Xeomin

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 Chronic Sialorrhea

  XEOMIN is indicated for the treatment of chronic sialorrhea in patients 2 years of age and older.
  )
• Upper limb spasticity in adults (
  1.2 Upper Limb Spasticity

  Upper Limb Spasticity in Adult Patients

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

  Upper Limb Spasticity in Pediatric Patients, Excluding Spasticity Caused by Cerebral Palsy

  XEOMIN is indicated for the treatment of upper limb spasticity in pediatric patients 2 to 17 years of age, excluding spasticity caused by cerebral palsy.
  )
• Upper limb spasticity in pediatric patients 2 to 17 years of age, excluding spasticity caused by cerebral palsy (
  1.2 Upper Limb Spasticity

  Upper Limb Spasticity in Adult Patients

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

  Upper Limb Spasticity in Pediatric Patients, Excluding Spasticity Caused by Cerebral Palsy

  XEOMIN is indicated for the treatment of upper limb spasticity in pediatric patients 2 to 17 years of age, excluding spasticity caused by cerebral palsy.
  )
• Cervical dystonia in adults (
  1.3 Cervical Dystonia

  XEOMIN is indicated for the treatment of cervical dystonia in adult patients.
  )
• Blepharospasm in adults (
  1.4 Blepharospasm

  XEOMIN is indicated for the treatment of blepharospasm in adult patients.
  )
• the appearance of upper facial lines in adults:
  • moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity (
    1.5 Upper Facial Lines (Glabellar Lines, Horizontal Forehead Lines, and Lateral Canthal Lines)

    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.
    )
  • moderate to severe horizontal forehead lines associated with frontalis muscle activity (
    1.5 Upper Facial Lines (Glabellar Lines, Horizontal Forehead Lines, and Lateral Canthal Lines)

    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.
    )
  • moderate to severe lateral canthal lines associated with orbicularis oculi muscle activity (
    1.5 Upper Facial Lines (Glabellar Lines, Horizontal Forehead Lines, and Lateral Canthal Lines)

    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.
    )

• 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 Recommended Dose for Chronic Sialorrhea

  Chronic Sialorrhea in Adult Patients

  The recommended total dose per treatment session is 100 Units. XEOMIN is injected into the parotid and submandibular glands on both sides (i.e., 4 injection sites per treatment session). The recommended total dose per treatment session is 100 Units. The dose is divided with a ratio of 3:2 between the parotid and submandibular glands (Table 1).

  Figure 1: Glands for Injection in Chronic Sialorrhea in Adult Patients

  

  Use the following guidelines if locating salivary glands using anatomic landmarks:

  • 1)To inject the
    parotid
    gland, find the midpoint on the line connecting the tragus and mandible angle (Site A and B, respectively, Figure 1), approximately at the height of the ear lobe. Deliver the injection one finger breadth anterior to this site (Star 1, Figure 1).
  • 2)To inject the
    submandibular
    gland, find the midpoint between the angle of the mandible and the tip of the chin (Site B and C, respectively, Figure 1). Deliver the injection one finger breadth medial to the inferior surface of the mandible at this site (Star 2, Figure 1).

  Table 1: Dosing by Gland for Treatment of Chronic Sialorrhea in Adult Patients

  Gland(s)	Units Per Side	Total
  Parotid gland(s)	30 Units	60 Units
  Submandibular gland(s)	20 Units	40 Units
  Both Glands	50 Units	100 Units

  The concentration used in the clinical study after reconstitution was 5 Units/0.1mL. Determine the timing for repeat treatment based on the actual clinical need of the individual patient, and no sooner than every 16 weeks.

  Figure 1

  Chronic Sialorrhea in Pediatric Patients

  XEOMIN is injected into the parotid and submandibular glands on both sides (i.e., 4 injection sites per treatment session). Ultrasound imaging is recommended to guide needle placement into the salivary glands. The body-weight adjusted dose is divided with a ratio of 3:2 between the parotid and submandibular glands (Table 2). XEOMIN has not been studied in children weighing less than 12 kg

  [see Clinical Studies (14.1)].

  Figure 2: Glands for Injection in Chronic Sialorrhea in Pediatric Patients

  

  Table 2: Dosing by Body Weight Class for Treatment of Chronic Sialorrhea in Pediatric Patients

  Body weight	Parotid gland, each side		Submandibular gland, each side		Total dose, both glands, both sides
  	Dose per gland	Volume per injection	Dose per gland	Volume per injection
  12 kg or more to less than 15 kg	6 Units	0.24 mL	4 Units	0.16 mL	20 Units
  15 kg or more to less than 19 kg	9 Units	0.36 mL	6 Units	0.24 mL	30 Units
  19 kg or more to less than 23 kg	12 Units	0.48 mL	8 Units	0.32 mL	40 Units
  23 kg or more to less than 27 kg	15 Units	0.6 mL	10 Units	0.4 mL	50 Units
  27 kg or more to less than 30 kg	18 Units	0.72 mL	12 Units	0.48 mL	60 Units
  30 kg or more	22.5 Units	0.9 mL	15 Units	0.6 mL	75 Units

  The concentration used in the clinical study after reconstitution was 2.5 Units/0.1 mL. Determine the timing for repeat treatment based on the actual clinical need of the individual patient, and no sooner than every 16 weeks.

  Figure 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 Recommended Dose for Chronic Sialorrhea

  Chronic Sialorrhea in Adult Patients

  The recommended total dose per treatment session is 100 Units. XEOMIN is injected into the parotid and submandibular glands on both sides (i.e., 4 injection sites per treatment session). The recommended total dose per treatment session is 100 Units. The dose is divided with a ratio of 3:2 between the parotid and submandibular glands (Table 1).

  Figure 1: Glands for Injection in Chronic Sialorrhea in Adult Patients

  

  Use the following guidelines if locating salivary glands using anatomic landmarks:

  • 1)To inject the
    parotid
    gland, find the midpoint on the line connecting the tragus and mandible angle (Site A and B, respectively, Figure 1), approximately at the height of the ear lobe. Deliver the injection one finger breadth anterior to this site (Star 1, Figure 1).
  • 2)To inject the
    submandibular
    gland, find the midpoint between the angle of the mandible and the tip of the chin (Site B and C, respectively, Figure 1). Deliver the injection one finger breadth medial to the inferior surface of the mandible at this site (Star 2, Figure 1).

  Table 1: Dosing by Gland for Treatment of Chronic Sialorrhea in Adult Patients

  Gland(s)	Units Per Side	Total
  Parotid gland(s)	30 Units	60 Units
  Submandibular gland(s)	20 Units	40 Units
  Both Glands	50 Units	100 Units

  The concentration used in the clinical study after reconstitution was 5 Units/0.1mL. Determine the timing for repeat treatment based on the actual clinical need of the individual patient, and no sooner than every 16 weeks.

  Figure 1

  Chronic Sialorrhea in Pediatric Patients

  XEOMIN is injected into the parotid and submandibular glands on both sides (i.e., 4 injection sites per treatment session). Ultrasound imaging is recommended to guide needle placement into the salivary glands. The body-weight adjusted dose is divided with a ratio of 3:2 between the parotid and submandibular glands (Table 2). XEOMIN has not been studied in children weighing less than 12 kg

  [see Clinical Studies (14.1)].

  Figure 2: Glands for Injection in Chronic Sialorrhea in Pediatric Patients

  

  Table 2: Dosing by Body Weight Class for Treatment of Chronic Sialorrhea in Pediatric Patients

  Body weight	Parotid gland, each side		Submandibular gland, each side		Total dose, both glands, both sides
  	Dose per gland	Volume per injection	Dose per gland	Volume per injection
  12 kg or more to less than 15 kg	6 Units	0.24 mL	4 Units	0.16 mL	20 Units
  15 kg or more to less than 19 kg	9 Units	0.36 mL	6 Units	0.24 mL	30 Units
  19 kg or more to less than 23 kg	12 Units	0.48 mL	8 Units	0.32 mL	40 Units
  23 kg or more to less than 27 kg	15 Units	0.6 mL	10 Units	0.4 mL	50 Units
  27 kg or more to less than 30 kg	18 Units	0.72 mL	12 Units	0.48 mL	60 Units
  30 kg or more	22.5 Units	0.9 mL	15 Units	0.6 mL	75 Units

  The concentration used in the clinical study after reconstitution was 2.5 Units/0.1 mL. Determine the timing for repeat treatment based on the actual clinical need of the individual patient, and no sooner than every 16 weeks.

  Figure 2

  )

• Upper Limb Spasticity in Adults: the recommended total dose is up to 400 Units, divided among affected muscles (
  2.3 Recommended Dose for Upper Limb Spasticity

  Upper Limb Spasticity in Adult Patients

  Tailor the dosage, frequency, and number of injection sites to the individual patient based on the size, number, and location of muscles to be treated, severity of spasticity, presence of local muscle weakness, patient's response to previous treatment, and adverse event history with XEOMIN. Administer repeat XEOMIN treatments no sooner than every 12 weeks. In patients not previously treated with a botulinum toxin, begin initial dosing at the low end of the recommended dosing range and titrate as clinically necessary. Most patients in clinical studies were retreated between 12 and 14 weeks.

  Table 3: XEOMIN Dosing by Muscle for Treatment of Adult Upper Limb Spasticity

  Clinical Pattern Muscle	Units (Range)	Number of injection sites per muscle
  Clenched Fist
  Flexor digitorum superficialis	25 Units-100 Units	2
  Flexor digitorum profundus	25 Units-100 Units	2
  Flexed Wrist
  Flexor carpi radialis	25 Units-100 Units	1-2
  Flexor carpi ulnaris	20 Units-100 Units	1-2
  Flexed Elbow
  Brachioradialis	25 Units-100 Units	1-3
  Biceps	50 Units-200 Units	1-4
  Brachialis	25 Units-100 Units	1-2
  Pronated Forearm
  Pronator quadratus	10 Units-50 Units	1
  Pronator teres	25 Units-75 Units	1-2
  Thumb-in-Palm
  Flexor pollicis longus	10 Units-50 Units	1
  Adductor pollicis	5 Units-30 Units	1
  Flexor pollicis brevis/Opponens pollicis	5 Units-30 Units	1

  Figure 3: Muscles Involved In Adult Upper Limb Spasticity

  

  Figure 3

  Upper Limb Spasticity in Pediatric Patients, Excluding Spasticity Caused by Cerebral Palsy

  Tailor the exact dosage, frequency, and number of injection sites to the individual patient based on size, number and localization of involved muscles; the severity of spasticity; and the presence of local muscle weakness.

  The maximum recommended dose is 8 Units/kg, divided among affected muscles, up to a maximum dose of 200 Units per single upper limb. If both upper limbs are treated, do not exceed a total XEOMIN dosage of 16 Units/kg, up to a maximum of 400 Units.

  Based on the selected dose, a reconstituted solution at a concentration between 1.25 Units/0.1 mL and 5 Units/0.1 mL is recommended

  [see Dosage and Administration (2.3)]

  . Determine the timing for repeat treatment based on the clinical need of the patient; administer repeat treatments no sooner than every 12 weeks. Most patients in clinical studies were retreated between 12 and 16 weeks.

  Table 4 includes the recommended dose ranges for the treatment of the clinical patterns of flexed elbow, flexed wrist, pronated forearm, clenched fist, and thumb-in-palm.

  Table 4: XEOMIN Dosing by Muscle for Treatment of Pediatric Upper Limb Spasticity, Excluding Spasticity Caused by Cerebral Palsy

  Clinical Pattern Muscle	Dosage		Number of Injection Sites per Muscle
  	Range (Units/kg)	Maximum (Units)
  Flexed Elbow
  Brachioradialis	1-2	50	1-2
  Biceps	2-3	75	1-3
  Brachialis	1-2	50	1-2
  Flexed Wrist
  Flexor carpi radialis	1	25	1
  Flexor carpi ulnaris	1	25	1
  Pronated Forearm
  Pronator quadratus	0.5	12.5	1
  Pronator teres	1-2	50	1-2
  Clenched Fist
  Flexor digitorum superficialis	1	25	1
  Flexor digitorum profundus	1	25	1
  Thumb-in-Palm
  Flexor pollicis longus	1	25	1
  Adductor pollicis	0.5	12.5	1
  Flexor pollicis brevis/ opponens pollicis	0.5	12.5	1

  Figure 4: Muscles Injected for Pediatric Upper Limb Spasticity

  

  Figure 4

  )
• 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 Recommended Dose for Upper Limb Spasticity

  Upper Limb Spasticity in Adult Patients

  Tailor the dosage, frequency, and number of injection sites to the individual patient based on the size, number, and location of muscles to be treated, severity of spasticity, presence of local muscle weakness, patient's response to previous treatment, and adverse event history with XEOMIN. Administer repeat XEOMIN treatments no sooner than every 12 weeks. In patients not previously treated with a botulinum toxin, begin initial dosing at the low end of the recommended dosing range and titrate as clinically necessary. Most patients in clinical studies were retreated between 12 and 14 weeks.

  Table 3: XEOMIN Dosing by Muscle for Treatment of Adult Upper Limb Spasticity

  Clinical Pattern Muscle	Units (Range)	Number of injection sites per muscle
  Clenched Fist
  Flexor digitorum superficialis	25 Units-100 Units	2
  Flexor digitorum profundus	25 Units-100 Units	2
  Flexed Wrist
  Flexor carpi radialis	25 Units-100 Units	1-2
  Flexor carpi ulnaris	20 Units-100 Units	1-2
  Flexed Elbow
  Brachioradialis	25 Units-100 Units	1-3
  Biceps	50 Units-200 Units	1-4
  Brachialis	25 Units-100 Units	1-2
  Pronated Forearm
  Pronator quadratus	10 Units-50 Units	1
  Pronator teres	25 Units-75 Units	1-2
  Thumb-in-Palm
  Flexor pollicis longus	10 Units-50 Units	1
  Adductor pollicis	5 Units-30 Units	1
  Flexor pollicis brevis/Opponens pollicis	5 Units-30 Units	1

  Figure 3: Muscles Involved In Adult Upper Limb Spasticity

  

  Figure 3

  Upper Limb Spasticity in Pediatric Patients, Excluding Spasticity Caused by Cerebral Palsy

  Tailor the exact dosage, frequency, and number of injection sites to the individual patient based on size, number and localization of involved muscles; the severity of spasticity; and the presence of local muscle weakness.

  The maximum recommended dose is 8 Units/kg, divided among affected muscles, up to a maximum dose of 200 Units per single upper limb. If both upper limbs are treated, do not exceed a total XEOMIN dosage of 16 Units/kg, up to a maximum of 400 Units.

  Based on the selected dose, a reconstituted solution at a concentration between 1.25 Units/0.1 mL and 5 Units/0.1 mL is recommended

  [see Dosage and Administration (2.3)]

  . Determine the timing for repeat treatment based on the clinical need of the patient; administer repeat treatments no sooner than every 12 weeks. Most patients in clinical studies were retreated between 12 and 16 weeks.

  Table 4 includes the recommended dose ranges for the treatment of the clinical patterns of flexed elbow, flexed wrist, pronated forearm, clenched fist, and thumb-in-palm.

  Table 4: XEOMIN Dosing by Muscle for Treatment of Pediatric Upper Limb Spasticity, Excluding Spasticity Caused by Cerebral Palsy

  Clinical Pattern Muscle	Dosage		Number of Injection Sites per Muscle
  	Range (Units/kg)	Maximum (Units)
  Flexed Elbow
  Brachioradialis	1-2	50	1-2
  Biceps	2-3	75	1-3
  Brachialis	1-2	50	1-2
  Flexed Wrist
  Flexor carpi radialis	1	25	1
  Flexor carpi ulnaris	1	25	1
  Pronated Forearm
  Pronator quadratus	0.5	12.5	1
  Pronator teres	1-2	50	1-2
  Clenched Fist
  Flexor digitorum superficialis	1	25	1
  Flexor digitorum profundus	1	25	1
  Thumb-in-Palm
  Flexor pollicis longus	1	25	1
  Adductor pollicis	0.5	12.5	1
  Flexor pollicis brevis/ opponens pollicis	0.5	12.5	1

  Figure 4: Muscles Injected for Pediatric Upper Limb Spasticity

  

  Figure 4

  )
• Cervical Dystonia: the recommended initial dose is 120 Units per treatment session (
  2.4 Recommended Dose for Cervical Dystonia

  The recommended initial dose of XEOMIN for cervical dystonia is 120 Units. In a placebo-controlled trial utilizing initial XEOMIN doses of 120 Units and 240 Units, no meaningful difference in effectiveness was demonstrated between the doses [see Clinical Studies (14.3)]. 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 Dsytonia

  

  Figure 5

  )
• Blepharospasm: the recommended initial dose is 50 Units (25 Units per eye) (
  2.5 Recommended Dose for Blepharospasm

  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)]

  .

  Figure 6

  )

• 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.

• Is intended for intramuscular or intraglandular injection in the parotid and submandibular glands only (
  2.7 Preparation and Reconstitution Technique

  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.

  Table 5: Diluent Volumes for Reconstitution of XEOMIN

  Volume of preservative-free 0.9% Sodium Chloride Injection, USP	50 Unit Vial: Resulting dose in Units per 0.1 mL	100 Unit Vial: Resulting dose in Units per 0.1 mL	200 Unit Vial: Resulting dose in Units per 0.1 mL
  0.25 mL	20 Units	-	-
  0.5 mL	10 Units	20 Units	40 Units
  1 mL	5 Units	10 Units	20 Units
  1.25 mL	4 Units	8 Units	16 Units
  2 mL	2.5 Units	5 Units	10 Units
  2.5 mL	2 Units	4 Units	8 Units
  4 mL	1.25 Units	2.5 Units	5 Units
  5 mL	1 Unit	2 Units	4 Units
  8 mLWhen using 8 mL of diluent for a 100 Unit or 200 Unit vial of XEOMIN, complete the following steps: Reconstitute a 100 Unit or 200 Unit vial of XEOMIN with 4 mL of preservative-free 0.9% Sodium Chloride Injection, USP, following instructions above. Withdraw 4 mL of preservative-free 0.9% Sodium Chloride Injection, USP, into an appropriately sized syringe for 8 mL in total. Using the same syringe, draw up the 4 mL of XEOMIN solution from the reconstituted vial and mix gently.	-	1.25 Units	2.5 Units
  16 mLWhen using 16 mL of diluent for a 200 Unit vial of XEOMIN, complete the following steps: Reconstitute a 200 Unit vial of XEOMIN with 4 mL of preservative-free 0.9% Sodium Chloride Injection, USP, following instructions above. Withdraw 12 mL of preservative-free 0.9% Sodium Chloride Injection, USP, into an appropriately sized syringe for 16 mL in total. Using the same syringe, draw up the 4 mL of XEOMIN solution from the reconstituted vial and mix gently.	-	-	1.25 Units
  )
• Use for only one injection session and for only one patient (
  2.7 Preparation and Reconstitution Technique

  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.

  Table 5: Diluent Volumes for Reconstitution of XEOMIN

  Volume of preservative-free 0.9% Sodium Chloride Injection, USP	50 Unit Vial: Resulting dose in Units per 0.1 mL	100 Unit Vial: Resulting dose in Units per 0.1 mL	200 Unit Vial: Resulting dose in Units per 0.1 mL
  0.25 mL	20 Units	-	-
  0.5 mL	10 Units	20 Units	40 Units
  1 mL	5 Units	10 Units	20 Units
  1.25 mL	4 Units	8 Units	16 Units
  2 mL	2.5 Units	5 Units	10 Units
  2.5 mL	2 Units	4 Units	8 Units
  4 mL	1.25 Units	2.5 Units	5 Units
  5 mL	1 Unit	2 Units	4 Units
  8 mLWhen using 8 mL of diluent for a 100 Unit or 200 Unit vial of XEOMIN, complete the following steps: Reconstitute a 100 Unit or 200 Unit vial of XEOMIN with 4 mL of preservative-free 0.9% Sodium Chloride Injection, USP, following instructions above. Withdraw 4 mL of preservative-free 0.9% Sodium Chloride Injection, USP, into an appropriately sized syringe for 8 mL in total. Using the same syringe, draw up the 4 mL of XEOMIN solution from the reconstituted vial and mix gently.	-	1.25 Units	2.5 Units
  16 mLWhen using 16 mL of diluent for a 200 Unit vial of XEOMIN, complete the following steps: Reconstitute a 200 Unit vial of XEOMIN with 4 mL of preservative-free 0.9% Sodium Chloride Injection, USP, following instructions above. Withdraw 12 mL of preservative-free 0.9% Sodium Chloride Injection, USP, into an appropriately sized syringe for 16 mL in total. Using the same syringe, draw up the 4 mL of XEOMIN solution from the reconstituted vial and mix gently.	-	-	1.25 Units
  )
• Instructions are specific for 50 Unit, 100 Unit, and 200 Unit vials (
  2.7 Preparation and Reconstitution Technique

  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.

  Table 5: Diluent Volumes for Reconstitution of XEOMIN

  Volume of preservative-free 0.9% Sodium Chloride Injection, USP	50 Unit Vial: Resulting dose in Units per 0.1 mL	100 Unit Vial: Resulting dose in Units per 0.1 mL	200 Unit Vial: Resulting dose in Units per 0.1 mL
  0.25 mL	20 Units	-	-
  0.5 mL	10 Units	20 Units	40 Units
  1 mL	5 Units	10 Units	20 Units
  1.25 mL	4 Units	8 Units	16 Units
  2 mL	2.5 Units	5 Units	10 Units
  2.5 mL	2 Units	4 Units	8 Units
  4 mL	1.25 Units	2.5 Units	5 Units
  5 mL	1 Unit	2 Units	4 Units
  8 mLWhen using 8 mL of diluent for a 100 Unit or 200 Unit vial of XEOMIN, complete the following steps: Reconstitute a 100 Unit or 200 Unit vial of XEOMIN with 4 mL of preservative-free 0.9% Sodium Chloride Injection, USP, following instructions above. Withdraw 4 mL of preservative-free 0.9% Sodium Chloride Injection, USP, into an appropriately sized syringe for 8 mL in total. Using the same syringe, draw up the 4 mL of XEOMIN solution from the reconstituted vial and mix gently.	-	1.25 Units	2.5 Units
  16 mLWhen using 16 mL of diluent for a 200 Unit vial of XEOMIN, complete the following steps: Reconstitute a 200 Unit vial of XEOMIN with 4 mL of preservative-free 0.9% Sodium Chloride Injection, USP, following instructions above. Withdraw 12 mL of preservative-free 0.9% Sodium Chloride Injection, USP, into an appropriately sized syringe for 16 mL in total. Using the same syringe, draw up the 4 mL of XEOMIN solution from the reconstituted vial and mix gently.	-	-	1.25 Units
  )
• Store in a refrigerator (2°C to 8°C) and use within 24 hours (
  2.7 Preparation and Reconstitution Technique

  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.

  Table 5: Diluent Volumes for Reconstitution of XEOMIN

  Volume of preservative-free 0.9% Sodium Chloride Injection, USP	50 Unit Vial: Resulting dose in Units per 0.1 mL	100 Unit Vial: Resulting dose in Units per 0.1 mL	200 Unit Vial: Resulting dose in Units per 0.1 mL
  0.25 mL	20 Units	-	-
  0.5 mL	10 Units	20 Units	40 Units
  1 mL	5 Units	10 Units	20 Units
  1.25 mL	4 Units	8 Units	16 Units
  2 mL	2.5 Units	5 Units	10 Units
  2.5 mL	2 Units	4 Units	8 Units
  4 mL	1.25 Units	2.5 Units	5 Units
  5 mL	1 Unit	2 Units	4 Units
  8 mLWhen using 8 mL of diluent for a 100 Unit or 200 Unit vial of XEOMIN, complete the following steps: Reconstitute a 100 Unit or 200 Unit vial of XEOMIN with 4 mL of preservative-free 0.9% Sodium Chloride Injection, USP, following instructions above. Withdraw 4 mL of preservative-free 0.9% Sodium Chloride Injection, USP, into an appropriately sized syringe for 8 mL in total. Using the same syringe, draw up the 4 mL of XEOMIN solution from the reconstituted vial and mix gently.	-	1.25 Units	2.5 Units
  16 mLWhen using 16 mL of diluent for a 200 Unit vial of XEOMIN, complete the following steps: Reconstitute a 200 Unit vial of XEOMIN with 4 mL of preservative-free 0.9% Sodium Chloride Injection, USP, following instructions above. Withdraw 12 mL of preservative-free 0.9% Sodium Chloride Injection, USP, into an appropriately sized syringe for 16 mL in total. Using the same syringe, draw up the 4 mL of XEOMIN solution from the reconstituted vial and mix gently.	-	-	1.25 Units
  )

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.

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

  Risk Summary

  There are no adequate data on the developmental risk associated with the use of XEOMIN in pregnant women. XEOMIN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. XEOMIN was embryotoxic in rats and increased abortions in rabbits when given at doses higher than the maximum recommended human dose (MRHD) for cervical dystonia (120 Units), on a body weight basis.

  In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

  Data

  Animal Data

  When XEOMIN was administered intramuscularly to pregnant rats during organogenesis (3 Units/kg, 10 Units/kg, or 30 Units/kg on gestational days [GDs] 6, 12, and 19; or 7 Units/kg on GDs 6 to 19; or 2 Units/kg, 6 Units/kg, or 18 Units/kg on GDs 6, 9, 12, 16, and 19), decreases in fetal body weight and skeletal ossification were observed at doses that were also maternally toxic. The no-effect level for embryotoxicity in rats was 6 Units/kg (3 times the MRHD for cervical dystonia on a body weight basis). Intramuscular administration to pregnant rabbits during organogenesis (1.25 Units/kg, 2.5 Units/kg, or 5.0 Units/kg on GDs 6, 18, and 28) resulted in an increased rate of abortion at the highest dose, which was also maternally toxic. In rabbits, the no-effect level for increased abortion was 2.5 Units/kg (similar to the MRHD for cervical dystonia on a body weight basis).
  )