Onabotulinumtoxina

BOTOX Cosmetic (onabotulinumtoxinA) is indicated in adult patients for the temporary improvement in the appearance of:

• moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity
• moderate to severe lateral canthal lines associated with orbicularis oculi activity
• moderate to severe forehead lines associated with frontalis muscle activity
• moderate to severe platysma bands associated with platysma muscle activity BOTOX Cosmetic is an acetylcholine release inhibitor and a neuromuscular blocking agent indicated in adult patients for the temporary improvement in the appearance of ( 1 ): Moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity Moderate to severe lateral canthal lines associated with orbicularis oculi activity Moderate to severe forehead lines associated with frontalis muscle activity Moderate to severe platysma bands associated with platysma muscle activity

For injection: 50 Units, vacuum-dried powder in a single-dose vial for reconstitution For injection: 100 Units, vacuum-dried powder in a single-dose vial for reconstitution For Injection: 50 Units or 100 Units vacuum-dried powder in a single-dose vial for reconstitution ( 3 )

Hypersensitivity to any botulinum toxin preparation or to any of the components in the formulation ( 4.1 , 5.4 ) Infection at the injection site ( 4.2 )

4.1 Known Hypersensitivity to Botulinum Toxin BOTOX Cosmetic is contraindicated in individuals with known hypersensitivity to any botulinum toxin preparation or to any of the components in the formulation [see Warnings and Precautions ( 5.4 )] .

4.2 Infection at the Injection Site(s) BOTOX Cosmetic is contraindicated in the presence of infection at the proposed injection site(s).

Potency Units of BOTOX Cosmetic cannot be compared to or converted into Units of any other preparations of botulinum toxin products ( 5.1 , 11 ) Spread of toxin effects; swallowing and breathing difficulties can lead to death. Seek immediate medical attention if respiratory, speech or swallowing difficulties occur ( 5.2 , 5.7 ) Potential serious adverse reactions after administration of BOTOX for unapproved uses ( 5.3 ) Adverse event reports have been received involving the cardiovascular system, some with fatal outcomes. Use caution when administering to patients with pre-existing cardiovascular disease. ( 5.5 ) Concomitant neuromuscular disorder may exacerbate clinical effects of treatment ( 5.6 ) Use with caution in patients with compromised respiratory function or dysphagia ( 5.7 )

5.1 Lack of Equivalency B etween Botulinum Toxin Products The potency Units of BOTOX Cosmetic are specific to the preparation and assay method utilized. BOTOX Cosmetic is not equivalent to other preparations of botulinum toxin products, and therefore, Units of biological activity of BOTOX Cosmetic cannot be compared to nor converted into Units of any other botulinum toxin products assessed with any other specific assay method [see Description ( 11 )] .

5.2 Spread of Toxin Effect Postmarketing safety data from BOTOX Cosmetic 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, 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 spread of toxin effects. The risk of symptoms is probably greatest in children treated for spasticity but symptoms can also occur in adults treated for spasticity and other conditions, and particularly in those patients who have an underlying condition that would predispose them to these symptoms. In unapproved uses 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 and spasticity. Advise patients or caregivers to seek immediate medical care if swallowing, speech or respiratory disorders occur. No definitive serious adverse event reports of distant spread of toxin effect associated with dermatologic use of BOTOX/BOTOX Cosmetic at the labeled dose of 20 Units (for glabellar lines), 24 Units (for lateral canthal lines), 40 Units (for forehead lines with glabellar lines), 44 Units (for simultaneous treatment of lateral canthal lines and glabellar lines), 64 Units (for simultaneous treatment of lateral canthal lines, glabellar lines, and forehead lines), or 100 Units (for severe primary axillary hyperhidrosis) have been reported. No definitive serious adverse event reports of distant spread of toxin effect associated with BOTOX for blepharospasm at the recommended dose (30 Units and below), strabismus, or chronic migraine at the labeled doses have been reported.

5.3 Serious Adverse Reactions with Unapproved Use Serious adverse reactions, including excessive weakness, dysphagia, and aspiration pneumonia, with some adverse reactions associated with fatal outcomes, have been reported in patients who received BOTOX injections for unapproved uses. In these cases, the adverse reactions were not necessarily related to distant spread of toxin, but may have resulted from the administration of BOTOX to the site of injection and/or adjacent structures. In several of the cases, patients had pre-existing dysphagia or other significant disabilities. There is insufficient information to identify factors associated with an increased risk for adverse reactions associated with the unapproved uses of BOTOX. The safety and effectiveness of BOTOX for unapproved uses have not been established.

5.4 Hypersensitivity Reactions Serious and/or immediate hypersensitivity reactions have been reported. These reactions include anaphylaxis, serum sickness, urticaria, soft tissue edema, and dyspnea. If such a reaction occurs, discontinue further injection of BOTOX Cosmetic and immediately institute appropriate medical therapy. One fatal case of anaphylaxis has been reported in which lidocaine was used as the diluent, and consequently the causal agent cannot be reliably determined.

5.5 Cardiovascular System There have been reports following administration of BOTOX/BOTOX Cosmetic of adverse events involving the cardiovascular system, including arrhythmia and myocardial infarction, some with fatal outcomes. Some of these patients had risk factors including pre-existing cardiovascular disease. Use caution when administering to patients with pre-existing cardiovascular disease.

5.6 Increased Risk of Clinically Significant Effects with Pre-Existing Neuromuscular Disorders Patients with neuromuscular disorders may be at increased risk of clinically significant effects including generalized muscle weakness, diplopia, ptosis, dysphonia, dysarthria, severe dysphagia and respiratory compromise from onabotulinumtoxinA [see Warnings and Precautions ( 5.2 , 5.7 )] . Monitor individuals with peripheral motor neuropathic diseases, amyotrophic lateral sclerosis or neuromuscular junction disorders (e.g., myasthenia gravis or Lambert-Eaton syndrome) when given botulinum toxin.

5.7 Dysphagia and Breathing Difficulties Treatment with BOTOX 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 oropharyngeal muscles that control swallowing or breathing [see Warnings and Precautions ( 5.2 )] . 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 with botulinum toxins may weaken neck muscles that serve as accessory muscles of ventilation. This may result in a critical loss of breathing capacity in patients with respiratory disorders who may have become dependent upon these accessory muscles. There have been postmarketing reports of serious breathing difficulties, including respiratory failure. Patients with smaller neck muscle mass and patients who require bilateral injections into the sternocleidomastoid muscle for the treatment of cervical dystonia have been reported to be at greater risk for dysphagia. Limiting the dose injected into the sternocleidomastoid muscle may reduce the occurrence of dysphagia. Injections into the levator scapulae may be associated with an increased risk of upper respiratory infection and 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 ( 5.2 )] .

5.8 Pre-existing Conditions at the Injection Site Use caution when BOTOX Cosmetic treatment is used in the presence of inflammation at the proposed injection site(s), ptosis, or when excessive weakness or atrophy is present in the targeted muscle(s). […]

The following adverse reactions to BOTOX Cosmetic (onabotulinumtoxinA) for injection are discussed in greater detail in other sections of the labeling: Spread of Toxin Effects [see Warnings and Precautions ( 5.2 )] Hypersensitivity [see Contraindications ( 4.1 ) and Warnings and Precautions ( 5.4 )] Dysphagia and Breathing Difficulties [see Warnings and Precautions ( 5.7 )] The most common adverse reactions are ( 6.1 ): Glabellar Lines: eyelid ptosis (3%) Lateral Canthal Lines: eyelid edema (1%) Forehead Lines: headache (9%) and brow ptosis (2%) To report SUSPECTED ADVERSE REACTIONS, contact AbbVie at 1-800-678-1605 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, the 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 clinical practice. BOTOX and BOTOX Cosmetic contain the same active ingredient in the same formulation, but have different labeled Indications and Usage. Therefore, adverse events observed with the use of BOTOX also have the potential to be observed with the use of BOTOX Cosmetic. In general, adverse reactions occur within the first week following injection of BOTOX Cosmetic and while in many cases are transient, may have a duration of several months or longer. Localized pain, infection, inflammation, tenderness, swelling, erythema, and/or bleeding/bruising may be associated with the injection. Needle-related pain and/or anxiety may result in vasovagal responses (including e.g., syncope, hypotension), which may require appropriate medical therapy. Local weakness of the injected muscle(s) represents the expected pharmacological action of botulinum toxin. However, weakness of nearby muscles may also occur due to spread of toxin [see Warnings and Precautions ( 5.2 )] . Glabellar Lines Table 5 lists selected adverse reactions reported by ≥1% of BOTOX Cosmetic treated subjects (N=405) aged 18 to 75 who were evaluated in the randomized, placebo-controlled clinical studies to assess the use of BOTOX Cosmetic in the improvement of the appearance of glabellar lines. Table 5: Adverse Reactions Reported by ≥1% of BOTOX Cosmetic treated Subjects and More Frequent than in Placebo-treated Subjects in Double-blind, Placebo-controlled Clinical Studies of Treatment of Glabellar Lines Adverse Reactions by System Organ Class BOTOX Cosmetic (N=405) Placebo (N=130) General Disorders and Administration Site Conditions Facial pain 6 (1%) 0 (0%) Nervous System Disorders Facial paresis 5 (1%) 0 (0%) Eye Disorders Eyelid ptosis 13 (3%) 0 (0%) Musculoskeletal and Connective Tissue Disorders Muscular Weakness 6 (1%) 0 (0%) Lateral Canthal Lines Table 6 lists selected adverse reactions reported within 90 days following injection by ≥1% of BOTOX Cosmetic treated subjects (N=526) aged 18 to 75 who were evaluated in two randomized, double-blind, placebo-controlled clinical studies to assess the use of BOTOX Cosmetic in the improvement of the appearance of lateral canthal lines alone. Table 6: Adverse Reaction Reported by ≥1% of BOTOX Cosmetic Treated Subjects and More Frequent than in Placebo-treated Subjects Within 90 Days, in Double-blind, Placebo-controlled Clinical Studies of Treatment of Lateral Canthal Lines Adverse Reactions by System Organ Class BOTOX Cosmetic 24 Units (N=526) Placebo (N=530) Eye disorders Eyelid edema 5 (1%) 0 (0%) Forehead Lines Table 7 lists selected adverse reactions reported by ≥1% of BOTOX Cosmetic treated subjects (N=665) aged 18 to 77 who were evaluated in two randomized, double-blind, placebo-controlled clinical studies to assess the use of BOTOX Cosmetic in the improvement of the appearance of forehead lines with glabellar lines. Table 7: Adverse Reactions Reported by ≥1% of BOTOX Cosmetic treated Subjects More Frequently than in Placebo-treated Subjects, in Double-blind, Placebo-controlled Clinical Studies of Treatment of Forehead Lines Adverse Reactions by System Organ Class BOTOX Cosmetic (20 Units forehead lines with 20 Units glabellar lines ) (N=665) Placebo (N=315) Nervous System Disorders Headache 58 (9%) 17 (5%) Eye Disorders Eyelid ptosis 12 (2%) 1 (0%) Skin and Subcutaneous Tissue Disorders Brow ptosis Skin tightness 13 (2%) 10 (2%) 0 (0%) 0 (0%) There were no additional adverse drug reactions reported with the simultaneous treatment of forehead lines, glabellar lines, and lateral canthal lines. Platysma Bands The safety of BOTOX Cosmetic (26 Units, 31 Units, or 36 Units) was evaluated in two double-blind, placebo-controlled, clinical trials with 407 BOTOX Cosmetic-treated subjects and 425 subjects receiving placebo. The safety profile of BOTOX Cosmetic treatment of platysma bands is consistent with the known safety profile of BOTOX Cosmetic for other indications. 6. 2 Postmarketing Experience 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. There have been spontaneous reports of death, sometimes associated with dysphagia, pneumonia, and/or other significant debility or anaphylaxis, after treatment with botulinum toxin [see Warnings and Precautions ( 5.4 , 5.7 )] . There have also been reports of adverse events involving the cardiovascular system, including arrhythmia and myocardial infarction, some with fatal outcomes. Some of these patients had risk factors including cardiovascular disease. New onset or recurrent seizures have also been reported, typically in patients who are predisposed to experiencing these events. The following adverse reactions by System Organ Class have been identified during post-approval use of BOTOX/BOTOX Cosmetic: Ear and labyrinth disorders Hypoacusis; tinnitus; vertigo Eye disorders Diplopia; dry eye; eyelid edema; lagophthalmos; strabismus; visual disturbances; vision blurred Gastrointestinal disorders Abdominal pain; diarrhea; dry mouth; nausea; vomiting General disorders and administration site conditions Denervation; malaise; pyrexia Metabolism and nutrition disorders Anorexia Musculoskeletal and connective tissue disorders Localized muscle twitching/involuntary muscle contractions; Mephisto sign; muscle atrophy; myalgia Nervous system disorders Brachial plexopathy; dysarthria; facial palsy; hypoaesthesia; localized numbness; myasthenia gravis; paresthesia; peripheral neuropathy; radiculopathy; syncope Respiratory, thoracic and mediastinal disorders Aspiration pneumonia; dyspnea; respiratory depression and/or respiratory failure Skin and subcutaneous tissue disorders Alopecia, including madarosis; hyperhidrosis; pruritus; skin rash (including erythema multiforme, dermatitis psoriasiform, and psoriasiform eruption)

No formal drug interaction studies have been conducted with BOTOX Cosmetic (onabotulinumtoxinA) for injection. Patients receiving concomitant treatment of BOTOX Cosmetic and aminoglycosides or other agents interfering with neuromuscular transmission (e.g., curare-like agents), or muscle relaxants, should be observed closely because the effect of BOTOX Cosmetic may be potentiated ( 7 )

7.1 Aminoglycosides and Other Agents Interfering with Neuromuscular Transmission Co-administration of BOTOX Cosmetic and aminoglycosides or other agents interfering with neuromuscular transmission (e.g., curare-like compounds) should only be performed with caution as the effect of the toxin may be potentiated.

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

7.3 Other Botulinum Neurotoxin Products The effect of administering different botulinum neurotoxin 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 BOTOX Cosmetic.

8.1 Pregnancy Risk Summary There are no studies or adequate data from postmarketing surveillance on the developmental risk associated with use of BOTOX Cosmetic in pregnant women. In animal studies, administrations of BOTOX Cosmetic during pregnancy resulted in adverse effects on fetal growth (decreased fetal body weight and skeletal ossification) at clinically relevant doses, which were associated with maternal toxicity [see Data]. The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. 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. Data Animal Data When BOTOX Cosmetic (4, 8, or 16 Units/kg) was administered intramuscularly to pregnant mice or rats two times during the period of organogenesis (on gestation days 5 and 13), reductions in fetal body weight and decreased fetal skeletal ossification were observed at the two highest doses. The no-effect dose for developmental toxicity in these studies (4 Units/kg) is approximately 4 times the average high human dose for glabellar lines, lateral canthal lines, and forehead lines of 64 Units on a body weight basis (Units/kg). When BOTOX Cosmetic was administered intramuscularly to pregnant rats (0.125, 0.25, 0.5, 1, 4, or 8 Units/kg) or rabbits (0.063, 0.125, 0.25, or

0.5 Units/kg) daily during the period of organogenesis (total of 12 doses in rats, 13 doses in rabbits), reduced fetal body weights and decreased fetal skeletal ossification were observed at the two highest doses in rats and at the highest dose in rabbits. These doses were also associated with significant maternal toxicity, including abortions, early deliveries, and maternal death. The developmental no-effect doses in these studies of 1 Unit/kg in rats is approximately equal the average high human dose of 64 Units based on Units/kg, and the developmental no-effect dose of

0.25 Units/kg in rabbits is less than the average high human dose based on Units/kg. When pregnant rats received single intramuscular injections (1, 4, or 16 Units/kg) at three different periods of development (prior to implantation, implantation, or organogenesis), no adverse effects on fetal development were observed. The developmental no-effect level for a single maternal dose in rats (16 Units/kg) is approximately 16 times the average high human dose of 64 Units based on Units/kg. 8. 2 Lactation Risk Summary There are no data on the presence of BOTOX Cosmetic in human or animal milk, the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for BOTOX Cosmetic and any potential adverse effects on the breastfed infant from BOTOX Cosmetic or from the underlying maternal conditions.

8.4 Pediatric Use The safety and effectiveness of BOTOX Cosmetic have not been established in pediatric patients.

8.5 Geriatric Use Glabellar Lines In the two initial glabellar lines clinical studies of BOTOX Cosmetic, the responder rates appeared to be higher for subjects younger than age 65 than for subjects 65 years or older [see Clinical Studies ( 14 )] . Lateral Canthal Lines In the two lateral canthal lines clinical studies of BOTOX Cosmetic, the responder rates appeared to be higher for subjects younger than age 65 than for subjects 65 years or older. Forehead Lines In the two forehead lines clinical studies of BOTOX Cosmetic, the responder rates appeared to be higher for subjects younger than age 65 than for subjects 65 years or older. Platysma Bands In the two platysma bands clinical studies of BOTOX Cosmetic, 3.6% of subjects (13 subjects) treated with BOTOX Cosmetic were 65 years or older. Although the responder rates appeared to be higher for subjects younger than age 65 than for subjects 65 years or older, clinical studies of BOTOX Cosmetic did not include sufficient numbers of subjects 65 years or older to determine whether they respond differently from younger subjects.

BOTOX Cosmetic blocks neuromuscular transmission by binding to acceptor sites on motor nerve terminals, entering the nerve terminals, and inhibiting the release of acetylcholine. This inhibition occurs as the neurotoxin cleaves SNAP-25, a pre-synaptic protein integral to the successful docking and release of acetylcholine from vesicles situated within nerve endings. When injected intramuscularly at therapeutic doses, BOTOX Cosmetic produces partial chemical denervation of the muscle resulting in a localized reduction in muscle activity. In addition, the muscle may atrophy, axonal sprouting may occur, and extrajunctional acetylcholine receptors may develop. There is evidence that reinnervation of the muscle may occur, thus slowly reversing muscle denervation produced by BOTOX Cosmetic.