2 weeks. It should be considered the possibility of repeated injections after reducing the effect of a previous injection (on average, 256-295 days), but not earlier than 3 months after previous injections into the bladder.Safety and efficacy of Potoke® in the treatment of urinary incontinence due to neurogenic hyperactivity detrusor in children (under the age of 18 years) have not been demonstrated.

Treatment of chronic migraine

The diagnosis of chronic migraine should be made by a neurologist, and the administration of the drug Botox® is possible only under the supervision of a neurologist, who is a specialist in the treatment of chronic migraine.

The recommended dose is 155-195 units. The drug is administered intramuscularly with a needle 30G length of 12.7 mm in 0.1 ml (5 units) in 31-39 points.

Injections should be distributed between 7 specific muscular areas of the head / neck in accordance with the table below. Patients with extremely thick neck muscles may require a 25 mm needle for injection in the neck. With the exception of the muscle of the proud, into which one injection is made (along the middle line), the drug is injected into all muscles on both sides, with half of the injection points located on the left side and the second half on the right side of the head and neck. In case of predominance of pains of any localization, additional administration of the drug on one or two sides in 1-3 certain muscular groups (occipital, temporal and trapezoidal) is possible.The maximum dose per muscle is shown in the table below.

The figures show the injection points:

A. Muscle, wrinkling eyebrow: 5 ED on each side

B. Muscles of the proud: 5 units in the middle line

C. Occipital-frontal muscle: 10 units on each side

D. Temporalis muscle: 20 U on each side

E. Occipital muscle: 15 units on each side

F. Neck paravertebral muscles: 10 units on each side

G. Trapezius muscle: 15 U on each side

The recommended frequency of repeated injections is every 12 weeks.

Table 4. Doses of Botox® on each muscle with chronic migraine:

Head / neck area	The total recommended dose (the number of points for injectionth^a)
Occipital-frontal muscle^b	20 units (4 points for injection)
Muscle wrinkling eyebrow^b	10 units (2 points for injection)
Muscle of the proud	5 units (1 point for injection)
Occipital muscle^b	from 30 units (6 points for injections) up to 40 units (8 points for injection)
Temporal muscle^b	from 40 units (8 points for injections) up to 50 units (10 points for injections)
Trapezius muscle^b	from 30 units (6 points for injections) up to 50 units (10 points for injections)
Cervical paravertebral muscles^b	20 units (4 points for injection)
Total dose range:	155-195 units (31-39 points for injection)

a) in 1 point of the / m injection - 0.1 ml - 5 ED of Botox®

(b) the dose is distributed on both sides

The safety and efficacy of Botox® in the treatment of chronic migraine in children (under the age of 18 years) have not been studied.

Temporal correction of the appearance of wrinkles in the upper third of the face (interbrow, frontal wrinkles, periorbital wrinkles, thinned "crow's feet") in adults

The optimal doses and the number of injection points in one muscle may differ for different patients, it is necessary to choose an individual dosing regimen. The recommended volume of administration to one point is 0.1 ml.

- Smeared wrinkles:

Botox® is diluted with 0.9% solution of sodium chloride for injection (100 units / 2.5 ml) and injected with a sterile needle size 30G.

At 4 units, injected into 5 points for injection: the muscle wrinkling eyebrow - 2 points on each side, in the muscle of the proud - 1 point. The total dose is 20 units.

To reduce the risk of developing ptosis, it is necessary to avoid injecting the drug near the muscle that lifts the upper eyelid, especially in patients with a well-defined muscle that lowers the eyebrow.

When the drug is injected into the muscle, the wrinkling eyebrow of the injection must be made into the central part of the muscle, retreating no less than 1 cm above the arch of the eyebrow.

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

- Periorbital wrinkles (crow's feet)

Botox® is inserted bilaterally into 3 points of the circular muscle of the eye with the highest degree of wrinkles with a smile (6 points in total). It is usually recommended to inject 2-6 units per point, to a depth of 2-3 mm, the total dose is 6-18 units per side.

Injections are made at a distance of at least 1 cm from the edge of the orbit, outside of the vertical line drawn through the lateral cantus and not approaching the lower edge of the zygomatic arch.

- Frontal wrinkles:

Botox® is administered intramuscularly to each of the 4 points of frontal muscle injection. It is recommended to enter 2-6 units per point, located on each side along the frontal folds with an interval of 1-2 cm so that the total dose is 8-24 units.

To reduce the risk of eyebrow ptosis, injections should be performed at a distance of at least 2-3 cm from the edge of the eyebrow.

For all indications for use

If the first procedure is not effective, i.e. absence of significant clinical improvement in comparison with baseline, 1 month after drug administration, it is necessary:

- clinical confirmation of the toxin action on the injected muscle (muscle), which may include an EMG study performed 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 toxin neutralizing antibodies;

- 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; EMG-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.

Side effects:

According to clinical studies, the following incidence of adverse reactions should be expected, depending on the indications for use: blepharospasm - 36%, cervical dystonia - 28%, cerebral palsy - 17%,focal spasticity of wrist and hand due to stroke - 16%, focal spasticity of ankle due to stroke - 15%.

In clinical studies of bladder hyperactivity, the incidence of adverse effects was 26% after the first Botox® and 22% after the second procedure.

In clinical studies in patients with urinary incontinence due to detrusor neurogenic hyperactivity, the incidence of adverse reactions was 32% on first use and decreased to 18% with repeated use of the drug.

In studies of chronic migraine, the response rate was 26% at the first injection and decreased to 11% with repeated administration.

According to clinical studies in patients with brow wrinkles who received a single dose of Botox®, the incidence of adverse reactions was 43.7%.

In a clinical study that included individuals who underwent peri-orbit correction for the type of "crow's feet" with Botox®, one or more adverse events were noted in 18.3% of patients.

For frontal wrinkles, the incidence of adverse reactions in patients ranged from 53% to 55%, depending on the dose of the drug.

As a rule, unwanted reactions appear during the first days after the injection and are transient. In rare cases, the duration of unwanted reactions can be several months or more. Local muscle weakness reflects the expected pharmacological action of botulinum toxin on the muscle. However, large doses can cause muscle weakness in addition to those directly localized at the injection site.

As with any injection procedure, local soreness, inflammation, paresthesia, hypoesthesia, hypersensitivity, swelling, erythema, localized infection, bleeding and / or hematomas associated with injection may be noted at the site of administration. Procedure-related pain and / or anxiety can lead to vasovagal reactions, including transient hypotension and syncope.

A rise in temperature and the appearance of an influenza-like syndrome are described.

Undesirable reactions (frequency for each nosology)

Frequency of occurrence of undesirable reactions is presented for each indication to the use of the drug on the basis of clinical experience.To describe the frequency of occurrence, the following criteria are adopted: very often (≥ 1/10); often (≥ 1/100, <1/10); infrequently (≥1 / 1000, <1/100); rarely (≥1 / 10000, <1/1000); very rarely (<1/10000).

Blepharospasm / hemifacial spasm Impaired nervous system:
Infrequently	Vertigo, paresis of facial muscles, paralysis of mimic muscles
Disorders from the side of the organ of vision:
Often	Blepharoptosis
Often	Point keratitis, lagophthalmus, dry eyes, photophobia and increased lacrimation, eye irritation
Infrequently	Keratitis, ectropion (eyelid eversion), diplopia, entropion (eyelid twist), deterioration and reduction of visual acuity
Rarely	Edema of the century
Rarely	Ulcerative keratitis, corneal epithelial defect, corneal perforation
Disturbances from the skin and subcutaneous tissues:
Often	Ecchymoses
Infrequently	Rash / dermatitis
Common racesconstruction and violations in place introduction:
Often	Irritation and swelling of the skin of the face
Infrequently	Fatigability
Cervical dystonia (spastic torticollis)
Infectious and parasitic diseases:
Often	Rhinitis and upper respiratory tract infections
Violations from the nervous system:
Often	Dizziness, hypertonia, hypoesthesia, somnolence and headache
Violations from the side of the organ of vision:
Infrequently	Diplopia and ptosis
Disturbances from the respiratory system, chest and mediastinal organs:
Infrequently	Shortness of breath and dysphonia
Disorders from the gastrointestinal-intestinal tract:
Often	Dysphagia
Often	Dry mouth and nausea
Disorders from the side of the skeleton-muscular and connective tissue:
Often	Muscle weakness
Often	Stiffness and painful movements
General disorders and disorders at the site of administration:
Often	Pain
Often	Asthenia, flu-like syndrome, general malaise
Infrequently	Fever
Focal spasticity the children with children cerebral palsy
Infectious and parasitic diseases
Often	Viral infections and infectious otitis media
Impaired nervous system:
Often	Combination, abnormalities of gait and paresthesia
Disturbances from the skin and subcutaneous fabrics:
Often	Rash
Disturbances from the musculoskeletal and connective tissue:
Often	Myalgia, muscle weakness and pain in the extremities
Disorders from the kidneys and urinary tract:
Often	Urinary incontinence with stress
Trauma, intoxication and complications of manipulation:
Often	Falls
General disorders and disorders at the site of administration:
Often	Malaise, pain at the injection site and asthenia
Focal spasticity of the wrist and hand in patients who have suffered a stroke
Disorders of the psyche:
Infrequently	Depression and insomnia
Impaired nervous system:
Often	Hypertonus
Infrequently	Hypoesthesia, headache, paresthesia, discoordination and amnesia
Hearing disorders and labyrinthine disturbances:
Infrequently	Dizziness
Vascular disorders:
Infrequently	Orthostatic hypotension
Disorders from the gastrointestinal tract:
Infrequently	Nausea and paresthesia of the mouth area
Disturbances from the skin and subcutaneous tissues:
Often	Ecchymoses and purpura
Infrequently	Dermatitis, itching, rash
Disturbances from the musculoskeletal connective tissue:
Often	Pain in the limbs and muscle weakness
Infrequently	Arthralgia, bursitis
General disorders and disorders at the site of administration:
Often	Pain at the injection site, fever, flu-like syndrome, injection site hemorrhage and skin irritation at the injection site
Infrequently	Asthenia, pain, hypersensitivity at the injection site, general malaise and peripheral edema
Focal spasticity of the ankle the patients who survived stroke
Disturbances from the skin and subcutaneous fabrics:
Often	Rashes
Disturbances from the musculoskeletal and connective tissue:
Often	Arthralgia, musculoskeletal stiffness
General disorders and disorders at the site of administration:
Often	Peripheral edema
When repeated injections, no changes were made to the safety profile
Strabismus (strabismus)
Violations from the side of the organ of vision:
Often	Ptosis, movement of the eyeball
Infrequently	Retrobulbar hemorrhage, eyeball damage, Ady-Holmes syndrome
Rarely	Hemorrhage in the vitreous body
Hyperactivity of the bladder
Infections and infestations
Often:	Urinary tract infection
Often:	Bacteriuria
Violations from the urinary system
Often:	Dizuria
Often:	Delayed urination, increased volume of residual urine *, pollakiuria, leukocyturia
* cases of increase in residual volume of urine after urination (PVR), not requiring a catheterization
Frequent side effects associated with the procedure of injection were dysuria and hematuria.
Urinary incontinence due to neurogenic detrusor hyperactivity
Infectious and parasitic diseases
Often	Urinary tract infections
Violations mentality:
Often	Insomnia
Disorders from the gastrointestinal tract:
Often	Constipation
Disturbances from the musculoskeletal and connective tissue:
Often	Muscle weakness, muscle cramps
Renal impairment and urinary tract:
Often	Retention of urine
Often	Hematuria , dysuria , diverticulum of the bladder
General disorders and disorders at the site of administration:
Often	Fatigability, gait disturbances
Trauma, intoxication and complications of manipulation:
Often	Autonomous dreflexia *, falls
undesirable side reactions associated with the procedure
Chronic migraines
Impaired nervous system:
Often	Headache, migraine, paresis of facial muscles
Violations from the side of the organ of vision:
Often	Blepharoptosis
Violations fromabout the skin and subcutaneous tissues:
Often	Itching, rash
Infrequently	Soreness of the skin
Disturbances from the musculoskeletal and connective tissue:
Often	Neck pain, myalgia, musculoskeletal pain, stiffness of muscles and joints, muscle spasms, muscle tension and muscle weakness
Infrequently	Pain in the jaw
Are common disorders and violations in the place of administration:
Often	Pain at the injection site
Disorders from the gastrointestinal tract:
Infrequently	Dysphagia
*The interbroowe wrinkles*
Infectious and parasitic diseaseI:
Infrequently	Infections
Violations psyche
Infrequently	Anxiety
Violations from the nervous system:
Often	Headache, paresthesia
Infrequently	Dizziness
Violations from the side of the organ of vision:
Often	Blepharoptosis
Infrequently	Blepharitis, pain in the eyes, visual impairment (including a decrease in its severity)
Violations from the gastrointestinal tof the
Often	Nausea
Infrequently	Dry mouth
Violations from the skin and subcutaneous tissues:
Often	Ecchymosis, erythema, a feeling of tightness of the skin
Infrequently	Swelling (face, eyelid, periorbital area), photosensitization, itching, dry skin
Violations from the musculoskeletal and connective tissue:
Often	Local muscle weakness
Infrequently	Muscle twitching
General disorders and disorders at the site of administration:
Often	Pain in the face, swelling of the injection site, pain / burning at the injection site
Infrequently	Flu-like syndrome, asthenia, fever
Periorbital wrinkles
Infectious and parasitic diseases:
Often	The flu-like syndrome
Violations from the nervous system:
Often	Headache
Violations from the side of the organ of vision:
Often	Omission of the lateral part of the upper eyelid, edema of the eyelid
General disorders and violations in the place of administration:
Often	Hemorrhages and hematomas at the injection site *,
Infrequently	Pain at the injection site *, paresthesia
* reaction youzby injection
*Frontal wrinkles*
Infectious and parasitic diseases:
Often	ARVI
Violations mentality:
Often	A sense of tension
Violations from the nervous system:
Often	Ptosis of eyebrows, headache
Violations from the side of the organ of vision:
Often	Edema of eyelids
Disorders from the gastrointestinal tract:
Often	Nausea
Violations from the skin and subcutaneous tissues:
Often	Itching forehead
General disorders and disorders at the site of administration:
Often	Pain in forehead, flu-like syndrome
Trauma, intoxication and complications of manipulation:
Often	Bruises / hemorrhages

Additional Information

The following list includes adverse reactions and other medical adverse events reported in the postmarketing period, regardless of indications for use, and which may not have been listed above.

Immune system disorders:

Anaphylactic shock, Quincke's edema, serum sickness and urticaria.

Disorders from the metabolism and nutrition:

Anorexia.

Disturbances from the nervous system:

Pleksonatiya brachial plexus, dysphonia, dysarthria, facial paresis, kinesthesia, muscle weakness, myasthenia gravis gravis, peripheral neuropathy, paresthesia, radiculopathy, convulsions, fainting and paralysis of the face.

Disturbances on the part of the organ of sight:

Closed-angle glaucoma (in the treatment of blepharospasm), strabismus, weakened clearness and other visual impairments.

Narushthe with hundredthe aboutbill hearing and labyrinthine disorders:

Deafness, noise in the ears and dizziness.

Violation of the heart:

Arrhythmia, myocardial infarction.

Disturbances from the respiratory system, organon of the thorax and mediastinum:

Aspiration pneumonia (in some cases with a fatal outcome), dyspnea, bronchospasm, respiratory depression and respiratory failure.

Disorders from the gastrointestinal tract:

Abdominal pain, diarrhea, constipation, dry mouth, dysphagia, nausea and vomiting.

Disturbances from the skin and subcutaneous tissues:

Alopecia, psoriasis dermatitis, erythema multiforme, hyperhidrosis, madarosis, pruritus and rash.

Disturbances from musculoskeletal and connective tissue:

Muscular atrophy and myalgia.

General disorders and disorders at the site of administration:

Atrophy due to denervation, malaise and fever.

Overdose:

Symptoms of overdose appear after a while after the injection. In case of accidental administration or swallowing of Botox®, 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. Excessive doses can cause local or distant, generalized and deep neuromuscular paralysis.

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. Patients with respiratory muscle paralysis require intubation and transfer to artificial ventilation of the lungs to improve the patient's condition. In addition to other measures of general supportive care, tracheotomy and prolonged artificial ventilation may be required.

Interaction:

Theoretically, the effect of botulinum toxin can be enhanced by simultaneous use with the antibiotics of the group of aminoglycosides or spectinomycin, as well as with other drugs affecting neuromuscular transmission (eg, muscle relaxants).

The effect of introducing different serotypes of botulinum neurotoxin simultaneously or at intervals of several months is unknown. Perhaps aggravation of neuromuscular weakness with the introduction of another botulinum toxin before the disappearance of the effects of the previously introduced botulinum toxin.

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

Special instructions:

Botox is used in specialized medical institutions. The drug is stored in a separate closed labeled box in the refrigerator.

The unused solution of the preparation remaining after the injection, as well as the auxiliary tools and materials in contact with the preparation (syringes, needles, etc.) should be disposed of in accordance with the current rules for the destruction of biological waste.

The recommended dose and frequency of Botox® should not be exceeded due to the potential risk of overdose, excessive muscle weakness, distant toxin distribution and the formation of neutralizing antibodies. In the initial course, treatment should begin with the lowest recommended dose for a specific indication for use.

Doctors and patients should be aware that side effects may occur, despite the good tolerability of previous injections. Care must be taken with each procedure.

Side effects associated with the spread of the toxin from the site of administration, sometimes with a fatal outcome, associated in some cases with dysphagia, pneumonia and / or severe muscle weakness, have been reported. These symptoms are consistent with the mechanism of action of botulinum toxin and appear in the period from several hours to several weeks after the injection. The risk of these side effects is greatest in patients with concomitant diseases and conditions predisposing to the development of these symptoms, including in children and adults receiving treatment for spasticity in high doses.

Patients receiving the drug in therapeutic doses may also experience severe muscle weakness.

TO Elderly and debilitated patients should be treated with caution.

The risk-benefit ratio for a particular patient should be assessed before initiating treatment with Botox®.

It was reported on the dysphagia that followed injections into areas other than the neck muscles. Botox® should be used with extreme caution and under constant monitoring in patients with subclinical or clinical signs of neuromuscular transmission, for example, with myasthenia gravis gravis or Lambert-Eaton syndrome, in patients with peripheral motor neuropathic diseases (eg, amyotrophic lateral sclerosis or motor neuropathy), as well as in patients with concomitant neurological pathology. These patients may have increased sensitivity to this group of drugs, even at therapeutic doses, which can lead to the development of severe muscle weakness and a high risk of clinically significant systemic effects, including severe dysphagia and breathing disorders.In such cases, botulinum toxin should be used under the supervision of a specialist and only if the benefit of the treatment exceeds the risk. Patients with dysphagia and aspiration in history should be treated with extreme caution.

Patients and carers should be advised to seek medical help immediately if swallowing, speech or breathing problems occur.

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.

Before the injection of Botox® it is necessary to clarify the anatomy of the relevant areas and any changes in anatomy as a result of the preceding operations; avoid injections into easily damaged anatomical structures.

Pneumothorax, associated with the procedure of injection, was observed after the administration of the drug Botox® in the chest area. Care should be taken when injecting into the lungs (especially their apexes) or other easily erect anatomical structures.

Serious adverse reactions, including fatalities, were noted in patients who received Botox® for unconfirmed indications - injections of the drug directly into the salivary glands, oro-lingua-pharyngeal region, esophagus and stomach. Some patients had previous dysphagia or severe weakness.

The development of serious and / or immediate hypersensitivity reactions against the background of the use of Botox®, such as anaphylaxis, serum sickness, urticaria, soft tissue edema or dyspnea, has been reported infrequently. Reactions have been reported in both cases of monotherapy with Botox®, and with its use in combination with other drugs that can cause such symptoms.

If such reactions develop, further administration of Botox should be discontinued and appropriate medical therapy, in particular epinephrine, should be started immediately.

As with any injection, there may be complications associated with the procedure. Injections can lead to local infections, tenderness, inflammation, paresthesia, hypesthesia, hypersensitivity, edema, erythema, bleeding / hematoma.Injury associated with injection and / or anxiety can lead to vasovagal reactions, for example, fainting, hypotension, etc. Caution should be exercised with weakness or atrophy of the muscles in which the drug is planned to be injected.

Rare undesirable reactions from the cardiovascular system, including arrhythmias and myocardial infarction, in some cases with a legal outcome are described. Some of these patients initially had risk factors, including diseases of the cardiovascular system.

There were first appeared or repeated epileptic seizures, as a rule, in patients predisposed to these conditions. The exact relationship between these phenomena and the introduction of toxin is not established. Seizures were noted mainly among patients with cerebral palsy.

The formation of neutralizing antibodies to botulinum toxin can reduce the effectiveness of Botox®, by inactivating the biological activity of the toxin. According to clinical studies, the administration of Botox® with greater frequency and in high doses can lead to an increase in the incidence of antibody formation. Potential formation of antibodies can be minimized by administration ofthe lowest effective doses with the maximum clinically acceptable intervals between injections.

Clinical fluctuations in the repeated use of Botox® (as well as for all botulinum toxins) may result from differences in the drug dilution technique, the intervals between injections and injected muscles, and small fluctuations in the activity values of the preparation, determined by the biological method.

Blepharospasm

The 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 can 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 can persist for 2 to 3 weeks after drug administration, it has been reported that the dysphagia persists until 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 has been shown that patients with a reduced mass of neck muscles, as well as patients with whom the drug is injected into the sternocleidomastoid muscles from both sides, are at increased risk of developing dysphagia. 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. Group at increased risk of dysphagia after administration of Botox^® are patients with subclinical dysphagia.

Focal spasticity associated with infantile cerebral palsy

Reports on postmarketing use indicate a possible systemic spread of toxin in children with concomitant diseases, primarily cerebral palsy. In general, in these cases, doses higher than those recommended (see the "Method of administration and dose" section) were used.

Rare spontaneous reports of death (sometimes associated with aspiration pneumonia) after treatment of children with severe cerebral palsy, including application not in accordance with the approved instruction (including the introduction to the neck area) are received. It is necessary to treat with extreme caution the treatment of children with severe neurologic status, dysphagia or having a recent history of aspiration pneumonia or lung disease. Patients with unsatisfactory health status should be treated only if the intended benefit for a particular patient exceeds the potential risk.

Focal spasticity the of patients who had a stroke

Botox^® is a treatment for focal spasticity, which was studied only in combination with standard treatments for these diseases. Apparently, Botox^® does not cause an increase in the volume of motion in the joints with a stable contracture.

Botox^® should not be used to treat focal ankle spasticity in stroke patients unless it is expected that a decrease in muscle tone will lead to improved functions (eg gait improvement), a reduction in symptoms (eg, pain reduction), or to ease patient care. In addition, functional improvements may be limited if treatment with Botox^® begins later than 2 years after a stroke or in patients with the least severe spasticity of the ankle (score on the modified Ashworth scale <3).

Caution should be exercised in the treatment of adult patients with post-spastic spasticity, which may be at increased risk of impairment. Botox^® should be used "with caution to treat spasticity of the ankle in elderly patients with severe concomitant diseases, therapy should be started only when the benefit of treatment exceeds the potential risk.

Botox^® should be used to treat patients with post-spastic spasticity of the lower extremities only after assessing their condition by doctors who have experience in the rehabilitation of stroke patients.

Strabismus (strabismus)

Botox^® Ineffective 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 Botox® in the treatment of strabism in more than 50 prismatic dioptres, 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 Botox®, 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, and 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.

Dysfunction of the bladder

Measures must be implemented precautions for cystoscopy.

In patients without a catheter, the volume of residual urine after urination should be assessed within 2 weeks after application and periodically as far as possible up to 12 weeks after treatment. In case of difficulty in urinating, patients should consult a doctor, as catheterization may be required.

Guybladder peractivity

Men with bladder hyperactivity and signs or symptoms of urinary tract obstruction should not be prescribed Botox®.

Urinary incontinence due to neurogenic hyperactivity detrusor

Perhaps the development of an autonomous disorder of reflexes due to the procedure. Emergency medical attention may be required. After introduction into the detrusor, Botox® acts on the efferent pathways of detrusor activity, blocking the release of acetylcholine. In addition, Botox® can inhibit afferent neurotransmitters and sensory pathways.

Chronic migraines

The safety and effectiveness of the drug Potoke as a means of preventing headache in patients with episodic migraine (headaches less than 15 days per month) or chronic tension headache have not been established. The safety and efficacy of Botox^® In patients with headaches due to excessive use of medicines.

Wrinkles of the upper third of the face (between the brows, frontal wrinkles, "crow's feet")

Rare blinking associated with the administration of botulinum toxin to the circular muscle of the eye can lead to corneal damage, persistent epithelial defects and corneal erosions, especially in patients with pathology of the VII pair of cranial nerves.

Botox^® 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 Vertical mimic inter-brow wrinkles with mechanical stretching of the skin.

Effect on the ability to drive transp. cf. and fur:

Botox® 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.

Form release / dosage:Lyophilizate for solution for intramuscular injection, 100 units.

Packaging:

100 units in a bottle.

The bottle is placed in a cardboard liner, which limits the mobility of the bottle in the box. The insert with the bottle is placed in a cardboard box along with the instruction.

Storage conditions:

The drug is transported and stored at a temperature of 2-8 ° C or in a freezer at a temperature of minus 5 ° C or lower in closed, sealed and marked containers in places inaccessible to children.

Shelf life:

3 years.

The drug should not be used after the expiry date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N011936 / 01

Date of registration:18.01.2008 / 26.07.2016

Expiration Date:Unlimited

The owner of the registration certificate:Allergen Pharmaceuticals AirlandAllergen Pharmaceuticals Airland Ireland

Manufacturer: & nbsp

ALLERGAN PHARMACEUTICALS IRELAND Ireland

Representation: & nbspAllergen of CIS SARL. LtdAllergen of CIS SARL. LtdRussia

Information update date: & nbsp17.04.2017