XEOMIN SIDE EFFECTS

SIDE EFFECTS

The following adverse reactions to XEOMIN are discussed in greater detail in other sections of the labeling:

• Spread of Effects from Toxin
• Lack of Interchangeability between Botulinum Toxin Products
• Hypersensitivity Reactions
• Dysphagia and Breathing Difficulties
• Corneal Exposure, Corneal Ulceration, and Ectropion in Patients Treated with XEOMIN for Blepharospasm
• Risk of Ptosis in Patients Treated for Glabellar Lines
• Human Albumin and Transmission of Viral Diseases

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. XEOMIN-treated patients were 21-80 years old (mean 65 years), and were predominantly male (71%) and White (99.5%).

Table 1: Adverse Reactions (≥3%) and Greater for XEOMIN than Placebo: Double-Blind Phase of the Placebo-Controlled Adult Chronic Sialorrhea Study

Adverse Reaction	XEOMIN 100 Units (N = 74) %	Placebo (N = 36) %
Tooth extraction	5	0
Dry mouth	4	0
Diarrhea	4	3
Hypertension	4	3
Fall	3	0
Bronchitis	3	0
Dysphonia	3	0
Back pain	3	0
Dry eye	3	0

 

Chronic Sialorrhea In Pediatric Patients

Table 7 lists the adverse reactions that occurred in ≥1% of XEOMIN-treated patients 6-17 years of age in the double-blind, placebo-controlled portion of the study in pediatric patients with chronic sialorrhea. 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. XEOMIN-treated patients were 2-17 years of age (mean 10 years), predominately male (63%) and White (100%).

Table 2: Adverse Reactions (≥1%) and Greater for XEOMIN than Placebo: Double-Blind Phase of the Placebo-Controlled Pediatric Chronic Sialorrhea Study

Adverse Reaction	XEOMIN (6-17 years) (N = 148) %	Placebo (6-17 years) (N = 72) %
Bronchitis	1	0
Headache	1	0
Nausea/Vomiting	1	0

 

The most frequently reported adverse reaction in patients ages 2-5 years after XEOMIN injections was nasopharyngitis (6%).

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 3 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.  In the controlled portion of these studies, 283 patients received ≥120 Units to 400 Units, of which 217 patients received at least 400 Units of XEOMIN, and 182 patients received placebo. XEOMIN-treated patients were 20-79 years of age (mean 56 years), and were predominantly male (58%), and White (84%).

Table 3: Adverse Reactions (≥2%) and Greater for XEOMIN than Placebo: Double-Blind Phase of Placebo-Controlled Adult Upper Limb Spasticity Study 1 and Study 2

Adverse Reaction	XEOMIN 400 Units (N = 217) %	Placebo (N = 182) %
Seizure	3	0
Nasopharyngitis	2	0
Dry mouth	2	1
Upper respiratory tract infection	2	1

 

Upper Limb Spasticity In Pediatric Patients

Table 9 lists the adverse reactions that occurred in ≥2% of XEOMIN-treated patients in Study 1 in pediatric patients 2 years of age and older with upper limb spasticity. In the controlled portion of Study 1, 350 patients were randomized to one of three doses of XEOMIN: 87 received 2 Units/kg per affected upper limb, 87 received 6 Units/kg per affected upper limb, and 176 received 8 Units/kg per affected upper limb . XEOMIN-treated patients were 2 to 17 years of age (mean 7 years), 63% were male, and 90% were White.

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.

Table 4: Adverse Reactions (≥2%) in Patients Treated with XEOMIN 2 Units/kg or 8 Units/kg: Double-Blind Phase of Study 1 in Pediatric Upper Limb Spasticity

Adverse Reactions	XEOMIN 2 Units/kg N=87 %	XEOMIN 8 Units/kg N=176 %
Infections and infestations
Nasopharyngitis	6	3
Bronchitis	2	3
Pharyngotonsillitis1	2	2
Upper respiratory tract infection	2	2
Respiratory tract infection viral	1	2
Injury, poisoning and procedural complications
Fall	0	2
Musculoskeletal and connective tissue disorders
Pain in extremity	0	2
1 Includes pharyngotonsillitis, pharyngitis and tonsillitis

 

Cervical Dystonia

The data described below reflect exposure to a single intramuscular dose of XEOMIN in a placebo-controlled, Phase 3 trial in patients with cervical dystonia. In this study, 159 patients received XEOMIN (78 were randomized to receive a total dose of 120 Units, and 81 were randomized to receive a total dose of 240 Units). XEOMIN-treated patients were 18 to 79 years old (mean 53 years), and were predominantly female (66%) and Caucasian (91%). 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 5 lists adverse reactions that occurred in ≥5% of XEOMIN-treated patients (in any treatment group) and greater than placebo.

Table 5: Adverse Reactions (≥5%) and Greater for XEOMIN than Placebo: Double-Blind Phase of the Placebo-Controlled Cervical Dystonia Study

Adverse Reaction	XEOMIN 120 Units (N=77)%	XEOMIN 240 Units (N=82)%	Placebo (N=74)%
Musculoskeletal and connective tissue disorders	23	32	11
Neck pain	7	15	4
Muscular weakness	7	11	1
Musculoskeletal pain	7	4	1
Gastrointestinal disorders	18	24	4
Dysphagia	13	18	3
Nervous system disorders	16	17	7
General disorders and administration site conditions	16	11	11
Injection site pain	9	4	7
Infections and infestations	14	13	11
Respiratory, thoracic and mediastinal disorders	13	10	3

 

Blepharospasm

Study 1 was a randomized, double-blind, placebo-controlled study that only included treatment-naive patients. In the controlled portion, 22 patients received XEOMIN 25 Units, 19 patients received 50 Units, and 20 patients received placebo. 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 6 lists the adverse reactions that occurred in ≥6% of XEOMIN-treated patients and greater than placebo.

Table 6: Adverse Reactions (≥6%) and Greater for XEOMIN than Placebo: Double-Blind Phase of the Placebo-Controlled Blepharospasm Study 1

Adverse Reaction	XEOMIN 50 U (N=19)%	Placebo (N=20)%
Eye disorders	21	10
Eyelid ptosis	16	0

 

Study 2 was a double-blind, placebo-controlled, flexible dose study with an open-label extension (OLEX) period. The study only included patients previously treated with onabotulinumtoxinA (Botox).In the controlled portion, 74 patients received XEOMIN at a mean dose of approximately 33 Units per eye (minimum 10 Units, maximum 50 Units). XEOMIN-treated patients were 22 to 79 years of age (mean 62 years), predominantly female (65%) and Caucasian (60%). Table 7 lists the adverse reactions that occurred in ≥5% of XEOMIN-treated patients and greater than placebo.

Table 7: Adverse Reactions (≥5%) and Greater for XEOMIN than Placebo: Double-Blind Phase of the Placebo-Controlled Blepharospasm Study 2

Adverse Reaction	XEOMIN (N=74)%	Placebo (N=34)%
Eye disorders	38	21
Eyelid ptosis	19	9
Dry eye	16	12
Visual impairment*	12	6
Gastrointestinal disorders	30	15
Dry mouth	16	3
Diarrhea	8	0
Infections and infestations	20	15
Nasopharyngitis	5	3
Respiratory tract infection	5	3
Nervous system disorders	14	9
Headache	7	3
General disorders and administration site conditions	11	9
Respiratory, thoracic and mediastinal disorders	11	3
Dyspnea	5	3
*including vision blurred

 

Glabellar Lines

In three placebo-controlled trials in 803 subjects with glabellar lines, 535 subjects received a single dose of 20 Units XEOMIN and 268 subjects received placebo. XEOMIN-treated subjects were 24 to 74 years old, and were predominantly female (88%). The most frequent adverse reactions in XEOMIN-treated subjects were: headache (5%), facial paresis (0.7%), injection site hematoma (0.6%) and eyelid edema (0.4%). Four serious adverse events occurred in two placebo-treated subjects. Six XEOMIN treated subjects experienced six serious adverse events. All serious adverse events were assessed as unrelated to study drug.

The adverse reactions below reflect exposure to XEOMIN with glabellar lines in placebo-controlled studies. Adverse reactions are adverse events in which there is some basis to believe there is a causal relationship between the drug and the occurrence of the adverse event.

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.

Table 8: Adverse Reactions in Placebo-Controlled Glabellar Lines Trials

Adverse Reaction	XEOMIN (N=535) %	Placebo (N=268) %
Nervous system disorders	6	2
Headache	5	2
Facial paresis (brow ptosis)	0.7	0
General disorders and administration site conditions	0.9	0.7
Injection site hematoma	0.6	0
Injection site pain	0.2	0
Facial pain	0.2	0
Injection site swelling Sensation of pressure	0 0	0.4 0.4
Eye disorders	0.9	0
Eyelid edema	0.4	0
Blepharospasm	0.2	0
Eye disorder	0.2	0
Eyelid ptosis	0.2	0

 

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.

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other botulinumtoxinA products may be misleading.

Of the 2649 patients treated with XEOMIN in clinical trials, 9 (0.3%) patients were positive for neutralizing antibodies after treatment whose antibody status at baseline was unknown and 4 (0.2%) additional patients developed neutralizing antibodies after treatment. No patients demonstrated a secondary lack of treatment response due to neutralizing antibodies.

Chronic Sialorrhea

Chronic Sialorrhea In Adult Patients

Of the 180 patients treated with XEOMIN in the main phase and extension period of the adult chronic sialorrhea clinical trial, 1 (0.6%) patient was positive for neutralizing antibodies after treatment. The patient had an antibody status unknown at baseline, and had not received a botulinum toxin treatment in the 12 months prior to enrollment in the study. No patients demonstrated a secondary lack of treatment response due to neutralizing antibodies.

Chronic Sialorrhea In Pediatric Patients

Of the 252 patients treated with XEOMIN in the main phase and open-label extension period of the pediatric chronic sialorrhea clinical trial , antibody measurements were only performed in patients with body weight of 30 kg or more, resulting in 80 patients tested for antibodies at baseline. Three patients tested positive for neutralizing antibodies at baseline and remained positive at the end of the study. No additional patients developed neutralizing antibodies, and none of the patients demonstrated a secondary lack of treatment response.

Upper Limb Spasticity

Upper Limb Spasticity In Adult Patients

Of the 456 patients treated with XEOMIN in the main phase and open-label extension period of the adult upper limb spasticity clinical trials (Study 1 and Study 2), 4 patients were positive for neutralizing antibodies at baseline, and 2 (0.4%) additional patients (with unknown antibody status at baseline) were positive after treatment. Both patients had not received a botulinum toxin treatment in the 12 months prior to enrollment in the studies. No patients demonstrated a secondary lack of treatment response due to neutralizing antibodies.

Upper Limb Spasticity In Pediatric Patients

Of the 907 patients treated with XEOMIN in clinical trials for treatment of pediatric spasticity, 7 patients were positive for neutralizing antibodies at baseline, and 4 (0.4%) additional patients (with unknown antibody status at baseline) were positive after treatment. All of these patients were treated with onabotulinumtoxinA and/or abobotulinumtoxinA prior to enrollment in the study. Patients who had never received a botulinum toxin treatment did not develop neutralizing antibodies after being treated with XEOMIN. Antibody measurements were not performed in patients with <21 kg body weight. No patients demonstrated a secondary lack of treatment response due to neutralizing antibodies.

Cervical Dystonia

Of the 227 patients treated with XEOMIN in the main phase and open-label extension period of the cervical dystonia clinical trial, 5 patients were positive for neutralizing antibodies at baseline, 1 (0.4%) patient (with unknown antibody status at baseline) was positive after treatment, and 4 (1.8%) additional patients developed neutralizing antibodies after treatment. All of these patients were pre-treated with onabotulinumtoxinA and/or abobotulinumtoxinA prior to enrollment in the study. No patients demonstrated a secondary lack of treatment response due to neutralizing antibodies.

Blepharospasm

Of the 163 patients treated with XEOMIN in the main phase and open-label extension period of the blepharospasm clinical trials (Study 1 and Study 2) , 1 (0.6%) patient (with unknown antibody status at baseline) was positive for neutralizing antibodies after treatment. The patient had not received a botulinum toxin treatment in the 12 months prior to enrollment in the studies. No patients demonstrated a secondary lack of treatment response due to neutralizing antibodies.

Glabellar Frown Lines

Of the 464 patients treated with XEOMIN in the main phase and open-label extension period of the glabellar frown lines clinical trials (GL-1 and GL-2), no patients developed neutralizing antibodies after treatment. No patients demonstrated a secondary lack of treatment response due to neutralizing antibodies.

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: eye swelling, eyelid edema, dysphagia, nausea, flu-like symptoms, injection site pain, injection site reaction, allergic dermatitis, localized allergic reactions like swelling, edema, erythema, pruritus or rash, herpes zoster, muscular weakness, muscle spasm, dysarthria, myalgia, and hypersensitivity.

 

SRC: NLM .