Xeomin Drug Information

Instructions for Safe Use

The potency Units of XEOMIN for injection are specific to the preparation and assay method utilized. 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.

Do not exceed the recommended maximum cumulative dose in a treatment session for any indication.

Recommended Dose for Chronic Sialorrhea Chronic Sialorrhea in Adult Patients The recommended total dose per treatment session is 100 Units. XEOMIN is injected into the parotid and submandibular glands on both sides (i.e., 4 injection sites per treatment session). The dose is divided with a ratio of 3:2 between the parotid and submandibular glands (Table 1).

Figure 1: Glands for Injection in Chronic Sialorrhea in Adult Patients Use the following guidelines if locating salivary glands using anatomic landmarks: 1 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). 2 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 (Star 2, Figure 1).

Table 1: Dosing by Gland for Treatment of Chronic Sialorrhea in Adult Patients The concentration used in the clinical study after reconstitution was 5 Units/0.1mL. Determine the timing for repeat treatment based on the actual clinical need of the individual patient, and no sooner than every 16 weeks. Ultrasound imaging is recommended to guide needle placement into the salivary glands.

XEOMIN has not been studied in children weighing less than 12 kg. Figure 2: Glands for Injection in Chronic Sialorrhea in Pediatric Patients Table 2: Dosing by Body Weight Class for Treatment of Chronic Sialorrhea in Pediatric Patients The concentration used in the clinical study after reconstitution was

Units/0.1 mL. Figure 2 2.3 Recommended Dose for Upper Limb Spasticity Upper Limb Spasticity in Adult Patients Tailor the dosage, frequency, and number of injection sites 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. Administer repeat XEOMIN treatments no sooner than every 12 weeks.

In patients not previously treated with a botulinum toxin, begin initial dosing at the low end of the recommended dosing range and titrate as clinically necessary. Most patients in clinical studies were retreated between 12 and 14 weeks. Table 3: XEOMIN Dosing by Muscle for Treatment of Adult Upper Limb Spasticity 1 Figure 3: Muscles Involved In Adult Upper Limb Spasticity Figure 3 Upper Limb Spasticity in Pediatric Patients Tailor the exact dosage, frequency, and number of injection sites 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, do not exceed a total XEOMIN dosage of 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.

Table 4 includes the recommended dose ranges for the treatment of the clinical patterns of flexed elbow, flexed wrist, pronated forearm, clenched fist, and thumb-in-palm. 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.

In patients previously treated with a botulinum toxin A, consider their past dose, response to treatment, duration of effect, and adverse event history when determining the XEOMIN dose. Do not exceed a total XEOMIN dose of 100 Units per treatment session (50 Units per eye). Inject XEOMIN 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 do not exceed a total dose of 50 Units per eye. Figure 6

Recommended Dose for Upper Facial Lines (Glabellar Lines, Horizontal Forehead Lines, and Lateral Canthal Lines) The maximum recommended dose of XEOMIN for simultaneous treatment of upper facial lines in adult patients is 64 Units, comprised of 20 Units for GL, 20 Units for HFL, and 24 Units for LCL. Administer retreatment with XEOMIN no more frequently than every three months. When not treating upper facial lines (GL, HFL, and LCL) simultaneously in adult patients, refer to the following instructions: Glabellar Lines Equally distribute GL treatment to five equal intramuscular injections of 4 Units each.

To reduce the complication of ptosis take the following steps: Avoid injection near the levator palpebrae superioris, particularly in patients with larger brow depressor complexes. Place corrugator injections at least 1 cm above the bony supraorbital ridge. Horizontal Forehead Lines in Conjunction with Glabellar Lines Treat HFL in conjunction with GL to minimize the potential for brow ptosis.

The maximum recommended dose for treatment of HFL (20 Units) in conjunction with GL (20 Units) is 40 Units. Place one injection in the horizontal extension of the lateral canthus approximately 1 cm lateral from the bony orbital rim. Place the other two injections approximately 1 cm above and below the area of the first injection (see Figure 7 ).

Give injections with the needle bevel tip up and oriented away from the eye. Avoid injections too close to the zygomaticus major muscle to prevent lip ptosis. Figure 7: Injection Sites for Upper Facial Lines (Glabellar Lines, Horizontal Forehead Lines, and Lateral Canthal Lines) Figure 7

Preparation and Reconstitution Technique Prior to injection, reconstitute each vial of XEOMIN with sterile, preservative-free 0.9% Sodium Chloride Injection, USP. 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 5 ).

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.

Do not use XEOMIN if the reconstituted solution has a cloudy appearance or contains floccular or particulate matter. After reconstitution, use XEOMIN for only one injection session and for only one patient. Administer reconstituted XEOMIN within 24 hours after dilution.

During this time period, store unused reconstituted XEOMIN in the original container in a refrigerator 2°C -8°C (36°F -46°F) for up to 24 hours until time of use. XEOMIN vials are for single-dose only. Discard any unused portion.

Diluent volumes for reconstitution of XEOMIN are indicated in Table 5.

If proposed injection sites are marked with a pen, DO NOT inject XEOMIN through the pen marks; otherwise a permanent tattooing effect may occur. For intramuscular injections, the number of injection sites is dependent upon the size of the muscle to be treated and the volume of reconstituted XEOMIN injected. Inject XEOMIN carefully when injected at sites close to sensitive structures, such as the carotid artery, lung apices, and esophagus.

Before administering XEOMIN, the healthcare provider should be familiar with the patient's anatomy and any anatomic alterations, e.g., due to prior surgical procedures. Chronic Sialorrhea Chronic Sialorrhea in Adult Patients Use a sterile needle (e.g., 27-30 gauge (0.30-0.40 mm diameter), 12.5 mm length) for intra-salivary gland administration for the treatment of chronic sialorrhea. Inject XEOMIN close to the center of the gland.

The salivary glands can be located using ultrasound imaging or surface anatomical landmarks. Ultrasound guidance is recommended for the localization of the involved salivary glands. Upper Limb Spasticity Upper Limb Spasticity in Adult Patients Use a 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 deeper musculature) in the intramuscular administration in the treatment of upper limb spasticity in adults.

Localization of the involved muscles with electromyographic guidance, nerve stimulation, or ultrasound techniques is recommended. Upper Limb Spasticity in Pediatric Patients Use a sterile needle (e.g., 30-gauge (0.30 mm diameter), 25 mm length for superficial muscles; or 27-gauge (0.40 mm diameter), 37 mm length for deeper musculature) in the intramuscular administration in the treatment of upper limb spasticity in pediatric patients. Localization of the involved muscles with electromyographic guidance, ultrasound, or nerve stimulation techniques may be useful.

Upper Facial Lines (Glabellar Lines, Horizontal Forehead Lines, and Lateral Canthal Lines) Use a sterile needle, 13 mm length for the intramuscular administration in the treatment of upper facial lines.

Monitoring to Assess Effectiveness

The median onset of XEOMIN treatment effect occurs within two to seven days after injection. The typical duration of effect of each treatment is up to 12-16 weeks; however, the duration of effect may vary in individual patients.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Chronic Sialorrhea Chronic Sialorrhea in Adult Patients Table 6 lists the adverse reactions that occurred in ≥3% of XEOMIN-treated patients in the double-blind, placebo-controlled phase of the study in adult patients with chronic sialorrhea. The most common adverse reactions (≥4%) were tooth extraction, dry mouth, diarrhea, and hypertension.

In the controlled portion of this study, 74 patients received 100 Units of XEOMIN, and 36 patients received placebo. Of the patients 6-17 years of age, 148 patients received a dose of XEOMIN according to body weight, and 72 patients received placebo. Thirty-five patients 2-5 years of age received an open-label dose of XEOMIN according to body weight.

In the open-label extension period, 222 patients 2-17 years of age received up to three additional treatments with XEOMIN every 16±2 weeks. The safety profile of XEOMIN during the open-label extension period was similar to that observed in the double-blind phase of the placebo-controlled pediatric chronic sialorrhea study. Upper Limb Spasticity Upper Limb Spasticity in Adult Patients Table 8 lists the adverse reactions that occurred in ≥2% of XEOMIN-treated patients in two placebo-controlled studies in adult patients with upper limb spasticity.

Study 1 and Study 2 were both double-blind, placebo-controlled studies, with an open-label extension. No relationship between increased dose and increased occurrence of adverse reactions was observed. The most common adverse reactions (≥3% of XEOMIN-treated patients) at the recommended dose of XEOMIN (8 Units/kg) were nasopharyngitis and bronchitis.

At study baseline, approximately 25% had mild, 50% had moderate, and 25% had severe cervical dystonia. Approximately 61% of XEOMIN-treated patients had previously received another botulinum toxin type A product. Table 10 lists adverse reactions that occurred in ≥5% of XEOMIN-treated patients (in any treatment group) and greater than placebo.

Table 10: Adverse Reactions (≥5%) and Greater for XEOMIN than Placebo: Double-Blind Phase of the Placebo-Controlled Cervical Dystonia Study 3 Blepharospasm Study 1 was a randomized, double-blind, placebo-controlled study that only included treatment-naïve patients. XEOMIN-treated patients were 23 to 78 years of age (mean 55 years). Fifty-nine percent of the patients were women, 77% were Asian, and 23% White.

No patients withdrew prematurely because of an adverse event. Table 11 lists the adverse reactions that occurred in ≥6% of XEOMIN-treated patients and greater than placebo. The study only included patients previously treated with onabotulinumtoxinA (Botox).

Table 12 lists the adverse reactions that occurred in ≥5% of XEOMIN-treated patients and greater than placebo. XEOMIN-treated subjects were 19 to 76 years old and were predominantly female (82%). The most frequent adverse reactions ≥1% and greater for XEOMIN than placebo are presented in Table 13.

In the two repeated dose upper facial lines (GL, HFL, and LCL) trials with up to three treatments of XEOMIN, adverse reactions were reported for 123 of the 720 subjects (17%). The incidence of these adverse reactions tended to decrease with subsequent treatments. In both trials, all randomized subjects were followed up for 120 days before they could enter the open-label extension (OLEX) period which comprised two additional treatment cycles, with durations of 120 days each plus up to 30 days for eligibility reassessments per cycle.

During OLEX period, eligible subjects received simultaneous upper facial lines injections of XEOMIN at a total dose of 64 U in all three facial areas (20 U in GL, 20 U in HFL, and 24 U in LCL area). XEOMIN-treated subjects were 24 to 74 years old, and were predominantly female (88%). In open-label, multiple-dose trials, adverse reactions were reported for 105 of the 800 subjects (13%).

Headache was the most common adverse reaction, reported in 7% of subjects, followed by injection site hematoma (1%). Adverse reactions reported in less than 1% of subjects were: facial paresis (brow ptosis), muscle disorder (elevation of eyebrow), injection site pain, and eyelid edema.

Postmarketing Experience

The following adverse reactions have been reported during post-approval use of XEOMIN. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: allergic dermatitis, dysarthria, dysphagia, eye swelling, eyelid edema, flu-like symptoms, herpes zoster, hypersensitivity, injection site pain, injection site reaction, localized allergic reactions (e.g., swelling, edema, erythema, pruritus or rash), muscle spasm, muscular weakness, myalgia, nausea, and persistent dry mouth (> 110 days).

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.

Pregnancy Risk Summary 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. XEOMIN was embryotoxic in rats and increased abortions in rabbits when given at doses higher than the maximum recommended human dose (MRHD) for cervical dystonia (120 Units), on a body weight basis.

In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. The no-effect level for embryotoxicity in rats was 6 Units/kg (3 times the MRHD for cervical dystonia on a body weight basis).

In rabbits, the no-effect level for increased abortion was 2.5 Units/kg (similar to the MRHD for cervical dystonia on a body weight basis).

Pediatric Use The safety and effectiveness of Xeomin have not been established in pediatric patients for the treatment of lower limb spasticity, cervical dystonia, and blepharospasm, or the temporary improvement in the appearance of upper facial lines: moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity moderate to severe horizontal forehead lines associated with frontalis muscle activity moderate to severe lateral canthal lines associated with orbicularis oculi muscle activity. Chronic Sialorrhea in Pediatric Patients The safety and effectiveness of Xeomin have been established by evidence from an adequate and well-controlled study of Xeomin in patients 6 to 17 years of age with chronic sialorrhea. Safety and effectiveness in pediatric patients below the age of 2 years have not been established.

Upper Limb Spasticity in Pediatric Patients The safety and effectiveness of Xeomin for the treatment of upper limb spasticity have been established by evidence from an adequate and well-controlled study of Xeomin in pediatric patients 2 to 17 years of age. Juvenile Animal Toxicity Data In a study in which juvenile rats received intramuscular injections of Xeomin Units/kg every other week from postnatal day 21 for 10 weeks, decreased limb use, decreased body weight gain, skeletal muscle atrophy, and decreased bone growth and density were observed at all doses. Male reproductive organ histopathology (atrophy of the germinal epithelium of the testis, associated with hypospermia) was observed at the mid and high doses, and mating behavior was impaired at the high dose.

A no-effect dose for adverse effects on development in juvenile animals was not established. The lowest dose tested (5 Units/kg) is less than the human dose of 400 Units on a body weight (kg) basis.

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. Known hypersensitivity to the active substance botulinum neurotoxin type A or to any of the excipients Infection at the proposed injection sites

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.

There is no significant information regarding overdose from clinical studies of XEOMIN. 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.