Letibotulinumtoxina

LETYBO 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. LETYBO is an acetylcholine release inhibitor and a neuromuscular blocking agent 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. ( 1 )

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

LETYBO is contraindicated in: Patients with known hypersensitivity to any botulinum toxin preparation or to any of the components in the LETYBO formulation [see Warnings and Precautions ( 5.4 )] . The presence of infection at the proposed injection site(s). Known hypersensitivity to any botulinum toxin preparation or to any of the components in the LETYBO formulation ( 4 ) Infection at the injection site ( 4 )

4.1 Known Hypersensitivity to Botulinum Toxin BRANDNAME 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) BRANDNAME is contraindicated in the presence of infection at the proposed injection site(s).

Spread of toxin effects; swallowing and breathing difficulties can lead to death. Seek immediate medical attention if respiratory, speech or swallowing difficulties occur. ( 5.1 , 5.3 , 5.7 ) Potency Units of LETYBO are not interchangeable with other preparations of botulinum toxin products. ( 5.2 , 11 ) Potential serious adverse reactions after LETYBO injections for unapproved uses. ( 5.3 ) If a hypersensitivity reaction occurs, discontinue LETYBO and immediately initiate appropriate therapy. ( 5.4 ) 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 Spread of Toxin Effects Postmarketing safety data from other approved botulinum toxins suggest that botulinum toxin effects may 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, blurred vision 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. In unapproved uses and approved indications, symptoms consistent with spread of toxin effects have been reported at doses comparable to or lower than the maximum recommended total dose [see Use in Specific Populations ( 8.4 )] . LETYBO is not approved for any conditions other than glabellar lines. Patients or caregivers should be advised to seek immediate medical care if swallowing, speech or respiratory difficulties occur.

5.2 Lack of Interchangeability between Botulinum Toxin Products The potency units of LETYBO are specific to the preparation and assay method utilized. They are not interchangeable with other preparations of botulinum toxin products and, therefore, units of biological activity of LETYBO 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 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 botulinum toxin injections for unapproved uses. In these cases, the adverse reactions may have resulted from the administration of botulinum toxin products to the site of injection and/or adjacent structures. In several of the cases, patients had preexisting 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 botulinum toxin products.

5.4 Hypersensitivity Reactions Serious and/or immediate hypersensitivity reactions have been reported for botulinum toxin products. These reactions include anaphylaxis, serum sickness, urticaria, soft tissue edema, and dyspnea. If such a reaction occurs, discontinue further injection of LETYBO and immediately institute appropriate medical therapy [see Contraindications ( 4 )] .

5.5 Cardiovascular System Adverse Reactions There have been reports following administration of botulinum toxins 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 typical doses of LETYBO. Monitor patients with peripheral motor neuropathic diseases, amyotrophic lateral sclerosis, or neuromuscular junction disorders (e.g., myasthenia gravis or Lambert-Eaton syndrome) for increased neuromuscular compromise following botulinum toxin treatment.

5.7 Dysphagia and Dyspnea Treatment with botulinum toxin products, including LETYBO, can result in dysphagia and dyspnea including respiratory failure. These reactions can occur within hours to weeks after injection with botulinum toxin. Patients with preexisting dysphagia and dyspnea may be more susceptible to these complications. In most cases, this has been a consequence of weakening of muscles in the area of injection that are involved in breathing or oropharyngeal muscles that control swallowing or breathing Deaths as a complication of severe dysphagia have been reported after treatment with botulinum toxin products. Dysphagia may persist for several months. Patients treated with botulinum toxin products, including LETYBO, may require immediate medical attention should they develop problems with swallowing, speech, or breathing. These reactions can occur within hours to weeks after injection with botulinum toxin [see Warnings and Precautions ( 5.1 )] .

5.8 Pre-existing Conditions at the Injection Site Use caution when LETYBO treatment is used in the presence of inflammation at the proposed injection site(s) or when excessive weakness or atrophy is present in the target muscle(s). Use caution when LETYBO treatment 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).

5.9 Ophthalmic Adverse Reactions in Patients Treated with Botulinum Toxin Products Dry eye has been reported with the use of botulinum toxin products in the treatment of glabellar lines. Reduced tear production, reduced blinking, and corneal disorders may occur with use of botulinum toxins, including LETYBO. If symptoms of dry eye (e.g., eye irritation, photophobia or visual changes) persist, consider referring patient to an ophthalmologist [see Warnings and Precautions ( 5.1 )] .

5.10 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 a remote risk for transmission of viral diseases and variant Creutzfeldt-Jakob disease (CJD). There is a theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD), which would also be considered remote. No cases of transmission of viral diseases or CJD or vCJD have ever been identified for licensed albumin or albumin contained in other licensed products.

The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Spread of Toxin Effects [see Warnings and Precautions ( 5.1 )] Hypersensitivity Reactions [see Contraindications ( 4 ) and Warnings and Precautions ( 5.4 )] Cardiovascular System Adverse Reactions [see Warnings and Precautions ( 5.5 )] Increased Neuromuscular Compromise in Patients with Pre-Existing Neuromuscular Disorders [see Warnings and Precautions ( 5.6 )] Dysphagia and Dyspnea [see Warnings and Precautions ( 5.7 )] Ophthalmic Adverse Reactions in Patients Treated for Glabellar Lines [see Warnings and Precautions ( 5.9 )] The most common adverse reaction is headache (2%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact HUGEL at 1‑888-674-5355 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. In the three randomized, placebo-controlled, Phase 3 clinical trials that assess the use of LETYBO for the temporary improvement in the appearance of moderate to severe glabellar lines (BLESS I, II and III), 911 out of the 955 subjects who received a single dose treatment of 20 Units LETYBO and 310 out of the 317 subjects who received a single dose of placebo were included in safety analyses [see Clinical Studies ( 14 )] . Table 2 lists the adverse reactions reported in more than one subject in the LETYBO group compared to the placebo in the placebo-controlled trials. Most adverse reactions occur within the first week following injection of LETYBO and while generally transient, may have a duration of several months or longer. Table 2: Adverse Reactions Reported in More Than One Subject in the LETYBO Group Compared to the Placebo Group in BLESS I, II and III Adverse Reaction Treatment LETYBO BLESS I, II, III N=911 n (%) PLACEBO BLESS I, II, III N=310 n (%) Headache* 17 (2%) 2 (1%) Brow ptosis** 3 (<1%) 0 Eyelid ptosis 3 (<1%) 0 Blepharospasm 2 (<1%) 0 * Includes headache, head discomfort, migraine, and procedural headache. ** Includes brow ptosis and brow heaviness. The most frequently reported injection site reactions included administrative site swelling, facial pain, folliculitis, periorbital hematoma; and injection site bruising, reaction, pain, hematoma, nodule, pruritus, and mass. BLESS I, II and III also included an open label, extension part with LETYBO. The extension allowed subjects who had completed the double-blind portion of the trials to receive up to 3 additional elective LETYBO 20-Unit treatments for moderate to severe glabellar lines over a 48-week period. Treatments were separated by at least a 3-month period. Of the 1,129 subjects enrolled in the open label extension part of the trials, the median number of treatments was 3. The adverse reaction profile was comparable to that reported in the randomized, single dose, double blind part of the trials. Headache was the most common adverse reaction, reported in 2% of subjects, followed by injection site reactions (1%) [including contusion/bruising, administration site swelling, facial pain, periorbital hematoma, skin swelling; and injection site reaction, bruising, hematoma, mass, and nodule] and eyelid ptosis in 0.5% of subjects. The incidence of these adverse reactions did not increase with multiple re-treatments.

6.2 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 to letibotulinumtoxinA-wlbg in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. Treatment with botulinum toxins may result in the formation of antibodies that may reduce the effectiveness of subsequent treatments by inactivating biological activity of the toxin. Among 1,195 subjects treated with letibotulinumtoxinA-wlbg, four subjects (0.3%) developed antibodies to letibotulinumtoxinA-wlbg following treatment with LETYBO. In the selected anti-drug antibodies positive samples that were further tested, there were no neutralizing anti-drug antibodies detected.

No drug interaction studies have been conducted with LETYBO. Certain drugs may potentiate the effects of LETYBO which may result in excessive neuromuscular weakness and heighten systemic anticholinergic effects. Use caution with concurrent use of LETYBO with the following products and monitor closely for excessive neuromuscular weakness: Aminoglycosides or other agents interfering with neuromuscular transmission Anticholinergic drugs Botulinum neurotoxin products administered as the same time or within several months of LETYBO Muscle relaxants administered before or after administration of LETYBO Aminoglycoside antibiotics, anticholinergic agents, or any other agents that interfere with neuromuscular transmission may potentiate the effect of LETYBO; co-administer only with caution and close observation. ( 7 )

8.1 Pregnancy Risk Summary Available data from case reports with LETYBO use in pregnant women are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Systemic exposure following intramuscular injection of letibotulinumtoxinA-wlbg was not assessed [see Clinical Pharmacology ( 12.3 )] . In an animal reproduction study, intramuscular administration of letibotulinumtoxinA‑wlbg to rats during pregnancy resulted in adverse effects on fetal growth (decreased fetal body weight and skeletal ossification) at maternally toxic doses 3 times the maximum recommended human dose (MRHD) (see Data) . The background risk of major birth defects and miscarriage for the indicated population 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 miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data An embryofetal development study was conducted in rats with letibotulinumtoxinA-wlbg. For comparison of animal to human doses based on a body weight comparison, the MRHD is set at 20 Units/subject (0.34 Units/kg for an average 60 kg subject). Administration to pregnant rats once daily during organogenesis (gestation days 5 to 16) caused decreased fetal body weight and decreased fetal skeletal ossification at doses ≥1 Unit/kg (3 times the MRHD. These treatment related effects were associated with maternal toxicity.

8.2 Lactation Risk Summary There are no data regarding the presence of letibotulinumtoxinA-wlbg in human or animal milk, its effects on the breastfed infant, or the effects on milk production. Systemic exposure following intramuscular injection of letibotulinumtoxinA-wlbg was not assessed [see Clinical Pharmacology ( 12.3 )] .The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LETYBO and any potential adverse effects on the breastfed infant from LETYBO or from the underlying maternal condition.

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

8.5 Geriatric Use The 3 clinical trials of LETYBO included 148 subjects age 65 and greater. Although no clinically meaningful differences in safety or efficacy were observed between older and younger subjects, clinical studies of LETYBO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

LETYBO blocks cholinergic transmission at the neuromuscular junction by inhibiting the release of acetylcholine. When injected intramuscularly at therapeutic doses, LETYBO is internalized into the nerve terminal, translocates into the neuronal cytosol where it cleaves SNAP25, a protein necessary for synaptic membrane docking and subsequent release of acetylcholine which produces a dose dependent decrease of muscle function. Recovery of muscle function is gradual due to degradation of the neurotoxin and formation of axonal sprouts. Muscle reinnervation occurs, leading to a slow reversal of the pharmacological effects of LETYBO.