Xeomin (Page 5 of 12)
5.5 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. As patients with previous eye surgery may have reduced corneal sensation, carefully assess corneal sensation before treatment. Vigorous treatment of any corneal 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 decrease the risk for ectropion, XEOMIN 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 the size.
5.6 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:
- Avoid injection near the levator palpebrae superioris, particularly in patients with larger brow depressor complexes.
- Corrugator injections should be placed at least 1 cm above the bony supraorbital ridge.
5.7 Human Albumin and Transmission of Viral Diseases
This product contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases and variant Creutzfeldt-Jakob disease (vCJD). There is a theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD), but if that risk actually exists, the risk of transmission would also be considered extremely remote. No cases of transmission of viral diseases, CJD, or vCJD have ever been identified for licensed albumin or albumin contained in other licensed products.
6 ADVERSE REACTIONS
The following adverse reactions to XEOMIN are discussed in greater detail in other sections of the labeling:
- Spread of Effects from Toxin [see Warnings and Precautions (5.1)]
- Lack of Interchangeability between Botulinum Toxin Products [see Warnings and Precautions (5.2)]
- Hypersensitivity Reactions [see Warnings and Precautions (5.3)]
- Dysphagia and Breathing Difficulties [see Warnings and Precautions (5.4)]
- Corneal Exposure, Corneal Ulceration, and Ectropion in Patients Treated with XEOMIN for Blepharospasm [see Warnings and Precautions (5.5)]
- Risk of Ptosis in Patients Treated for Glabellar Lines [see Warnings and Precautions (5.6)]
- Human Albumin and Transmission of Viral Diseases [see Warnings and Precautions (5.7)]
6.1 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 [see Clinical Studies (14.1)]. 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%).
| 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 [see Clinical Studies (14.1)]. 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%).
| 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 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 [see Clinical Studies (14.2)]. 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%).
| 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 [ see Clinical Studies (14.2)]. 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.
| Adverse Reactions | XEOMIN 2 Units/kg N=87 % | XEOMIN 8 Units/kg N=176 % |
|---|---|---|
| ||
| Infections and infestations | ||
| Nasopharyngitis | 6 | 3 |
| Bronchitis | 2 | 3 |
| Pharyngotonsillitis * | 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 |
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 [see Clinical Studies (14.3) ]. 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 10 lists adverse reactions that occurred in ≥5% of XEOMIN-treated patients (in any treatment group) and greater than placebo.
| 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-naïve patients [see Clinical Studies (14.3)]. 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 11 lists the adverse reactions that occurred in ≥6% of XEOMIN-treated patients and greater than placebo.
| 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) [see Clinical Studies (14.4)]. 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 12 lists the adverse reactions that occurred in ≥5% of XEOMIN-treated patients and greater than placebo.
| 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 |
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.
| 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 | 0 | 0.4 |
| Sensation of pressure | 0 | 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.
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