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. Light chain is characterized by Zn²⁺dependent protease activity.It is specific for the cytoplasmic regions of the synaptosomal-associated protein with a molecular weight of 25,000 Daltons (SNAP-25), taking 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 is 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 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 processes are partially effective and subsequently regress, in then time as 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);

- Bladder dysfunction:

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 symptoms of migraine that meets the criteria of chronic migraine (headaches are present 15 days a month or more, of them not less than 8 days - 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.

Carefully:

- In elderly patients with a history of history and concomitant drug therapy;

- in patients with dysphagia and aspiration in history;

- in children with severe neurologic disorders, dysphagia, pulmonary disease, or recent aspiration pneumonia;

- in patients with a history of history;

- if there is inflammation in the places of the proposed injections or in case of severe weakness or atrophy in the muscle in which the drug is planned to be injected;

- in patients with peripheral motor neuropathy (eg, with amyotrophic lateral sclerosis or motor neuropathy);

- in patients with subclinical or clinical signs of neuromuscular transmission (for example, in the case of myasthenia gravis or syndrome Eaton Lambert);

- when the drug is administered in the immediate vicinity of the lungs, especially their apexes;

- in patients who have a high risk of developing an angle-closure glaucoma, including an anatomical narrowing of the anterior chamber angle.

Pregnancy and lactation:

Pregnancy

Controlled studies of botulinum toxin type A with the participation of pregnant women were not conducted. The results of studies in animals revealed the presence of reproductive toxicity. The potential risk to humans is not defined. Botox® should not be used in pregnancy time and in women of childbearing age who do not use reliable contraception, except in cases of extreme necessity.

Breastfeeding period

It is not known whether Botox® is excreted in breast milk. During breastfeeding, the use of Botox® can not be recommended.

Influence on reproductive function

Data on the effect of botulinum toxin type A on the reproductive function of women have not been obtained.The results of reproductive studies in males and female rats showed a decrease in fertility.

Dosing and Administration:

Detailed recommendations are given for each specific indication below.

The introduction of Botox® should be carried out only by physicians of the appropriate qualification who have received special training for this type of treatment and using the necessary equipment.

When starting therapy, the minimum recommended dose should be used. In subsequent injections, this dose may be gradually increased to the maximum recommended dose, if necessary. In the treatment of adult patients for one or more indications, the maximum cumulative dose, as a rule, should not exceed 360 units if the 3-month interval is observed. Universal optimal doses and the number of intramuscular injections are not determined for all indications. In such cases, the individual treatment regimen for a particular patient should be determined by the physician. Optimal doses should be selected by titration, but the recommended maximum dose of the drug should not be exceeded.

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 liner, which makes it possible to quickly remove the spilled product.

The dissolution of the Botox® preparation produces only 0.9% solution of sodium chloride for injection, carrying out the following actions: the vial with the drug is placed on the working surface (as indicated above), the protective plastic lid is removed from it, the upper part of the aluminum cap, together with the rubber stopper, is treated with alcohol . Then the rubber stopper is punctured with a sterile needle measuring 23-25 G and the necessary amount of solvent is introduced into the vial. If the solvent is not drawn into the vial under the action of a vacuum, the vial is destroyed.

Instruction for dissolution and subsequent dilution of the contents of the bottle with Botox preparation® for the treatment of urinary incontinence due to idiopathic hyperactivity of the bladder:

- To dissolve the contents of the bottle containing 200 units of Botox ®, add 8 ml of 0.9% solution of sodium chloride for injection, which does not contain preservative, into the vial and mix gently.

- Collect 4 ml of the resulting solution from the vial into a 10 ml syringe.

- For the final dilution, add 6 ml of a 0.9% solution of sodium chloride for injection containing no preservative into a 10 ml syringe and mix gently.

As a result, a 10 ml syringe will contain 100 units of diluted Botox® preparation. The reconstituted and diluted solution in the syringe must be used immediately. This drug is intended for single use only and any unused amount of reconstituted drug solution must be disposed of in accordance with local requirements for biological waste. It is also necessary to dispose of the unused 0.9% solution of sodium chloride.

Instruction for dissolution and subsequent dilution of the contents of the bottle with Botox preparation® for the treatment of incontinence urine, conditional neurogenic detrusor hyperactivity:

- To dissolve the contents of the bottle containing 200 units of Botox®, add 6 ml of 0.9% solution of sodium chloride for injections containing no preservative to the bottle and carefully mix.

- Collect from the bottle 2 ml of the solution obtained in each of 3 syringes with a capacity of 10 ml.

- For the final dilution, add 8 ml of a 0.9% solution of sodium chloride for injection containing no preservative into each of the 3 10 ml syringes and mix gently.

As a result, these 3 syringes, each with a capacity of 10 ml each, will contain a total of 200 units of diluted Botox® preparation.

The reconstituted and diluted solution in the syringes must be used immediately. Unused 0.9% sodium chloride solution must be disposed of.

Table 1 dissolves the preparation of Botox® for the treatment of blepharospasm and hemifacial spasm, cervical dystonia, focal spasticity in children with cerebral palsy, focal spasticity in patients who have had stroke, strabismus, chronic migraine and to correct wrinkles in the upper third of the face.

Final dose (ED in 0.1 ml)	The amount of solvent (0.9% solution of sodium chloride for injection) added to the vial (ml)
20	1
10	2
5	4
4	5
2,5	8
2,0	10
1,25	Not applicable

The solvent in the vial (see table above) should be added carefully: by gentle rotational movements of the vial, mixing the lyophilized 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 with no visible visible inclusions; slight opalescence can be observed.

The reconstituted solution of Botox® can be stored in the refrigerator at a temperature of 2-8 ° C for 24 hours in the original vial. The date and time of breeding should be recorded on the label.

After dilution the drug can be used within 24 hours provided it is properly stored. The unused solution must be disposed of (see section "Special instructions").

Units of action of botulinum toxin in preparations of different manufacturers are not interchangeable.

The recommended doses, expressed in terms of action for Botox®, are not interchangeable with the units of action of any other botulinum toxics produced by other manufacturers.

The introduction of Botox® should be carried out only by physicians of appropriate qualifications who have received special training for this type of treatment.

It is allowed to carry out injections on an outpatient basis.

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

Mortar Botox Solution^®injected with a needle measuring 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 sections of the circular muscle of the eye and into the lower eyelid into the lateral part of the circular muscle of the eye.

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 of patients with hemifacial spasm is carried out in the same way as with unilateral blepharospasm, if necessary, injections of the drug are also performed to other affected muscles. 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)

Mortar Botox Solution^® injected with a needle measuring 25-30G/ 0,50-0,30 mm. 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 who have not previously received therapy botulinum toxin, as a The initial effective dose should be the minimum effective 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 sides. When the head is tilted forward, the drug is injected into the sternocleidomastoid muscles from both sides.

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 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® is injected with a needle size 23-26G/ 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 flexor muscles of the forearm, when crossing 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 hand in patients who have suffered a stroke

Solution Botox® is injected with a 25G, 27G or 30G needle. 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 repeated injections 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.

To establish the localization of muscles involved in the pathological process, it is recommended to use EMG control, stimulation of nerve fibers or ultrasound.

The exact dosage should be determined on an individual basis in accordance with the size, amount and location of the muscles involved in the pathological process, the severity of spasticity, muscle weakness and the patient's response to the previous treatment.

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 area is 300 units, distributed on three muscles.

Table 3. Doses of Botox® on 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:

- When inserted 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 should not be performed until the clinical effect ofthe previous procedure, 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 antiplatelet drugs at least 3 days before the injection. Patients receiving anticoagulants should take 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 the diagnosis and treatment of bladder dysfunctions (eg, urologists or urogynecologists).

Idiopathic hyperactivity of the bladder

Before the introduction of the drug, it is possible to perform an intravascular instillation of a dilute solution of a local anesthetic with or without sedation.Before conducting an intravesical instillation of a local anesthetic, it is necessary to empty the bladder and wash it with a sterile 0.9% solution of sodium chloride.

The recommended dose of Botox® is 100 units in the form of 0.5 ml (5 U) injections at 20 detrusor points.

Divorced 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 0.9% sodium chloride solution 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 of 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 0.9% sodium chloride solution is administered so that the total dose is completely administered. after completion of injections, a 0.9% solution of sodium chloride is released, 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. should consider the possibility of repeated injections after reducing the effect of the previous injection (the average duration of the effect in clinical trials of the 3 phase was 166 days (about 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, in accordance with the approach adopted in the clinic, use an intravesical injection 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, catheterization of the bladder and its washing with a sterile 0.9% solution of sodium chloride is necessary before the next stages of injection of Botox®.

The recommended dose of Botox® is 200 units, with 1 ml (about 6.7 units) injected into 30 detrusor points. diluted Botox ® (200 U / 30 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 filled with a sufficient amount of 0.9% sodium chloride solution in order to adequately visualize injection points; however, overextension of the bladder should be avoided. Before the injection, the injection needle 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 0.9% sodium chloride solution is administered until the full dose is reached. after completion of injections, a 0.9% solution of sodium chloride is released, 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. should consider the possibility of repeated injections after reducing the effect of the previous injection (an average of 256-295 days), but not earlier than 3 months after previous injections into the bladder.

safety and efficacy of botox® in the treatment of urinary incontinence,due to neurogenic hyperactivity detrusor in children (under the age of 18 years) have not been demonstrated.

chronic migraine treatment

The diagnosis of chronic migraine should be made by a neurologist, and the administration of 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 12.7 mm to 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. In patients with extremely thick neck muscles, a 25 mm needle for injection in the neck region may be required. except for the muscles of the proud, into which one injection is made (along the midline), 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 the case of predominance of pains of any localization, additional administration of the drug on one or two sides in 1-3 certain muscle 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 units on each side

at. muscle of the proud: 5 units in the middle line

from. cervical-frontal muscle: to 10 units on each side

d. temporal muscle: 20 units on each side

e. occipital muscle: 15 units on each side

f. cervical paravertebral muscles: 10 units on each side

g. trapezius muscle: 15 units 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	total recommended dose (number of injection points^a)
cervical-frontal muscle^b	20 units (4 points for injection)
muscle, wrinkled 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)
temporalis muscle^b	from 40 units (8 points for injections) up to 50 units (10 points for injection)
trapezius muscle^b	from 30 units (6 points for injections) up to 50 units (10 points for injection)
cervical paravertebral muscles^b	20 units (4 points for injection)
range of total dose:	155-195 units (31-39 points for injection)

a) at 1 injection point / m injection - 0.1 ml - 5 units 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.

temporary correction of appearance of the wrinkles of the upper third of the face (interbrow, frontal wrinkles, peri-orbit crow's feet) in adults

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 injection into one point is 0.1 ml.

- brow wrinkles:

botox diluted with 0.9% solution of sodium chloride for injection (200 units / 5 ml) and injected with a sterile needle size 30g.

for 0.1 ml (4 units) is introduced into 5 points: the muscle, wrinkling eyebrow - 2 points on each side, 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 is injected, it is necessary to inject 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 persists for 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 greatest expression of wrinkles with a smile (6 points in total). It is usually recommended to enter 2-6 units at each point, to a depth of 2-3 mm, the total dose is 6-18 units on each 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 the frontal muscle injection. it is recommended to inject 2-6 units into the points located on each side along the frontal folds at intervals of 1-2 cm so that the total dose is 8 to 24 units.

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

general recommendations for all indications for use

If the first procedure is not effective, i.e. absence of significant clinical improvement, compared with the 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 neutralizing antibody toxin;

- 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 met during the repeated procedure: dose correction in view of the analysis of the reasons for the ineffectiveness of the previous procedure, em-control, the interval between procedures should be at least 3 months.

if there is no effect of the drug administration or a decrease in its severity after repeated injections, other methods of treatment should be recommended.

special patient groups

use in the elderly

in general, except for the use of the drug for the treatment of idiopathic hyperactivity of the bladder, proper studies on the regimen of the drug in elderly people have not been carried out. It is recommended to use the lowest effective dose at the most clinically justified interval between injections of the drug.Care should be taken when treating elderly patients with a history of medical history and concomitant medication.

use in children

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

dts -	2 years
Blepharospasm, hemifacial spasm -	12 years
cervical dystonia -	12 years
spasticity of the upper and lower limb after a stroke -	18 years
chronic migraine -	18 years
idiopathic hyperactivity of the bladder and detrusor neurogenic hyperactivity -	18 years

post-registration information about the possible spread of the toxin from the point of administration rarely concerned children with concomitant diseases, mainly with infantile cerebral palsy. in general, the dose used in these cases exceeded the recommended dose.

application in renal and hepatic insufficiency

No data.

Side effects:

According to clinical studies, the following incidence of adverse reactions should be expected, depending on the indications for use: blepharospasm - 35%, 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 2 clinical double-blind studies in patients with brow wrinkles who received a single dose of Botox®, the incidence of undesirable reactions without indicating the relationship with the study drug 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 tenderness, inflammation, paresthesia, hypoesthesia, skin tightening, puffiness, erythema, localized infection, bleeding and / or hematomas can be noted at the injection site. 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
General disorders and disorders at the site of administration:
Often	Irritation and swelling of the skin of the face
Infrequently	Fatigability
*Cervical dystonia (spasmodic 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 in 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 in patients who have had stroke
Disturbances from the skin and subcutaneous fabrics:
Often	Rash
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
Idiopathic hyperactivity of the bladder
Infectious and parasitic diseases:
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
Urinary incontinence due to neurogenic hyperactivity detrusor
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 spasms
kidney disorders 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 disturbance
trauma, intoxication and complications of manipulation:
often	autonomic dysreflexia *, falls
undesirable side reactions associated with the procedure
chronic migraine
disorders of the 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
disorders of 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
general disorders and disorders at the site of administration:
often	pain at the injection site
disorders of the gastrointestinal tract:
infrequently	dysphagia
interbroken wrinkles
infectious and parasitic diseaseI:
infrequently	infection
violations mentality:
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	puffiness (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	influenza-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 disorders at the site of administration:
often	hemorrhages and hematomas at the injection site *,
infrequently	pain at the injection site *, paresthesia
* reactions caused by injection
frontal wrinkles
infectious and parasitic diseases:
often	orvi
violations mentality:
often	feeling of tension
violations from the nervous system:
Often	ptosis of eyebrows, headache
violations from the side of the organ of vision:
Often	swelling of eyelids
disorders of 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 the 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,which were received in the postmarketing period, regardless of the indications for use, and which may not have been listed above.

disorders of the immune system:

anaphylactic shock, angioedema, serum sickness and urticaria.

metabolic and nutritional disorders:

anorexia.

disorders of the nervous system:

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

impairment of the organ of vision:

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

disorders of the hearing organ and labyrinthine disorders:

hearing loss, tinnitus and dizziness.

cardiac disorders:

arrhythmia, myocardial infarction.

disorders of the respiratory system, chest and mediastinal organs:

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

disorders of the gastrointestinal tract:

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

disorders of the skin and subcutaneous tissue:

alopecia, psoriasis dermatitis, erythema multiforme, hyperhidrosis, madarose, itching and rash.

disorders of the 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:

No case of systemic toxicity due to accidental injection of Botox^® was not observed. Excessive doses can cause local, distant or generalized neuromuscular paralysis (see section "Special instructions"). Symptoms of overdose, as a rule, do not appear immediately after the injection.

In case of accidental administration of an excessive dose or ingestion of Botox®, the patient should be under medical observation for several weeks to identify clinical manifestations and symptoms of muscle weakness local or remote from the injection site and which may include: ptosis, diplopia, dysphagia, speech disorder, general weakness or respiratory failure.It should be possible to provide immediate medical assistance, including in a hospital.

In the case of damage to the muscles of the pharynx and esophagus, aspiration can occur with the subsequent development of aspiration pneumonia.

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

In case of an overdose, anti-butulinic serum may be used. However, the introduction of serum is not able to stop the clinical effects of botulinum toxin that have already developed at the time of its introduction.

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.

Special instructions:

Botox® is used in specialized medical institutions, as well as outpatient in a procedural room with antishock therapy. 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 muscular weakness, distant spread of toxin and formation of neutralizing antibodies (see section "Overdose"). 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.

Older and weaker 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, capable of causing similar 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.

Care must be taken 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 fatal 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 higher doses can lead to an increase in the incidence of antibody formation. Potential antibody formation can be minimized by administering the 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, as well as small fluctuations in the values of drug activity 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 corneal exfoliation, a persistent epithelial defect, and ulceration of the cornea, especially in patients with disorders from the VII pair of cranial nerves. 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 methods can be used.

In the soft tissues of the eyelids, ecchymoses easily arise. This phenomenon can be minimized by applying light pressure to the injection site immediately after injection.

Due to the anticholinergic activity of botulinum toxin, caution should be exercised in treating patients at risk of developing an angle-closure glaucoma, including patients with anatomical narrowing of the angle of the eye.

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; was reported about a case of dysphagia lasting 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 risk of developing 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 explained by 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 be one of the reasons for limiting the intake of food and water, which leads to loss of body weight and dehydration.Patients with subclinical dysphagia may have an increased risk of dysphagia of a more severe degree after the injection of Botox®.

Focal spasticity, associated with infantile cerebral palsy

Reports on the post-marketing use of the drug indicate a possible in rare cases, the systemic spread of toxin, mainly in children with concomitant diseases, and, in the first place, cerebral palsy. As a rule, in these cases, doses higher than those recommended (see the "Side effect" section) were used.

In the framework of spontaneous reports of death, as its cause is called aspiration pneumonia, which develops in rare cases after treatment with botulinum toxin in children with severe infantile cerebral palsy, including the use of unapproved indications (in the neck area). Caution should be exercised when prescribing Botox® to children with severe neurologic disorders, dysphagia, lung disease, or recent aspiration pneumonia. Treatment of patients with an initially poor state of health should only be carried out,when the potential benefit for a particular patient outweighs the risks.

Focal spasticity the patients, suffered a stroke

The Botox ® preparation, intended for the treatment of focal spasticity, was studied only within the framework of conventional standard treatment regimens and is not intended as a substitute for these treatment methods. It is unlikely that Botox® will help improve joint movements with persistent 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 (for example, pain reduction), or to facilitating the care of a patient . 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 ankle spasticity in elderly patients with severe concomitant diseases, therapy should be started only when the benefit of the 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 physicians with experience in the rehabilitation of stroke patients.

Strabismus (strabismus)

Botox® 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 Botox® in the treatment of strabism in 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 Botox®, it is possible to penetrate the needle into the orbit with the development of retrobulbar hemorrhages that can worsen the blood supply to the retina,in this regard, during the procedure, it is recommended to have instruments for performing orbital decompression.

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

Appropriate precautions should be taken when performing cystoscopy.

In patients who have not undergone catheterization, the residual volume of urine after urination should be determined within 2 weeks after treatment and then, if necessary, for 12 weeks. Patients should be instructed to consult a doctor if they experience difficulty urinating, as they may require catheterization.

Idiopathic hyperactivity of the bladder

Men with idiopathic hyperactivity of the bladder and signs or symptoms of obstruction of the urinary tract should not prescribe Botox®.

Urinary incontinence, due to neurogenic hyperactivity detrozora

Perhaps the development of an autonomous disorder of reflexes due to the procedure.Emergency medical attention may be required.

After the introduction of detox Botox^®affects the efferent pathway of detrusor activity, blocking the release of acetylcholine. In addition, Botox® can inhibit afferent neurotransmitters and sensory pathways.

Chronic migraines

The safety and efficacy of Botox® as a prophylaxis for headache in patients with episodic migraine headaches (headaches for <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 drug use have not been studied.

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

Rare blinking associated with the administration of botulinum toxin to the circular muscle of the eye can lead to damage cornea, persistent defects epithelium and erosions of the cornea, 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,

- in ptosis, dermatochalasis, deep scars, in patients with dense skin or in the absence of significant smoothing of vertical facial wrinkles during mechanical stretching of the skin.

Important information

If several bottles with different units of activity of Botox® are used for one procedure, the amount of solvent recommended for reconstitution / dilution of the preparation should be carefully checked in order to obtain the required activity (indicated in 0.1 ml of diluted drug) for each vial. For preparations of Botox® 100 ED and Botox® 200 ED, different amounts of solvent are used. Each syringe must be appropriately labeled.

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

Studies to study the effect of the drug on the ability to drive vehicles and work with mechanisms have not been carried out. Botox® can cause 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, 200 units.

Packaging:

For 200 units in a vial. 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:

At a temperature of 2 to 8 ° C or minus 5 ° C and below.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002949

Date of registration:08.04.2015

Expiration Date:08.04.2020

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

Manufacturer: & nbsp