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.

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

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.

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.

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.

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, an unapproved use for DAXXIFY, 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. 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 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)].

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 Neuromuscular Compromise in Patients with 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 Facial Anatomy in the Treatment of Glabellar Lines

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 in Patients Treated for Glabellar Lines

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.

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

12.1 Mechanism of Action

DAXXIFY blocks neuromuscular transmission at the neuromuscular junction by inhibiting the release of acetylcholine. This inhibition occurs as the neurotoxin cleaves SNAP-25, a protein necessary for the successful docking and release of acetylcholine vesicles within nerve endings. Recovery of neurotransmission occurs gradually as the neuromuscular junction recovers from SNAP25 cleavage and as new nerve endings are formed.

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.

12.6 Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of DAXXIFY.

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 5.

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.

14.2 Cervical Dystonia

The efficacy of DAXXIFY was evaluated in a randomized, double-blind, placebo-controlled, multicenter trial in a total of 301 patients (NCT03608397). The mean age of patients was 58 years, 65% were women, and 96% were White. At study baseline, 84% of patients had previously received a botulinum toxin as treatment for cervical dystonia. Patients had a clinical diagnosis of cervical dystonia with baseline Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total score ≥ 20, TWSTRS severity score ≥15, TWSTRS disability score ≥3, and TWSTRS pain score ≥1. For patients who had previously received a botulinum toxin treatment for cervical dystonia, the trial required that ≥14 weeks had passed since the most recent botulinum toxin administration.

Patients were randomized (3:3:1) to receive a single administration of 2.5 mL of either DAXXIFY 125 Units (n=125), DAXXIFY 250 Units (n=130), or placebo (n=46), divided amongst the affected muscles as selected by the investigator. Table 6 indicates the treated muscles, along with the number of patients treated and DAXXIFY units.

The primary efficacy endpoint was the mean change in the TWSTRS total score from baseline averaged over weeks 4 and 6. TWSTRS evaluates the severity of dystonia, patient-perceived disability from dystonia, and pain, with a range of possible scores from 0 to 85. The mean change from baseline in the total TWSTRS score was significantly greater for both dosage groups of DAXXIFY than for placebo (Table 7).

A similar pattern of significant improvement versus placebo was observed in the clinician global impression of change (CGIC) and patient global impression of change (PGIC) scales.

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 (5.1) (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 (5.1)].

Ophthalmic Adverse Reactions

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)].