These Highlights Do Not Include All The Information Needed To Use Xeomin®

Upper Limb Spasticity in Adult Patients

XEOMIN is indicated for the treatment of upper limb spasticity in adult patients.

Storage and Handling

Store unopened vials of XEOMIN at or below 25°C (77°F). Refrigeration of unopened vials is not required. Do not use after the expiration date on the vial. Reconstituted XEOMIN may be stored in a refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours until time of use [see Dosage and Administration (2.7)].

Excessive doses of XEOMIN may be expected to produce neuromuscular weakness with a variety of symptoms, particularly when treated intramuscularly. Respiratory support may be required where excessive doses cause paralysis of the respiratory muscles. In the event of overdose, the patient should be medically monitored for symptoms of excessive muscle weakness or muscle paralysis [see Warnings and Precautions (5.1, 5.4)]. Symptomatic treatment may be necessary.

Symptoms of overdose are not likely to be present immediately following injection. Should accidental injection or oral ingestion occur, the person should be medically supervised for several weeks for signs and symptoms of excessive muscle weakness or paralysis.

There is no significant information regarding overdose from clinical studies of XEOMIN.

In the event of overdose, antitoxin raised against botulinum toxin is available from the Centers for Disease Control and Prevention (CDC) in Atlanta, GA. However, the antitoxin will not reverse any botulinum toxin-induced effects already apparent by the time of antitoxin administration. In the event of suspected or actual cases of botulinum toxin poisoning, please contact your local or state Health Department to process a request for antitoxin through the CDC. If you do not receive a response within 30 minutes, please contact the CDC directly at 770-488-7100. More information can be obtained at http://www.cdc.gov/ncidod/srp/drugs/formulary.html#1a.

The active ingredient of XEOMIN is botulinum toxin type A produced from fermentation of Hall strain Clostridium botulinum serotype A. The botulinum toxin complex is purified from the culture supernatant and then the active ingredient is separated from the proteins (hemagglutinins and non-hemagglutinins) through a series of steps yielding the active neurotoxin with molecular weight of 150 kDa, without accessory proteins. XEOMIN is a sterile white to off-white lyophilized powder intended for intramuscular or intra-salivary gland injection after reconstitution with preservative-free 0.9% Sodium Chloride Injection, USP [see Dosage Forms and Strengths (3)]. One vial of XEOMIN contains 50 Units, 100 Units, or 200 Units of incobotulinumtoxinA, human albumin (1 mg), and sucrose (4.7 mg).

The primary release procedure for XEOMIN uses a cell-based potency assay to determine the potency relative to a reference standard. One Unit corresponds to the median intraperitoneal lethal dose (LD₅₀) in mice. As the method for conducting the assay is specific to XEOMIN, Units of biological activity of XEOMIN cannot be converted into Units of any other botulinum toxin assessed with other specific assays.

XEOMIN is indicated for the treatment of blepharospasm in adult patients.

The safety and effectiveness of XEOMIN have not been established in pediatric patients for the treatment of lower limb spasticity, cervical dystonia, and blepharospasm, or the temporary improvement in the appearance of upper facial lines:

• moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity
• moderate to severe horizontal forehead lines associated with frontalis muscle activity
• moderate to severe lateral canthal lines associated with orbicularis oculi muscle activity [see Warnings and Precautions (5.1)].

Reconstituted XEOMIN is intended for intramuscular or intra-salivary gland injection only.

If proposed injection sites are marked with a pen, DO NOT inject XEOMIN through the pen marks; otherwise a permanent tattooing effect may occur.

For intramuscular injections, the number of injection sites is dependent upon the size of the muscle to be treated and the volume of reconstituted XEOMIN injected.

Inject XEOMIN carefully when injected at sites close to sensitive structures, such as the carotid artery, lung apices, and esophagus. Before administering XEOMIN, the healthcare provider should be familiar with the patient's anatomy and any anatomic alterations, e.g., due to prior surgical procedures.

As with all therapeutic proteins, there is a potential for 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 XEOMIN.

Of the 2649 patients treated with XEOMIN in clinical trials [see Clinical Studies (14)], 9 (0.3%) patients were positive for neutralizing antibodies after treatment whose antibody status at baseline was unknown and 4 (0.2%) additional patients developed neutralizing antibodies after treatment. No patients demonstrated a secondary lack of treatment response due to neutralizing antibodies.

XEOMIN is contraindicated in patients with:

• Known hypersensitivity to any botulinum toxin product or to any of the components in the formulation [see Warnings and Precautions (5.3) and Description (11)].
• Infection at the proposed injection site(s) because it could lead to severe local or disseminated infection.

The following adverse reactions to XEOMIN are discussed in greater detail in other sections of the labeling:

• Spread of Effects from Toxin [see Warnings and Precautions (5.1)]
• Lack of Unit Equivalency between Botulinum Toxin Products [see Warnings and Precautions (5.2)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.3)]
• Dysphagia and Breathing Difficulties [see Warnings and Precautions (5.4)]
• Corneal Exposure, Corneal Ulceration, and Ectropion in Patients Treated with XEOMIN for Blepharospasm [see Warnings and Precautions (5.5)]
• Risk of Ptosis in Patients Treated for Glabellar Lines [see Warnings and Precautions (5.6)]
• Human Albumin and Transmission of Viral Diseases [see Warnings and Precautions (5.7)]

Aminoglycosides or other agents that interfere with neuromuscular transmission may potentiate the effect of XEOMIN; co-administer only with caution and close observation (7)

Excessive weakness may also be exaggerated by administration of a muscle relaxant before or after administration of XEOMIN.

XEOMIN is indicated for the treatment of cervical dystonia in adult patients.

Using currently available analytical technology, it is not possible to detect XEOMIN in the peripheral blood following intramuscular or intraglandular injection at the recommended doses.

XEOMIN is indicated for the treatment of chronic sialorrhea in patients 2 years of age and older.

XEOMIN has been investigated in a randomized, double-blind, placebo-controlled, multicenter trial (NCT00407030) in a total of 233 patients with cervical dystonia. Patients had a clinical diagnosis of predominantly rotational cervical dystonia, with baseline Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total score ≥20, TWSTRS severity score ≥10, 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 ≥10 weeks had passed since the most recent botulinum toxin administration. Patients with swallowing disorders or any significant neuromuscular disease that might interfere with the study were excluded from enrollment. Patients were randomized (1:1:1) to receive a single administration of XEOMIN 240 Units (n=81), XEOMIN 120 Units (n=78), or placebo (n=74). Each patient received a single administration of 4.8 mL of reconstituted study agent (XEOMIN 240 Units, XEOMIN 120 Units, or placebo). The investigator at each site decided which muscles would receive injections of the study agent, the number of injection sites, and the volume at each site. The muscles most frequently injected were the splenius capitis/semispinalis, trapezius, sternocleidomastoid, scalene, and levator scapulae muscles. Table 22 indicates the average XEOMIN dose, and percentage of total dose, injected into specific muscles in the pivotal clinical trial.

Most patients received a total of 2-10 injections into the selected muscles. Patients were assessed by telephone at one week post-injection, during clinic visits at Weeks 4 and 8, and then by telephone assessments or clinic visits every two weeks up to Week 20.

The mean age of the study patients was 53 years, 66% of the patients were women, and 91% were White. At study baseline, 61% of patients had previously received a botulinum toxin as treatment for cervical dystonia. The study was completed by 94% of study patients. Three patients discontinued the study prematurely due to adverse events: two patients in the 240 Unit group experienced musculoskeletal pain and muscle weakness, and one patient in the 120 Unit group experienced nausea and dizziness.

The primary efficacy endpoint was the change in the TWSTRS total score from baseline to Week 4 post-injection, in the intent-to-treat (ITT) population, with missing values replaced by the patient's baseline value. 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 in the total TWSTRS score was significantly greater for both XEOMIN groups than for the placebo group (Table 23).

The efficacy of XEOMIN was similar in patients who were botulinum toxin naïve and those who had received botulinum toxin prior to this study.

Examination of age and gender subgroups did not identify differences in response to XEOMIN among these subgroups.

XEOMIN is an acetylcholine release inhibitor and neuromuscular blocking agent indicated for the treatment or improvement of:

• Chronic sialorrhea in patients 2 years of age and older (1.1)
• Upper limb spasticity in adults (1.2)
• Upper limb spasticity in pediatric patients 2 to 17 years of age, excluding spasticity caused by cerebral palsy (1.2)
• Cervical dystonia in adults (1.3)
• Blepharospasm in adults (1.4)
• the appearance of upper facial lines in adults:
  • moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity (1.5)
  • moderate to severe horizontal forehead lines associated with frontalis muscle activity (1.5)
  • moderate to severe lateral canthal lines associated with orbicularis oculi muscle activity (1.5)

XEOMIN blocks cholinergic transmission at the neuromuscular and salivary neuroglandular junction by inhibiting the release of acetylcholine from peripheral cholinergic nerve endings. This inhibition occurs according to the following sequence: neurotoxin binding to cholinergic nerve terminals, internalization of the neurotoxin into the nerve terminal, translocation of the light-chain part of the molecule into the cytosol of the nerve terminal, and enzymatic cleavage of SNAP25, a presynaptic target protein essential for the release of acetylcholine. In both muscles and glands, impulse transmission is re-established by the formation of new nerve endings.

Use of anticholinergic drugs after administration of XEOMIN may potentiate systemic anticholinergic effects.

• Respiratory, speech, or swallowing difficulties: increased risk if bilateral neck muscle injections are needed, or with pre-existing muscular disorders; immediate medical attention may be required (5.1, 5.4)
• The potency Units of XEOMIN cannot be compared to or converted into Units of any other preparations of botulinum toxin products (5.2)
• Corneal exposure and ulceration: protective measures may be required (5.5)

Postmarketing safety data from XEOMIN and other approved botulinum toxins suggest that botulinum toxin effects may, in some cases, 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 probably 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 lower limb spasticity in children, and in approved indications, symptoms consistent with spread of toxin effect have been reported at doses comparable to or lower than doses used to treat cervical dystonia.

Patients or caregivers should be advised to seek immediate medical care if swallowing, speech, or respiratory disorders occur.

Chronic Sialorrhea:

• Chronic Sialorrhea in Adults: the recommended total dose is 100 Units per treatment session consisting of 30 Units per parotid gland and 20 Units per submandibular gland, no sooner than every 16 weeks (2.2)
• Chronic Sialorrhea in Pediatric Patients: the recommended dose is based on body weight administered in a 3:2 dose ratio into the parotid and submandibular glands, respectively, no sooner than every 16 weeks; ultrasound guidance recommended (2.2)

Upper limb spasticity, cervical dystonia, and blepharospasm: the optimum dose, frequency, and number of injection sites in the treated muscle(s) should be based on severity and prior treatment response in patients previously treated with botulinum toxin; individualize dosing for each patient:

• Upper Limb Spasticity in Adults: the recommended total dose is up to 400 Units, divided among affected muscles (2.3)
• Upper Limb Spasticity in Pediatric Patients, excluding spasticity caused by cerebral palsy: the recommended total dose is 8 Units/kg (maximum 200 Units) per single upper limb or 16 Units/kg (maximum 400 U) in both upper limbs, divided among affected muscles (2.3)
• Cervical Dystonia: the recommended initial dose is 120 Units per treatment session (2.4)
• Blepharospasm: the recommended initial dose is 50 Units (25 Units per eye) (2.5)

Upper Facial Lines (Glabellar Lines, Horizontal Forehead Lines, and Lateral Canthal Lines): When treating all three areas simultaneously (glabellar lines, horizontal forehead lines, and lateral canthal lines), the maximum recommended dose is 64 Units (2.6). When not treating simultaneously:

• Glabellar Lines: four Units into each of five sites, for a maximum dose of 20 Units
• Horizontal Forehead Lines treated simultaneously with Glabellar Lines: for HFL four Units into each of five sites (20 Units) and four Units into each of five GL sites (20 Units), for a maximum dose of 40 Units
• Lateral Canthal Lines: four Units into each of three sites per side (six injection sites in total), for a maximum dose of 12 Units per side (24 Units in total)

Administer retreatment with XEOMIN no more frequently than every three months.

Reconstituted XEOMIN:

• Is intended for intramuscular or intraglandular injection in the parotid and submandibular glands only (2.7)
• Use for only one injection session and for only one patient (2.7)
• Instructions are specific for 50 Unit, 100 Unit, and 200 Unit vials (2.7)
• Store in a refrigerator (2°C to 8°C) and use within 24 hours (2.7)

For injection: 50 Units, 100 Units, or 200 Units lyophilized powder in a single-dose vial for reconstitution only with preservative-free 0.9% Sodium Chloride Injection, USP.

The following adverse reactions have been reported during post-approval use of XEOMIN. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: allergic dermatitis, dysarthria, dysphagia, eye swelling, eyelid edema, flu-like symptoms, herpes zoster, hypersensitivity, injection site pain, injection site reaction, localized allergic reactions (e.g., swelling, edema, erythema, pruritus or rash), muscle spasm, muscular weakness, myalgia, nausea, and persistent dry mouth (> 110 days).

The potency Units of XEOMIN for injection are specific to the preparation and assay method utilized. Units of biological activity of XEOMIN cannot be compared to or converted into Units of any other botulinum toxin products assessed with any other specific assay method [see Warnings and Precautions (5.2) and Description (11)].

Reconstituted XEOMIN is intended for intramuscular or intra-salivary gland injection only.

Do not exceed the recommended maximum cumulative dose in a treatment session for any indication.

• Pregnancy: based on animal data, may cause fetal harm (8.1)

Serious hypersensitivity reactions have been reported with botulinum toxin products. Hypersensitivity reactions include anaphylaxis, serum sickness, urticaria, soft tissue edema, and dyspnea. If serious and/or immediate hypersensitivity reactions occur, discontinue further injection of XEOMIN and institute appropriate medical therapy immediately. The use of XEOMIN in patients with a known hypersensitivity to any botulinum neurotoxin or to any of the excipients (human albumin, sucrose), could lead to a life-threatening allergic reaction [see Contraindications (4)].

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.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

In treatment-naïve patients, the recommended initial dose of XEOMIN is 50 Units (25 Units per eye). In patients previously treated with a botulinum toxin A, consider their past dose, response to treatment, duration of effect, and adverse event history when determining the XEOMIN dose.

Do not exceed a total XEOMIN dose of 100 Units per treatment session (50 Units per eye).

Inject XEOMIN into the lateral and medial orbicularis oculi muscle of the upper lid; lateral canthus and the lateral orbicularis oculi muscle of the lower lid; and the corrugator muscle, if necessary (see Figure 6). The number and location of injections may be changed in response to adverse reactions or based on the patient's response to treatment, but do not exceed a total dose of 50 Units per eye.

Figure 6: Injection Sites for Blepharospasm

Determine the frequency of XEOMIN repeat treatments by clinical response but administer repeat treatments no more frequent than every 12 weeks [see Clinical Studies (14.4)].

The median onset of XEOMIN treatment effect occurs within two to seven days after injection. The typical duration of effect of each treatment is up to 12-16 weeks; however, the duration of effect may vary in individual patients.

The effect of administering different botulinum toxin products at the same time or within several months of each other is unknown. Excessive neuromuscular weakness may be exacerbated by administration of another botulinum toxin prior to the resolution of the effects of a previously administered botulinum toxin.

Postmarketing reports indicate that the effects of XEOMIN and all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. These 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. The risk of symptoms is probably greatest in children treated for spasticity but symptoms can also occur in adults treated for spasticity and other conditions, particularly in those patients who have underlying conditions that would predispose them to these symptoms. In unapproved uses, including lower limb spasticity in children, and in approved indications, cases of spread of effect have been reported at doses comparable to those used to treat cervical dystonia and at lower doses [see Warnings and Precautions (5.1)].

Treatment with XEOMIN and other botulinum toxin products can result in swallowing or breathing difficulties. 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 muscles may be involved [see Warnings and Precautions (5.4)].

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 of cervical dystonia with botulinum toxins may weaken neck muscles that serve as accessory muscles of ventilation. This may result in critical loss of breathing capacity in patients with respiratory disorders who may have become dependent upon these accessory muscles. There have been post-marketing reports of serious breathing difficulties, including respiratory failure, in patients with cervical dystonia treated with botulinum toxin products.

Patients with smaller neck muscle mass and patients who require bilateral injections into the sternocleidomastoid muscles have been reported to be at greater risk of dysphagia. In general, limiting the dose injected into the sternocleidomastoid muscle may decrease the occurrence of dysphagia.

Patients treated with botulinum toxin may require immediate medical attention should they develop problems with swallowing, speech or respiratory disorders. These reactions can occur within hours to weeks after injection with botulinum toxin [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].

Patients with neuromuscular disorders with peripheral motor neuropathic diseases, amyotrophic lateral sclerosis, or neuromuscular junctional disorders (e.g., myasthenia gravis or Lambert-Eaton syndrome) may be at increased risk for severe dysphagia and respiratory compromise from typical doses of XEOMIN.

The recommended initial dose of XEOMIN for cervical dystonia is 120 Units. In previously treated patients, their past dose, response to treatment, duration of effect, and adverse event history should be taken into consideration when determining the XEOMIN dose.

In the treatment of cervical dystonia, XEOMIN is usually injected into the sternocleidomastoid, levator scapulae, splenius capitis, scalenus, and/or the trapezius muscle(s) (see Figure 5). This list is not exhaustive, as any of the muscles responsible for controlling head position may require treatment [see Clinical Studies (14.3)]. The dose and number of injection sites in each treated muscle should be individualized based on the number and location of the muscle(s) to be treated, the degree of spasticity/dystonia, muscle mass, body weight, and response to any previous botulinum toxin injections.

The frequency of XEOMIN repeat treatments should be determined by clinical response, but should generally be no more frequent than every 12 weeks [see Clinical Studies (14.3)].

Figure 5: Muscles Involved in Cervical Dystonia

Prior to injection, reconstitute each vial of XEOMIN with sterile, preservative-free 0.9% Sodium Chloride Injection, USP [see Dosage Form and Strengths (3)]. A 20-27 gauge short bevel needle is recommended for reconstitution. Draw up an appropriate amount of preservative-free 0.9% Sodium Chloride Injection, USP into a syringe (see Table 5). Clean the exposed portion of the rubber stopper of the vial with alcohol (70%) prior to insertion of the needle. After vertical insertion of the needle through the rubber stopper, the vacuum will draw the saline into the vial. Gently inject any remaining saline into the vial to avoid foam formation. If the vacuum does not pull the saline into the vial, then XEOMIN must be discarded. Remove the syringe from the vial and mix XEOMIN with the saline by carefully swirling and inverting/flipping the vial – do not shake vigorously. Reconstituted XEOMIN is a clear, colorless solution free of particulate matter. Do not use XEOMIN if the reconstituted solution has a cloudy appearance or contains floccular or particulate matter.

After reconstitution, use XEOMIN for only one injection session and for only one patient. Administer reconstituted XEOMIN within 24 hours after dilution. During this time period, store unused reconstituted XEOMIN in the original container in a refrigerator 2°C -8°C (36°F -46°F) for up to 24 hours until time of use. XEOMIN vials are for single-dose only. Discard any unused portion.

Diluent volumes for reconstitution of XEOMIN are indicated in Table 5.

1 vial

Rx Only

NDC 0259-1605-01

incobotulinumtoxinA

XEOMIN^®

for Injection

For Intramuscular

and Intraglandular Use

WARNING: Dosing Units of botulinum toxins are

not interchangeable between commercial products.

MERZ

50 units/vial

Dispense the enclosed Medication

Guide to each patient.

1 vial

Rx Only

NDC 0259-1610-01

incobotulinumtoxinA

XEOMIN^®

for Injection

For Intramuscular

and Intraglandular Use

WARNING: Dosing Units of botulinum toxins are

not interchangeable between commercial products.

MERZ

100 units/vial

Dispense the enclosed Medication

Guide to each patient.

1 vial

Rx Only

NDC 0259-1620-01

incobotulinumtoxinA

XEOMIN^®

for Injection

For Intramuscular

and Intraglandular Use

WARNING: Dosing Units of botulinum toxins are

not interchangeable between commercial products.

MERZ

200 units/vial

Dispense the enclosed Medication

Guide to each patient.

Use caution when XEOMIN is used where the targeted muscle shows excessive weakness or atrophy.

Use caution when XEOMIN 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).

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.

Do not exceed the recommended dosage and frequency of administration of XEOMIN.

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.
• Corrugator injections should be placed at least 1 cm above the bony supraorbital ridge.

The potency Units of XEOMIN are specific to the preparation and assay method utilized. Units of biological activity of XEOMIN cannot be compared to or converted into Units of any other botulinum toxin products assessed with any other specific assay method [see Description (11)].

1 vial

Rx Only

NDC 0259-4150-01

incobotulinumtoxinA

XEOMIN^®

for Injection

For Intramuscular

and Intraglandular Use

WARNING: Dosing Units of botulinum toxins are

not interchangeable between commercial products.

MERZ

50 units/vial

Dispense the enclosed Medication

Guide to each patient.

1 vial

Rx Only

NDC 0259-4110-01

incobotulinumtoxinA

XEOMIN^®

for Injection

For Intramuscular

and Intraglandular Use

WARNING: Dosing Units of botulinum toxins are

not interchangeable between commercial products.

MERZ

100 units/vial

Dispense the enclosed Medication

Guide to each patient.

Co-administration of XEOMIN and aminoglycosides or other agents interfering with neuromuscular transmission (e.g., tubocurarine-type muscle relaxants) should only be performed with caution as these agents may potentiate the effect of the toxin.

Reduced blinking from injection of botulinum toxin products in the orbicularis muscle can lead to corneal exposure, persistent epithelial defect, and corneal ulceration, especially in patients with VII nerve disorders. As patients with previous eye surgery may have reduced corneal sensation, carefully assess corneal sensation before treatment. Vigorous treatment of any corneal epithelial defect should be employed. This may require protective drops, ointment, therapeutic soft contact lenses, or closure of the eye by patching or other means. Because of its anticholinergic effects, XEOMIN should be used with caution in patients at risk of developing narrow angle glaucoma. To decrease the risk for ectropion, XEOMIN should not be injected into the medial lower eyelid area.

Ecchymosis easily occurs in the soft tissues of the eyelid. Immediate gentle pressure at the injection site can limit the size.

XEOMIN is indicated in adult patients for the temporary improvement in the appearance of upper facial lines:

• moderate to severe glabellar lines (GL) associated with corrugator and/or procerus muscle activity
• moderate to severe horizontal forehead lines (HFL) associated with frontalis muscle activity
• moderate to severe lateral canthal lines (LCL) associated with orbicularis oculi muscle activity.

Two randomized, double-blind, multi-center, placebo-controlled clinical trials, Trial 1071 (NCT04594213) and Trial 1070 (NCT04622254), were conducted to evaluate XEOMIN for use in the simultaneous intramuscular treatment of upper facial lines (GL, HFL, and LCL). Each trial included an extension period with two additional open-label treatment cycles. In these two trials a total of 730 adult subjects with GL, HFL, and LCL of at least moderate severity at maximum frown as assessed by the investigator and subject were randomized and treated.

In Trial 1071, a total of 362 subjects were randomized and treated. Of the randomized subjects, 179 subjects were treated with XEOMIN in all three treatment areas (receiving 64 U in total: 20 in GL, 20 U in HFL, 24 U in LCL area), 92 subjects were treated with XEOMIN in the GL and HFL areas (receiving 20 U in the GL area and 20 U in HFL area), and 91 subjects were treated with placebo (receiving equal volume of placebo).

In Trial 1070, a total of 368 subjects were randomized and treated. Of the randomized subjects, 184 subjects were treated with XEOMIN in all three treatment area (receiving 64 U in total: 20 in GL, 20 U in HFL, 24 U in LCL area), 90 subjects were treated with XEOMIN in the LCL area (receiving 24 U in LCL area, 12 U per side), and 94 subjects were treated with placebo (receiving equal volume of placebo).

The mean age of the 730 treated and randomized subjects was 46.5 years. The majority of subjects were female (84%) and White (92%). Fifteen percent (15%) of subjects identified as Hispanic or Latino.

For both trials, the severity of upper facial lines (GL, HFL, and LCL) was assessed at maximum contraction using the 5-point photonumerical Merz Aesthetic Scales (MAS; 0=none, 1= mild, 2=moderate, 3=severe, 4=very severe). The MAS assessment was performed independently by both investigators and subjects. The primary timepoint was Day 30 following the first treatment.

For each upper facial area (GL, HFL, or LCL), treatment success was defined as a score of 0 (none) or 1 (mild) and at least two-grade improvement from baseline to Day 30 as rated on the corresponding scale for GL, HFL, and LCL at maximum contraction as assessed by both the investigator and the subject. The percentage of subjects with treatment success in each treatment area is presented in Table 25.

The maximum recommended dose of XEOMIN for simultaneous treatment of upper facial lines [i.e., glabellar lines (GL), horizontal forehead lines (HFL) and lateral canthal lines (LCL)] in adult patients is 64 Units, comprised of 20 Units for GL, 20 Units for HFL, and 24 Units for LCL.

Administer retreatment with XEOMIN no more frequently than every three months.

When not treating upper facial lines (GL, HFL, and LCL) simultaneously in adult patients, refer to the following instructions:

Upper Limb Spasticity in Adult Patients

XEOMIN is indicated for the treatment of upper limb spasticity in adult patients.

Storage and Handling

Store unopened vials of XEOMIN at or below 25°C (77°F). Refrigeration of unopened vials is not required. Do not use after the expiration date on the vial. Reconstituted XEOMIN may be stored in a refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours until time of use [see Dosage and Administration (2.7)].

Excessive doses of XEOMIN may be expected to produce neuromuscular weakness with a variety of symptoms, particularly when treated intramuscularly. Respiratory support may be required where excessive doses cause paralysis of the respiratory muscles. In the event of overdose, the patient should be medically monitored for symptoms of excessive muscle weakness or muscle paralysis [see Warnings and Precautions (5.1, 5.4)]. Symptomatic treatment may be necessary.

Symptoms of overdose are not likely to be present immediately following injection. Should accidental injection or oral ingestion occur, the person should be medically supervised for several weeks for signs and symptoms of excessive muscle weakness or paralysis.

There is no significant information regarding overdose from clinical studies of XEOMIN.

In the event of overdose, antitoxin raised against botulinum toxin is available from the Centers for Disease Control and Prevention (CDC) in Atlanta, GA. However, the antitoxin will not reverse any botulinum toxin-induced effects already apparent by the time of antitoxin administration. In the event of suspected or actual cases of botulinum toxin poisoning, please contact your local or state Health Department to process a request for antitoxin through the CDC. If you do not receive a response within 30 minutes, please contact the CDC directly at 770-488-7100. More information can be obtained at http://www.cdc.gov/ncidod/srp/drugs/formulary.html#1a.

The active ingredient of XEOMIN is botulinum toxin type A produced from fermentation of Hall strain Clostridium botulinum serotype A. The botulinum toxin complex is purified from the culture supernatant and then the active ingredient is separated from the proteins (hemagglutinins and non-hemagglutinins) through a series of steps yielding the active neurotoxin with molecular weight of 150 kDa, without accessory proteins. XEOMIN is a sterile white to off-white lyophilized powder intended for intramuscular or intra-salivary gland injection after reconstitution with preservative-free 0.9% Sodium Chloride Injection, USP [see Dosage Forms and Strengths (3)]. One vial of XEOMIN contains 50 Units, 100 Units, or 200 Units of incobotulinumtoxinA, human albumin (1 mg), and sucrose (4.7 mg).

The primary release procedure for XEOMIN uses a cell-based potency assay to determine the potency relative to a reference standard. One Unit corresponds to the median intraperitoneal lethal dose (LD₅₀) in mice. As the method for conducting the assay is specific to XEOMIN, Units of biological activity of XEOMIN cannot be converted into Units of any other botulinum toxin assessed with other specific assays.

XEOMIN is indicated for the treatment of blepharospasm in adult patients.

The safety and effectiveness of XEOMIN have not been established in pediatric patients for the treatment of lower limb spasticity, cervical dystonia, and blepharospasm, or the temporary improvement in the appearance of upper facial lines:

• moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity
• moderate to severe horizontal forehead lines associated with frontalis muscle activity
• moderate to severe lateral canthal lines associated with orbicularis oculi muscle activity [see Warnings and Precautions (5.1)].

Reconstituted XEOMIN is intended for intramuscular or intra-salivary gland injection only.

If proposed injection sites are marked with a pen, DO NOT inject XEOMIN through the pen marks; otherwise a permanent tattooing effect may occur.

For intramuscular injections, the number of injection sites is dependent upon the size of the muscle to be treated and the volume of reconstituted XEOMIN injected.

Inject XEOMIN carefully when injected at sites close to sensitive structures, such as the carotid artery, lung apices, and esophagus. Before administering XEOMIN, the healthcare provider should be familiar with the patient's anatomy and any anatomic alterations, e.g., due to prior surgical procedures.

As with all therapeutic proteins, there is a potential for 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 XEOMIN.

Of the 2649 patients treated with XEOMIN in clinical trials [see Clinical Studies (14)], 9 (0.3%) patients were positive for neutralizing antibodies after treatment whose antibody status at baseline was unknown and 4 (0.2%) additional patients developed neutralizing antibodies after treatment. No patients demonstrated a secondary lack of treatment response due to neutralizing antibodies.

XEOMIN is contraindicated in patients with:

• Known hypersensitivity to any botulinum toxin product or to any of the components in the formulation [see Warnings and Precautions (5.3) and Description (11)].
• Infection at the proposed injection site(s) because it could lead to severe local or disseminated infection.

The following adverse reactions to XEOMIN are discussed in greater detail in other sections of the labeling:

• Spread of Effects from Toxin [see Warnings and Precautions (5.1)]
• Lack of Unit Equivalency between Botulinum Toxin Products [see Warnings and Precautions (5.2)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.3)]
• Dysphagia and Breathing Difficulties [see Warnings and Precautions (5.4)]
• Corneal Exposure, Corneal Ulceration, and Ectropion in Patients Treated with XEOMIN for Blepharospasm [see Warnings and Precautions (5.5)]
• Risk of Ptosis in Patients Treated for Glabellar Lines [see Warnings and Precautions (5.6)]
• Human Albumin and Transmission of Viral Diseases [see Warnings and Precautions (5.7)]

Aminoglycosides or other agents that interfere with neuromuscular transmission may potentiate the effect of XEOMIN; co-administer only with caution and close observation (7)

Excessive weakness may also be exaggerated by administration of a muscle relaxant before or after administration of XEOMIN.

XEOMIN is indicated for the treatment of cervical dystonia in adult patients.

Using currently available analytical technology, it is not possible to detect XEOMIN in the peripheral blood following intramuscular or intraglandular injection at the recommended doses.

XEOMIN is indicated for the treatment of chronic sialorrhea in patients 2 years of age and older.

XEOMIN has been investigated in a randomized, double-blind, placebo-controlled, multicenter trial (NCT00407030) in a total of 233 patients with cervical dystonia. Patients had a clinical diagnosis of predominantly rotational cervical dystonia, with baseline Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total score ≥20, TWSTRS severity score ≥10, 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 ≥10 weeks had passed since the most recent botulinum toxin administration. Patients with swallowing disorders or any significant neuromuscular disease that might interfere with the study were excluded from enrollment. Patients were randomized (1:1:1) to receive a single administration of XEOMIN 240 Units (n=81), XEOMIN 120 Units (n=78), or placebo (n=74). Each patient received a single administration of 4.8 mL of reconstituted study agent (XEOMIN 240 Units, XEOMIN 120 Units, or placebo). The investigator at each site decided which muscles would receive injections of the study agent, the number of injection sites, and the volume at each site. The muscles most frequently injected were the splenius capitis/semispinalis, trapezius, sternocleidomastoid, scalene, and levator scapulae muscles. Table 22 indicates the average XEOMIN dose, and percentage of total dose, injected into specific muscles in the pivotal clinical trial.

Most patients received a total of 2-10 injections into the selected muscles. Patients were assessed by telephone at one week post-injection, during clinic visits at Weeks 4 and 8, and then by telephone assessments or clinic visits every two weeks up to Week 20.

The mean age of the study patients was 53 years, 66% of the patients were women, and 91% were White. At study baseline, 61% of patients had previously received a botulinum toxin as treatment for cervical dystonia. The study was completed by 94% of study patients. Three patients discontinued the study prematurely due to adverse events: two patients in the 240 Unit group experienced musculoskeletal pain and muscle weakness, and one patient in the 120 Unit group experienced nausea and dizziness.

The primary efficacy endpoint was the change in the TWSTRS total score from baseline to Week 4 post-injection, in the intent-to-treat (ITT) population, with missing values replaced by the patient's baseline value. 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 in the total TWSTRS score was significantly greater for both XEOMIN groups than for the placebo group (Table 23).

The efficacy of XEOMIN was similar in patients who were botulinum toxin naïve and those who had received botulinum toxin prior to this study.

Examination of age and gender subgroups did not identify differences in response to XEOMIN among these subgroups.

XEOMIN is an acetylcholine release inhibitor and neuromuscular blocking agent indicated for the treatment or improvement of:

• Chronic sialorrhea in patients 2 years of age and older (1.1)
• Upper limb spasticity in adults (1.2)
• Upper limb spasticity in pediatric patients 2 to 17 years of age, excluding spasticity caused by cerebral palsy (1.2)
• Cervical dystonia in adults (1.3)
• Blepharospasm in adults (1.4)
• the appearance of upper facial lines in adults:
  • moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity (1.5)
  • moderate to severe horizontal forehead lines associated with frontalis muscle activity (1.5)
  • moderate to severe lateral canthal lines associated with orbicularis oculi muscle activity (1.5)

XEOMIN blocks cholinergic transmission at the neuromuscular and salivary neuroglandular junction by inhibiting the release of acetylcholine from peripheral cholinergic nerve endings. This inhibition occurs according to the following sequence: neurotoxin binding to cholinergic nerve terminals, internalization of the neurotoxin into the nerve terminal, translocation of the light-chain part of the molecule into the cytosol of the nerve terminal, and enzymatic cleavage of SNAP25, a presynaptic target protein essential for the release of acetylcholine. In both muscles and glands, impulse transmission is re-established by the formation of new nerve endings.

Use of anticholinergic drugs after administration of XEOMIN may potentiate systemic anticholinergic effects.

• Respiratory, speech, or swallowing difficulties: increased risk if bilateral neck muscle injections are needed, or with pre-existing muscular disorders; immediate medical attention may be required (5.1, 5.4)
• The potency Units of XEOMIN cannot be compared to or converted into Units of any other preparations of botulinum toxin products (5.2)
• Corneal exposure and ulceration: protective measures may be required (5.5)

Postmarketing safety data from XEOMIN and other approved botulinum toxins suggest that botulinum toxin effects may, in some cases, 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 probably 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 lower limb spasticity in children, and in approved indications, symptoms consistent with spread of toxin effect have been reported at doses comparable to or lower than doses used to treat cervical dystonia.

Patients or caregivers should be advised to seek immediate medical care if swallowing, speech, or respiratory disorders occur.

Chronic Sialorrhea:

• Chronic Sialorrhea in Adults: the recommended total dose is 100 Units per treatment session consisting of 30 Units per parotid gland and 20 Units per submandibular gland, no sooner than every 16 weeks (2.2)
• Chronic Sialorrhea in Pediatric Patients: the recommended dose is based on body weight administered in a 3:2 dose ratio into the parotid and submandibular glands, respectively, no sooner than every 16 weeks; ultrasound guidance recommended (2.2)

Upper limb spasticity, cervical dystonia, and blepharospasm: the optimum dose, frequency, and number of injection sites in the treated muscle(s) should be based on severity and prior treatment response in patients previously treated with botulinum toxin; individualize dosing for each patient:

• Upper Limb Spasticity in Adults: the recommended total dose is up to 400 Units, divided among affected muscles (2.3)
• Upper Limb Spasticity in Pediatric Patients, excluding spasticity caused by cerebral palsy: the recommended total dose is 8 Units/kg (maximum 200 Units) per single upper limb or 16 Units/kg (maximum 400 U) in both upper limbs, divided among affected muscles (2.3)
• Cervical Dystonia: the recommended initial dose is 120 Units per treatment session (2.4)
• Blepharospasm: the recommended initial dose is 50 Units (25 Units per eye) (2.5)

Upper Facial Lines (Glabellar Lines, Horizontal Forehead Lines, and Lateral Canthal Lines): When treating all three areas simultaneously (glabellar lines, horizontal forehead lines, and lateral canthal lines), the maximum recommended dose is 64 Units (2.6). When not treating simultaneously:

• Glabellar Lines: four Units into each of five sites, for a maximum dose of 20 Units
• Horizontal Forehead Lines treated simultaneously with Glabellar Lines: for HFL four Units into each of five sites (20 Units) and four Units into each of five GL sites (20 Units), for a maximum dose of 40 Units
• Lateral Canthal Lines: four Units into each of three sites per side (six injection sites in total), for a maximum dose of 12 Units per side (24 Units in total)

Administer retreatment with XEOMIN no more frequently than every three months.

Reconstituted XEOMIN:

• Is intended for intramuscular or intraglandular injection in the parotid and submandibular glands only (2.7)
• Use for only one injection session and for only one patient (2.7)
• Instructions are specific for 50 Unit, 100 Unit, and 200 Unit vials (2.7)
• Store in a refrigerator (2°C to 8°C) and use within 24 hours (2.7)

For injection: 50 Units, 100 Units, or 200 Units lyophilized powder in a single-dose vial for reconstitution only with preservative-free 0.9% Sodium Chloride Injection, USP.

The following adverse reactions have been reported during post-approval use of XEOMIN. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: allergic dermatitis, dysarthria, dysphagia, eye swelling, eyelid edema, flu-like symptoms, herpes zoster, hypersensitivity, injection site pain, injection site reaction, localized allergic reactions (e.g., swelling, edema, erythema, pruritus or rash), muscle spasm, muscular weakness, myalgia, nausea, and persistent dry mouth (> 110 days).

The potency Units of XEOMIN for injection are specific to the preparation and assay method utilized. Units of biological activity of XEOMIN cannot be compared to or converted into Units of any other botulinum toxin products assessed with any other specific assay method [see Warnings and Precautions (5.2) and Description (11)].

Reconstituted XEOMIN is intended for intramuscular or intra-salivary gland injection only.

Do not exceed the recommended maximum cumulative dose in a treatment session for any indication.

• Pregnancy: based on animal data, may cause fetal harm (8.1)

Serious hypersensitivity reactions have been reported with botulinum toxin products. Hypersensitivity reactions include anaphylaxis, serum sickness, urticaria, soft tissue edema, and dyspnea. If serious and/or immediate hypersensitivity reactions occur, discontinue further injection of XEOMIN and institute appropriate medical therapy immediately. The use of XEOMIN in patients with a known hypersensitivity to any botulinum neurotoxin or to any of the excipients (human albumin, sucrose), could lead to a life-threatening allergic reaction [see Contraindications (4)].

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.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

In treatment-naïve patients, the recommended initial dose of XEOMIN is 50 Units (25 Units per eye). In patients previously treated with a botulinum toxin A, consider their past dose, response to treatment, duration of effect, and adverse event history when determining the XEOMIN dose.

Do not exceed a total XEOMIN dose of 100 Units per treatment session (50 Units per eye).

Inject XEOMIN into the lateral and medial orbicularis oculi muscle of the upper lid; lateral canthus and the lateral orbicularis oculi muscle of the lower lid; and the corrugator muscle, if necessary (see Figure 6). The number and location of injections may be changed in response to adverse reactions or based on the patient's response to treatment, but do not exceed a total dose of 50 Units per eye.

Figure 6: Injection Sites for Blepharospasm

Determine the frequency of XEOMIN repeat treatments by clinical response but administer repeat treatments no more frequent than every 12 weeks [see Clinical Studies (14.4)].

The median onset of XEOMIN treatment effect occurs within two to seven days after injection. The typical duration of effect of each treatment is up to 12-16 weeks; however, the duration of effect may vary in individual patients.

The effect of administering different botulinum toxin products at the same time or within several months of each other is unknown. Excessive neuromuscular weakness may be exacerbated by administration of another botulinum toxin prior to the resolution of the effects of a previously administered botulinum toxin.

Postmarketing reports indicate that the effects of XEOMIN and all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. These 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. The risk of symptoms is probably greatest in children treated for spasticity but symptoms can also occur in adults treated for spasticity and other conditions, particularly in those patients who have underlying conditions that would predispose them to these symptoms. In unapproved uses, including lower limb spasticity in children, and in approved indications, cases of spread of effect have been reported at doses comparable to those used to treat cervical dystonia and at lower doses [see Warnings and Precautions (5.1)].

Treatment with XEOMIN and other botulinum toxin products can result in swallowing or breathing difficulties. 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 muscles may be involved [see Warnings and Precautions (5.4)].

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 of cervical dystonia with botulinum toxins may weaken neck muscles that serve as accessory muscles of ventilation. This may result in critical loss of breathing capacity in patients with respiratory disorders who may have become dependent upon these accessory muscles. There have been post-marketing reports of serious breathing difficulties, including respiratory failure, in patients with cervical dystonia treated with botulinum toxin products.

Patients with smaller neck muscle mass and patients who require bilateral injections into the sternocleidomastoid muscles have been reported to be at greater risk of dysphagia. In general, limiting the dose injected into the sternocleidomastoid muscle may decrease the occurrence of dysphagia.

Patients treated with botulinum toxin may require immediate medical attention should they develop problems with swallowing, speech or respiratory disorders. These reactions can occur within hours to weeks after injection with botulinum toxin [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].

Patients with neuromuscular disorders with peripheral motor neuropathic diseases, amyotrophic lateral sclerosis, or neuromuscular junctional disorders (e.g., myasthenia gravis or Lambert-Eaton syndrome) may be at increased risk for severe dysphagia and respiratory compromise from typical doses of XEOMIN.

The recommended initial dose of XEOMIN for cervical dystonia is 120 Units. In previously treated patients, their past dose, response to treatment, duration of effect, and adverse event history should be taken into consideration when determining the XEOMIN dose.

In the treatment of cervical dystonia, XEOMIN is usually injected into the sternocleidomastoid, levator scapulae, splenius capitis, scalenus, and/or the trapezius muscle(s) (see Figure 5). This list is not exhaustive, as any of the muscles responsible for controlling head position may require treatment [see Clinical Studies (14.3)]. The dose and number of injection sites in each treated muscle should be individualized based on the number and location of the muscle(s) to be treated, the degree of spasticity/dystonia, muscle mass, body weight, and response to any previous botulinum toxin injections.

The frequency of XEOMIN repeat treatments should be determined by clinical response, but should generally be no more frequent than every 12 weeks [see Clinical Studies (14.3)].

Figure 5: Muscles Involved in Cervical Dystonia

Prior to injection, reconstitute each vial of XEOMIN with sterile, preservative-free 0.9% Sodium Chloride Injection, USP [see Dosage Form and Strengths (3)]. A 20-27 gauge short bevel needle is recommended for reconstitution. Draw up an appropriate amount of preservative-free 0.9% Sodium Chloride Injection, USP into a syringe (see Table 5). Clean the exposed portion of the rubber stopper of the vial with alcohol (70%) prior to insertion of the needle. After vertical insertion of the needle through the rubber stopper, the vacuum will draw the saline into the vial. Gently inject any remaining saline into the vial to avoid foam formation. If the vacuum does not pull the saline into the vial, then XEOMIN must be discarded. Remove the syringe from the vial and mix XEOMIN with the saline by carefully swirling and inverting/flipping the vial – do not shake vigorously. Reconstituted XEOMIN is a clear, colorless solution free of particulate matter. Do not use XEOMIN if the reconstituted solution has a cloudy appearance or contains floccular or particulate matter.

After reconstitution, use XEOMIN for only one injection session and for only one patient. Administer reconstituted XEOMIN within 24 hours after dilution. During this time period, store unused reconstituted XEOMIN in the original container in a refrigerator 2°C -8°C (36°F -46°F) for up to 24 hours until time of use. XEOMIN vials are for single-dose only. Discard any unused portion.

Diluent volumes for reconstitution of XEOMIN are indicated in Table 5.

1 vial

Rx Only

NDC 0259-1605-01

incobotulinumtoxinA

XEOMIN^®

for Injection

For Intramuscular

and Intraglandular Use

WARNING: Dosing Units of botulinum toxins are

not interchangeable between commercial products.

MERZ

50 units/vial

Dispense the enclosed Medication

Guide to each patient.

1 vial

Rx Only

NDC 0259-1610-01

incobotulinumtoxinA

XEOMIN^®

for Injection

For Intramuscular

and Intraglandular Use

WARNING: Dosing Units of botulinum toxins are

not interchangeable between commercial products.

MERZ

100 units/vial

Dispense the enclosed Medication

Guide to each patient.

1 vial

Rx Only

NDC 0259-1620-01

incobotulinumtoxinA

XEOMIN^®

for Injection

For Intramuscular

and Intraglandular Use

WARNING: Dosing Units of botulinum toxins are

not interchangeable between commercial products.

MERZ

200 units/vial

Dispense the enclosed Medication

Guide to each patient.

Use caution when XEOMIN is used where the targeted muscle shows excessive weakness or atrophy.

Use caution when XEOMIN 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).

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.

Do not exceed the recommended dosage and frequency of administration of XEOMIN.

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.
• Corrugator injections should be placed at least 1 cm above the bony supraorbital ridge.

The potency Units of XEOMIN are specific to the preparation and assay method utilized. Units of biological activity of XEOMIN cannot be compared to or converted into Units of any other botulinum toxin products assessed with any other specific assay method [see Description (11)].

1 vial

Rx Only

NDC 0259-4150-01

incobotulinumtoxinA

XEOMIN^®

for Injection

For Intramuscular

and Intraglandular Use

WARNING: Dosing Units of botulinum toxins are

not interchangeable between commercial products.

MERZ

50 units/vial

Dispense the enclosed Medication

Guide to each patient.

1 vial

Rx Only

NDC 0259-4110-01

incobotulinumtoxinA

XEOMIN^®

for Injection

For Intramuscular

and Intraglandular Use

WARNING: Dosing Units of botulinum toxins are

not interchangeable between commercial products.

MERZ

100 units/vial

Dispense the enclosed Medication

Guide to each patient.

Co-administration of XEOMIN and aminoglycosides or other agents interfering with neuromuscular transmission (e.g., tubocurarine-type muscle relaxants) should only be performed with caution as these agents may potentiate the effect of the toxin.

Reduced blinking from injection of botulinum toxin products in the orbicularis muscle can lead to corneal exposure, persistent epithelial defect, and corneal ulceration, especially in patients with VII nerve disorders. As patients with previous eye surgery may have reduced corneal sensation, carefully assess corneal sensation before treatment. Vigorous treatment of any corneal epithelial defect should be employed. This may require protective drops, ointment, therapeutic soft contact lenses, or closure of the eye by patching or other means. Because of its anticholinergic effects, XEOMIN should be used with caution in patients at risk of developing narrow angle glaucoma. To decrease the risk for ectropion, XEOMIN should not be injected into the medial lower eyelid area.

Ecchymosis easily occurs in the soft tissues of the eyelid. Immediate gentle pressure at the injection site can limit the size.

XEOMIN is indicated in adult patients for the temporary improvement in the appearance of upper facial lines:

• moderate to severe glabellar lines (GL) associated with corrugator and/or procerus muscle activity
• moderate to severe horizontal forehead lines (HFL) associated with frontalis muscle activity
• moderate to severe lateral canthal lines (LCL) associated with orbicularis oculi muscle activity.

Two randomized, double-blind, multi-center, placebo-controlled clinical trials, Trial 1071 (NCT04594213) and Trial 1070 (NCT04622254), were conducted to evaluate XEOMIN for use in the simultaneous intramuscular treatment of upper facial lines (GL, HFL, and LCL). Each trial included an extension period with two additional open-label treatment cycles. In these two trials a total of 730 adult subjects with GL, HFL, and LCL of at least moderate severity at maximum frown as assessed by the investigator and subject were randomized and treated.

In Trial 1071, a total of 362 subjects were randomized and treated. Of the randomized subjects, 179 subjects were treated with XEOMIN in all three treatment areas (receiving 64 U in total: 20 in GL, 20 U in HFL, 24 U in LCL area), 92 subjects were treated with XEOMIN in the GL and HFL areas (receiving 20 U in the GL area and 20 U in HFL area), and 91 subjects were treated with placebo (receiving equal volume of placebo).

In Trial 1070, a total of 368 subjects were randomized and treated. Of the randomized subjects, 184 subjects were treated with XEOMIN in all three treatment area (receiving 64 U in total: 20 in GL, 20 U in HFL, 24 U in LCL area), 90 subjects were treated with XEOMIN in the LCL area (receiving 24 U in LCL area, 12 U per side), and 94 subjects were treated with placebo (receiving equal volume of placebo).

The mean age of the 730 treated and randomized subjects was 46.5 years. The majority of subjects were female (84%) and White (92%). Fifteen percent (15%) of subjects identified as Hispanic or Latino.

For both trials, the severity of upper facial lines (GL, HFL, and LCL) was assessed at maximum contraction using the 5-point photonumerical Merz Aesthetic Scales (MAS; 0=none, 1= mild, 2=moderate, 3=severe, 4=very severe). The MAS assessment was performed independently by both investigators and subjects. The primary timepoint was Day 30 following the first treatment.

For each upper facial area (GL, HFL, or LCL), treatment success was defined as a score of 0 (none) or 1 (mild) and at least two-grade improvement from baseline to Day 30 as rated on the corresponding scale for GL, HFL, and LCL at maximum contraction as assessed by both the investigator and the subject. The percentage of subjects with treatment success in each treatment area is presented in Table 25.

The maximum recommended dose of XEOMIN for simultaneous treatment of upper facial lines [i.e., glabellar lines (GL), horizontal forehead lines (HFL) and lateral canthal lines (LCL)] in adult patients is 64 Units, comprised of 20 Units for GL, 20 Units for HFL, and 24 Units for LCL.

Administer retreatment with XEOMIN no more frequently than every three months.

When not treating upper facial lines (GL, HFL, and LCL) simultaneously in adult patients, refer to the following instructions: