Jeuveau

1 INDICATIONS AND USAGE JEUVEAU 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. JEUVEAU 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

Glabellar Lines Administration: 0.1 mL (4 Units) by intramuscular injection into each of five sites, for a total dose of 20 Units ( 2.2 , 2.3 )

2.1Instructions for Safe Use The

potency Units of JEUVEAU (prabotulinumtoxinA-xvfs) for injection 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 JEUVEAU cannot be compared to nor converted into units of any other botulinum toxin products assessed with any other specific assay method . Retreatment of JEUVEAU should be administered no more frequently than every three months. Consideration of the cumulative dose is necessary when treating adult patients with JEUVEAU for glabellar lines if other botulinum toxin products are or have been used to treat other indications approved for those products.

The safe and effective use of JEUVEAU depends upon proper storage of the product, selection of the correct dose, and proper reconstitution and administration techniques. Physicians administering JEUVEAU must understand the relevant neuromuscular and/or orbital anatomy of the area involved and any alterations to the anatomy due to prior surgical procedures .

2.2Preparation and Dilution Technique

JEUVEAU is supplied in a single-dose 100 Unit vial. Prior to intramuscular injection, reconstitute each vacuum-dried vial of JEUVEAU with only sterile, preservative-free 0.9% Sodium Chloride Injection, USP to obtain a reconstituted solution at a concentration of 4 Units/0.1 mL and a total treatment dose of 20 Units in 0.5 mL . 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 saline. Gently mix JEUVEAU with 0.9% Sodium Chloride Injection USP by rotating the vial. JEUVEAU should be administered within 24 hours after reconstitution. During this time period, unused reconstituted JEUVEAU should be stored in a refrigerator between 2° to 8°C (36°F to 46°F) in the original carton to protect from light for up to 24 hours until time of use.

Do not freeze reconstituted JEUVEAU. JEUVEAU vials are for single-dose only. After reconstitution, JEUVEAU should be used for only one injection session and for only one patient. Discard any remaining solution after administration. Table 1. Dilution Instructions for JEUVEAU Vials (100 Units) Diluent Preservative-free 0.9% Sodium Chloride Injection, USP Added to 100 Unit Vial Resulting Dose Units per 0.1 mL 2.5 mL 4 Units Reconstituted JEUVEAU should be clear, colorless, and free of particulate matter otherwise it should not be injected.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

2.3Administration Glabellar

facial lines arise from the activity of the corrugator and orbicularis oculi muscles. These muscles move the brow medially and the procerus and depressor supercilii pull the brow inferiorly. This creates a frown or “furrowed brow”. The location, size, and use of the muscles vary markedly among individuals.

Lines induced by facial expression occur perpendicular to the direction of action of contracting facial muscles. An effective dose for facial lines is determined by gross observation of the patient’s ability to activate the superficial muscles injected. In order to reduce the complication of eyelid ptosis the following steps should be taken: • Avoid injection near the levator palpebrae superioris, particularly in patients with larger brow depressor complexes. • Lateral corrugator injections should be placed at least 1 cm above the bony supraorbital ridge. • Ensure the injected volume/dose is accurate and where feasible kept to a minimum. • Avoid injecting JEUVEAU closer than 1 centimeter above the central eyebrow.

Draw at least 0.5 mL of the properly reconstituted JEUVEAU into a sterile syringe and expel any air bubbles in the syringe barrel. Remove the needle used to reconstitute the product and attach a 30-33 gauge needle. Confirm the patency of the needle. Inject a dose of 0.1 mL (4 Units) intramuscularly into each of five sites: the inferomedial and superior middle of each corrugator, and one in the mid-line of the procerus muscle for a total dose of 20 Units . Figure 1 Figure 1-2

5 WARNINGS AND PRECAUTIONS • Potency Units of JEUVEAU are not interchangeable with other preparations of botulinum toxin products ( 5.2 , 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 JEUVEAU injections for unapproved uses • 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 • Concomitant neuromuscular disorder may exacerbate clinical effects of treatment • Use with caution in patients with compromised respiratory function or dysphagia

5.1Spread 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, 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, 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 . JEUVEAU is not approved for the 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.

5.2Lack of Interchangeability

between Botulinum Toxin Products The potency Units of JEUVEAU 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 JEUVEAU cannot be compared to nor converted into units of any other botulinum toxin products assessed with any other specific assay method .

5.3Serious 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 were not necessarily related to distant spread of toxin, but 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 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.

5.4Hypersensitivity 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, further injection of JEUVEAU should be discontinued and appropriate medical therapy immediately instituted.

The use of JEUVEAU in patients with a known hypersensitivity to any botulinum neurotoxin or to any of the components in the formulation could lead to a life threatening allergic reaction .

5.5Cardiovascular 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.

5.6Increased Risk of Clinically Significant Effects

with Pre-Existing Neuromuscular Disorders Individuals with peripheral motor neuropathic diseases, amyotrophic lateral sclerosis, or neuromuscular junction disorders (e.g., myasthenia gravis or Lambert-Eaton syndrome) were excluded from the clinical studies of JEUVEAU. 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 JEUVEAU.

5.7Dysphagia and Breathing Difficulties Treatment with

botulinum toxin products, including JEUVEAU, can result in swallowing or breathing difficulties. Patients with preexisting swallowing or breathing difficulties 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.

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, including JEUVEAU, 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 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.

Injections into the levator scapulae for the treatment cervical dystonia may be associated with an increased risk of upper respiratory infection and dysphagia. JEUVEAU is not approved for the treatment of cervical dystonia. Patients treated with botulinum toxin products, including JEUVEAU, 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 .

5.8Pre-existing Conditions at the Injection Site Caution

should be used when JEUVEAU 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). Caution should be used when JEUVEAU treatment is used in patients who have marked facial asymmetry, ptosis, excessive dermatochalasis, deep dermal scarring, thick sebaceous skin, or when subjects do not respond to 20 Units of botulinum toxin (e.g., the inability to substantially lessen glabellar lines even by physically spreading them apart). Do not exceed the recommended dosage and frequency of administration of JEUVEAU.

5.9Ophthalmic 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 JEUVEAU. If symptoms of dry eye (e.g., eye irritation, photophobia, or visual changes) persist, consider referring patients to an ophthalmologist .

5.10Human 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 an extremely remote risk for transmission of viral diseases and variant Creutzfeldt-Jakob disease (vCJD). There is a theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD), but if that risk actually exists, the risk of transmission would also be considered extremely remote.

No cases of transmission of viral diseases, CJD, or vCJD have ever been identified for licensed albumin or albumin contained in other licensed products.

4 CONTRAINDICATIONS • Hypersensitivity to any botulinum toxin preparation or to any of the components in the formulation • Infection at the injection site

4.1Known Hypersensitivity to Botulinum Toxin

JEUVEAU is contraindicated in individuals with known hypersensitivity to any botulinum toxin preparation or to any of the components in the formulation .

4.2Infection at the Injection Site(s)

JEUVEAU is contraindicated in the presence of infection at the proposed injection site(s).

8.1Pregnancy Risk Summary The

limited available data on JEUVEAU use in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes. An embryofetal developmental study conducted with JEUVEAU in pregnant rats revealed no treatment-related effects to the developing fetus when JEUVEAU was administered intramuscularly during organogenesis at doses up to 12 times the maximum recommended human dose (MRHD) . The estimated 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 In an embryofetal developmental study, intramuscular doses up to 4 Unit/kg JEUVEAU were administered to pregnant rats once daily during organogenesis (gestation days 6 to 16). No maternal or embryofetal toxicities were observed at doses up to 4 Unit/kg (12 times the MRHD of 20 Units, based on Unit/kg comparison).

The following serious adverse reactions are discussed in greater detail in other sections of the labeling: • Spread of Toxin Effects • Hypersensitivity • Dysphagia and Breathing Difficulties The most common adverse reactions are headache (12%), eyelid ptosis (2%), upper respiratory tract infection (3%), and increased white blood cell count (1%) To report SUSPECTED ADVERSE REACTIONS, contact Evolus at [1-877-386-5871] or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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 general, most adverse reactions occur within the first week following injection of JEUVEAU and while generally 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 syncope and 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 effect . Glabellar Lines The adverse reactions below reflect exposure to JEUVEAU in the treatment of glabellar lines in placebo-controlled trials . Table 2.

Adverse Reactions Reported at Higher Frequency (≥1%) in the JEUVEAU Group Compared to the Placebo Group JEUVEAU EV-001, EV-002 N=492 n (%) PLACEBO EV-001, EV-002, N=162 n (%) Headache 57 (12%) 21 (13%) Eyelid Ptosis 8 (2%) 0 (0%) Upper Respiratory Tract Infection 13 (3%) 1 (1%) White blood cell count increase 6 (1%) 0 (0%) Two multi-center, open label, 1-year repeat dose safety trials, EV-004 [NCT02184988] and EV-006 [NCT02428608], were also conducted with JEUVEAU. Both trials evaluated repeat treatments of 20 units of JEUVEAU, up to a maximum total of 80 units, for the treatment of moderate to severe glabellar lines in adult subjects. Of the 922 subjects enrolled, the median number of treatments was three. The adverse events profile was similar to that reported in single dose trials.

6.2Immunogenicity 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 prabotulinumtoxinA-xvfs 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 1,414 subjects treated with prabotulinumtoxinA-xvfs, 2 subjects were found to have pre-existing antibodies and 2 subjects had treatment-emergent antibodies.