BOTOX, OnabotulinumtoxinA Form

OnabotulinumtoxinA (Botox®) is an acetylcholine release inhibitor and a neuromuscular blocking agent. Prophylaxis X X X X X X X X X X X X X Adults Pediatrics Treatment FDA Approved Indication(s) Indication Overactive bladder Urinary incontinence Migraine Upper/lower limb spasticity (includes CP)
Cervical dystonia (focal dystonia) Axillary hyperhidrosis Blepharospasm (focal dystonia) Strabismus Off-Label Uses Laryngeal dystonia Oromandibular dystonia Upper extremity dystonia Upper extremity essential tremor Esophageal achalasia HD and IAS achalasia Chronic anal fissure Sialorrhea Abbreviations: cerebral palsy (CP); Hirschsprung disease (HD), internal anal sphincter (IAS) achalasia. *See criteria set entitled Focal Dystonia and Essential Tremor X X X X X X X X X X X X X X X X X X X X X X X X X Botox is indicated for: • Treatment of:
o Overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and frequency, in adults who have an inadequate response to or are intolerant of an anticholinergic medication o Urinary incontinence due to detrusor over-activity associated with a neurologic condition [e.g., spinal cord injury (SCI), multiple sclerosis (MS)] in adults who have an inadequate response to or are intolerant of an anticholinergic medication o Neurogenic detrusor overactivity (NDO) in pediatric patients 5 years of age and older who have an inadequate response to or are intolerant of anticholinergic medication o Spasticity in patients 2 years of age and older Page 1 of 22

CLINICAL POLICY
OnabotulinumtoxinA o Cervical dystonia (CD) in adult patients, to reduce the severity of abnormal head position and neck pain o Severe axillary hyperhidrosis that is inadequately managed by topical agents in adult patients o Blepharospasm associated with dystonia in patients ≥ 12 years of age o Strabismus in patients ≥ 12 years of age
• Prophylaxis of headaches in adult patients with chronic migraine (≥ 15 days per month with headache lasting 4 hours a day or longer)
Limitation(s) of use:
• Safety and effectiveness of Botox have not been established for: o Prophylaxis of episodic migraine (14 headache days or fewer per month) o Treatment of hyperhidrosis in body areas other than axillary. Weakness of hand muscles and blepharoptosis may occur in patients who receive Botox for palmar hyperhidrosis and facial hyperhidrosis, respectively. Patients should be evaluated for potential causes of
secondary hyperhidrosis (e.g., hyperthyroidism) to avoid symptomatic treatment of hyperhidrosis without the diagnosis and/or treatment of the underlying disease.
o Treatment of axillary hyperhidrosis in pediatric patients under 18 year of age • Botox has not been shown to improve upper extremity functional abilities, or range of motion at a joint affected by a fixed contracture. Policy/Criteria Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria.
Index I. Initial Approval Criteria A. Overactive Bladder and Urinary Incontinence B. Chronic Migraine C. Upper and Lower Limb Spasticity (includes cerebral palsy) D. Cervical Dystonia (focal dystonia) E. Axillary Hyperhidrosis (excessive underarm sweating) F. Blepharospasm (focal dystonia - abnormal eyelid muscle contraction) G. Strabismus (eye misalignment) H. Focal Dystonia and Essential Tremor (off-label) I. Esophageal Achalasia (off-label) J. Hirschsprung Disease and Internal Anal Sphincter Achalasia (off-label) K. Chronic Anal Fissure (off-label) L. Chronic Sialorrhea (off-label) M. Other diagnoses/indications II. Continued Approval Criteria A. Chronic Migraine B. Esophageal Achalasia C. All Other Indications in Section I D. Other diagnoses/indications III. Diagnoses/Indications for which coverage is NOT authorized:
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CLINICAL POLICY
OnabotulinumtoxinA IV. Appendices V. Dosage and Administration VI. Product Availability VII. References It is the policy of health plans affiliated with Centene Corporation® that Botox is medically necessary when one of the following criteria is met:
I. Initial Approval Criteria
A. Overactive Bladder and Urinary Incontinence (must meet all):

1. Diagnosis of one of the following (a or b): a. OAB, and member’s history is positive for urinary urgency, frequency, and nocturia with or without incontinence;
   b. Urinary incontinence, and member’s history is positive for an associated neurologic condition (e.g., spinal cord injury, spinal dysraphism, multiple sclerosis);
2. Prescribed by or in consultation with a neurologist or urologist;
   3. Age ≥ 5 years;
   4. Member meets one of the following, unless clinically significant adverse effects are experienced or all are contraindicated (a or b, see Appendix B): a. Adult: failure of one of the following, each used for at least 30 days (i or ii): i. Two anticholinergic agents; ii. One oral beta-3 agonist medication; b. Pediatric: failure of at least two anticholinergic agents, each used for at least 30 days;
3. Botox is not prescribed concurrently with other botulinum toxin products;
   
   6. Botulinum toxin therapy for cosmetic or medical conditions has not been administered within the last 12 weeks;
4. Treatment plan details number of Units per indication and treatment session;
   8. Request meets one of the following (a or b):
      a. OAB: Dose does not exceed 100 Units per treatment session; b. Urinary incontinence associated with a neurologic condition:
      i. Weight ≥ 34 kg: dose does not exceed 200 Units per treatment session; ii. Weight < 34 kg: dose does not exceed 6 units/kg per treatment session. Approval duration:
      Medicaid/HIM – 12 months Commercial – 6 months or to member’s renewal date, whichever is longer B. Chronic Migraine (must meet all):
5. Diagnosis of chronic migraine (i.e., ≥ 15 headache days per month for at least 3 months with headache lasting 4 hours a day or longer);

6. Prescribed by or in consultation with a neurologist or pain specialist;

   3. Age ≥ 18 years;
   4. Failure of at least 2 of the following oral migraine preventative therapies, each for 8 weeks and from different therapeutic classes, unless clinically significant adverse effects are experienced or all are contraindicated (a, b, or c): Page 3 of 22

   CLINICAL POLICY
   OnabotulinumtoxinA a. Antiepileptics (e.g., divalproex sodium, sodium valproate, topiramate); b. Beta-blockers (e.g., metoprolol, propranolol, timolol); c. Antidepressants (e.g., amitriptyline, venlafaxine);

7. If currently receiving calcitonin gene-related peptide (CGRP) therapy for migraine prophylaxis and request is for concurrent use of Botox and CGRP therapy (i.e., not switching from one agent to another), all of the following (a, b, and c): a. Sufficient evidence is provided from at least two high-quality, published studies in reputable peer-reviewed journals or evidence-based clinical practice guidelines that provide all of the following (i – iv): Case studies or chart reviews are not considered high-quality evidence i. Adequate representation of the member’s clinical characteristics, age, and diagnosis;
   ii. Adequate representation of the prescribed drug regimen;
   iii. Clinically meaningful outcomes such as a reduction in monthly migraine or headache days; iv. Appropriate experimental design and method to address research questions (see Appendix E for additional information); b. Member has experienced and maintained positive response to CGRP monotherapy as evidenced by a reduction in migraine days per month from baseline following at least 6 months for treatments administered quarterly (every 3 months) (e.g., Ajovy®, Vyepti™) or 3 months for treatments administered at least monthly (e.g., Aimovig®, Ajovy®, Emgality®, Nurtec® ODT, Qulipta™); c. Despite CGRP monotherapy, member continues to experience chronic migraine (i.e., ≥ 15 headache days per month for at least 3 months with headache lasting 4 hours a day or longer) and/or severe migraine headaches that result in disability and functional impairment;
8. Botox is not prescribed concurrently with other botulinum toxin products;
   
   7. Botulinum toxin therapy for cosmetic or medical conditions has not been administered within the last 12 weeks;
9. Treatment plan details number of Units per indication and treatment session;
   9. Dose does not exceed 155 Units per treatment session. Approval duration:
      Medicaid/HIM – 12 months
      Commercial – 6 months or to member’s renewal date, whichever is longer C. Upper and Lower Limb Spasticity (includes cerebral palsy) (must meet all):
10. Diagnosis of upper or lower limb spasticity (e.g., associated with paralysis, central nervous system demyelinating diseases such as multiple sclerosis, cerebral palsy, stroke);
11. Prescribed by or in consultation with a neurologist, orthopedist, or physiatrist;
    3. Age ≥ 2 years;
    4. Botox is not prescribed concurrently with other botulinum toxin products;
    5. Botulinum toxin therapy for cosmetic or medical conditions has not been administered within the last 12 weeks;

12. Treatment plan details number of Units per indication and treatment session; Page 4 of 22

    CLINICAL POLICY
    OnabotulinumtoxinA

13. Request meets one of the following (a or b): a. Age ≥ 18 years: Upper and/or lower limb: Dose does not exceed 400 Units per treatment session; b. Age 2 through 17 years (i, ii, and iii): i. Upper limb: Dose does not exceed the lower of 6 Units/kg body weight or 200 Units per treatment session; ii. Lower limb: Dose does not exceed the lower of 8 Units/kg body weight or 300 Units per treatment session; iii. If upper and lower limb spasticity are treated in the same treatment session, number of Units per treatment session does not exceed the lower of 10 Units/kg body weight or 340 Units per treatment session. Approval duration:
    Medicaid/HIM – 12 months
    Commercial – 6 months or to member’s renewal date, whichever is longer D. Cervical Dystonia (focal dystonia) (must meet all):
14. Diagnosis of CD;
    2. Prescribed by or in consultation with a neurologist, orthopedist, or physiatrist;
    3. Age ≥ 16 years;
    4. Member is experiencing involuntary contractions of the neck and shoulder muscles (e.g., splenius capitis, sternocleidomastoid, levator scapulae, scalene, trapezius, semispinalis capitis) resulting in abnormal postures or movements of the neck, shoulders or head;
15. Contractions are causing pain and functional impairment;
    
    6. Botox is not prescribed concurrently with other botulinum toxin products;
    7. Botulinum toxin therapy for cosmetic or medical conditions has not been administered within the last 12 weeks;
16. Treatment plan details number of Units per indication and treatment session;
    9. Request meets one of the following (a or b): a. Age ≥ 18 years: Dose does not exceed 100 Units total in the sternocleidomastoid (SCM) muscle and 300 Units per treatment session;
       b. Age 16 through 17 years: Dose does not exceed 100 Units total in the SCM muscle and the lower of 10 Units/kg body weight or 300 Units per treatment session. Approval duration:
       Medicaid/HIM – 12 months Commercial – 6 months or to member’s renewal date, whichever is longer E. Primary Axillary Hyperhidrosis (excessive underarm sweating) (must meet all):
17. Diagnosis of primary axillary hyperhidrosis;
    2. Prescribed by or in consultation with a neurologist or dermatologist;
    3. Age ≥ 18 years;
    4. Failure of a 6-month trial of topical aluminum chloride, unless contraindicated or clinically significant adverse effects are experienced;

18. Botox is not prescribed concurrently with other botulinum toxin products;
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    CLINICAL POLICY
    OnabotulinumtoxinA

19. Botulinum toxin therapy for cosmetic or medical conditions has not been administered within the last 12 weeks;
20. Treatment plan details number of Units per indication and treatment session;
    8. Dose does not exceed 100 Units per treatment session. Approval duration:
       Medicaid/HIM – 12 months
       Commercial – 6 months or to member’s renewal date, whichever is longer F. Blepharospasm (focal dystonia - abnormal eyelid muscle contraction) (must meet all):
21. Diagnosis of blepharospasm;
    2. Prescribed by or in consultation with a neurologist or ophthalmologist;
    3. Age ≥ 12 years;
    4. Member is experiencing significant disability in daily functional activities due to interference with vision;
22. Botox is not prescribed concurrently with other botulinum toxin products;
    
    6. Botulinum toxin therapy for cosmetic or medical conditions has not been administered within the last 12 weeks;
23. Treatment plan details number of Units per indication and treatment session;
    8. Dose does not exceed 2.5 Units per muscle, 7.5 Units per eye, and 15 Units per treatment session.
       Approval duration:
       Medicaid/HIM – 12 months
       Commercial – 6 months or to member’s renewal date, whichever is longer G. Strabismus (eye misalignment) (must meet all):
    9. Diagnosis of one of the following (a, b, or c): a. Vertical strabismus (superior and inferior rectus muscles, superior and inferior oblique muscles); b. Horizontal strabismus (medial and lateral rectus muscles) (i or ii): i. Horizontal strabismus < 20 prism diopters; ii. Horizontal strabismus 20 to 50 prism diopters; c. Persistent sixth cranial nerve (VI; abducens nerve) palsy of ≥ one month involving the lateral rectus muscle;
24. Prescribed by or in consultation with a neurologist or ophthalmologist;
    3. Age ≥ 12 years;
    4. Botox is not prescribed concurrently with other botulinum toxin products;
    5. Botulinum toxin therapy for cosmetic or medical conditions has not been administered within the last 12 weeks;

25. Treatment plan details number of Units per indication and treatment session;

    7. Request meets one of the following (a, b, or c): a. Vertical strabismus, or horizontal strabismus < 20 prism diopters: Dose does not exceed 2.5 Units per muscle and 5 Units per treatment session; b. Horizontal strabismus 20 to 50 prism diopters: Dose does not exceed 5 Units per muscle and 10 Units per treatment session; c. VI nerve palsy: Dose does not exceed 2.5 Units per treatment session (limited to treatment of one eye). Page 6 of 22

    CLINICAL POLICY
    OnabotulinumtoxinA Approval duration:
    Medicaid/HIM – 12 months
    Commercial – 6 months or to member’s renewal date, whichever is longer H. Focal Dystonia and Essential Tremor (off-label) (must meet all):

26. Diagnosis of one of the following (a, b, c, or d): a. Laryngeal dystonia;
    b. Oromandibular dystonia (OMD); c. Upper extremity (UE) dystonia; d. UE essential tremor;
27. Prescribed by or in consultation with a neurologist, ENT specialist, orthopedist, or physiatrist;
28. Age meets one of the following (a or b): a. For UE dystonia: Age ≥ 2 years; b. For all other indications: Age ≥ 18 years;
29. For UE dystonia: Failure of a trial of carbidopa/levodopa or trihexyphenidyl (see Appendix B), unless clinically significant adverse effects are experienced or both are contraindicated;
30. Botox is not prescribed concurrently with other botulinum toxin products;
    
    6. Botulinum toxin therapy for cosmetic or medical conditions has not been administered within the last 12 weeks;
31. Treatment plan details number of Units per indication and treatment session;
    8. Request meets one of the following (a or b): a. Laryngeal dystonia: Dose does not exceed 25 Units per treatment session; b. UE dystonia, UE essential tremor, OMD: Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use and member age (prescriber must submit supporting evidence; Units per treatment session does not exceed the lower of 10 Units/kg body weight or 340 Units for pediatrics, or 400 Units for adults). Approval duration:
       Medicaid/HIM – 12 months
       Commercial – 6 months or to member’s renewal date, whichever is longer I. Esophageal Achalasia (off-label) (must meet all):
32. Diagnosis of esophageal achalasia;
    2. Prescribed by or in consultation with a gastroenterologist;
    3. Age ≥ 18 years;
    4. Member is not a candidate for pneumatic dilation or laparoscopic surgical myotomy (e.g., due to age, comorbidity);
33. Botox is not prescribed concurrently with other botulinum toxin products;
    
    6. Botulinum toxin therapy for cosmetic or medical conditions has not been administered within the last 12 weeks;

34. Treatment plan details number of Units per indication and treatment session;

    8. Dose does not exceed 100 Units per treatment session. Page 7 of 22

    CLINICAL POLICY
    OnabotulinumtoxinA Approval duration:
    Medicaid/HIM – 12 months
    Commercial – 6 months or to member’s renewal date, whichever is longer J. Hirschsprung Disease, Internal Anal Sphincter Achalasia (off-label) (must meet all):

35. Diagnosis of one of the following (a or b):
    a. Hirschsprung disease (HD) and (i or ii): i. Member has an HD subtype known as ultra-short segment HD; ii. Botox is prescribed for constipation post-surgery; b. Internal anal sphincter (IAS) achalasia;
36. Prescribed by or in consultation with a gastroenterologist;
    3. Age ≥ 2 years;
    4. Failure of a trial of stool softeners and laxatives (see Appendix B), unless clinically adverse effects are experienced or all are contraindicated;
37. Botox is not prescribed concurrently with other botulinum toxin products;
    
    6. Botulinum toxin therapy for cosmetic or medical conditions has not been administered within the last 12 weeks;
38. Treatment plan details number of Units per indication and treatment session;
    8. Dose does not exceed 100 Units per treatment session. Approval duration:
       Medicaid/HIM – 12 months
       Commercial – 6 months or to member’s renewal date, whichever is longer K. Chronic Anal Fissure (off-label) (must meet all):
39. Diagnosis of chronic anal fissure;
    2. Prescribed by or in consultation with a gastroenterologist or colorectal surgeon;
    3. Age ≥ 18 years;
    4. Failure of nitroglycerin ointment unless contraindicated or clinically significant adverse effects are experienced;
40. Failure of one of the following (a or b), unless contraindicated or clinically significant adverse effects are experienced (see Appendix B); a. Oral/topical nifedipine;
    b. Oral/topical diltiazem;
41. Botox is not prescribed concurrently with other botulinum toxin products;
    
    7. Botulinum toxin therapy for cosmetic or medical conditions has not been administered within the last 12 weeks;
42. Treatment plan details number of Units per indication and treatment session;
    9. Dose does not exceed 25 Units per treatment session. Approval duration:
       Medicaid/HIM – 12 months
       Commercial – 6 months or to member’s renewal date, whichever is longer L. Chronic Sialorrhea (off-label) (must meet all):

43. Diagnosis of chronic sialorrhea for at least the last three months due to one of the following (a or b): Page 8 of 22

    CLINICAL POLICY
    OnabotulinumtoxinA a. Underlying neurologic disorder (e.g., Parkinson disease, atypical parkinsonism, stroke, traumatic brain injury, cerebral palsy, amyotrophic lateral sclerosis); b. Craniofacial abnormality (e.g., Goldenhar syndrome);

44. Prescribed by or in consultation with a neurologist or physiatrist;
    3. Age ≥ 18 years;
    4. Failure of at least one anticholinergic drug (see Appendix B), unless clinically significant adverse effects are experienced or all are contraindicated;
    5. Botox is not prescribed concurrently with other botulinum toxin products;
    6. Botulinum toxin therapy for cosmetic or medical conditions has not been administered within the last 12 weeks;
45. Treatment plan provided detailing number of Units per indication and treatment session;
46. Dose does not exceed 100 Units per treatment session; Approval duration:
    Medicaid/HIM – 12 months
    Commercial – 6 months or to member’s renewal date, whichever is longer M. Other diagnoses/indications (must meet 1 or 2):
47. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or
48. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
    II. Continued Approval
    A. Chronic Migraine (must meet all):
49. Member meets one of the following (a or b): a. Currently receiving medication via Centene benefit or member has previously met initial approval criteria; b. Member is currently receiving medication and is enrolled in a state and product with continuity of care regulations (refer to state specific addendums for CC.PHARM.03A and CC.PHARM.03B);

50. If receipt of ≥ 2 Botox treatment sessions, member has experienced and maintained a 30% reduction in monthly migraine headache frequency from baseline;

    3. Botox is not prescribed concurrently with other botulinum toxin products;
       Page 9 of 22

    CLINICAL POLICY
    OnabotulinumtoxinA

51. Botulinum toxin therapy for cosmetic or medical conditions has not been administered within the last 12 weeks;
52. Treatment plan details number of Units per indication and treatment session;
    6. If request is for a dose increase, new dose does not exceed 155 Units per treatment session. Approval duration:
       Medicaid/HIM – 12 months
       Commercial – 6 months or to member’s renewal date, whichever is longer B. Esophageal Achalasia (must meet all):
53. Member meets one of the following (a or b): a. Currently receiving medication via Centene benefit or member has previously met initial approval criteria; b. Member is currently receiving medication and is enrolled in a state and product with continuity of care regulations (refer to state specific addendums for CC.PHARM.03A and CC.PHARM.03B);
    2. Member is responding positively to therapy;
    3. Botox is not prescribed concurrently with other botulinum toxin products;
    4. Botulinum toxin therapy for cosmetic or medical conditions has not been administered within the last 12 weeks;
54. If member has previously received ≥ 2 Botox treatment sessions for esophageal achalasia, it has been at least 24 weeks since the last treatment session;
    
    6. Treatment plan details number of Units per indication and treatment session;
    7. If request is for a dose increase, new dose does not exceed 100 Units per treatment session. Approval duration:
       Medicaid/HIM – 12 months Commercial – 6 months or to member’s renewal date, whichever is longer C. All Other Indications in Section I (must meet all):
    8. Member meets one of the following (a or b): a. Currently receiving medication via Centene benefit or member has previously met initial approval criteria; b. Member is currently receiving medication and is enrolled in a state and product with continuity of care regulations (refer to state specific addendums for CC.PHARM.03A and CC.PHARM.03B);
    9. Member is responding positively to therapy;
    10. Botox is not prescribed concurrently with other botulinum toxin products;
    11. Botulinum toxin therapy for cosmetic or medical conditions has not been administered within the last 12 weeks;

55. Treatment plan details number of Units per indication and treatment session;

    6. If request is for a dose increase, request meets one of the following (a - i): a. OAB: Dose does not exceed 100 Units per treatment session; b. Urinary incontinence associated with a neurologic condition: Dose does not exceed 200 Units per treatment session; Page 10 of 22

    CLINICAL POLICY
    OnabotulinumtoxinA c. Upper/lower limb spasticity (i or ii): i. Age ≥ 18 years: Upper and/or lower limb: Dose not exceed 400 Units per treatment session; ii. Age 2 through 17 years (a, b, and c): a) Upper limb: Dose does not exceed the lower of 6 Units/kg body weight or 200 Units per treatment session; b) Lower limb: Dose does not exceed the lower of 8 Units/kg body weight or 300 Units per treatment session; c) If upper and lower limb spasticity are treated in the same treatment session, number of Units per treatment session does not exceed the lower of 10 Units/kg body weight or 340 Units per treatment session; d. CD (i or ii): i. Age ≥ 18 years: Dose does not exceed 100 Units total in the SCM muscle and 300 Units per treatment session;
    ii. Age 16 through 17 years: Dose does not exceed 100 Units total in the SCM muscle and the lower of 10 Units/kg body weight or 300 Units per treatment session; e. Primary axillary hyperhidrosis: Dose does not exceed 100 Units per treatment session; f. Blepharospasm: Dose does not exceed 5 Units per muscle, 15 Units per eye, and 30 Units per treatment session;
    g. Strabismus (i or ii): i. Vertical and horizontal strabismus: Dose does not exceed the lower of a two- fold increase or 25 Units per muscle and 50 Units per treatment session; ii. VI nerve palsy: Dose does not exceed the lower of a two-fold increase or 25 Units per muscle and 25 Units per treatment session; h. Focal dystonia and essential tremor (i or ii): i. Laryngeal dystonia: Dose does not exceed 25 Units per treatment session; ii. UE dystonia, UE essential tremor, OMD: Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use and member age (prescriber must submit supporting evidence; number of Units per treatment session does not exceed the lower of 10 Units/kg body weight or 340 Units for pediatrics, or 400 Units for adults); i. HD, IAS achalasia, chronic anal fissure, sialorrhea: Dose does not exceed 100 Units per treatment session. Approval duration:
    Medicaid/HIM – 12 months
    Commercial – 6 months or to member’s renewal date, whichever is longer D. Other diagnoses/indications (must meet 1 or 2):

56. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: Page 11 of 22

    CLINICAL POLICY
    OnabotulinumtoxinA CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or

57. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid. III. Diagnoses/Indications for which coverage is NOT authorized: A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off label use policies – CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid, or evidence of coverage documents; B. Cosmetic treatment of hyperfunctional wrinkles of the upper face including glabellar frown lines, deep forehead wrinkles and periorbital wrinkles (crow’s feet);
    C. Episodic migraine (≤ 14 headache days per month): Safety and efficacy have not been established per the package insert;
    D. Total treatment dose per session does not exceed the lower of 10 Units/kg body weight or 340 Units in a 3-month interval for pediatrics and 400 Units for adults. IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key
    CD: cervical dystonia CGRP: calcitonin gene-related peptide
    FDA: Food and Drug Administration HD: Hirschsprung disease IAS: internal anal sphincter MS: multiple sclerosis NDO: neurogenic detrusor overactivity OAB: overactive bladder OMD: oromandibular dystonia SCI: spinal cord injury SCM: sternocleidomastoid UE: upper extremity Appendix B: Therapeutic Alternatives
    This table provides a listing of preferred alternative therapy recommended in the approval criteria. The drugs listed here may not be a formulary agent for all relevant lines of business and may require prior authorization.
    Drug Name Dosing Regimen Dose Limit/ Maximum Dose Overactive bladder, urinary incontinence oxybutynin (Ditropan/XL, Gelnique) (anticholinergic agent) • Immediate-release tablets (adults and children): 5 mg orally two to three times daily • Extended-release tablets: 5-10 mg orally once daily • Immediate- release: 20 mg/day • Extended- release: 30 mg/day Page 12 of 22

    CLINICAL POLICY
    OnabotulinumtoxinA Drug Name Dosing Regimen • Topical gel: Apply contents of one sachet topically once daily Dose Limit/ Maximum Dose • Gel: one sachet/day tolterodine tartrate (Detrol/LA) (anticholinergic agent) • Immediate-release tablets: 2 mg orally 4 mg/day twice daily • Extended-release tablets: 4 mg orally once daily • Adults and children weighing more than 60 kg: 5 mg PO once daily • Children weighing between 46 to 60 kg: 4 mg PO once daily • Children weighing between 16 to 45 kg: 3 mg PO once daily • Children weighing between 9 to 15 kg: 2 mg once daily 25 mg orally once daily Refer to prescribing information for dosing regimens. 10 mg/day 50 mg/day Refer to prescribing information solifenacin (Vesicare) (anticholinergic agent) Myrbetriq (mirabegron)
    (beta-3 agonist) Chronic migraine Examples of oral migraine preventive therapies -
    • Anticonvulsants: divalproex (Depakote®), topiramate (Topamax®) • Beta blockers: propranolol (Inderal®), metoprolol (Lopressor®), timolol
    • Antidepressants/tricyclic antidepressants: amitriptyline (Elavil®), venlafaxine (Effexor®) Primary axillary hyperhidrosis Drysol® (aluminum chloride) Dystonia carbidopa/levodopa (Sinemet®, Duopa®, Rytary®) trihexyphenidyl HD, IAS achalasia Dulcolax® Apply topically once daily 25 mg/100 mg PO QD, and increase by 1 tablet every 3 to 5 days. 30 mg PO QD 5 to 15 mg PO or 10 mg PR QD One application/day 1,200 mg/day of levodopa 30 mg/day 30 mg/day Page 13 of 22

    CLINICAL POLICY
    OnabotulinumtoxinA Drug Name Dosing Regimen Dose Limit/ Maximum Dose (bisacodyl) MiraLax® (Polyethylene glycol 3350) Colace® (Docusate sodium) Chronic anal fissure nitroglycerin 0.2% ointment (Rectiv®) nifedipine or diltiazem (oral or topical ointment/gel-compounded) benztropine mesylate (oral tablets - 0.5 mg, 1 mg, 2 mg) 17 grams of polyethylene glycol 3350 in 4-8 oz water by mouth once daily 50-200 mg PO QD-QID 17 grams/day 200 mg/day 15 to 30 mg (2.5 to 5 cm as squeezed from the tube, about 1 to 2 inches), applied topically to skin every 8 hours while awake and at bedtime; application frequency may be increased to every 6 hours if needed; alternatively, a regimen providing a 12-hour nitrate-free interval may be used; apply dosage once each morning, then 6 hours later PO: At provider discretion
    Intra-anal: 0.2% ointment or gel, applied around fissure(s) 2 times daily for 6-8 weeks • Pediatrics: chronic drooling: children ≥ 3 years and adolescents ≤ 16 years: oral solution (Cuvposa): 20 mcg/kg/dose 3 times daily, titrate in increments of 20 mcg/kg/dose every 5 to 7 days as tolerated to response up to a maximum dose of 100 mcg/kg/dose 3 times daily; not to exceed 1,500 to 3,000 mcg/dose. (FDA labeled) Mean doses of 3.8 mg/day have been used in adults and pediatrics ≥ 4 years. Benztropine typically is administered in divided doses titrating up as needed.
    (Off-label - Sridharan 2018, Lakraj 2013; Micromedex, package insert) 75 mg (12.5 cm as squeezed from the tube)/day Varies See regimen information See regimen information Sialorrhea: examples of anticholinergic drugs glycopyrrolate (Glycate® oral tablets, Cuvposa® oral solution) • Adults: 1 mg PO TID
    (Off-label: Lakraj 2013) Therapeutic alternatives are listed as Brand name® (generic) when the drug is available by brand name only and generic (Brand name®) when the drug is available by both brand and generic. Appendix C: Contraindications and Boxed Warnings • Contraindication(s): o Hypersensitivity to any botulinum toxin preparation or to any of the components in the formulation Page 14 of 22

    CLINICAL POLICY
    OnabotulinumtoxinA o Infection at the proposed injection site o Intradetrusor injections: urinary tract infection or urinary retention • Boxed warning(s): distant spread of toxin effect Appendix D: Botulinum Toxin Product Interchangeability • Potency Units of Botox are not interchangeable with other botulinum toxin product preparations (e.g., Dysport®, Myobloc®, Xeomin®). Appendix E: Guideline Support for Botulinum Toxin Use Indication Focal Dystonia and Essential Tremor, and Headache
    Blepharospasm, cervical dystonia, adult spasticity, and headache Migraine prevention Guideline Academy of Neurology (2016) Laryngeal dystonia Oromandibular dystonia Focal limb dystonia - UE* Essential tremor - UE Sialorrhea OAB/urinary incontinence American Academy of Neurology and the American Headache Society (Neurology 2012, Headache 2021) American Academy of Otolaryngology-Head and Neck Surgery Foundation (AAO-HNS, 2018) American Academy of Oral Medicine (2018) American Academy of Neurology (2008) American Academy of Neurology (2008, 2011) American Academy of Cerebral Palsy and Developmental Medicine (AACPDM, 2018); International Parkinson and Movement Disorder Society (2018) American Urological Association Society of Urodynamics (2019) Gastrointestinal Conditions (see guidelines for required oral medication information) American College of Gastroenterology (2020) Esophageal achalasia American Pediatric Surgical Association (2017) HD and IAS achalasia American College of Gastroenterology (2021) Chronic anal fissure American Academy of Neurology (AAN) classifies Botox use for hemifacial spasm and motor tics as category C, and notes that data are inadequate to make a recommendation for lower limb dystonia. All other AAN Botox recommendations above are classified as category B - probably effective.
    *Policy criteria requiring failure of oral medication for dystonias are limited to dystonias affecting the limbs (see Cloud and Jinnah, 2010). V. Dosage and Administration
    Indication Adults: OAB Pediatric NDO Dosing Regimen Up to 5 Units IM per injection across up to 20 injection sites in the detrusor muscle for a total of up to 100 Units per treatment session • Weight ≥ 34 kg: 200 units
    • Weight < 34 kg: 6 units/kg (see table below) Maximum Dose See dosing regimens for maximum dose Frequency: Page 15 of 22

    Maximum Dose • Esophageal acalasia: one treatment session every 24 weeks. • All other indications: one treatment session every 12 weeks. CLINICAL POLICY
    OnabotulinumtoxinA Indication Adults: urinary incontinence associated with neurologic condition Adults: chronic migraine Adults: upper and lower limb spasticity Pediatrics: upper
    and limb spasticity Adults: CD Pediatrics: CD Adults: axillary hyperhidrosis Adults and pediatrics: blepharospasm Dosing Regimen Body weight (kg) Botox (mL) Diluent (mL) Final dose of Botox in dosing syringe 72 units 12 to > 14 kg 84 units 14 to < 16 kg 96 units 16 to < 18 kg 108 units 18 to < 20 kg 120 units 20 to < 22 kg 132 units 22 to < 24 kg 144 units 24 to < 26 kg 156 units 26 to < 28 kg 168 units 28 to < 30 kg 180 units 30 to < 32 kg 192 units 32 to < 34 kg Up to approximately 6.7 Units IM per injection across up to 30 injection sites in the detrusor muscle for a total of up to 200 Units per treatment session 6.4 5.8 5.2 4.6 4 3.4 2.8 2.2 1.6 1 0.4 3.6 4.2 4.8 5.4 6 6.6 7.2 7.8 8.4 9 9.6 Up to 5 Units IM per injection across up to 7 head/neck muscles for a total of up to 155 Units per treatment session Up to 50 Units IM per injection and up to 400 Units per treatment session • Upper limb spasticity: Up to the lower of 6 Units/kg or 200 Units IM per treatment session • Lower limb spasticity: Up to the lower of 8 Units/kg or 300 Units IM per treatment session • Upper and lower limb spasticity: Up to the lower of 10 Units/kg or 340 Units IM per treatment session Up to 50 Units IM per injection, 100 Units total in the sternocleidomastoid (SCM) muscle, and 300 Units per treatment session Up to 50 Units IM per injection, 100 Units total in the SCM muscle, and the lower of 10 Units/kg body weight or 300 Units per treatment session Up to 50 Units IM per axilla per treatment session • Botox naive: Up to 2.5 Units IM per muscle, 7.5 Units per eye, and 15 Units per treatment session • Botox experienced: Up to 5 Units IM per muscle, 15 Units per eye, and 30 Units per treatment session Page 16 of 22

    Maximum Dose CLINICAL POLICY
    OnabotulinumtoxinA Indication Adults and pediatrics: strabismus Off-label uses Laryngeal dystonia UE dystonia, UE essential tremor, OMD
    Esophageal achalasia HD, IAS achalasia Chronic anal fissure Dosing Regimen • Botox naive:
    o Vertical muscles, or horizontal strabismus < 20 prism diopters: Up to 2.5 Units IM per muscle and 5 Units per treatment session o Horizontal strabismus 20 to 50 prism diopters: Up to 5 Units IM per muscle and 10 Units per treatment session o VI nerve palsy: 2.5 Units IM in the medial rectus muscle and 2.5 Units per treatment session • Botox experienced:
    o Vertical and horizontal strabismus: Up to the lower of a two-fold increase or 25 Units IM per muscle and 50 Units per treatment session o VI nerve palsy: Up to the lower of a two-fold increase or 25 Units IM per muscle and 25 Units per treatment session Up to 25 Units IM per treatment session. (Off-label - Micromedex 2020) Dose is supported by practice guidelines or peer- reviewed literature for the relevant off-label use and member age (prescriber must submit supporting evidence; number of Units per treatment session does not exceed the lower of 10 Units/kg body weight or 340 Units IM for pediatrics, or 400 Units IM for adults). Up to 100 Units IM per treatment session. (Off-label - Vaezi 2013) Up to 100 Units IM per treatment session. (Off-label - Langer 2017) Up to 100 Units IM per treatment session.
    (Off-label – ACG Guidelines 2021) VI. Product Availability
    Vials: 100 Units, 200 Units VII.