Xeomin (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Merz Pharma, GmbH & Co. KGaA (Germany)

Contact Information

Merz Pharma LLC (Russia)

ATC Code

M03AX01 (Botulinum toxin)

Active Substance

Botulinum toxin A

Botulinum toxin A (Ph.Eur. European Pharmacopoeia)

Dosage Forms

	Xeomin	Lyophilisate for solution for injection 50 U: vial 1, 2, 3 or 6 pcs.
		Lyophilisate for solution for injection 100 U: vial 1, 2, 3 or 6 pcs.

Dosage Form, Packaging, and Composition

Lyophilisate for solution for injection from white to almost white.

Excipients: sucrose – 4.7 mg, human serum albumin – 1 mg.

Vials (1) – plastic trays (1) – cardboard packs with first opening control.
Vials (1) – plastic trays (1) – cardboard packs with first opening control (2) – cardboard packs.
Vials (1) – plastic trays (1) – cardboard packs with first opening control (3) – cardboard packs.
Vials (1) – plastic trays (1) – cardboard packs with first opening control (6) – cardboard packs.

Lyophilisate for solution for injection from white to almost white.

Excipients: sucrose – 4.7 mg, human serum albumin – 1 mg.

Vials (1) – plastic trays (1) – cardboard packs with first opening control.
Vials (1) – plastic trays (1) – cardboard packs with first opening control (2) – cardboard packs.
Vials (1) – plastic trays (1) – cardboard packs with first opening control (3) – cardboard packs.
Vials (1) – plastic trays (1) – cardboard packs with first opening control (6) – cardboard packs.

* botulinum toxin produced by the bacterium Clostridium botulinum type A strain, free from complexing proteins.

Clinical-Pharmacological Group

Muscle relaxant. Acetylcholine release inhibitor

Pharmacotherapeutic Group

Peripheral muscle relaxant

Pharmacological Action

Xeomin acts selectively on peripheral cholinergic nerve endings, inhibiting the release of acetylcholine. The introduction into cholinergic nerve endings occurs in 3 stages: binding of the molecule to the external components of the membrane, internalization of the toxin by endocytosis, and translocation of the endopeptidase domain of the toxin from the endosome into the cytosol. In the cytosol, the endopeptidase domain of the toxin molecule selectively cleaves SNAP-25, an important protein component of the mechanism controlling the membrane movement of exovesicles, thus stopping the release of acetylcholine. The final effect is relaxation of the injected muscle.

The effect of the drug begins within 4-7 days after injection. The effect of each procedure generally lasts 3-4 months, although it may last significantly longer or shorter.

Pharmacokinetics

Data on the pharmacokinetics of Xeomin are not provided.

Indications

• Adults:
  • Blepharospasm and hemifacial spasm;
  • Idiopathic cervical dystonia (spasmodic torticollis) predominantly of the rotational form;
  • Spasticity of the upper limb and spasticity of the lower limb with ankle joint involvement;
  • Chronic sialorrhea;
  • Hyperkinetic facial folds (facial wrinkles).

• Children aged 2 to 18 years:
  • Spasticity of the upper and lower limbs;
  • Chronic sialorrhea in children aged 2 to 18 years.

ICD codes

Dosage Regimen

For intramuscular and intraglandular administration only. Do not administer into the vascular bed.

Treatment with Xeomin should be carried out only by physicians of appropriate qualification, with experience in this type of treatment using the tools required for the procedure.

Doses and injection sites are determined individually for each patient.

Reconstitution of the drug

The drug is reconstituted with sodium chloride injection solution.

When diluting the drug, it is forbidden to open the vial by removing the stopper.

The protective plastic cap is removed from the vial. Immediately before reconstitution of the vial contents, the central part of the stopper is treated with alcohol.

The solution for injection is prepared by vertically piercing the rubber stopper with a sterile needle and carefully, to avoid foam formation, injecting sodium chloride solution isotonic 9 mg/ml (0.9%) for injection into the vial. Needles with a short bevel numbers 20-27 G are recommended for reconstitution. Disconnect the syringe from the vial and mix the lyophilisate with the solvent until completely dissolved by gently rotating and inverting the vial. Vigorously shaking the vial is prohibited. Dissolution time is not more than 10 sec. After dissolution, a clear colorless solution should be formed.

The drug should not be used if the resulting solution after dissolution is opaque or contains visible flakes and particles.

The drug is dissolved in the necessary volume of solvent according to the table.

Intervals between injections, as a rule, should not be less than 16 weeks and should be determined based on the individual needs of the patient.

Hyperkinetic facial folds (facial wrinkles)

The use of the drug for the treatment of facial wrinkles in persons under 18 years of age and over 65 years of age is not recommended due to the lack of clinical experience.

Vertical wrinkles between the eyebrows (glabellar lines): the recommended injection volume of 0.1 ml (4 U) is administered into each of the 5 sites: 2 injections into the m. corrugator on both sides and 1 injection into the m. procerus, which corresponds to a total dose of 20 U. In some cases, it is possible to increase the total dose to 30 U.

Before and during the injection, pressure should be applied with the thumb and forefinger below the upper edge of the orbit to prevent diffusion of the solution into this area. During the injection, the needle should be directed upward and medially. To reduce the risk of eyelid ptosis, injections near the levator palpebrae superioris muscle and at the attachment site of the orbicularis oculi muscle should be avoided. Injections into the m. corrugator should be performed in the medial part of the muscle and in the central part of the muscle belly, at least 1 cm above the upper edge of the orbit.

To reduce the risk of brow ptosis, injections close to the orbital rim that cause paralysis of the lower muscle tissues should be avoided.

Reduction in the severity of vertical wrinkles between the eyebrows (glabellar lines) usually develops within 2-3 days, the maximum effect is observed by day 30 and usually lasts up to 4 months after injection. Intervals between injections should not be less than 3 months. If the treatment result is unsatisfactory, alternative treatment methods are used.

To prevent drooping of the corners of the mouth, injections too close to the m. zygomaticus should be avoided.

Special handling and disposal precautions

Immediately after the injection, all used vials, the remaining solution in the vial and the syringe should be autoclaved (temperature 120°±2°C (35.6°F), steam pressure 0.11 MPa (or 1.1 atm.), holding time 45±2 min.) or inactivated with one of the following solutions: 70% ethanol, 50% isopropanol, sodium hydroxide solution (0.1N NaOH) or sodium hypochlorite solution (at least 0.1% NaOCl) (for at least 18 h.).

Spilled drug should be wiped with an absorbent wipe soaked in sodium hydroxide solution.

Used vials, syringes and auxiliary materials should not be emptied of the remaining solution. After inactivation, they are disposed of in accordance with established requirements.

In case of contact of the drug with the skin, the solution should be washed off with plenty of water.

In case of contact of the drug with the eyes, the eyes should be thoroughly rinsed with water or an eye wash solution.

In case of contact of the drug with a wound, cut or scratch, it should be thoroughly washed with water.

Adverse Reactions

Adverse reactions (ARs) are usually observed in the first week after drug use and are temporary. ARs may be associated with the active substance and/or with the administration procedure. The expected pharmacological effect of botulinum toxin use is localized muscle weakness.

ARs are classified by frequency of occurrence: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000), frequency unknown (cannot be estimated from available data).

Blepharospasm

General adverse reactions

Adverse reactions at the injection site

As with any injection, it may be associated with pain at the injection site, inflammation, paresthesia, hypesthesia, tenderness, swelling, edema, erythema, itching, localized infection, hematoma, bleeding and bruising.

Needle-stick pain and anxiety may lead to vasovagal reactions, including transient symptomatic arterial hypotension, nausea, tinnitus and fainting.

Toxin spread

When using Xeomin for neurological indications, ARs associated with the spread of the toxin to points remote from the injection sites (increased muscle weakness, dysphagia, aspiration pneumonia with fatal outcome) have been reported very rarely. Some of these reactions can be life-threatening, and there have been reports of fatalities. Such ARs cannot be completely excluded when using the drug for aesthetic indications.

Hypersensitivity reactions

Serious reactions and/or immediate hypersensitivity reactions, including anaphylactic reactions, serum sickness, urticaria, soft tissue swelling and difficulty breathing have been rarely observed. These reactions have been reported to be associated with the use of a complex preparation containing botulinum toxin type A, both as monotherapy and in combination with other agents that can cause such reactions. In cases of serious reactions (e.g., anaphylactic reactions) and/or immediate hypersensitivity reactions, appropriate therapy should be prescribed.

Antibody formation

Too frequent procedures (drug administration) may increase the risk of antibody formation, which may lead to lack of effect.

ARs may occur due to errors in the selection of target muscles, causing temporary paralysis of nearby muscles.

When treated with therapeutic doses, patients may experience increased muscle weakness.

Cases of dysphagia have been reported after injections not into the neck muscles.

Cases of seizures, both first-time and recurrent, have been reported in adults and children with spasticity of the upper and lower limbs, usually in patients predisposed to these conditions. The exact relationship between these phenomena and injections of botulinum toxin type A has not been established.

Post-registration experience

Muscle atrophy, flu-like symptoms and hypersensitivity reactions such as swelling, edema (other than at the injection site), erythema, itching, rash (local and generalized) and breathing difficulties have been reported.

Contraindications

• Hypersensitivity to the components of the drug;
• Neuromuscular transmission disorders (myasthenia gravis, Lambert-Eaton syndrome);
• Presence of infection and inflammatory process at the injection sites;
• Children under 2 years of age (for indications: spasticity of the upper and lower limbs in children; chronic sialorrhea in children);
• Age under 18 years for other indications (efficacy and safety of use have not been established).

With caution

• In patients with bleeding disorders;
• If the patient is receiving anticoagulant therapy or taking other substances in anticoagulant doses;
• In patients with amyotrophic lateral sclerosis;
• In patients with other diseases that lead to peripheral neuromuscular dysfunction;
• In patients with severe muscle weakness or atrophy of the target muscles.

Use in Pregnancy and Lactation

During pregnancy, Xeomin should be used only if necessary, if the potential benefit outweighs the risk.

Use during breastfeeding is not recommended.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Special Precautions

Patients with neuromuscular disorders may be at increased risk of significant muscle weakness, especially with intramuscular injection. Drugs containing botulinum toxin should be used in such patients under special supervision and only if the expected benefit of treatment outweighs the risk.

Treatment should be carried out with caution in patients with a history of dysphagia and aspiration. Therapy for cervical dystonia in such patients should be carried out with extreme caution.

The use of the drug for aesthetic purposes in such patients is not recommended.

Extreme caution should be exercised when treating pediatric patients with a severe degree of neurological asthenia, dysphagia, or those who have recently had aspiration pneumonia or lung disease. Treatment of such patients should be carried out only if the potential benefit for the particular patient outweighs the risk.

In case of swallowing, speech and breathing disorders, seek medical help immediately.

When treating spasmodic torticollis, upper limb spasticity in adults and upper limb spasticity in children, the drug should be administered with caution to sites in close proximity to the carotid arteries, lung apices and esophagus.

Due to the anticholinergic effect, the drug should be used with caution in patients at risk of developing narrow-angle glaucoma.

Patients should be informed that injections of Xeomin for the treatment of spasmodic torticollis may cause moderate to severe dysphagia with a risk of aspiration and breathing difficulties.

To reduce the risk of eyelid ptosis, injections near the levator palpebrae superioris muscle should be avoided. Diffusion of botulinum toxin type A into the inferior oblique muscle of the eye may lead to diplopia. Avoiding injections into the medial part of the lower eyelid can reduce the number of such adverse reactions.

Reduction in the number of blinks after injection of a drug containing botulinum toxin into the orbicularis oculi muscle may lead to corneal exposure, persistent epithelial defect and corneal ulceration.

When treating spasticity of the upper and lower limbs, adult patients with a sedentary lifestyle should be reminded of the need to gradually restore activity after injection of Xeomin. The effect of Xeomin for the treatment of spasticity in adults was studied against the background of standard rehabilitation measures; the drug is not intended to replace these treatment methods. Xeomin is not suitable for increasing the range of motion in a joint affected by persistent contracture.

Caution should be exercised when treating spasticity of the lower limb in adults, especially elderly patients, who may be at increased risk of falling.

For the treatment of spasticity of the upper and lower limbs and chronic sialorrhea in children, Xeomin can only be used in children aged 2 years and older.

Spontaneous reports of possible spread of toxin to points remote from the injection sites when using botulinum toxin type A drugs in children with comorbidities, mainly cerebral palsy, have been very rare. As a rule, the dose used in these cases exceeded the recommended dose for these drugs.

There are rare spontaneous reports of fatal cases, sometimes associated with aspiration pneumonia in children with severe cerebral palsy following treatment with botulinum toxin preparations, including for unregistered indications (e.g., injections in the neck area).

The safety and efficacy of Xeomin for the treatment of upper and lower limb spasticity and chronic sialorrhea in children under 2 years of age have not been studied.

The drug should be used only as prescribed by a physician.

Effect on the Ability to Drive and Operate Machinery

Due to the nature of the diseases treated with the drug, the patient’s ability to operate machinery may be impaired. In addition, side effects of the drug, such as asthenia, muscle weakness, blurred vision, fatigue, dizziness, and eyelid ptosis may occur and adversely affect the patient’s ability to drive or engage in other potentially hazardous activities; accordingly, the patient should refrain from such activities until their abilities have fully recovered.

Overdose

Symptoms: Exceeding the recommended dosages of botulinum toxin type A may lead to the development of pronounced muscle paralysis in areas distant from the injection sites (in particular: generalized weakness, ptosis, diplopia, difficulty breathing, speaking, and swallowing, as well as paralysis of the respiratory muscles, leading to aspiration pneumonia).

Treatment: In case of overdose, medical monitoring for symptoms of progressive muscle weakness and muscle paralysis is necessary. Symptomatic treatment may be required. In case of paralysis of the respiratory muscles, intubation and artificial ventilation are necessary until the condition normalizes.

In case of overdose, administration of an antitoxin (botulism antiserum) is advisable within the first 3 hours.

Drug Interactions

Caution should be exercised when used concomitantly with peripheral muscle relaxants or during antibiotic therapy with aminoglycosides or spectinomycin (an enhancement of the effect of Xeomin is possible). Additionally, when using Xeomin for the indication of chronic sialorrhea, irradiation of the head and neck area, including the salivary glands, and/or concomitant use of anticholinergic agents (e.g., atropine, glycopyrronium, scopolamine) may potentiate the effect of the toxin. The effect of the drug may be reduced by the action of 4-aminoquinoline derivatives.

Storage Conditions

The drug should be stored and transported out of the reach of children, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

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.