Xeomin Information
Xeomin (Botulinum) Dosage And Administration
The potency Units of Xeomin (Botulinum) (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 (Botulinum) cannot be compared to or converted into units of any other botulinum toxin products assessed with any other specific assay method .
The recommended initial total dose of Xeomin (Botulinum) for cervical dystonia is 120 Units. In a placebo-controlled trial utilizing initial Xeomin (Botulinum) 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 (Botulinum) dose.
In the treatment of cervical dystonia, Xeomin (Botulinum) 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. 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 (Botulinum) repeat treatments should be determined by clinical response, but should generally be no more frequent than every 12 weeks.
The recommended initial total dose of Xeomin (Botulinum) should be the same dose as the patient's previous treatment of onabotulinumtoxinA (Botox), although responses to Xeomin (Botulinum) 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 10-50 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 10-50 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 (Botulinum) should be between 1.25-2.5 Units/injection site.
The total initial dose of Xeomin (Botulinum) 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. Xeomin (Botulinum) dosing has not been established in patients with blepharospasm who have not been previously treated with onabotulinumtoxinA (Botox).
The frequency of Xeomin (Botulinum) repeat treatments should be determined by clinical response but should generally be no more frequent than every 12 weeks.
Prior to injection, reconstitute each vial of Xeomin (Botulinum) with sterile, preservative-free 0.9% Sodium chloride Injection USP. Draw up an appropriate amount of 0.9% saline solution into a syringe (see). Clean the exposed portion of the rubber stopper of the vial with alcohol (70%) prior to insertion of the needle. Gently inject the saline solution into the vial. If the vacuum does not pull the solvent into the vial, then Xeomin (Botulinum) must be discarded. Gently mix Xeomin (Botulinum) with the saline by rotating the vial. Reconstituted Xeomin (Botulinum) is a clear, colorless solution free of particulate matter. Xeomin (Botulinum) should not be used if the reconstituted solution has a cloudy appearance or contains floccular or particulate matter.
Diluent volumes for reconstitution of Xeomin (Botulinum) are indicated in.
Reconstituted Xeomin (Botulinum) solution should be administered within 24 hours after dilution. During this time period, reconstituted Xeomin (Botulinum) should be stored in a refrigerator 2-8°C (36-46°F) [.
Reconstituted Xeomin (Botulinum) is intended for intramuscular injection only. After reconstitution, Xeomin (Botulinum) should be used for only one injection session and for only one patient. 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 for administration.
Localization of the involved muscles with electromyographic guidance or nerve stimulation techniques may be useful.
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 (Botulinum) injected.
Xeomin (Botulinum) should be injected carefully when injected at sites close to sensitive structures, such as the carotid artery, lung apices and esophagus. Before administering Xeomin (Botulinum) , the physician should be familiar with the patient's anatomy and any anatomic alterations, e.g., due to prior surgical procedures.
Xeomin (Botulinum) Dosage Forms And Strengths
Single-use, sterile 50 Units or 100 Units lyophilized powder for reconstitution only with sterile, preservative-free 0.9% Sodium chloride Injection USP prior to injection
Xeomin (Botulinum) Warnings And Precautions
The potency Units of Xeomin (Botulinum) 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 (Botulinum) cannot be compared to or converted into units of any other botulinum toxin products assessed with any other specific assay method.
Post-marketing safety data from Xeomin (Botulinum) 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 adults, 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.
Treatment with Xeomin (Botulinum) 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.
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.
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 (Botulinum) 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.
Xeomin (Botulinum) Adverse Reactions
The following adverse reactions to Xeomin (Botulinum) are discussed in greater detail in other sections of the labeling.
Hypersensitivity [ Dysphagia and Breathing Difficulties in Treatment of cervical dystonia []Spread of Effects from Toxin
Xeomin (Botulinum) Drug Interactions
No formal drug interaction studies have been conducted with Xeomin (Botulinum) .
Coadministration of Xeomin (Botulinum) and aminoglycoside antibiotics 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.
Use of anticholinergic drugs after administration of Xeomin (Botulinum) may potentiate systemic anticholinergic effects.
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. Excessive weakness may also be exaggerated by administration of a muscle relaxant before or after administration of Xeomin (Botulinum) .
Xeomin (Botulinum) Overdosage
Excessive doses of Xeomin (Botulinum) may be expected to produce neuromuscular weakness with a variety of symptoms. 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.
There is no significant information regarding overdose from clinical studies in cervical dystonia and blepharospasm.
In the event of overdose, antitoxin raised against botulinum toxin is available from the Centers for Disease Control and Prevention (CDC) in Atlanta, GA. However, the antitoxin will not reverse any botulinum toxin-induced effects already apparent by the time of antitoxin administration. In the event of suspected or actual cases of botulinum toxin poisoning, please contact your local or state Health Department to process a request for antitoxin through the CDC. If you do not receive a response within 30 minutes, please contact the CDC directly at 770-488-7100. More information can be obtained at http://www.cdc.gov/ncidod/srp/drugs/formulary.html#1a.
Xeomin (Botulinum) Description
The active ingredient of Xeomin (Botulinum) is botulinum toxin type A produced from fermentation of Hall strainserotype A. The botulinum toxin complex is purified from the culture supernatant and then the active ingredient is separated from the proteins (hemaglutinins and non-hemaglutinins) through a series of steps yielding the active neurotoxin with molecular weight of 150 kDa, without accessory proteins. Xeomin (Botulinum) is a sterile white to off-white lyophilized powder intended for intramuscular injection after reconstitution with 0.9% Saline for Injection, USP (without preservative). One vial of Xeomin (Botulinum) contains 50 or 100 Units of incobotulinumtoxinA, 1 mg of human albumin, and 4.7 mg sucrose. One Unit corresponds to the mouse median lethal dose (LD) when the reconstituted product is injected intraperitoneally into mice under defined conditions. The method for conducting the assay is specific to Xeomin (Botulinum) , units of biological activity of Xeomin (Botulinum) cannot be converted into units of any other botulinum toxin assessed with other specific assays.
Xeomin (Botulinum) Clinical Studies
Xeomin (Botulinum) has been investigated in a Phase 3, randomized, double-blind, placebo-controlled, multi-center trial in a total of 233 patients with cervical dystonia. Patients had a clinical diagnosis of predominantly rotational cervical dystonia, with baseline Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total score ≥20, TWSTRS severity score ≥10, TWSTRS disability score ≥3, and TWSTRS pain score ≥1. For patients who had previously received a botulinum toxin treatment for cervical dystonia, the trial required that ≥10 weeks had passed since the most recent botulinum toxin administration. Patients with swallowing disorders or any significant neuromuscular disease that might interfere with the study were excluded from enrollment. Patients were randomized (1:1:1) to receive a single administration of Xeomin (Botulinum) 240 Units (n=81), Xeomin (Botulinum) 120 Units (n=78), or placebo (n=74). Each patient received a single administration of 4.8 mL of reconstituted study agent (Xeomin (Botulinum) 240 Units, Xeomin (Botulinum) 120 Units, or placebo). The investigator at each site decided which muscles would receive injections of the study agent, the number of injection sites, and the volume at each site. The muscles most frequently injected were the splenius capitis/semispinalis, trapezius, sternocleidomastoid, scalene, and levator scapulae muscles. Table 2 indicates the average Xeomin (Botulinum) dose, and percentage of total dose, injected into specific muscles in the pivotal clinical trial.
Most patients received a total of 2-10 injections into the selected muscles. Patients were assessed by telephone at one week post-injection, during clinic visits at Weeks 4 and 8, and then by telephone assessments or clinic visits every two weeks up to Week 20.
The mean age of the study patients was 53 years, and 66% of the patients were women. At study baseline, 61% of patients had previously received a botulinum toxin as treatment for cervical dystonia. The study was completed by 94% of study patients. Three patients discontinued the study prematurely due to adverse events: two patients in the 240 Unit group experienced musculoskeletal pain and muscle weakness, and one patient in the 120 Unit group experienced nausea and dizziness.
The primary efficacy endpoint was the change in the TWSTRS total score from baseline to Week 4 post-injection, in the intent-to-treat (ITT) population, with missing values replaced by the patient's baseline value. In the ITT population, the difference between the Xeomin (Botulinum) 240 Unit group and the placebo group in the change of the TWSTRS total score from baseline to Week 4 was -9.0 points, 95% confidence interval (CI) -12.0; -5.9 points; the difference between the Xeomin (Botulinum) 120 Unit group and the placebo group in the change of the TWSTRS total score from baseline to Week 4 was -7.5 points, 95% CI -10.4; -4.6 points.
Figure 1 illustrates the cumulative percentage of patients from each of the three treatment groups who had attained the specified change in TWSTRS Score from baseline versus 4 weeks post-injection. Three change scores have been identified for illustrative purposes, and the percent of patients in each group achieving that result is shown.
Figure 1: Cumulative Percentage of Patients with Specified Changes from Baseline TWSTRS Total Score at Week 4
The curves demonstrate that both patients assigned to placebo and Xeomin (Botulinum) have a wide range of responses, but that the active treatment groups are more likely to show greater improvements. A curve for an effective treatment would be shifted to the left of the curve for placebo, while an ineffective or deleterious treatment would be superimposed upon or shifted to the right of the curve for placebo.
Comparison of each Xeomin (Botulinum) group to the placebo group was statistically significant at p
Examination of age and gender subgroups did not identify differences in response to Xeomin (Botulinum) among these subgroups. There were too few African-American patients to adequately assess efficacy in that population.
Xeomin (Botulinum) has been investigated in a Phase 3, randomized, double-blind, placebo-controlled, multi-center trial in a total of 109 patients with blepharospasm. Patients had a clinical diagnosis of benign essential blepharospasm, with baseline Jankovic Rating Scale (JRS) Severity subscore ≥2, and a stable satisfactory therapeutic response to previous administrations of onabotulinumtoxinA (Botox). At least 10 weeks had to have elapsed since the most recent onabotulinumtoxinA administration. Patients with any significant neuromuscular disease that might interfere with the study were excluded from enrollment. Patients were randomized (2:1) to receive a single administration of Xeomin (Botulinum) (n=75) or placebo (n=34). Each patient in the Xeomin (Botulinum) group received a Xeomin (Botulinum) treatment (dose, volume, dilution, and injection sites per muscle) that was similar to the most recent onabotulinumtoxinA injection sessions prior to study entry. The highest dose permitted in this study was 50 Units per eye; the mean Xeomin (Botulinum) dose was 33 Units per eye.
In the most frequently injected sites, the median dose per injection site, and the median number (and range) of injection sites per eye are presented.
Patients were assessed during clinic visits at Weeks 3 and 6, and then by telephone or at clinic visits every two weeks up to Week 20.
The mean age of the study patients was 62 years, and 65% of the patients were women. The study was completed by 94% of study patients. Approximately one third of patients had other dystonic phenomena; in all but 1% this was limited to facial, cervical, perioral and mandibular muscles. No patients discontinued the study prematurely due to adverse events.
The primary efficacy endpoint was the change in the JRS Severity subscore from baseline to Week 6 post-injection, in the intent-to-treat (ITT) population, with missing values replaced by the patient's most recent value (i.e., last observation carried forward). In the ITT population, the difference between the Xeomin (Botulinum) group and the placebo group in the change of the JRS Severity subscore from baseline to Week 6 was -1.0 (95% CI -1.4; -0.5) points. Comparison of the Xeomin (Botulinum) group to the placebo group was statistically significant at p
Figure 2: Frequency Distribution of Changes from Baseline JRS Severity Subscore at Week 6
Examination of age and gender subgroups did not identify substantial differences in response to Xeomin (Botulinum) among these subgroups. There were too few African-American patients to assess efficacy in that population.
Xeomin (Botulinum) How Supplied/storage And Handling
Xeomin (Botulinum) is reconstituted prior to use with sterile unpreserved 0.9% sodium chloride solution for injection. Reconstitution and dilution should be performed in accordance with good clinical practice.
Seefor reconstitution instructions.
Xeomin (Botulinum) should not be used if the reconstituted solution (prepared as above) has a cloudy appearance or contains floccular or particulate matter.
Any reconstituted toxin solution for injection that has been stored for more than 24 hours, as well as any unused solution for injection, should be discarded.
All vials, including expired vials, or equipment used with the drug should be disposed of carefully as is done with all medical waste.
Xeomin (Botulinum) Patient Counseling Information
Provide a copy of the Medication Guide and review the contents with the patient.
Patients or caregivers should be advised to seek immediate medical care if swallowing, speech or respiratory disorders arise.
Previously immobile or sedentary patients should be reminded to gradually resume activities following the injection of Xeomin (Botulinum) .
Patients should be informed that injections of Xeomin (Botulinum) may cause dyspnea, or mild to severe dysphagia, with the risk of aspiration.
Patients should be counseled that if loss of strength, muscle weakness, blurred vision, or drooping eyelids occur, they should avoid driving a car or engaging in other potentially hazardous activities.
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