Xeomin

>10%

Cervical dystonia

• Nervous system disorders (16%)
• Dysphagia (13%)
• Respiratory, thoracic, and mediastinal disorders (13%)

Blepharospasm

• Eyelid ptosis (19%)
• Dry eye (16%)
• Xerostomia (16%)
• Nervous system disorders (14%)
• Visual impairment, including blurred vision (12%)
• Respiratory, thoracic, and mediastinal disorders (11%)

1-10%

Cervical dystonia

• Injection site pain (9%)
• Neck pain (7%)
• Muscular weakness (7%)
• Musculoskeletal pain (7%)

Blepharospasm

• Diarrhea (8%)
• Headache (7%)
• Dyspnea (5%)
• Nasopharyngitis (5%)
• Respiratory tract infection (5%)

Glabellar lines

• Headache (5.4%)

Postmarketing Reports

Allergic disorders: Hypersensitivity, eye swelling/edema, allergic dermatitis

Gastroenterology: Nausea

Body as a whole: Flu-like symptoms

Local reactions: Injection site pain, injection site reaction, localized allergic reactions (eg, swelling, edema, erythema, pruritus, rash)

Infection: Herpes zoster

Musculoskeletal: Muscular weakness, muscle spasm, myalgia

Neurologic: Dysarthria, dysphagia

Pregnancy Category: C; based on animal data, may cause fetal harm

Lactation: Unknown whether distributed in breast milk, do not nurse

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

This medication may impair your vision or depth perception. Be careful if you drive or do anything that requires you to be able to see clearly.

Avoid going back to your normal physical activities too quickly after receiving an injection.

• Merz Pharmaceuticals, LLC

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may not appear right away, but can include severe muscle weakness, trouble swallowing, weak or shallow breathing, or loss of movement in any part of your body.

• It is used to treat muscle problems that lead to spasms.
• It is used to treat muscle problems around the eye.
• It is used to treat spasms of the neck.
• It is used to lower the number of lines and wrinkles of the face.

Use Xeomin as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• This medicine will be given to you by a doctor.
• It is given as a shot into a muscle.

What do I do if I miss a dose?

• Call the doctor for an office visit.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Upper Limb Spasticity

Xeomin (incobotulinumtoxinA) is indicated for the treatment of upper limb spasticity in adult patients.

Cervical Dystonia

Xeomin (incobotulinumtoxinA) is indicated for the treatment of adults with cervical dystonia in both botulinum toxin-naïve and previously treated patients.

Blepharospasm

Xeomin (incobotulinumtoxinA) is indicated for the treatment of adults with blepharospasm who were previously treated with onabotulinumtoxinA (Botox).

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.

Mechanism of Action

Xeomin blocks cholinergic transmission at the neuromuscular 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. Impulse transmission is re-established by the formation of new nerve endings.

Pharmacodynamics

The return of increased muscle tone following injection typically occurs within 3 to 4 months.

Pharmacokinetics

General characteristics of the active substance:

Using currently available analytical technology, it is not possible to detect Xeomin in the peripheral blood following intramuscular injection at the recommended doses.

Upper Limb Spasticity

The efficacy and safety of Xeomin for the treatment of upper limb spasticity was evaluated in two Phase 3, randomized, multi-center, double-blind studies.

Study 1 and Study 2 were both prospective, double-blind, placebo-controlled, randomized, multi-center trials with an open-label extension period (OLEX) to investigate the efficacy and safety of Xeomin in the treatment of post-stroke spasticity of the upper limb. For patients who had previously received botulinum toxin treatment in any body region, Study 1 and Study 2 required that ≥ 12 months and ≥ 4 months, respectively, had passed since the most recent botulinum toxin administration.

Study 1 consisted of a 12-week main phase followed by three 12-week OLEX treatment cycles for a total exposure duration of 48 weeks. The study included 317 treatment-naïve patients who were at least three months post-stroke in the main study period (210 Xeomin and 107 placebo). During the main period, Xeomin (fixed total dose of 400 Units) and placebo were administered intramuscularly to the defined primary target clinical pattern chosen from among the flexed elbow, flexed wrist, or clenched fist patterns and to other affected muscle groups. 296 treated patients completed the main phase and participated in the first OLEX cycle. Each OLEX cycle consisted of a single treatment session (Xeomin 400 Units total dose, distributed among all affected muscles) followed by a 12 week observation period.

Study 2 consisted of a 12 - 20 week main phase followed by an OLEX period of 48 – 69 weeks for up to 89 weeks of exposure to Xeomin. The study included 148 treatment-naïve and pre-treated patients with a confirmed diagnosis of post-stroke spasticity of the upper limb who were at least six months post-stroke (73 Xeomin and 75 placebo). During the main period, for each patient, the clinical patterns of flexed wrist and clenched fist were treated with fixed doses (90 Units and 80 Units, respectively). Additionally, if other upper limb spasticity patterns were present, the elbow, forearm and thumb muscles could be treated with fixed doses of Xeomin per muscle. 145 patients completed the main phase and participated in the OLEX period, during which time the dosing of each involved muscle could be adapted individually. During the main and OLEX periods, the maximum total dose per treatment session and 12-week interval was 400 Units.

The average Xeomin doses injected into specific muscles and the number of injection sites per muscle in Study 1 and Study 2 are presented in Table 7.

In Study 1, the primary efficacy variable was the change from baseline in Ashworth Scale (AS) score of the primary target clinical pattern determined by the investigator at the Week 4 visit. The Ashworth Scale is a clinical measure of the severity of spasticity by judging resistance to passive movement. The spasticity of the elbow flexors, wrist flexors, finger flexors, and thumb muscles as well as the forearm pronators was assessed on the 0 to 4-point Ashworth scale at each visit.

The co-primary efficacy variable of Study 1 was the Investigator's Global Impression of Change Scales (GICS) after 4 Weeks of treatment with Xeomin or placebo. The GICS is a global measure of a subject's functional improvement. Investigators were asked to evaluate the subject's global change in spasticity of the upper limb due to treatment, compared to the condition before the last injection. The response was assessed using a 7-point Likert scale that ranges from –3 (very much worse) to +3 (very much improved). A greater percentage of Xeomin-treated subjects (43%) than placebo-treated subjects (23%) reported 'very much improved' and 'much improved' in their spasticity (see Figure 3).

Xeomin was considered to be superior to placebo in Study 1 only if statistical significance was reached in both the AS and GICS variables.

Cervical Dystonia

Xeomin 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 240 Units (n=81), Xeomin 120 Units (n=78), or placebo (n=74). Each patient received a single administration of 4.8 mL of reconstituted study agent (Xeomin 240 Units, Xeomin 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 9 indicates the average Xeomin 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 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 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 4 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 4: 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 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 group to the placebo group was statistically significant at p<0.001. Initial Xeomin doses of 120 Units and 240 Units demonstrated no significant difference in effectiveness between the doses. The efficacy of Xeomin was similar in patients who were botulinum toxin naïve and those who had received botulinum toxin prior to this study.

Examination of age and gender subgroups did not identify differences in response to Xeomin among these subgroups. There were too few African-American patients to adequately assess efficacy in that population.

Blepharospasm

Xeomin 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 (n=75) or placebo (n=34). Each patient in the Xeomin group received a Xeomin 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 dose was 33 Units per eye.

In Table 10 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 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 group to the placebo group was statistically significant at p<0.001.

Figure 5: 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 among these subgroups. There were too few African-American patients to assess efficacy in that population.

Glabellar Lines

Two identically designed randomized, double-blind, multi-center, placebo controlled clinical trials (Studies GL-1 and GL-2) were conducted to evaluate Xeomin for use in the temporary improvement of moderate to severe glabellar lines. The studies enrolled 547 healthy patients (≥18 years old) with glabellar lines of at least moderate severity at maximum frown. Three hundred sixty six subjects were treated with 20 Units of Xeomin and 181 subjects were treated with placebo. Subjects were excluded if they had marked ptosis, deep dermal scarring, or an inability to lessen glabellar lines, even by physically spreading them apart. The mean age of study subjects was 46 years. The majority of patients were female (86% and 93% in Studies GL-1 and GL-2, respectively), and predominantly Caucasian (89% and 65% respectively). The study subjects received either 20 Units of Xeomin or an equal amount of placebo. The total dose was delivered in 5 equally divided intramuscular injections of 4 Units each to specific sites (see Figure 2). Subjects were followed up for 120 days.

Investigators and subjects assessed efficacy at maximum frown on Day 30 of treatment using a 4-point scale (0=none, 1=mild, 2=moderate, 3=severe). Composite treatment success was defined as a 2-grade improvement on this scale compared to baseline for both the investigator's and subject's assessments on Day 30. The percentage of subjects with treatment success was greater on the Xeomin arm than the placebo arm at Day 30 in both studies (see Table 11). The percentage of subjects with composite treatment success at each visit are presented in Figure 6.

Figure 6: Percentage of Subjects with Composite Treatment Success by Visit – Observed Cases (GL-1 and GL-2)

incobotulinumtoxinA

Xeomin®
for Injection

200 units/vial

For Intramuscular Use.
Single-dose vial; Discard unused portion.
Usual dosage: see package insert.

Xeomin (incobotulinumtoxinA, also called botulinum toxin type A), is made from the bacteria that causes botulism. Botulinum toxin blocks nerve activity in the muscles, causing a temporary reduction in muscle activity.

Xeomin is used to treat cervical dystonia (severe spasms in the neck muscles). It is also used to treat muscle spasms (stiffness) in the arms.

Xeomin is also used to treat certain eye muscle conditions caused by nerve disorders. This includes uncontrolled blinking or spasm of the eyelids, and a condition in which the eyes do not point in the same direction.

Xeomin is also used to temporarily lessen the appearance of facial wrinkles (sometimes called "frown lines") between the eyebrows, and for upper limb spasticity in adults.

Xeomin is injected into a muscle. A doctor, nurse, or other healthcare provider will give you this injection. Xeomin injections should be spaced at least 3 months apart.

Xeomin injections should be given only by a trained medical professional.

Your injection may be given into more than one area at a time, depending on the condition being treated.

While receiving Xeomin injections for an eye muscle conditions, you may need to use eye drops, ointment, a special contact lens or other device to protect the surface of your eye. Follow your doctor's instructions.

It may take up to 7 days after injection before neck muscle spasm symptoms begin to improve.

The effects of a Xeomin injection are temporary. Your symptoms may return completely within 3 months after an injection. After repeat injections, it may take less and less time before your symptoms return, especially if your body develops antibodies to the botulinum toxin. Do not seek botulinum toxin injections from more than one medical professional at a time. If you switch healthcare providers, be sure to tell your new provider how long it has been since your last botulinum toxin injection.

Using Xeomin more often than prescribed will not make it more effective and may result in serious side effects.