Relatox^® (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Microgen NPO, JSC (Russia)

ATC Code

M03AX01 (Botulinum toxin)

Active Substance

Botulinum toxin A – haemagglutinin complex

Dosage Forms

	Relatox®	Lyophilisate for preparation of solution for injections 50 U: vial 1 pc. in a set with solvent or without it
		Lyophilisate for preparation of solution for injections 100 U: vial 1 pc. in a set with solvent or without it

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of solution for injections in the form of a powder or compacted porous mass of white color or white with a yellowish tint; reconstituted solution is a clear colorless liquid.

Excipients: gelatin, maltose monohydrate.

50 U – glass vials (1) – polymer containers (1) – cardboard packs.
50 U – glass vials (1) – polymer jars (1) – cardboard packs.
50 U – glass vials (1) – polymer containers (1) in a set with solvent* (amp. 5 ml 1 pc.) – cardboard packs.
50 U – glass vials (1) – polymer jars (1) in a set with solvent* (amp. 5 ml 1 pc.) – cardboard packs.

*marketed in a set with solvent: sodium chloride, solvent for preparation of dosage forms for injections 0.9% (P N002009/01) 5 ml in an ampoule, placed in a blister pack.
Solvent composition per 1 ml (when the drug is supplied with solvent*) sodium chloride – 9 mg, water for injections – up to 1 ml.

Lyophilisate for preparation of solution for injections in the form of a powder or compacted porous mass of white color or white with a yellowish tint; reconstituted solution is a clear colorless liquid.

Excipients: gelatin, maltose monohydrate.

100 U – glass vials (1) – polymer containers (1) – cardboard packs.
100 U – glass vials (1) – polymer jars (1) – cardboard packs.
100 U – glass vials (1) – polymer containers (1) in a set with solvent* (amp. 5 ml 2 pcs.) – cardboard packs.
100 U – glass vials (1) – polymer jars (1) in a set with solvent* (amp. 5 ml 2 pcs.) – cardboard packs.

*marketed in a set with solvent: sodium chloride, solvent for preparation of dosage forms for injections 0.9% (P N002009/01) 5 ml in an ampoule, placed in a blister pack.
Solvent composition per 1 ml (when the drug is supplied with solvent*) sodium chloride – 9 mg, water for injections – up to 1 ml.

Clinical-Pharmacological Group

Muscle relaxant. Acetylcholine release inhibitor

Pharmacotherapeutic Group

Peripheral-acting muscle relaxant

Pharmacological Action

Muscle relaxant. It is a botulinum toxin isolated from Clostridium botulinum type A in a complex with haemagglutinin. The molecule of the active substance consists of a heavy chain (with a molecular weight of 100,000 daltons) and a light chain (with a molecular weight of 50,000 daltons) linked by a disulfide bridge. The heavy chain has a high affinity for binding to specific receptors located on the surface of target neurons. The light chain has Zn²⁺-dependent protease activity specific to the cytoplasmic regions of the synaptosome-associated protein with a molecular weight of 25,000 daltons (SNAP-25) 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; this process takes 30 minutes. The second stage is the internalization of the bound toxin into the cytosol via endocytosis. After internalization, the light chain acts as a Zn²⁺-dependent protease of the cytosol, selectively cleaving SNAP-25, which at the third stage leads to blockade of acetylcholine release from the presynaptic terminals of cholinergic neurons. The final effect of this process is persistent chemodenervation.

When administered intramuscularly, botulinum toxin type A develops 2 effects: direct inhibition of extrafusal muscle fibers by inhibiting alpha motor neurons at the level of the neuromuscular synapse and inhibition of muscle spindle activity by inhibiting the gamma motor neuron cholinergic synapse on the intrafusal fiber. A decrease in gamma activity leads to relaxation of the intrafusal fibers of the muscle spindle and reduces the activity of 1a afferents. This leads to a decrease in the activity of muscle stretch receptors, as well as the efferent activity of alpha and gamma motor neurons. The clinical manifestations are pronounced muscle relaxation at the injection site and a significant reduction in pain in them.

Along with the process of denervation in these muscles, the process of reinnervation occurs through the appearance of lateral processes of nerve terminals, which leads to the restoration of muscle contractions 4-6 months after the injection.

Pharmacokinetics

The botulinum toxin type A-haemagglutinin complex concentrates for some time at the site of its intramuscular injection before entering the systemic circulation. Subsequently, the active substance is very quickly metabolized with the formation of simpler molecular structures.

It is excreted in the form of metabolites mainly by the kidneys.

Indications

Adults and children over 2 years: symptomatic treatment of focal spasticity.

Adults: idiopathic overactive bladder, urinary incontinence due to neurogenic detrusor overactivity; blepharospasm, axillary hyperhidrosis, hemifacial spasm, paralytic strabismus, spasmodic torticollis; chronic migraine; temporary improvement in the appearance of hyperkinetic folds (facial wrinkles) of the face from moderate to severe in adults up to 65 years of age, when the severity of these wrinkles has a serious psychological impact on the patient.

ICD codes

Dosage Regimen

Determine the dose and injection points individually for each patient based on the size, severity, and location of the affected muscles.

Use the lowest recommended dose for the specific indication during the initial treatment course.

Administer intramuscularly or intradermally according to the approved indication.

For focal spasticity in adults and children over 2 years, tailor the total dose to the size, number, and location of muscles involved.

For hyperkinetic facial wrinkles, inject directly into the hyperfunctional facial muscles; avoid injection near the levator palpebrae superioris to prevent eyelid ptosis.

For axillary hyperhidrosis, administer intradermal injections into the affected area; a starch-iodine test can help identify the injection field.

For chronic migraine, administer a fixed total dose as a series of injections into specific head and neck muscles.

For overactive bladder, administer via cystoscopy as multiple intradetrusor injections; a local anesthetic with or without sedation may be used.

Use EMG guidance for more precise localization of the target muscles when necessary.

Do not exceed the recommended doses or frequency of administration.

Maintain the maximum clinically acceptable interval between injection sessions.

Reconstitute the lyophilisate only with the provided 0.9% sodium chloride solution; use the reconstituted solution immediately.

Adverse Reactions

The nature of adverse reactions depends on the dose and the area of administration of the drug.

From the immune system very rarely – immediate and delayed type allergic reactions.

From the nervous system very often – brow ptosis; often – headache, dizziness, discomfort in the head; infrequently – hypesthesia, paresthesia, asymmetry of the corners of the mouth; rarely – dizziness, drowsiness, impaired coordination; very rarely – difficulty closing the eyelids, lagophthalmos, paresis of facial muscles, paralysis of facial muscles, impaired articulation, numbness of the lips; possibly – brachial plexus plexopathy, dysphonia, dysarthria, facial paresis, muscle weakness, myasthenia gravis, peripheral neuropathy, convulsions, fainting and facial paralysis. The listed reactions may occur depending on the area of administration.

Mental disorders often – feeling of tension, insomnia; rarely – depression.

From the organ of vision very often – eyelid edema; rarely – ophthalmoplegic syndrome; very rarely – accommodation disorder, dry eyes, photophobia and increased lacrimation.

From the digestive system often – dysphagia; rarely – nausea; possibly – abdominal pain, diarrhea, constipation, dry mouth, vomiting.

From the musculoskeletal system and connective tissue often – muscle weakness; infrequently – arthralgia, limb pain, neck pain; very rarely – drooping of the interbrow area, lateral parts of the eyebrows, ptosis.

From the skin and subcutaneous tissue often – compensatory sweating; infrequently – skin itching; possibly – alopecia, psoriasiform dermatitis, erythema multiforme, hyperhidrosis, madarosis, itching and rash.

From metabolism possibly – anorexia.

From the respiratory system possibly – aspiration pneumonia (in some cases with fatal outcome), dyspnea, bronchospasm, respiratory depression and respiratory failure.

General disorders often – flu-like syndrome; rarely – short-term increase in body temperature to subfebrile values (up to 37.5°C (99.5°F)).

Local reactions: often – pain at the injection site, irritation and swelling, induration, erythema, skin tightness, hyperemia at the injection site; infrequently – microhematomas, ecchymoses, punctate keratitis; very rarely – diffuse hyperemia.

Contraindications

Hypersensitivity to botulinum toxin type A; Myasthenia gravis, myasthenic and myasthenic-like syndromes (including Lambert-Eaton syndrome), inflammatory process at the site of the intended injection(s); elevated body temperature; acute phase of infectious and non-infectious diseases; pregnancy, breastfeeding; age under 2 years for the indication “Spasticity of the upper and lower limbs in children 2-17 years with cerebral palsy”, age under 7 years for the indication “Spasticity of the lower limbs with predominant involvement of the quadriceps femoris muscle” (efficacy and safety not established); age under 18 years for other indications (efficacy and safety not established).

Depending on the injection area: pronounced gravitational ptosis of facial tissues, pronounced “hernias” in the area of the upper and lower eyelids, 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 bladder catheterization after treatment if necessary.

With caution

Elderly patients with a burdened history and concomitant drug therapy; history of dysphagia and aspiration; children with severe neurological disorders, dysphagia, lung disease or who have recently had aspiration pneumonia; patients with a burdened history; pronounced weakness or atrophy in the muscle into which this agent is planned to be injected; patients with peripheral motor neuropathy (e.g., in amyotrophic lateral sclerosis or motor neuropathy); subclinical or clinical signs of impaired neuromuscular transmission (e.g., in myasthenia gravis or Lambert-Eaton syndrome); when injected in close proximity to the lungs, especially their apices; in patients at high risk of developing angle-closure glaucoma, including anatomical narrowing of the anterior chamber angle.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Pediatric Use

Used in children over 2 years of age according to indications.

Geriatric Use

Use with caution in elderly patients with a burdened history and concomitant drug therapy.

Special Precautions

Injections of botulinum toxin type A should be performed by a highly qualified physician with special training and permission from the manufacturing company.

Complications after injection are extremely rare and can occur when the needle injures vital structures (nerves, blood vessels, trachea) in case of unqualified performance of the procedure. Complications in the form of anaphylaxis have not been described, nevertheless, when performing an injection, it is necessary to have means for emergency relief of anaphylactic reactions.

The risk-benefit ratio for a particular patient should be assessed before starting treatment with this agent.

It is not recommended to exceed the recommended doses and frequency of administration of this agent due to the potential risk of overdose, excessive muscle weakness, distant spread of the toxin and the formation of neutralizing antibodies. During the initial course, treatment should be started with the lowest recommended dose for a specific indication for use.

Doctors and patients should be aware that side effects may occur despite good tolerance of previous injections. Caution and attentiveness must be exercised during each procedure.

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

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

Dysphagia has been reported following injections into areas other than the neck muscles.

Patients with subclinical or clinical signs of impaired neuromuscular transmission, for example, in myasthenia gravis or Lambert-Eaton syndrome, patients with peripheral motor neuropathic diseases (e.g., amyotrophic lateral sclerosis or motor neuropathy), as well as patients with concomitant neurological pathology may have increased sensitivity to this group of drugs even in 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 respiratory disorders. In such cases, this agent should be used under the supervision of a specialist and only when the benefit of treatment outweighs the risk.

Patients and caregivers should be advised to seek immediate medical attention if swallowing, speech, or breathing problems occur.

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

Before injection, it is necessary to clarify the anatomy of the relevant areas and any changes in anatomy as a result of previous surgeries; injections into easily damaged anatomical structures should be avoided.

Pneumothorax associated with the injection procedure was observed after administration of this agent into the chest area. Caution should be exercised when injecting into the area of the lungs (especially their apices) or other easily vulnerable anatomical structures.

Serious adverse reactions, including fatal ones, have been observed in patients who received this agent for unapproved indications – injections directly into the salivary glands, oro-linguo-pharyngeal region, esophagus and stomach. Some patients had pre-existing dysphagia or severe weakness.

Caution should be exercised in case of weakness or atrophy of the muscles into which the drug is planned to be injected.

Rare adverse reactions from the cardiovascular system have been described, including arrhythmias and myocardial infarction, in some cases with fatal outcome. Some of these patients initially had risk factors, including cardiovascular diseases.

The formation of neutralizing antibodies to botulinum toxin may reduce its effectiveness.

According to clinical studies, administration of this agent more frequently and in higher doses may lead to an increase in the number of cases 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 upon repeated use of botulinum toxins may be the result of differences in the dilution technique of the drug used, intervals between injections and injected muscles, as well as small fluctuations in the values of the drug’s activity determined by the biological method.

Effect on ability to drive vehicles and mechanisms

Since this agent can cause asthenia, muscle weakness, dizziness and visual disorders, it may pose a danger when driving vehicles and mechanisms.

Drug Interactions

The effect of botulinum toxin type A is enhanced with simultaneous use of antibiotics of the aminoglycoside group, erythromycin, tetracycline, lincomycin, polymyxins, agents that reduce neuromuscular transmission (including curare-like muscle relaxants).

The effect of administering various serotypes of botulinum neurotoxin simultaneously or at intervals of several months is unknown. Neuromuscular weakness may be exacerbated by the administration of another botulinum toxin before the effects of the previously administered botulinum toxin have worn off.

Storage Conditions

Store at 2°C (36°F) to 8°C (46°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.