Botox^® (Lyophilisate) Instructions for Use

ATC Code

M03AX01 (Botulinum toxin)

Active Substance

Botulinum toxin A – haemagglutinin complex

Clinical-Pharmacological Group

Muscle relaxant. Acetylcholine release inhibitor

Pharmacotherapeutic Group

Peripheral-acting muscle relaxant

Pharmacological Action

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

The heavy chain has a high affinity for specific receptors located on the surface of target neurons. The light chain is characterized by Zn²⁺-dependent protease activity. It is specific for cytoplasmic sites of synaptosome-associated protein with a molecular weight of 25,000 Daltons (SNAP-25), which is involved in exocytosis processes.

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

The second stage is the 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 at the third stage leads to blockade of acetylcholine release from presynaptic terminals of cholinergic neurons.

The final result is prolonged chemodenervation.

Clinically, a pronounced relaxation of the muscles into which the injection was made is noted. In denervated muscles, a 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, while the primary neuromuscular transmission is activated.

Pharmacokinetics

The pharmacological effect of Botox^® develops at the injection site. It has been proven that presynaptic uptake and retrograde axonal transport of the drug from the site of administration is insignificant.

At therapeutic doses, Botox^® does not penetrate the blood-brain barrier.

Antibodies to botulinum toxin type A may form after repeated injections in 1-5% of cases. Antibody production is facilitated by the administration of large doses of the drug, as well as repeated administration in small doses at short intervals (less than 14 days). If antibodies to botulinum toxin type A are formed, the effect of its further use may be reduced.

Indications

• Blepharospasm;
• Hemifacial spasm;
• Cervical dystonia (spasmodic torticollis);
• Focal spasticity of the wrist and hand in patients who have had a stroke;
• Paralytic strabismus;
• Local muscle spasm in cerebral palsy in children aged 2 years and older;
• Correction of facial wrinkles.

ICD codes

Dosage Regimen

Lyophilisate

Rules for preparation and storage of the injection solution

The preparation of the injection solution and the drawing of the solution into the syringe should be carried out on a work surface covered with a paper towel on a polyethylene backing, which makes it possible to quickly remove spilled drug. Botox^® should be reconstituted only with 0.9% sodium chloride injection solution. The injection solution is prepared by piercing the stopper with a sterile needle and injecting the required amount of solvent into the vial. If no vacuum-induced suction of the solvent into the vial is observed, the vial should be destroyed. Before piercing, the central part of the rubber stopper should be treated with alcohol. A sterile needle size 23-25 G should be used to pierce the stopper.

Table 1. Concentrations of the drug obtained upon dilution

The solvent should be carefully introduced into the vial (see table above), mixing the powder with the solvent by gently rotating the vial. Vigorous shaking of the vial and foam formation can lead to denaturation of the drug. The finished solution is a clear, colorless or slightly yellowish liquid without foreign inclusions; slight opalescence may be observed.

Reconstituted Botox^® can be stored in a refrigerator at a temperature of 2°-8°C (17.6°F) for 24 hours. The finished solution is administered using an insulin syringe with a non-removable needle. After reconstitution, the product must be used within 24 hours if stored correctly. Unused solution must be disposed of.

The units of activity of botulinum toxin in different drugs are not interchangeable. The recommended doses, expressed in units of activity for Botox^®, differ from those for other botulinum toxin drugs.

No adequate studies on the dosing of the drug in elderly patients have been conducted. The same doses as for adults are used, but it is recommended to use the minimum effective dose.

Botox^® injections should be performed by a qualified physician who has completed a special training course and has received permission from the manufacturing company. Injections are allowed to be performed on an outpatient basis in a procedure room.

The dose of Botox^® and the injection points are determined individually for each patient according to the severity and location of muscle hyperactivity. In some cases, electromyography (EMG) is used to more accurately determine the localization of the pathological process.

Treatment of blepharospasm and hemifacial spasm

The Botox^® solution is administered with a 27-30G/0.4-0.3 mm needle. For the treatment of bilateral blepharospasm, the drug is injected superficially into the upper eyelid in the medial and lateral parts of the orbicularis oculi muscle and into the lower eyelid, in the lateral part of the orbicularis oculi muscle. Other injection points: the pretarsal part of the orbicularis oculi muscle, the eyebrow area and the forehead area (if the spasm occurring there affects vision). To prevent the occurrence of ptosis as a complication of the procedure, it is necessary to avoid injecting the drug near the levator palpebrae superioris muscle. To prevent diplopia as a complication of the procedure, it is necessary to avoid injecting the drug into the medial part of the lower eyelid.

The initial dose is 1.25-2.5 Units of the drug at each injection point. The total initial dose should not exceed 25 Units on each side. The effect of the drug appears within the first three days after the procedure and reaches its maximum severity 1-2 weeks after it. The duration of the drug’s effect reaches 3 months, after which the procedure can be repeated.

If the effect of the initial treatment is considered insufficient, the dose can be increased by no more than twice upon repeated administration of the drug. However, the administration of more than 5 Units of the drug at each injection point is not accompanied by a significant improvement in the clinical effect.

When treating blepharospasm, the total dose of Botox^® over 12 weeks should not exceed 100 Units.

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

The Botox^® solution is administered with a 25-30G/0.5-0.3 mm needle.

In the treatment of spasmodic torticollis, the drug solution is injected into the most tense neck muscles at a dose of no more than 50 Units per point.

No more than 100 Units of the drug should be injected into the sternocleidomastoid muscle.

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

When treating spasmodic torticollis, the drug is injected into the sternocleidomastoid muscle on the side opposite to the rotation, and into the splenius muscle on the side of the rotation.

In cases accompanied by shoulder elevation, the drug should be additionally injected into the trapezius muscle and the levator scapulae muscle on the affected side.

When the head is tilted backward, the drug is injected into the splenius and trapezius muscles on both sides.

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

During subsequent administrations, the doses of the drug may be adjusted depending on the previous clinical result and the observed side effects.

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

In complex forms of torticollis or weak treatment effect, EMG of the neck muscles should be performed to more accurately determine the location of the tense 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 local muscle spasm in cerebral palsy

The Botox^® solution is administered with a 23-26G/0.6-0.45 mm needle.

When treating spasticity and equinovarus foot deformity in children with cerebral palsy, the drug solution is injected into 2 points of each head of the gastrocnemius muscle (medial and lateral). In hemiplegia, the drug can be injected into the forearm flexor muscles; with scissoring of the thighs, additionally into the thigh adductor muscles. The total dose of the drug per procedure is determined at the rate of 4-6 Units/kg of body weight and is distributed evenly among all muscles into which injections are made. The total dose should not exceed 200 Units.

Clinical improvement appears within the first 7-14 days after the injection. The drug is re-administered when the severity of the clinical effect is reduced 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 at least a 6-month interval between procedures. Orthopedic correction, muscle stretching and physiotherapy can contribute to improving the clinical effect of Botox^® injections.

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

The Botox^® solution is administered with a 25G, 27G or 30G needle into superficial muscles and with a longer needle into deeply located muscles.

EMG control or nerve fiber stimulation methods can be used to determine the location of the muscles involved in the pathological process. Injecting Botox^® into several points can contribute to its more uniform distribution in the muscle, which is especially justified when injecting the drug into large muscles.

The selection 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 previous treatment.

Table 2. Dosages of Botox^® when injected into hand muscles

Positive changes in muscle tone were noted within 2 weeks after the injection, the maximum clinical effect was observed, as a rule, no later than 4-6 weeks.

In cases where the attending physician considers it necessary to re-administer the drug, this can be done after the effect of the drug on muscle tone has decreased. The interval between injections should be at least 12 weeks. Changes in the degree and nature of muscle spasticity before re-administration of the drug may require adjustment of the Botox^® dose and determination of new injection points. The minimum effective dose should be used.

In patients with focal spasticity, Botox^® is used in combination with the standard treatment regimen. The drug is not intended for use as a replacement for these treatments.

Treatment of paralytic strabismus

The Botox^® solution is administered with a 27G needle.

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

For small deviations of the eyeball, minimal doses of the drug are used; when treating more pronounced deviation, the dose is increased.

Initial doses

• When injected into muscles that perform vertical movements of the eyeball (superior and inferior rectus muscles) and for horizontal strabismus less than 20 prism diopters: from 1.25 to 2.5 Units for any muscle;
• For horizontal strabismus from 20 to 50 prism diopters: from 2.5 to 5 Units for any muscle;
• For abducens nerve (VI nerve) palsy persisting for 1 month or more: from 1.25 to 2.5 Units into 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 over the same time periods. Rare cases of the effect lasting more than 6 months have been described.

Approximately half of the patients require re-administration of the drug after the first injection due to an inadequate clinical response of the muscles to the first procedure or due to mechanical factors: significant deviation or limitation of eyeball mobility, as well as if it is impossible to stabilize the position of the eyes through the motor component of binocular fusion. It is recommended to examine patients 7-14 days after each injection to assess the effect of the procedure. In patients with incomplete relaxation of the target muscle, the dose of the drug can be doubled during subsequent administration.

Re-administration of the drug should be carried out only after the clinical effect of the previous procedure has decreased, which is expressed in a persistent restoration of the function of the injected and nearby muscles.

The maximum recommended dose for a single injection into any muscle when treating strabismus is 25 Units.

Correction of facial wrinkles

It is not recommended to use Botox^® for the correction of vertical glabellar lines in patients under 18 and over 65 years of age.

The Botox^® solution (100 Units/2.5 ml) is administered with a 30G needle.

4 Units are injected into each of 5 injection points: into the musculus corrugator – 2 points on each side, into the musculus procerus – 1 point. The total dose is 20 Units.

Before the injection, it is necessary to firmly press the thumb and forefinger to the skin below the orbital rim to prevent the spread of the drug below this level. When performing the injection, the needle should be directed upward and medially. To reduce the risk of ptosis, it is necessary to avoid injecting the drug near the levator palpebrae superioris muscle, especially in patients with a well-defined depressor supercilii muscle. When injecting the drug into the musculus corrugator, the injection should be performed in the central part of the muscle, stepping back at least 1 cm above the brow arch.

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

The interval between procedures should be at least 3 months. If there is no effect from the drug administration or a decrease in its severity after repeated injections, other treatment methods should be recommended.

For all indications for use

If the first procedure is ineffective, i.e., there is no significant clinical improvement compared to the initial state 1 month after drug administration, it is necessary

• Clinical confirmation of the effect of the toxin on the injected muscle(s), 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;
• Re-evaluation of the advisability of treatment with botulinum toxin type A;
• In the absence of any adverse effects associated with the first administration of the drug, the following conditions must be met during the repeated procedure: dose correction taking into account the analysis of the reasons for the ineffectiveness of the previous procedure; EMG control; the interval between procedures should be at least 3 months.

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

Adverse Reactions

As a rule, adverse reactions occur within the first days after the injection and are transient. In rare cases, the duration of adverse reactions may be several months or longer.

Local muscle weakness reflects the expected pharmacological action of botulinum toxin on the muscle. However, high doses may cause weakness in muscles beyond those directly localized at the injection site.

Dysphagia has been reported following injections into sites other than the neck muscles. If swallowing, speech, or breathing disorders occur, the patient should immediately consult a doctor.

As with any injection, local tenderness and/or bruising may be noted at the injection site. Fever and the occurrence of flu-like syndrome have been described.

Adverse reactions (frequency for each indication)

Blepharospasm/hemifacial spasm

Cervical dystonia (spasmodic torticollis)

Local muscle spasm in infantile cerebral palsy

Focal spasticity of the wrist and hand in patients who have had a stroke

Paralytic strabismus

Correction of facial wrinkles

Additional information

Side effects associated with the spread of the toxin from the injection site and its remote action (severe muscle weakness, dysphagia, aspiration/aspiration pneumonia, in some cases with fatal outcome) are very rare.

Patients receiving the drug in therapeutic doses may experience severe muscle weakness. The high-risk group for these side effects includes patients with concomitant neurological disorders, including difficulty swallowing. Botulinum toxin preparations in these patients should be used under the supervision of a specialist and only when the treatment effect outweighs the possible risks. Treatment of patients with a history of dysphagia or aspiration should be carried out with particular caution.

Rare adverse reactions from the cardiovascular system, including arrhythmias and myocardial infarction, have been described. Some of these patients initially had risk factors, including cardiovascular disease.

Severe immediate and delayed hypersensitivity reactions, including anaphylactic reactions, serum sickness, urticaria, soft tissue edema, and dyspnea, are rare. The occurrence of such reactions has been described both during monotherapy with Botox^® and when used in combination with other agents causing similar reactions.

Very rare cases of angle-closure glaucoma after botulinum toxin injections for the treatment of blepharospasm have been described.

Epileptic seizures have been described in patients predisposed to these conditions. The exact relationship between these phenomena and the administration of the toxin has not been established. Seizures were noted predominantly among patients with cerebral palsy.

Injection-related anxiety can lead to vasovagal reactions.

The following other side effects have been described during the time the drug has been on the market: dysarthria, abdominal pain, decreased visual acuity, fever, focal facial paralysis, hypoesthesia, malaise, myalgia, pruritus, diarrhea, anorexia, hypoacusis, tinnitus, radiculopathy, syncope, myasthenia, erythema multiforme, psoriasiform dermatitis, vomiting, brachial plexus plexopathy.

Contraindications

General

• Proven hypersensitivity to any component of the drug;
• Inflammatory process at the intended injection site(s);
• Acute phase of infectious diseases;
• Pregnancy;
• Lactation.

For blepharospasm and correction of facial muscles

• Significant gravitational ptosis of facial tissues;
• Significant “hernias” in the area of the upper and lower eyelids.

Use in Pregnancy and Lactation

Botox^® is contraindicated for use during pregnancy and lactation.

Special Precautions

Botox^® is dispensed, stored, and used in specialized medical institutions. The drug is stored in a separate closed labeled box in a refrigerator.

Immediately after the injections, the remaining drug solution in the vial or syringe must be inactivated with a sodium hypochlorite solution (0.5%). Alternatively, the contents of unused vials should be reconstituted with a small amount of water and then autoclaved. All auxiliary materials that have been in contact with the drug must be disposed of in accordance with the rules for the disposal of biological waste. Spilled drug solution should be wiped with an absorbent wipe soaked in a 1% sodium hypochlorite solution.

In cases of prior surgical intervention in the facial area, the time interval between the surgical operation and the administration of Botox^® should be at least 3 months.

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

Botox^® should be used with caution in cases of significant weakness or atrophy in the muscle targeted by the drug. Botox^® must be used with caution when treating patients with peripheral motor neuropathic diseases (e.g., amyotrophic lateral sclerosis or motor neuropathy).

Botox^® should be used with extreme caution and under constant supervision in patients with subclinical or clinical signs of impaired neuromuscular transmission, for example in myasthenia gravis or Lambert-Eaton syndrome; this group of patients has increased sensitivity to this drug, which can lead to the development of severe muscle weakness. Patients with neuromuscular diseases may be at risk of developing clinically significant systemic effects, including severe dysphagia and respiratory disorders, when usual doses of Botox^® are administered; treatment of such patients should be carried out with caution.

Blepharospasm

Infrequent blinking associated with the injection of botulinum toxin into the orbicularis oculi muscle can lead to the occurrence of pathological changes in the cornea. The sensitivity of the cornea of previously operated eyes should be carefully studied, injection into the area of the lower eyelid should be avoided to prevent the development of ectropion, and any defects in the epithelial cover should be actively treated. Protective drops, ointments, therapeutic soft contact lenses, eye patching or other methods may be used for this purpose.

Ecchymoses easily occur in the soft tissues of the eyelids. To reduce their frequency, light pressure should be applied to the injection site immediately after drug administration.

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

Cervical dystonia (spasmodic torticollis)

Patients with spasmodic torticollis should be informed about the possibility of developing dysphagia of varying severity: from mild to severe. Dysphagia can persist for 2 to 3 weeks after drug administration, with one case of dysphagia lasting up to 5 months reported. Dysphagia can be a potential cause of aspiration, dyspnea, requiring intubation. In rare cases, aspiration pneumonia with a fatal outcome may develop.

The frequency of dysphagia can be reduced by limiting the dose of the drug injected into the sternocleidomastoid muscle to 100 IU or less. It has been shown that the high-risk group for developing dysphagia includes patients with reduced neck muscle mass, as well as patients who receive the drug injected into both sternocleidomastoid muscles. The development of dysphagia is associated with the penetration of the toxin into the muscular layer of the esophageal wall. Injection of the drug into the levator scapulae muscle may be associated with an increased risk of upper respiratory tract infections and dysphagia.

Dysphagia can contribute to limited intake of food and water, leading to weight loss and dehydration. The high-risk group for developing dysphagia after Botox^® administration includes patients with subclinical dysphagia.

Focal spasticity associated with infantile cerebral palsy, and spasticity in patients who have had a stroke

Botox^® apparently does not increase the range of motion in joints with persistent contracture.

Paralytic strabismus

Botox^® is not effective in chronic paralytic strabismus. In combination with surgical treatment, it only reduces the contracture of the antagonist muscles. The effectiveness of Botox^® in the treatment of strabismus over 50 prism diopters, restrictive strabismus, Duane’s syndrome with lateral rectus muscle weakness, secondary strabismus caused by excessive surgical resection of the antagonist muscle, is doubtful. To increase the effectiveness of treatment, repeated administration of the drug over time can be resorted to.

During the administration of Botox^®, the needle may penetrate the orbit with the development of retrobulbar hemorrhages, which can impair retinal blood supply; therefore, it is recommended to have instruments for orbital decompression available during the procedure.

The state of paralysis of one or more extraocular muscles can lead to disorientation in space, double vision. The severity of symptoms can be reduced by covering the affected eye.

Correction of facial wrinkles

Infrequent blinking associated with the injection of Botox^® into the orbicularis oculi muscle can create conditions for frequent contact of the cornea with environmental factors, the occurrence of epithelial defects and corneal erosions, especially in patients with damage to the VII cranial nerve.

Botox^® must be used with caution in the following cases:

• In cases of significant facial asymmetry;
• In the presence of ptosis, dermatochalasis, deep scars;
• In patients with thick skin or in the absence of significant smoothing of vertical glabellar frown lines upon mechanical stretching of the skin.

Effect on the ability to drive vehicles and operate machinery

Botox^® can lead to asthenia, muscle weakness, dizziness, and visual disturbances. If such symptoms develop, it may create a hazard when driving a car or operating machinery.

Overdose

Symptoms of overdose appear some time after the injection. In case of accidental administration or ingestion of the drug, the patient should be under medical supervision for several days to detect clinical manifestations and symptoms of general weakness or muscle paralysis.

Patients with symptoms of botulinum toxin A poisoning (general weakness, ptosis, diplopia, difficulty swallowing, speech disorder, or respiratory muscle paresis) should be hospitalized. A case of severe generalized muscle paralysis due to drug overdose has been described.

In case of paralysis of the respiratory muscles, intubation and transfer to artificial ventilation are required until the patient’s condition improves.

Drug Interactions

When used concomitantly, the effect of Botox^® is potentiated by aminoglycoside antibiotics, erythromycin, tetracycline, polymyxins, agents that reduce neuromuscular transmission (especially curare-like muscle relaxants).

Drug interaction studies have not been conducted. Clinically significant cases of drug interaction have not been described.

Storage Conditions

The drug is transported and stored at a temperature from 2°C (35.6°F) to 8°C (46.4°F) or in a freezer at a temperature of -5°C (23°F) and below in closed, sealed, and labeled containers in places inaccessible to children.

Shelf Life

The shelf life is 2 years. The drug must not be used after the expiration date printed on the packaging.

Dispensing Status

Botox^® is dispensed to specialized medical institutions.

Important Safety Information

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