DAXXIFY

DaxibotulinumtoxinA-lanm is an acetylcholine release inhibitor and neuromuscular blocking agent. DaxibotulinumtoxinA-lanm is a 150 kDa botulinum toxin without accessory proteins purified from the bacterium Clostridium botulinum type A. DAXXIFY (daxibotulinumtoxinA-lanm) for injection is supplied as a sterile, preservative-free, white to off- white lyophilized powder in a single-dose vial for intramuscular use after reconstitution. DAXXIFY is formulated with a 35 amino acid peptide excipient (RTP004) that prevents surface adsorption and promotes thermal stability of DAXXIFY. Each vial contains 50 Units or 100 Units of daxibotulinumtoxinA-lanm, L- histidine (0.14 mg), L-histidine HCl monohydrate (0.65 mg), polysorbate 20 (0.1 mg), RTP004 peptide (11.7 mcg), and trehalose dihydrate (36 mg).

DAXXIFY is an acetylcholine release inhibitor and neuromuscular-blocking agent indicated for: Temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/ or procerus muscle activity in adult patients. ( 1.1 ) The treatment of cervical dystonia in adult patients. ( 1.2 ) 1.1 Glabellar Lines DAXXIFY 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. 1.2 Cervical Dystonia DAXXIFY is indicated for the treatment of cervical dystonia in adult patients.

Glabellar Lines : the recommended dose is 0.1 mL (8 Units) by intramuscular injection into each of five sites, for a total dose of 40 Units. ( 2.2 ) Cervical Dystonia : the recommended dose is 125 Units to 250 Units given intramuscularly as a divided dose among affected muscles. ( 2.3 ) 2.1 Important Administration Instructions The potency units of DAXXIFY for injection are specific to the preparation and test method utilized. They are not interchangeable with other preparations of botulinum toxin products, and, therefore, units of biological activity of DAXXIFY cannot be compared to, or converted into, units of any other botulinum toxin products assessed with any other specific test method [see Warnings and Precautions (5.2) and Description (11) ]. The safe and effective use of DAXXIFY depends upon proper storage of the product, selection of the correct dose, and proper reconstitution and administration techniques. DAXXIFY should be administered no more frequently than every three months for any indication. Consideration of the cumulative dose is necessary when treating adult patients with DAXXIFY. Physicians should be aware of whether patients are receiving treatment with other botulinum toxin products for other indications. Reconstituted DAXXIFY is intended for intramuscular injection only. After reconstitution, only use each DAXXIFY vial for only one injection session and for only one patient. Discard any remaining solution in vial immediately after administration. Reconstitution instructions are provided specifically for the 50 Unit and the 100 Unit vials (Table 1; Table 2). 2.2 Recommended Dosage and Administration for Glabellar Lines Recommended Dosage for Glabellar Lines The total recommended dose is 40 Units per treatment session divided into five equal intramuscular injections of 8 Units each (two injections in each corrugator muscle and one injection in the procerus muscle). Administration for Glabellar Lines Glabellar lines arise from the contraction of the corrugator and procerus muscles. These can be identified by palpation of the glabellar muscle mass while having the patient frown maximally. Contraction of the corrugator muscles compresses the skin, creating a vertical line or lines surrounded by ridges of tensed muscle. Because the exact location, size, and activity of the muscles can vary markedly among individuals, physicians administering DAXXIFY must understand the relevant anatomy of the area involved and any alterations to the anatomy due to prior surgical procedures and diseases [see Warnings and Precautions (5.3) ] . After assessment, the location of the corrugator muscle injection sites may need to be adjusted based on individual facial anatomy and the pattern of muscle contraction. The upper eyelid margin position should be carefully examined for separation or weakness of the levator palpebrae superioris muscle. Evaluate the range of upper eyelid excursion while manually immobilizing the frontalis to assess degree of levator function and frontalis compensation. 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. Ensure the injected volume/dose is accurate and administer in a steady, controlled manner. Do not inject DAXXIFY less than 1 centimeter above the superior orbital rim. To inject DAXXIFY, clean the exposed portion of the stopper with an alcohol swab and aseptically withdraw at least 0.5 mL of the reconstituted solution from the vial into a sterile syringe. Replace the needle used to withdraw the product with a 30- to 33-gauge sterile needle for injection. Expel any air bubbles prior to administration. Advance the needle through the skin into the underlying muscle while applying finger pressure on the superior medial orbital rim. Inject a dose of 8 Units (0.1 mL) into each of the 5 injection sites: 2 injections into medial corrugator and lateral corrugator muscles respectively, and 1 injection in the procerus muscle (Figure 1). FIGURE 1: INJECTION SITES FOR GLABELLAR LINES FIGURE 1 2.3 Recommended Dosage for Cervical Dystonia The recommended dose of DAXXIFY for the treatment of cervical dystonia ranges from 125 Units to 250 Units given intramuscularly as a divided dose among affected muscles. In patients previously treated with another botulinum toxin, their past dose, response to treatment, duration of effect, and adverse event history should be taken into consideration when determining the initial DAXXIFY dose. A description of the average DAXXIFY dose and percentage of total dose injected into specific muscles in the pivotal clinical trials can be found in Section 14. Limiting the dose injected into the sternocleidomastoid muscle may reduce the occurrence of dysphagia. Dose Modification in Cervical Dystonia When dose modification is necessary, dose adjustment can be made in 50 to75 Unit increments according to the individual patient's response. The total dose administered in a single treatment is recommended to be between 125 Units and 250 Units. 2.4 Preparation and Dilution Technique DAXXIFY is supplied in single-dose 50 Unit and 100 Unit vials. Prior to intramuscular injection, reconstitute each vial of DAXXIFY with the required amount of sterile, preservative-free 0.9% Sodium Chloride Injection, USP to obtain a reconstituted solution at the appropriate concentration described in Tables 1 and 2. TABLE 1: DAXXIFY 50 Unit Vials Dilution Volume for Reconstitution Indication Diluent Preservative-free 0.9% Sodium Chloride Injection, USP Added to 50 Unit Vial Resulting Dose in Units per 0.1 mL Glabellar Lines, Adults 0.6 mL 8 Units TABLE 2: DAXXIFY 100 Unit Vials Dilution Volume for Reconstitution Indication Diluent Preservative-free 0.9% Sodium Chloride Injection, USP Added to 100 Unit Vials Resulting Dose in Units per 0.1 mL Glabellar Lines, Adults 1.2 mL 8 Units Cervical Dystonia, Adults 1 mL or 2 mL 10 Units or 5 Units Slowly inject the diluent into the vial. Discard the vial if a vacuum does not pull the diluent into the vial. Dispose of any unused diluent. Gently mix DAXXIFY with 0.9% Sodium Chloride Injection, USP by rotating the vial. Reconstituted DAXXIFY solution is clear to slightly opalescent and colorless and free of particulate matter. Inspect visually the reconstituted DAXXIFY for particulate matter and discoloration prior to administration. Do not use if the solution is cloudy or discolored or contains flakes or particles. Administer DAXXIFY within 72 hours after reconstitution. During this time period, store unused reconstituted DAXXIFY in a refrigerator between 2°C to 8°C (36°F to 46°F) and protected from light. Do not freeze reconstituted DAXXIFY. Dispose of any unused DAXXIFY.

DAXXIFY is contraindicated in: patients with known hypersensitivity to any botulinum toxin preparation, DAXXIFY, or any of the components in the DAXXIFY formulation [see Warnings and Precautions (5.4) ]. the presence of infection at the proposed injection sites. Known hypersensitivity to any botulinum toxin preparation, DAXXIFY, or any of the components in the DAXXIFY formulation. ( 4 ) Infection at the injection sites. ( 4 )

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Spread of Toxin Effect [see Warnings and Precautions (5.1) ] Hypersensitivity Reactions [see 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 Breathing Difficulties [see Warnings and Precautions (5.7) ] Ophthalmic Adverse Reactions in Patients Treated for Glabellar Lines [see Warnings and Precautions (5.9) ] The most commonly observed adverse reactions are: Glabellar Lines (≥1%): headache (6%), eyelid ptosis (2%), and facial paresis (1%). ( 6.1 ) Cervical Dystonia (≥5%): headache (9%), injection site pain (8%), injection site erythema (5%), muscular weakness (5%), and upper respiratory tract infection (5%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Revance Therapeutics, Inc. at 1-877-373-8669 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial 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. The most common side effects from treatment with DAXXIFY usually occur within one to two weeks after injection and, while generally transient, may have a duration of several weeks or months. Glabellar Lines In the two randomized, placebo-controlled, Phase 3 clinical trials that assess the use of DAXXIFY for the temporary improvement in the appearance of moderate to severe glabellar lines, GL-1 and GL-2, 406 subjects received a single-dose treatment of 40 Units DAXXIFY, and 203 subjects received placebo. The most frequent adverse reactions are presented in Table 3. TABLE 3: Most Common Adverse Reactions ≥1% and More Frequent than Placebo in Pooled Double- Blind, Placebo-Controlled Trials for Glabellar Lines Adverse Reaction DAXXIFY N=406 n (%) Placebo N=203 n (%) Headache 26 (6%) 4 (2%) Eyelid ptosis 9 (2%) 0 (0%) Facial paresis Facial paresis, including facial asymmetry. 5 (1%) 0 (0%) Injection site reactions were reported in 6% of subjects treated with DAXXIFY and in 6% of subjects treated with placebo (these reactions included injection site pain, injection site erythema, injection site oedema, injection site bruising, injection site hematoma, injection site papule, and injection site pruritus). In an 84-week, open-label, repeat-dose safety study in glabellar lines, 2691 subjects were treated with 40 Units of DAXXIFY. Of these, 2380 subjects received one treatment with DAXXIFY, 882 received two treatments with DAXXIFY, and 568 subjects received three treatments with DAXXIFY. Adverse reactions were reported in 535 of the 2691 subjects (20%). The adverse reaction profile was similar to that reported in single-dose trials. Injection site reactions were the most common adverse reactions, reported in 9% of subjects [including injection site pain (4%), injection site erythema (3%), injection site oedema (3%), injection site bruising (1%), injection site papule (<1%), and injection site pruritus (<1%)], followed by headache (5%), edema (2%), erythema (2%), and eyelid ptosis in 1% of subjects. The incidence of these adverse reactions did not increase with multiple re- treatments. Cervical Dystonia In the randomized, placebo-controlled, Phase 3 clinical trial to assess the use of DAXXIFY for the treatment of cervical dystonia, 255 patients received a dose of DAXXIFY (n=125 for 125 Units and n=130 for 250 Units), and 46 patients received placebo. Table 4 lists adverse reactions that occurred in ≥2% of patients treated with DAXXIFY and more frequently than placebo. TABLE 4: Most Common Adverse Reactions ≥2% and More Frequent than Placebo in the Phase 3 Double-Blind, Placebo-Controlled Clinical Trial for Cervical Dystonia Adverse Reaction DAXXIFY 125 Units N=125 n (%) DAXXIFY 250 Units N = 130 n (%) Placebo N=46 n (%) Headache 11 (9%) 9 (7%) 1 (2%) Injection site pain 10 (8%) 7 (5%) 2 (4%) Injection site erythema 6 (5%) 3 (2%) 1 (2%) Muscular weakness 6 (5%) 3 (2%) 0 (0%) Musculoskeletal pain 5 (4%) 5 (4%) 0 (0%) Nasopharyngitis 4 (3%) 3 (2%) 0 (0%) Arthralgia 3 (2%) 1 (1%) 0 (0%) Upper respiratory tract infection 2 (2%) 7 (5%) 2 (4%) Spinal pain 3 (2%) 4 (3%) 1 (2%) Atrioventricular block first degree 2 (2%) 0 (0%) 0 (0%) Urinary tract infection 3 (2%) 0 (0%) 0 (0%) Dysphagia 2 (2%) 5 (4%) 0 (0%) In a 52-week, open-label, repeat-dose safety study in cervical dystonia, 357 subjects (271 from the randomized trial, 86 newly enrolled) received up to 4 treatments with DAXXIFY. Of these, 28 subjects received one treatment with DAXXIFY, 95 subjects received two treatments, 169 received three treatments, and 65 received four treatments with DAXXIFY. Adverse reactions were reported in 138 patients (20%).

No formal drug interaction studies have been conducted with DAXXIFY. However, the potential for certain drugs to potentiate the effects of DAXXIFY warrants consideration given the potential risks involved and should be used with caution. Aminoglycosides or other agents interfering with neuromuscular transmission Anticholinergic drugs Botulinum neurotoxin products Muscle relaxants Aminoglycoside antibiotics, anticholinergic agents, or any other agents that interfere with neuromuscular transmission may potentiate the effect of DAXXIFY; co-administer only with caution and close observation. ( 7 )

Storage and Handling Unopened DAXXIFY vials should be stored at room temperature 20°C to 25°C (68°F to 77°F) or refrigerated at 2°C to 8° C (36°F to 46°F) in the original carton to protect from light.