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XEOMIN (incobotulinumtoxinA) for injection
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use XEOMIN ® safely and effectively. See full prescribing information for XEOMIN.
XEOMIN (incobotulinumtoxinA) for injection, for intramuscular use
Initial U.S. Approval: 2010
WARNING: DISTANT SPREAD OF TOXIN EFFECT
See full prescribing information for complete boxed warning.
The effects of XEOMIN and all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. 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. The risk of symptoms is probably greatest in children treated for spasticity but symptoms can also occur in adults, particularly in those patients who have underlying conditions that would predispose them to these symptoms. (5.1)
RECENT MAJOR CHANGES
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Indications and Usage, Upper Limb Spasticity (1.1) |
12/2015 |
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Dosage and Administration, Upper Limb Spasticity (2.1) |
12/2015 |
INDICATIONS AND USAGE
XEOMIN is an acetylcholine release inhibitor and neuromuscular blocking agent indicated for the treatment or improvement of adult patients with:
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upper limb spasticity (1.1)
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cervical dystonia (1.2)
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blepharospasm with onabotulinumtoxinA (Botox®) prior treatment (1.3)
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temporary improvement in the appearance of moderate to severe glabellar lines with corrugator and/or procerus muscle activity (1.4)
DOSAGE AND ADMINISTRATION
Upper limb spasticity, cervical dystonia, and blepharospasm: the optimum dose, frequency, and number of injection sites in the treated muscle(s) should be based on severity and prior treatment response; individualize dosing for each patient:
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Upper Limb Spasticity in Adults: the recommended total dose is up to 400 Units no sooner than every 12 weeks (2.2)
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Cervical Dystonia: recommended initial total dose is 120 Units per treatment session (2.3)
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Blepharospasm: base initial dosing on previous dosing for onabotulinumtoxinA (Botox); if not known, the recommended starting dose is 1.25 Units-2.5 Units per injection site (2.4)
Glabellar Lines: recommended dose is 20 Units per treatment session divided into five equal intramuscular injections of 4 Units each (two injections in each corrugator muscle and one injection in the procerus muscle; wait a minimum of three months before retreatment (2.5)
Reconstituted XEOMIN:
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is intended for intramuscular injection only (2.7)
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use for only one injection session and for only one patient (2.7)
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instructions are specific for 50 unit, 100 unit, and 200 unit vials (2.7)
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store in a refrigerator (2°C to 8°C) and use within 24 hours (2.7)
DOSAGE FORMS AND STRENGTHS
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For injection: 50 Units, 100 Units, or 200 Units lyophilized powder in a single-dose vial for reconstitution with preservative–free 0.9% Sodium Chloride Injection, USP (3)
CONTRAINDICATIONS
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Known hypersensitivity to the active substance botulinum neurotoxin type A or to any of the excipients (4.1)
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Infection at the proposed injection sites (4.2)
WARNINGS AND PRECAUTIONS
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Respiratory, speech, or swallowing difficulties: Increased risk if bilateral neck muscle injections are needed or with pre-existing muscular disorders; immediate medical attention may be required (5.1, 5.3)
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The potency Units of XEOMIN are not interchangeable with other preparations of botulinum toxin products (5.2)
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Corneal exposure and ulceration: protective measures may be required (5.4)
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Risk of ptosis: follow dosage recommendations (5.5)
ADVERSE REACTIONS
The most commonly observed adverse reactions at rates specified below and greater than placebo are:
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Upper Limb Spasticity: (≥2% of patients) seizure, nasopharyngitis, dry mouth, upper respiratory tract infection (6.1)
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Cervical Dystonia: (≥5% of patients) dysphagia, neck pain, muscle weakness, injection site pain, and musculoskeletal pain (6.1)
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Blepharospasm: (≥5% of patients) eyelid ptosis, dry eye, dry mouth, diarrhea, headache, visual impairment, dyspnea, nasopharyngitis, and respiratory tract infection (6.1)
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Glabellar Lines: (>1% of patients) headache (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Merz Pharmaceuticals, LLC at 888-493-6646 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Aminoglycoside antibiotics or other agents that interfere with neuromuscular transmission may potentiate the effect of XEOMIN; co-administer only with caution and close observation (7)
USE IN SPECIFIC POPULATIONS
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Pregnancy: based on animal data, may cause fetal harm (8.1)
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Pediatric Use: XEOMIN has not been studied in the pediatric age group and is therefore not recommended in pediatric patients (8.4)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 12/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
1.1 Upper Limb Spasticity
XEOMIN (incobotulinumtoxinA) is indicated for the treatment of upper limb spasticity in adult patients.
1.2 Cervical Dystonia
XEOMIN (incobotulinumtoxinA) is indicated for the treatment of adults with cervical dystonia in both botulinum toxin-naïve and previously treated patients.
1.3 Blepharospasm
XEOMIN (incobotulinumtoxinA) is indicated for the treatment of adults with blepharospasm who were previously treated with onabotulinumtoxinA (Botox).
1.4 Glabellar Lines
XEOMIN (incobotulinumtoxinA) is indicated for the temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in adult patients.
2 DOSAGE AND ADMINISTRATION
2.1 Instructions for Safe Use
The potency Units of XEOMIN (incobotulinumtoxinA) 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 [see Warnings and Precautions (5.2) and Description (11)]. Reconstituted Xeomin is intended for intramuscular injection only.
The recommended maximum cumulative dose for any indication should not exceed 400 Units in a treatment session.
2.2 Upper Limb Spasticity
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 spasticity patients not previously treated with botulinum toxins, 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 12-14 weeks.
Figure 1: Muscles Involved In Adult Upper Limb Spasticity
2.3 Cervical Dystonia
The recommended initial total 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 [see Clinical Studies (14.2)]. 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). This list is not exhaustive, as any of the muscles responsible for controlling head position may require treatment [see Clinical Studies (14.2)]. 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 [see Clinical Studies (14.2)].
2.4 Blepharospasm
The recommended initial total dose of XEOMIN should be the same dose as the patient's previous treatment of onabotulinumtoxinA (Botox), although responses to XEOMIN and onabotulinumtoxinA (Botox) may differ in individual patients. In a placebo-controlled trial in which patients were dosed with the same number of Units as they had received previously with onabotulinumtoxinA (Botox), the mean dose per eye was about 33 Units (range 10 Units-50 Units), and the mean number of injections per eye was 6. The maximum dose per eye in the controlled trials was 50 Units, with a range of 10 Units-50 Units. In the controlled trial, few patients received a total dose of greater than 75 Units.
If the previous dose of Botox is not known, the initial dose of XEOMIN should be between 1.25 Units-2.5 Units/injection site.
The total initial dose of XEOMIN in both eyes should not exceed 70 Units (35 Units/eye).
The number and location of injection sites should be based on the severity of blepharospasm, and previous dose and response to onabotulinumtoxinA (Botox) injections. Subsequent dosing should be tailored to the individual patient, based on response, up to a maximum dose of 35 Units per eye [see Clinical Studies 14.3]. XEOMIN dosing has not been established in patients with blepharospasm who have not been previously treated with onabotulinumtoxinA (Botox).
The frequency of XEOMIN repeat treatments should be determined by clinical response but should generally be no more frequent than every 12 weeks [see Clinical Studies (14.3)].
2.5 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.
2.6 Special Populations
The safety and effectiveness of XEOMIN in the treatment of upper limb spasticity, cervical dystonia, blepharospasm, and glabellar lines in patients below 18 years of age have not been assessed [see Warnings and Precautions (5.1)].
2.7 Preparation and Reconstitution Technique
Prior to injection, reconstitute each vial of XEOMIN with sterile, preservative-free 0.9% Sodium Chloride Injection, USP [see Dosage Form and Strengths (3)]. A 20-27 gauge short bevel needle is recommended for reconstitution. Draw up an appropriate amount of preservative-free 0.9% Sodium Chloride Injection, USP into a syringe (see Table 2 and [Dosage Form and Strengths (3)]). Clean the exposed portion of the rubber stopper of the vial with alcohol (70%) prior to insertion of the needle. After vertical insertion of the needle through the rubber stopper, the vacuum will draw the saline into the vial. Gently inject any remaining saline into the vial to avoid foam formation. If the vacuum does not pull the saline into the vial, then XEOMIN must be discarded. Remove the syringe from the vial and mix XEOMIN with the saline by carefully swirling and inverting/flipping the vial – do not shake vigorously. Reconstituted XEOMIN is a clear, colorless solution free of particulate matter. XEOMIN should not be used if the reconstituted solution has a cloudy appearance or contains floccular or particulate matter.
After reconstitution, XEOMIN should be used for only one injection session and for only one patient. Reconstituted XEOMIN solution should be administered within 24 hours after dilution. During this time period, reconstituted XEOMIN should be stored in the original container in a refrigerator 2°C -8°C (36°F -46°F).
Diluent volumes for reconstitution of XEOMIN are indicated in Table 2.
2.8 Administration
Reconstituted XEOMIN is intended for intramuscular injection only.
If proposed injection sites are marked with a pen, the product must not be injected through the pen marks; otherwise a permanent tattooing effect may occur.
The number of injection sites is dependent upon the size of the muscle to be treated and the volume of reconstituted XEOMIN injected.
XEOMIN should be injected carefully when injected at sites close to sensitive structures, such as the carotid artery, lung apices, and esophagus. Before administering XEOMIN, the physician should be familiar with the patient's anatomy and any anatomic alterations, e.g., due to prior surgical procedures.
Upper Limb Spasticity and Cervical Dystonia
A suitable sterile needle (e.g., 26-gauge (0.45 mm diameter), 37 mm length for superficial muscles; or 22-gauge (0.70 mm diameter), 75 mm length for injections into deeper muscles) should be used in the administration in the treatment of upper limb spasticity and cervical dystonia.
Localization of the involved muscles with electromyographic guidance or nerve stimulation techniques may be useful.
Blepharospasm
A suitable sterile needle (e.g., 30-gauge (0.40 mm diameter), 12.5 mm length should be used in the administration in the treatment of blepharospasm.
Glabellar Lines
A suitable sterile needle 30-33 gauge (0.3-0.2 mm diameter), 13 mm length should be used in the administration in the treatment of glabellar lines.
2.9 Monitoring to Assess Effectiveness
The median first onset of XEOMIN effect occurs within seven days after injection. The typical duration of effect of each treatment is up to 3 months; however, the effect may last significantly longer, or shorter, in individual patients.
3 DOSAGE FORMS AND STRENGTHS
For injection: 50 Units, 100 Units, or 200 Units lyophilized powder in a single-dose vial for reconstitution only with preservative-free 0.9% Sodium Chloride Injection, USP.
4 CONTRAINDICATIONS
4.1 Hypersensitivity
Hypersensitivity reactions have been reported with botulinum toxin products (anaphylaxis, serum sickness, urticaria, soft tissue edema, and dyspnea). If serious and/or immediate hypersensitivity reactions occur further injection of XEOMIN should be discontinued and appropriate medical therapy immediately instituted. 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. XEOMIN is contraindicated in patients with known hypersensitivity to any botulinum toxin preparation or to any of the components in the formulation [see Warnings and Precautions (5.3) and Description (11)].
4.2 Infection at Injection Site
Use in patients with an infection at the injection site could lead to severe local or disseminated infection. XEOMIN is contraindicated in the presence of infection at the proposed injection site(s).
5 WARNINGS AND PRECAUTIONS
5.1 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. The risk of symptoms is probably greatest in children treated for spasticity but symptoms can occur in adults treated for spasticity and other conditions, and particularly in those patients who have underlying conditions that would predispose them to these symptoms. In unapproved uses, including spasticity in children, and in approved indications, symptoms consistent with spread of toxin effect have been reported at doses comparable to or lower than doses used to treat cervical dystonia.
Patients or caregivers should be advised to seek immediate medical care if swallowing, speech, or respiratory disorders occur.
5.2 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 [see Description (11)].
5.3 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 [See Warnings and Precautions (5.1)].
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.
Treatment of cervical dystonia with botulinum toxins may weaken neck muscles that serve as accessory muscles of ventilation. This may result in critical loss of breathing capacity in patients with respiratory disorders who may have become dependent upon these accessory muscles. There have been post-marketing reports of serious breathing difficulties, including respiratory failure, in patients with cervical dystonia treated with botulinum toxin products.
Patients with smaller neck muscle mass and patients who require bilateral injections into the sternocleidomastoid muscles have been reported to be at greater risk of dysphagia. In general, limiting the dose injected into the sternocleidomastoid muscle may decrease the occurrence of dysphagia.
Patients treated with botulinum toxin may require immediate medical attention should they develop problems with swallowing, speech or respiratory disorders. These reactions can occur within hours to weeks after injection with botulinum toxin [See Warnings and Precautions (5.1) and Adverse Reactions (6.1)].
Patients with neuromuscular disorders with peripheral motor neuropathic diseases, amyotrophic lateral sclerosis, or neuromuscular junctional disorders (e.g., myasthenia gravis or Lambert-Eaton syndrome) may be at increased risk for severe dysphagia and respiratory compromise from typical doses of XEOMIN.
5.4 Corneal Exposure, Corneal Ulceration, and Ectropion in Patients Treated for Blepharospasm
Reduced blinking from injection of botulinum toxin products in the orbicularis muscle can lead to corneal exposure, persistent epithelial defect and corneal ulceration, especially in patients with VII nerve disorders. Careful testing of corneal sensation in eyes previously operated upon, avoidance of injection into the lower lid area to avoid ectropion, and vigorous treatment of any epithelial defect should be employed. This may require protective drops, ointment, therapeutic soft contact lenses, or closure of the eye by patching or other means. Because of its anticholinergic effects, XEOMIN should be used with caution in patients at risk of developing narrow angle glaucoma. To prevent ectropion, botulinum toxin products should not be injected into the medial lower eyelid area.
Ecchymosis easily occurs in the soft tissues of the eyelid. Immediate gentle pressure at the injection site can limit that risk.
5.5 Risk of Ptosis in Patients Treated for Glabellar Lines
Do not exceed the recommended dosage and frequency of administration of XEOMIN.
In order to reduce the complication of ptosis the following steps should be taken:
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Avoid injection near the levator palpebrae superioris, particularly in patients with larger brow depressor complexes.
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Corrugator injections should be placed at least 1 cm above the bony supra
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