Glands for Injection in Chronic Sialorrhea in Pediatric Patients

XEOMIN (incobotulinumtoxinA) for injection

Share this
Advertisement

XEOMIN (incobotulinumtoxinA) for injection

The active ingredient of XEOMIN is botulinum toxin type A produced from fermentation of Hall strain Clostridium botulinum serotype A. The botulinum toxin complex is purified from the culture supernatant and then the active ingredient is separated from the proteins (hemagglutinins and non-hemagglutinins) through a series of steps yielding the active neurotoxin with molecular weight of 150 kDa, without accessory proteins. XEOMIN is a sterile white to off-white lyophilized powder intended for intramuscular or intra-salivary gland injection after reconstitution with preservative-free 0.9% Sodium Chloride Injection, USP. One vial of XEOMIN contains 50 Units, 100 Units, or 200 Units of incobotulinumtoxinA, human albumin (1 mg), and sucrose (4.7 mg).

The primary release procedure for XEOMIN uses a cell-based potency assay to determine the potency relative to a reference standard. One Unit corresponds to the median intraperitoneal lethal dose (LD50) in mice. As the method for conducting the assay is specific to XEOMIN, Units of biological activity of XEOMIN cannot be converted into Units of any other botulinum toxin assessed with other specific assays.

Indications and usage

XEOMIN is an acetylcholine release inhibitor and neuromuscular blocking agent indicated for the treatment or improvement of:

  • Chronic sialorrhea in patients 2 years of age and older
  • Upper limb spasticity in adults
  • Upper limb spasticity in pediatric patients 2 to 17 years of age, excluding spasticity caused by cerebral palsy
  • Cervical dystonia in adults
  • Blepharospasm in adults
  • Temporary improvement in the appearance of moderate to severe glabellar lines with corrugator and/or procerus muscle activity in adults

Mechanism of Action

XEOMIN blocks cholinergic transmission at the neuromuscular and salivary neuroglandular junction by inhibiting the release of acetylcholine from peripheral cholinergic nerve endings. This inhibition occurs according to the following sequence: neurotoxin binding to cholinergic nerve terminals, internalization of the neurotoxin into the nerve terminal, translocation of the light-chain part of the molecule into the cytosol of the nerve terminal, and enzymatic cleavage of SNAP25, a presynaptic target protein essential for the release of acetylcholine. In both muscles and glands, impulse transmission is re-established by the formation of new nerve endings.

Dosage and administration

The potency Units of XEOMIN for injection are specific to the preparation and assay method utilized. They are not interchangeable with other preparations of botulinum toxin products and, therefore, units of biological activity of XEOMIN cannot be compared to or converted into Units of any other botulinum toxin products assessed with any other specific assay method. Reconstituted XEOMIN is intended for intramuscular or intra-salivary gland injection only.

The recommended maximum cumulative dose for any indication should not exceed 400 Units in a treatment session.

Chronic Sialorrhea in Adult Patients

XEOMIN is injected into the parotid and submandibular glands on both sides (i.e., 4 injection sites per treatment session). The recommended total dose per treatment session is 100 Units. The dose is divided with a ratio of 3:2 between the parotid and submandibular glands

Use the following guidelines if locating salivary glands using anatomic landmarks:

  • To inject the parotid gland, find the midpoint on the line connecting the tragus and mandible angle (Site A and B, respectively, Figure 1), approximately at the height of the ear lobe. Deliver the injection one finger breadth anterior to this site (Star 1, Figure 1).
  • To inject the submandibular gland, find the midpoint between the angle of the mandible and the tip of the chin (Site B and C, respectively, Figure 1). Deliver the injection one finger breadth medial to the inferior surface of the mandible at this site

Chronic Sialorrhea in Pediatric Patients

XEOMIN is injected into the parotid and submandibular glands on both sides (i.e., 4 injection sites per treatment session). Ultrasound imaging is recommended to guide needle placement into the salivary glands. The body-weight adjusted dose is divided with a ratio of 3:2 between the parotid and submandibular glands. XEOMIN has not been studied in children weighing less than 12 kg

Upper Limb Spasticity

Upper Limb Spasticity in Adult Patients: The dosage, frequency, and number of injection sites should be tailored to the individual patient based on the size, number, and location of muscles to be treated, severity of spasticity, presence of local muscle weakness, patient’s response to previous treatment, and adverse event history with XEOMIN. The frequency of XEOMIN treatments should be no sooner than every 12 weeks. In patients not previously treated with a botulinum toxin, initial dosing should begin at the low end of the recommended dosing range and titrated as clinically necessary. Most patients in clinical studies were retreated between 12 and 14 weeks.

Upper Limb Spasticity in Pediatric Patients, Excluding Spasticity Caused by Cerebral Palsy: The exact dosage, frequency, and number of injection sites should be tailored to the individual patient based on size, number and localization of involved muscles; the severity of spasticity; and the presence of local muscle weakness.

The maximum recommended dose is 8 Units/kg, divided among affected muscles, up to a maximum dose of 200 Units per single upper limb. If both upper limbs are treated, total XEOMIN dosage should not exceed 16 Units/kg, up to a maximum of 400 Units.

Based on the selected dose, a reconstituted solution at a concentration between 1.25 Units/0.1 mL and 5 Units/0.1 mL is recommended. The timing for repeat treatment should be determined based on the clinical need of the patient; the frequency of repeat treatments should be no sooner than every 12 weeks. Most patients in clinical studies were retreated between 12 and 16 weeks.

Cervical Dystonia

The recommended initial dose of XEOMIN for cervical dystonia is 120 Units. In a placebo-controlled trial utilizing initial XEOMIN doses of 120 Units and 240 Units, no meaningful difference in effectiveness was demonstrated between the doses. In previously treated patients, their past dose, response to treatment, duration of effect, and adverse event history should be taken into consideration when determining the XEOMIN dose.

In the treatment of cervical dystonia, XEOMIN is usually injected into the sternocleidomastoid, levator scapulae, splenius capitis, scalenus, and/or the trapezius muscle(s) (see Figure 5). This list is not exhaustive, as any of the muscles responsible for controlling head position may require treatment. The dose and number of injection sites in each treated muscle should be individualized based on the number and location of the muscle(s) to be treated, the degree of spasticity/dystonia, muscle mass, body weight, and response to any previous botulinum toxin injections.

The frequency of XEOMIN repeat treatments should be determined by clinical response, but should generally be no more frequent than every 12 weeks

Blepharospasm

In treatment-naïve patients, the recommended initial dose of XEOMIN is 50 Units (25 Units per eye). In patients previously treated with a botulinum toxin A, their past dose, response to treatment, duration of effect, and adverse event history should be taken into consideration when determining the XEOMIN dose

The total dose of XEOMIN should not exceed 100 Units per treatment session (50 Units per eye).

XEOMIN is injected into the lateral and medial orbicularis oculi muscle of the upper lid; lateral canthus and the lateral orbicularis oculi muscle of the lower lid; and the corrugator muscle, if necessary (see Figure 6). The number and location of injections may be changed in response to adverse reactions or based on the patient’s response to treatment, but the total dose should not exceed 50 Units per eye.

Advertisement

The frequency of XEOMIN repeat treatments should be determined by clinical response but should generally be no more frequent than every 12 weeks.

Glabellar Lines

The total recommended XEOMIN dose is 20 Units per treatment session divided into five equal intramuscular injections of 4 Units each. The five injection sites are: two injections in each corrugator muscle and one injection in the procerus muscle.

Retreatment with XEOMIN should be administered no more frequently than every three months.

Contraindications

XEOMIN is contraindicated in patients with:

  • Known hypersensitivity to any botulinum toxin product or to any of the components in the formulation
  • Infection at the proposed injection site(s) because it could lead to severe local or disseminated infection.

Warnings and precautions

Spread of Toxin Effect: Postmarketing safety data from XEOMIN and other approved botulinum toxins suggest that botulinum toxin effects may, in some cases, be observed beyond the site of local injection. The symptoms are consistent with the mechanism of action of botulinum toxin and may include asthenia, generalized muscle weakness, diplopia, blurred vision, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence, and breathing difficulties. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening and there have been reports of death related to the spread of toxin effects.

Lack of Interchangeability between Botulinum Toxin Products: The potency Units of XEOMIN are specific to the preparation and assay method utilized. They are not interchangeable with the other preparations of botulinum toxin products and, therefore, Units of biological activity of XEOMIN cannot be compared to or converted into Units of any other botulinum toxin products assessed with any other specific assay method.

Hypersensitivity Reactions: Serious hypersensitivity reactions have been reported with botulinum toxin products. Hypersensitivity reactions include anaphylaxis, serum sickness, urticaria, soft tissue edema, and dyspnea. If serious and/or immediate hypersensitivity reactions occur, discontinue further injection of XEOMIN and institute appropriate medical therapy immediately. The use of XEOMIN in patients with a known hypersensitivity to any botulinum neurotoxin or to any of the excipients (human albumin, sucrose), could lead to a life-threatening allergic reaction.

Dysphagia and Breathing Difficulties: Treatment with XEOMIN and other botulinum toxin products can result in swallowing or breathing difficulties. Patients with pre-existing swallowing or breathing difficulties may be more susceptible to these complications. In most cases, this is a consequence of weakening of muscles in the area of injection that are involved in breathing or swallowing. When distant effects occur, additional respiratory muscles may be involved.

Deaths as a complication of severe dysphagia have been reported after treatment with botulinum toxin. Dysphagia may persist for several months, and require use of a feeding tube to maintain adequate nutrition and hydration. Aspiration may result from severe dysphagia, and is a particular risk when treating patients in whom swallowing or respiratory function is already compromised.

Human Albumin and Transmission of Viral Diseases: This product contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases and variant Creutzfeldt-Jakob disease (vCJD). There is a theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD), but if that risk actually exists, the risk of transmission would also be considered extremely remote. No cases of transmission of viral diseases, CJD, or vCJD have ever been identified for licensed albumin or albumin contained in other licensed products.

Adverse reactions

The most commonly observed adverse reactions at rates specified below and greater than placebo are:

Chronic Sialorrhea:

  • Chronic Sialorrhea in Adults (≥4% of patients): tooth extraction, dry mouth, diarrhea, and hypertension
  • Chronic Sialorrhea in Pediatric Patients (≥1% of patients): bronchitis, headache, and nausea/vomiting

Spasticity:

  • Upper Limb Spasticity in Adults (≥2% of patients): seizure, nasopharyngitis, dry mouth, and upper respiratory tract infection
  • Upper Limb Spasticity in Pediatric Patients (≥3% of patients): nasopharyngitis and bronchitis

Cervical Dystonia (≥5% of patients): dysphagia, neck pain, muscle weakness, injection site pain, and musculoskeletal pain

Blepharospasm (≥10% of patients): eyelid ptosis, dry eye, visual impairment, and dry mouth

Glabellar Lines (>1% of patients): headache

Drug interactions

Aminoglycosides and Other Agents Interfering with Neuromuscular Transmission: Co-administration of XEOMIN and aminoglycosides or other agents interfering with neuromuscular transmission (e.g., tubocurarine-type muscle relaxants) should only be performed with caution as these agents may potentiate the effect of the toxin.

Anticholinergic Drugs: Use of anticholinergic drugs after administration of XEOMIN may potentiate systemic anticholinergic effects.

Other Botulinum Neurotoxin Products: The effect of administering different botulinum toxin products at the same time or within several months of each other is unknown. Excessive neuromuscular weakness may be exacerbated by administration of another botulinum toxin prior to the resolution of the effects of a previously administered botulinum toxin.

Muscle Relaxants: Excessive weakness may also be exaggerated by administration of a muscle relaxant before or after administration of XEOMIN.

Use in specific populations

Pregnancy: There are no adequate data on the developmental risk associated with the use of XEOMIN in pregnant women. XEOMIN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lactation: There are no data on the presence of XEOMIN in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for XEOMIN and any potential adverse effects on the breastfed infant from XEOMIN or from the underlying maternal conditions.

Pediatric Use: Safety and effectiveness of XEOMIN in patients less than 18 years of age have not been established for lower limb spasticity, cervical dystonia, blepharospasm, or glabellar frown lines.

Overdosage

Excessive doses of XEOMIN may be expected to produce neuromuscular weakness with a variety of symptoms, particularly when treated intramuscularly. Respiratory support may be required where excessive doses cause paralysis of the respiratory muscles. In the event of overdose, the patient should be medically monitored for symptoms of excessive muscle weakness or muscle paralysis. Symptomatic treatment may be necessary.

Symptoms of overdose are not likely to be present immediately following injection. Should accidental injection or oral ingestion occur, the person should be medically supervised for several weeks for signs and symptoms of excessive muscle weakness or paralysis.

Storage and Handling

Unopened vials of XEOMIN should be stored at or below 25°C (77°F). Refrigeration of unopened vials is not required. Do not use after the expiration date on the vial. Reconstituted XEOMIN may be stored in a refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours until time of use

Advertisement
Share this

Leave a Reply