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 (5.12), 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. 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 (5.8)] . 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.

DAXXIFY should be administered no more frequently than every three months. 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.

Reconstitution instructions are provided specifically for the 50 Unit and the 100 Unit vials (Table 1; Table 2).

2.2 Recommended Dosage

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).

2.3 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 a concentration of 8 Units/0.1 mL (see Tables 1 and 2).

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.

2.4 Administration

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.

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

4.1 Hypersensitivity

DAXXIFY is contraindicated in patients with known hypersensitivity to any botulinum toxin preparation, DAXXIFY or any of the components in the DAXXIFY formulation.

4.2 Infection at Injection Site

DAXXIFY is contraindicated in the presence of infection at the proposed injection sites.

5.1 Spread of Toxin Effect

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, 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 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 upper limb spasticity in children and approved indications, symptoms consistent with spread of toxin effect have been reported at doses comparable to or lower than the maximum recommended total dose. DAXXIFY is not approved for treatment of spasticity or any conditions other than glabellar lines. Patients or caregivers should be advised to seek immediate medical care if swallowing, speech or respiratory difficulties occur.

Although no serious adverse reactions of distant spread of toxin effect associated with DAXXIFY have been reported in clinical studies of 40 Units for glabellar lines, these reactions are possible.

5.2 Lack of Interchangeability between Botulinum Toxin Products

The potency Units of DAXXIFY are specific to the preparation and assay method utilized. They are not interchangeable with other preparation of botulinum toxin products therefore, Units of biological activity of DAXXIFY cannot be compared to or converted to 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 some 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 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 DAXXIFY and immediately institute appropriate medical therapy. The use of DAXXIFY in patients with a known hypersensitivity to any botulinum toxin preparation, DAXXIFY or any of its formulation components could lead to a life threatening allergic reaction. [ see Contraindications (4.1)]

5.5 Cardiovascular System

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 Pre-Existing Neuromuscular Disorders

Monitor patients with peripheral motor neuropathic diseases, amyotrophic lateral sclerosis, or neuromuscular junctional disorders (e.g., myasthenia gravis or Lambert-Eaton syndrome) for increased neuromuscular compromise following botulinum toxin treatment. 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 DAXXIFY.

5.7 Dysphagia and Breathing Difficulties

Treatment with botulinum toxin products, including DAXXIFY, can result in swallowing or breathing difficulties. These reactions can occur within hours to weeks after injection with botulinum toxin. 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 mechanisms may be involved. [see Warnings and Precautions (5.3)]

Deaths as a complication of severe dysphagia have been reported after treatment with botulinum toxin products. Dysphagia may persist for several months. 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, including DAXXIFY, 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 from other botulinum toxin products of serious breathing difficulties, including respiratory failure.

Patients treated with botulinum toxin may require immediate medical attention should they develop problems with swallowing, speech or respiratory disorders.

5.8 Pre-existing Conditions at the Injection Site

Use caution when administering DAXXIFY to patients with surgical alterations to the facial anatomy, marked facial asymmetry, excessive dermatochalasis, deep dermal scarring, thick sebaceous skin, inflammation at the injection site(s), pre-existing eyelid or eyebrow ptosis, when excessive weakness or atrophy is present in the target muscles, or the inability to substantially lessen glabellar lines even by physically spreading them apart.

5.9 Ophthalmic Adverse Reactions

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 DAXXIFY. If symptoms of dry eye (e.g., eye irritation, photophobia, or visual changes) persist, consider referring patient to an ophthalmologist.

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.

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 in the studies described below with the incidence of antibodies in other studies or to other products can 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 2786 subjects receiving up to 3 treatments with DAXXIFY in the phase 3 studies, 12 Subjects (0.4%) had preexisting binding antibodies to daxibotulinumtoxinA-lanm and 75 (3%) had preexisting binding antibodies to the 35 amino acid peptide excipient RTP004. A total of 20 (0.8%) subjects developed treatment-emergent binding antibodies to daxibotulinumtoxinA-lanm and 33 (1.2%) subjects developed treatment-emergent binding antibodies to RTP004. No subjects developed neutralizing antibodies to DAXXIFY.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness of DAXXIFY in patients less than 18 years of age have not been established.

8.5 Geriatric Use

Among the 406 subjects treated with DAXXIFY in the placebo-controlled clinical trials, 36 subjects were 65 years or older. There was no increase in the incidence of treatment-related adverse events in patients over 65 years treated with DAXXIFY. Clinical studies of DAXXIFY did not include sufficient numbers of subjects aged 65 and older to determine whether they responded differently from younger subjects. [see Clinical Studies (14)]

12.1 Mechanism of Action

DAXXIFY blocks cholinergic transmission at the neuromuscular junction by inhibiting the release of acetylcholine. When injected into skeletal muscle, DAXXIFY is internalized into the nerve terminal, translocates into the neuronal cytosol where it cleaves SNAP25, a protein necessary for synaptic vesicle membrane docking and subsequent release of acetylcholine which produces a dose dependent decrease of muscle function. Recovery of activity is gradual and results from the degradation of neurotoxin light chain in the neurons with a contribution from the formation of axonal sprouts. Muscle reinnervation occurs, leading to a slow reversal of the pharmacological effects of DAXXIFY.

12.2 Pharmacodynamics

No formal pharmacodynamics studies have been conducted with DAXXIFY.

12.3 Pharmacokinetics

Using currently available analytical technology, it is not possible to detect DAXXIFY in the peripheral blood following intramuscular injection at the recommended dose.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of DAXXIFY.

Genotoxicity studies have not been conducted for DAXXIFY.

In fertility and early embryonic development studies in rats, intramuscular administration of (3, 10 or 20 Units/kg in males and 3, 10 or 30 Units/kg in females) to either male or female rats prior to mating and during mating (7 doses, 1 week apart for males; and 4 doses, 1 week apart for females) to untreated animals, caused reduced fertility at doses associated with paternal or maternal toxicity as indicated by reductions in body weight gain and food intake. No effects on fertility were noted at 3 Units/kg in males or 10 Units/kg in females, which are approximately 4 and 15 times, respectively, the MRHD.

14.1 Glabellar Lines

Two randomized, double-blind, multi-center, placebo-controlled clinical trials, Studies GL-1 and GL-2, were conducted to evaluate DAXXIFY for use in the temporary improvement of moderate-to-severe glabellar lines in adults. The 2 trials enrolled a total of 609 subjects (≥18 years old) with glabellar lines of at least moderate severity at maximum frown. A total of 405 subjects were randomized and 406 were treated with 40 Units of DAXXIFY and 204 subjects were randomized and 203 were treated with an equal volume of placebo. Subjects were excluded if they had eyelid ptosis, deep dermal scarring, excessive dermatochalasis or an inability to lessen glabellar lines by physically spreading them apart. Enrolled subjects were 21 to 75 years old, with a mean age of 50 years, were predominantly female (87%) and Caucasian (86%). The total dose was delivered in 5 equally divided intramuscular injections of 8 Units each to specific sites in the glabellar (Figure 1). Subjects were followed for at least 24 weeks after treatment.

Efficacy was determined through the assessment by investigators and subjects of frown wrinkle severity at maximum frown using a 4-point scale (0 = none, 1 = mild, 2 = moderate, 3 = severe). The primary efficacy endpoint (treatment success) was defined as achieving a score of 0 or 1 (none or mild) and an improvement of at least 2 points from baseline for both the investigator's and subject's assessments at Week 4. The percentages of subjects with treatment success at Week 4 are presented in Table 4.

Figure 2 shows the proportion of subjects, over 36 weeks, rated as 0 or 1 (none or mild) by the investigator, 0 or 1 by the subject, and 0 or 1 with at least a 2-point improvement from their baseline based on both the investigator and subject ratings. Subjects were followed through at least Week 24 and then were discontinued from the study when both the investigator and subject scores returned to baseline. Subjects who returned to baseline levels prior to Week 36 were counted as non-responders following study discontinuation.

FIGURE 2: Proportion of subjects rated as 0 or 1 (none or mild) by investigator, 0 or 1 by the subject, and 0 or 1 with at least 2-point improvement from their baseline (based on both the investigator and subject ratings) in Study GL-1 and Study GL-2.

Treatment Success is defined as a score of 0 or 1 (none or mild) and ≥ 2-grade improvement from baseline on both the investigator and subject assessment.

How Supplied

DAXXIFY (daxibotulinumtoxinA-lanm) for injection is a sterile lyophilized powder supplied in a single-dose vial in the following sizes:

Carton containing one 50 Units/Vial NDC 72960-111-01
Carton containing one 100 Units/Vial NDC 72960-112-01

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.

Swallowing, Speaking or Breathing Difficulties, or other Unusual Symptoms

Advise patients or caregivers to seek immediate medical care if swallowing, speech or respiratory disorders arise or existing symptoms worsen. [see Warnings and Precautions (5.7)]

Ability to Operate Machinery or Vehicles

Advise patients if they develop any unusual symptoms such as loss of strength, muscle weakness, blurred vision, or drooping eyelids occur, they should avoid driving a car or engaging in other potentially hazardous activities. [see Warnings and Precautions (5)]

Ophthalmic Adverse Reaction

Inform patients that DAXXIFY injection may cause eye dryness. Advise patients to report symptoms of eye dryness (e.g., eye pain, eye irritation, photosensitivity, or changes in vision) to their doctor. [see Warnings and Precautions (5.9)]