Incobotulinumtoxina

XEOMIN is an acetylcholine release inhibitor and neuromuscular blocking agent indicated for the treatment or improvement of: Chronic sialorrhea in patients 2 years of age and older ( 1.1 ) Upper limb spasticity in patients 2 years of age and older ( 1.2 ) Cervical dystonia in adults ( 1.3 ) Blepharospasm in adults ( 1.4 ) the appearance of upper facial lines in adults: moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity ( 1.5 ) moderate to severe horizontal forehead lines associated with frontalis muscle activity ( 1.5 ) moderate to severe lateral canthal lines associated with orbicularis oculi muscle activity ( 1.5 )

1.1 Chronic Sialorrhea XEOMIN is indicated for the treatment of chronic sialorrhea in patients 2 years of age and older.

1.2 Upper Limb Spasticity XEOMIN is indicated for the treatment of upper limb spasticity in patients 2 years of age and older.

1.3 Cervical Dystonia XEOMIN is indicated for the treatment of cervical dystonia in adult patients.

1.4 Blepharospasm XEOMIN is indicated for the treatment of blepharospasm in adult patients.

1.5 Upper Facial Lines (Glabellar Lines, Horizontal Forehead Lines, and Lateral Canthal Lines) XEOMIN is indicated in adult patients for the temporary improvement in the appearance of upper facial lines: moderate to severe glabellar lines (GL) associated with corrugator and/or procerus muscle activity moderate to severe horizontal forehead lines (HFL) associated with frontalis muscle activity moderate to severe lateral canthal lines (LCL) associated with orbicularis oculi muscle activity.

For injection: 50 Units, 100 Units, or 200 Units lyophilized powder in a single-dose vial for reconstitution only with preservative-free 0.9% Sodium Chloride Injection, USP. For injection: 50 Units, 100 Units, or 200 Units lyophilized powder in a single-dose vial ( 3 )

XEOMIN is contraindicated in patients with: Known hypersensitivity to any botulinum toxin product or to any of the components in the formulation [see Warnings and Precautions (5.3) and Description (11) ] . 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 ( 4 , 5.3 ) Infection at the proposed injection sites ( 4 )

Respiratory, speech, or swallowing difficulties: increased risk if bilateral neck muscle injections are needed, or with pre-existing muscular disorders; immediate medical attention may be required ( 5.1 , 5.4 ) The potency Units of XEOMIN cannot be compared to or converted into Units of any other preparations of botulinum toxin products ( 5.2 ) Corneal exposure and ulceration: protective measures may be required ( 5.5 )

5.1 Spread of Toxin Effect Postmarketing safety data from XEOMIN 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 lower limb spasticity in children, 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.

5.2 Lack of Unit Equivalency Between Botulinum Toxin Products The potency Units of XEOMIN 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 [see Description (11) ] .

5.3 Hypersensitivity Reactions Serious hypersensitivity reactions have been reported with botulinum toxin products. Hypersensitivity reactions include anaphylaxis, serum sickness, urticaria, soft tissue edema, and dyspnea. If serious and/or immediate hypersensitivity reactions occur, discontinue further injection of XEOMIN and institute appropriate medical therapy immediately. The use of XEOMIN in patients with a known hypersensitivity to any botulinum neurotoxin or to any of the excipients (human albumin, sucrose), could lead to a life-threatening allergic reaction [see Contraindications (4) ].

5.4 Dysphagia and Breathing Difficulties Treatment with XEOMIN 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 [see Warnings and Precautions (5.4) ] . 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 [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ] . Patients with neuromuscular disorders with peripheral motor neuropathic diseases, amyotrophic lateral sclerosis, or neuromuscular junctional disorders (e.g., myasthenia gravis or Lambert-Eaton syndrome) may be at increased risk for severe dysphagia and respiratory compromise from typical doses of XEOMIN.

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.

5.8 Pre-existing Conditions at the Injection Site Use caution when XEOMIN is used where the targeted muscle shows excessive weakness or atrophy. Use caution when XEOMIN is used in patients who have marked facial asymmetry, with surgical alterations to the facial anatomy, pre-existing eyelid or eyebrow ptosis, when excessive weakness or atrophy is present in the target muscles, excessive dermatochalasis, deep dermal scarring, thick sebaceous skin (e.g., the inability to substantially lessen glabellar lines even by physically spreading them apart).

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 Unit Equivalency 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) ] The most commonly observed adverse reactions at rates specified below and greater than placebo are: Chronic Sialorrhea: Chronic Sialorrhea in Adults (≥4% of patients) : tooth extraction, dry mouth, diarrhea, and hypertension ( 6.1 ) Chronic Sialorrhea in Pediatric Patients (≥1% of patients): bronchitis, headache, and nausea/vomiting ( 6.1 ) Spasticity: Upper Limb Spasticity in Adults (≥2% of patients) : seizure, nasopharyngitis, dry mouth, and upper respiratory tract infection ( 6.1 ) Upper Limb Spasticity in Pediatric Patients (≥3% of patients) : nasopharyngitis and bronchitis ( 6.1 ) Cervical Dystonia (≥5% of patients) : dysphagia, neck pain, muscle weakness, injection site pain, and musculoskeletal pain ( 6.1 ) Blepharospasm (≥10% of patients) : eyelid ptosis, dry eye, visual impairment, and dry mouth ( 6.1 ) Upper facial lines (Glabellar Lines, Horizontal Forehead Lines, and Lateral Canthal Lines): (>1% of patients) : injection site bruising ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Merz Pharmaceuticals, LLC at 888-493-6646 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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%). Table 6: 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 [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%). Table 7: 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 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%). Table 8: 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 [ 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. Table 9: 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 Pharyngotonsillitis Includes pharyngotonsillitis, pharyngitis and tonsillitis 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. […]

Aminoglycosides or other agents that interfere with neuromuscular transmission may potentiate the effect of XEOMIN; co-administer only with caution and close observation ( 7 )

7.1 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.

7.2 Anticholinergic Drugs Use of anticholinergic drugs after administration of XEOMIN may potentiate systemic anticholinergic effects.

7.3 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.

7.4 Muscle Relaxants Excessive weakness may also be exaggerated by administration of a muscle relaxant before or after administration of XEOMIN.

Pregnancy: based on animal data, may cause fetal harm ( 8.1 )

8.1 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. Data Animal Data When XEOMIN was administered intramuscularly to pregnant rats during organogenesis (3 Units/kg, 10 Units/kg, or 30 Units/kg on gestational days [GDs] 6, 12, and 19; or 7 Units/kg on GDs 6 to 19; or 2 Units/kg, 6 Units/kg, or 18 Units/kg on GDs 6, 9, 12, 16, and 19), decreases in fetal body weight and skeletal ossification were observed at doses that were also maternally toxic. The no-effect level for embryotoxicity in rats was 6 Units/kg (3 times the MRHD for cervical dystonia on a body weight basis). Intramuscular administration to pregnant rabbits during organogenesis (1.25 Units/kg,

2.5 Units/kg, or

5.0 Units/kg on GDs 6, 18, and 28) resulted in an increased rate of abortion at the highest dose, which was also maternally toxic. 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).

8.2 Lactation Risk Summary There are no data on the presence of XEOMIN in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for XEOMIN and any potential adverse effects on the breastfed infant from XEOMIN or from the underlying maternal conditions.

8.4 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 [see Warnings and Precautions (5.1) ] . 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 [see Clinical Studies (14.1) ] . Use of XEOMIN in patients 2 to 5 years of age is supported by the findings of efficacy and safety in patients 6 years and older with chronic sialorrhea, and by safety data in patients 2 to 5 years of age. Safety and effectiveness in pediatric patients below the age of 2 years have not been established [see Warnings and Precautions (5.1) ]. 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 [see Warnings and Precautions (5.1) , Adverse Reactions (6.1) , and Clinical Studies (14.2) ]. Safety and effectiveness in pediatric patients below the age of 2 years have not been established [see Warnings and Precautions (5.1) ]. Juvenile Animal Toxicity Data In a study in which juvenile rats received intramuscular injections of Xeomin (0, 5, 10, or 30 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.

8.5 Geriatric Use Chronic Sialorrhea Of the total number of 184 patients in the placebo-controlled study in chronic sialorrhea in adult patients [see Clinical Studies (14.1) ] , 107 were 65 years of age and over (46 treated with XEOMIN 100 Units, 44 treated with XEOMIN 75 Units, and 17 received placebo). No differences in safety or effectiveness were observed between older and younger patients. Other clinical studies have not identified differences in responses between older and younger patients, but increased sensitivity in older patients cannot be ruled out. Upper Limb Spasticity Of the total number of 283 patients in the placebo-controlled studies in upper limb spasticity in adult patients [see Clinical Studies (14.2) ], 118 were 65 years of age and over (70 treated with XEOMIN and 48 received placebo), which included 12 patients 75 years of age and over (7 treated with XEOMIN and 5 received placebo). No overall differences in safety or effectiveness were observed between older and younger adult patients. Other clinical studies have not identified differences in responses between older and younger adult patients, but increased sensitivity in older patients cannot be ruled out. Cervical Dystonia Of the total number of 233 patients in the placebo-controlled study in cervical dystonia [see Clinical Studies (14.3) ] , 29 were 65 years of age and over (19 treated with XEOMIN and 10 received placebo). Of these, ten XEOMIN-treated patients and four placebo-treated patients experienced an adverse event. For patients 65 years of age and over treated with XEOMIN, the most common adverse events were dysphagia (21%) and asthenia (11%). Blepharospasm Of the total number of 169 patients in the placebo-controlled studies in blepharospasm [see Clinical Studies (14.4) ] , 61 were 65 years of age and over (45 treated with XEOMIN and 16 received placebo). No overall difference in effectiveness was observed between older and younger patients. Upper Facial Lines (Glabellar Lines, Horizontal Forehead Lines, and Lateral Canthal Lines) Of the total number of 547 subjects in the placebo-controlled clinical studies for glabellar lines [see Clinical Studies (14.5) ] , 21 subjects were 65 years of age and over. Of the total number of 730 subjects in the placebo-controlled clinical studies for upper facial lines GL, HFL, and LCL [see Clinical Studies (14.5) ] , 46 subjects were 65 years of age and over. Clinical trials of XEOMIN showed no increase in the incidence of adverse events related to treatment with XEOMIN in patients 65 years of age and over but the trials did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently from younger adult subjects.

XEOMIN blocks cholinergic transmission at the neuromuscular and salivary neuroglandular 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. In both muscles and glands, impulse transmission is re-established by the formation of new nerve endings.