Botulinum Toxins A and B – Commercial Medical Benefit Drug Policy

Botulinum Toxins A and B

Page 1 of 27

UnitedHealthcare Commercial Medical Benefit Drug Policy

Effective 04/01/2024

UnitedHealthcare

Commercial

Medical Benefit Drug Policy

Botulinum Toxins A and B

Policy Number: 2024D0017AK

Effective Date: April 1, 2024



Instructions for Use

Table of Contents Page

Coverage Rationale ....................................................................... 1

Applicable Codes .......................................................................... 3

Background.................................................................................. 11

Benefit Considerations ................................................................ 11

Clinical Evidence ......................................................................... 11

U.S. Food and Drug Administration ........................................... 21

References ................................................................................... 22

Policy History/Revision Information ........................................... 27

Instructions for Use ..................................................................... 27

Coverage Rationale

 See Benefit Considerations

This policy refers to the following botulinum toxin types A and B:

Dysport

(abobotulinumtoxinA)

Daxxify

(daxibotulinumtoxinA-lanm)

Xeomin

(incobotulinumtoxinA)

Botox

(onabotulinumtoxinA)

Myobloc

(rimabotulinumtoxinB)

General Requirements (applicable to all requests)

All of the following:

o Diagnosis; and

o Botulinum toxin administration is no more frequent than every 12 weeks, regardless of diagnosis; and

o One of the following:

 Prescriber attests dosing is in accordance with the United States Food and Drug Administration (FDA) approved

labeling; or

 For indications without FDA approved dosing, prescriber attests there is published clinical evidence to support the

dosing

Diagnosis-Specific Requirements

The information below indicates additional requirements for those indications having specific criteria in the list of proven

indications.

Dysport (abobotulinumtoxinA) is proven in the treatment of the following conditions:

Achalasia

Anal fissures, chronic

7,8,81

Blepharospasm associated with dystonia

10,81

Cervical dystonia (also known as spasmodic torticollis)

10,19,81,83,84

Related Commercial Policies

• Occipital Nerve Injections and Ablation (Including

Occipital Neuralgia and Headache)

• Treatment of Temporomandibular Joint Disorders

Community Plan Policy

• Botulinum Toxins A and B

Botulinum Toxins A and B

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UnitedHealthcare Commercial Medical Benefit Drug Policy

Effective 04/01/2024

Detrusor overactivity (also known as detrusor hyperreflexia) or detrusor-sphincter dyssynergia due to spinal cord

injury or disease

15,17,18,53,54,63,81

Hand dystonia (writer's, musician’s, or typist's cramp)

19,81,83

Hand tremor

19,81

Hemifacial spasm (seventh cranial nerve disorders)

19,81

Hyperhidrosis

1,15,81

including gustatory sweating (Frey's Syndrome)

9,15,38

Oromandibular dystonia

Sialorrhea

15,57,81

Spasmodic dysphonia (laryngeal dystonia)

3,19

Spasticity associated with:

1,6,39,81

o Cerebral palsy

o Multiple sclerosis

o Neuromyelitis optica (NMO)

o Stroke

o Other injury, disease, or tumor of the brain or spinal cord

Strabismus

1,19,81

Tongue dystonia

Torsion dystonia

Voice tremor

Daxxify (daxibotulinumtoxinA-lanm) is proven in the treatment of the following condition:

Cervical dystonia (also known as spasmodic torticollis)

102

Xeomin (incobotulinumtoxinA) is proven in the treatment of the following conditions:

Blepharospasm associated with dystonia

70,76

Cervical dystonia (spasmodic torticollis)

70,76,83-4

Sialorrhea

Spasticity associated with:

65-6,70,76

o Cerebral palsy

o Multiple sclerosis

o Neuromyelitis optica (NMO)

o Stroke

o Other injury, disease, or tumor of the brain or spinal cord

Botox (onabotulinumtoxinA) is proven in the treatment of the following conditions:

Achalasia

Anal fissures, chronic

8,80

Blepharospasm associated with dystonia

1,19,80

Cervical dystonia (also known as spasmodic torticollis)

1,10,80,83-4

Detrusor overactivity (also known as detrusor hyperreflexia) or detrusor-sphincter dyssynergia due to spinal cord

injury or disease

15,17,18,53,54,63,80

Hand dystonia (writer's, musician’s, or typist's cramp)

19,80,83

Hand tremor

19,80

Hemifacial spasm (seventh cranial nerve disorders)

19,80

Hyperhidrosis

1,80

including gustatory sweating (Frey's Syndrome)

9,15,38

Migraine headache, chronic

Botox is proven for the prophylaxis of chronic migraine when the following criterion is met:

o Diagnosis of chronic migraine defined by all of the following

1,71,80

 Greater than or equal to 15 headache days per month

 Greater than or equal to 8 migraine days per month

 Headaches last 4 hours per day or longer

Oromandibular dystonia

Overactive bladder

1,80

Sialorrhea

15,57,80

Botulinum Toxins A and B

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UnitedHealthcare Commercial Medical Benefit Drug Policy

Effective 04/01/2024

Spasmodic dysphonia (laryngeal dystonia)

3-5,19,80

Spasticity associated with:

1,6,39,80

o Cerebral palsy

o Multiple sclerosis

o Neuromyelitis optica (NMO)

o Stroke

o Other injury, disease, or tumor of the brain or spinal cord

Strabismus

1,19,80

Tongue dystonia

Torsion dystonia

Voice tremor

Myobloc (rimabotulinumtoxinB) is proven in the treatment of the following conditions:

Cervical dystonia (also known as spasmodic torticollis)

2,83-84

Detrusor overactivity (also known as detrusor hyperreflexia)

15,18

Sialorrhea

15,56-7

Spasticity associated with:

o Cerebral palsy

o Multiple sclerosis

o Neuromyelitis optica (NMO)

o Stroke

o Other injury, disease, or tumor of the brain or spinal cord

Unproven

Daxxify, Dysport, Myobloc, and Xeomin are unproven and not medically necessary for the treatment of chronic migraine

headache.

14,15,24,25-6,64,75,81

Botox, Daxxify, Dysport, Myobloc, and Xeomin are unproven and not medically necessary for the treatment of the

following conditions:

Acquired nystagmus

Anismus (pelvic floor dyssynergia)

Benign prostatic hyperplasia

13,18,33,68,80,81

Brachial plexus palsy

46,80,81

Chronic daily headache

15,36,80,81

Chronic low back pain

36,80

Chronic prostatic pain

Cricopharyngeal dysphagia

20-23

Epiphora following salivary gland transplantation

Esophageal spasm

Gastroparesis (including diabetic gastroparesis)

58-62, 80,90-91

Gustatory epiphora (Crocodile tears)

Head tremor

Lateral epicondylitis (tennis elbow)

51,52

Lichen simplex

Lower urinary tract (voiding) dysfunction

11,18

Motor tics

Myofascial pain syndrome

45,72,81

Nasal hypersecretion

50,67

Pain and/or wound healing after hemorrhoidectomy

Pancreas divisum

Pelvic floor spasticity (and associated pain conditions)

Piriformis syndrome

Post-parotidectomy sialoceles

Post-thoracotomy pseudoangina

Proctalgia fugax

Severe bruxism

41-42

Severe paradoxical vocal cord movement

Sphincter of Oddi dysfunction

Stiff-person syndrome

Temporomandibular disorders

43-44,48

Tension headache

15,27,78

Thyroid associated ophthalmopathy

Tourette's syndrome

Traumatic sixth nerve palsy

Trigeminal neuralgia

32,73-4

Trismus and stridor in amyotrophic lateral sclerosis

Applicable Codes

The following list(s) of procedure and/or diagnosis codes is provided for reference purposes only and may not be all inclusive.

Listing of a code in this policy does not imply that the service described by the code is a covered or non-covered health service.

Benefit coverage for health services is determined by the member specific benefit plan document and applicable laws that may

Botulinum Toxins A and B

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UnitedHealthcare Commercial Medical Benefit Drug Policy

Effective 04/01/2024

require coverage for a specific service. The inclusion of a code does not imply any right to reimbursement or guarantee claim

payment. Other Policies and Guidelines may apply.

HCPCS Code

Description

Brand Name

J0585 Injection, onabotulinumtoxinA, 1 unit Botox

J0586 Injection, abobotulinumtoxinA, 5 units Dysport

J0587 Injection, rimabotulinumtoxinB, 100 units Myobloc

J0588 Injection, incobotulinumtoxinA, 1 unit Xeomin

J0589 Injection, daxibotulinumtoxina-lanm, 1 unit Daxxify

Diagnosis Code Description

Applies to HCPCS Code

J0585 J0586 J0587 J0588 J0589

C71.0 Malignant neoplasm of cerebrum, except lobes and

ventricles

X X X X

C71.1 Malignant neoplasm of frontal lobe X X X X

C71.2 Malignant neoplasm of temporal lobe X X X X

C71.3 Malignant neoplasm of parietal lobe X X X X

C71.4 Malignant neoplasm of occipital lobe X X X X

C71.5 Malignant neoplasm of cerebral ventricle X X X X

C71.6 Malignant neoplasm of cerebellum X X X X

C71.7 Malignant neoplasm of brain stem X X X X

C71.8 Malignant neoplasm of overlapping sites of brain X X X X

C71.9 Malignant neoplasm of brain, unspecified X X X X

C72.0 Malignant neoplasm of spinal cord X X X X

D33.0 Benign neoplasm of brain, supratentorial X X X X

D33.1 Benign neoplasm of brain, infratentorial X X X X

D33.2 Benign neoplasm of brain, unspecified X X X X

D33.4 Benign neoplasm of spinal cord X X X X

D43.0 Neoplasm of uncertain behavior of brain,

supratentorial

X X X X

D43.1 Neoplasm of uncertain behavior of brain, infratentorial X X X X

D43.2 Neoplasm of uncertain behavior of brain, unspecified X X X X

D43.4 Neoplasm of uncertain behavior of spinal cord X X X X

D49.6 Neoplasm of unspecified behavior of brain X X X X

G04.1 Tropical spastic paraplegia X X X X

G11.4 Hereditary spastic paraplegia X X X X

G24.09 Other drug induced dystonia X X

G24.1 Genetic torsion dystonia X X

G24.2 Idiopathic nonfamilial dystonia X X

G24.3 Spasmodic torticollis X X X X X

G24.4 Idiopathic orofacial dystonia X X

G24.5 Blepharospasm X X X

G24.8 Other dystonia X X

G24.9 Dystonia, unspecified X X

Botulinum Toxins A and B

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UnitedHealthcare Commercial Medical Benefit Drug Policy

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Diagnosis Code Description

Applies to HCPCS Code

J0585 J0586 J0587 J0588 J0589

G25.89

Other specified extrapyramidal and movement

disorders

X X

G35 Multiple sclerosis X X X X

G36.0 Neuromyelitis optica X X X X

G43.701 Chronic migraine without aura, not intractable, with

status migrainosus

G43.709 Chronic migraine without aura, not intractable, without

status migrainosus

G43.711 Chronic migraine without aura, intractable, with status

migrainosus

G43.719 Chronic migraine without aura, intractable, without

status migrainosus

G43.E01 Chronic migraine with aura, not intractable, with status

migrainosus

G43.E09 Chronic migraine with aura, not intractable, without

status migrainosus

G43.E11 Chronic migraine with aura, intractable, with status

migrainosus

G43.E19 Chronic migraine with aura, intractable, without status

migrainosus

G51.0 Palsy (spasm) of conjugate gaze X X

G51.1 Geniculate ganglionitis X X

G51.2 Melkersson's syndrome X X

G51.31 Clonic hemifacial spasm, right X X

G51.32 Clonic hemifacial spasm, left X X

G51.33 Clonic hemifacial spasm, bilateral X X

G51.39 Clonic hemifacial spasm, unspecified X X

G51.4 Facial myokymia X X

G51.8 Other disorders of facial nerve X X

G51.9 Disorder of facial nerve, unspecified X X

G80.0 Spastic quadriplegic cerebral palsy X X X X

G80.1 Spastic diplegic cerebral palsy X X X X

G80.2 Spastic hemiplegic cerebral palsy X X X X

G80.3 Athetoid cerebral palsy X X X X

G80.4 Ataxic cerebral palsy X X X X

G80.8 Other cerebral palsy X X X X

G80.9 Cerebral palsy, unspecified X X X X

G81.10 Spastic hemiplegia affecting unspecified side X X X X

G81.11 Spastic hemiplegia affecting right dominant side X X X X

G81.12 Spastic hemiplegia affecting left dominant side X X X X

G81.13 Spastic hemiplegia affecting right nondominant side X X X X

G81.14 Spastic hemiplegia affecting left nondominant side X X X X

G83.4 Cauda equina syndrome X X X

Botulinum Toxins A and B

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UnitedHealthcare Commercial Medical Benefit Drug Policy

Effective 04/01/2024

Diagnosis Code Description

Applies to HCPCS Code

J0585 J0586 J0587 J0588 J0589

H50.89 Other specified strabismus X X

H51.0 Palsy (spasm) of conjugate gaze X X

I60.10 Nontraumatic subarachnoid hemorrhage from

unspecified middle cerebral artery

X X X X

I60.11 Nontraumatic subarachnoid hemorrhage from right

middle cerebral artery

X X X X

I60.12 Nontraumatic subarachnoid hemorrhage from left

middle cerebral artery

X X X X

I61.0 Nontraumatic intracerebral hemorrhage in

hemisphere, subcortical

X X X X

I61.1 Nontraumatic intracerebral hemorrhage in

hemisphere, cortical

X X X X

I61.2 Nontraumatic intracerebral hemorrhage in

hemisphere, unspecified

X X X X

I61.3 Nontraumatic intracerebral hemorrhage in brain stem X X X X

I61.4 Nontraumatic intracerebral hemorrhage in cerebellum X X X X

I61.5 Nontraumatic intracerebral hemorrhage,

intraventricular

X X X X

I61.6

Nontraumatic intracerebral hemorrhage, multiple

localized

X X X X

I61.8 Other nontraumatic intracerebral hemorrhage X X X X

I61.9 Nontraumatic intracerebral hemorrhage, unspecified X X X X

I63.00

Cerebral infarction due to thrombosis of unspecified

precerebral artery

X X X X

I63.011 Cerebral infarction due to thrombosis of right vertebral

artery

X X X X

I63.012

Cerebral infarction due to thrombosis of left vertebral

artery

X X X X

I63.013 Cerebral infarction due to thrombosis of bilateral

vertebral arteries

X X X X

I63.019

Cerebral infarction due to thrombosis of unspecified

vertebral artery

X X X X

I63.02 Cerebral infarction due to thrombosis of basilar artery X X X X

I63.031

Cerebral infarction due to thrombosis of right carotid

artery

X X X X

I63.032 Cerebral infarction due to thrombosis of left carotid

artery

X X X X

I63.033

Cerebral infarction due to thrombosis of bilateral

carotid arteries

X X X X

I63.039 Cerebral infarction due to thrombosis of unspecified

carotid artery

X X X X

I63.09

Cerebral infarction due to thrombosis of other

precerebral artery

X X X X

I63.10 Cerebral infarction due to embolism of unspecified

precerebral artery

X X X X

Botulinum Toxins A and B

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UnitedHealthcare Commercial Medical Benefit Drug Policy

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Diagnosis Code Description

Applies to HCPCS Code

J0585 J0586 J0587 J0588 J0589

I63.111

Cerebral infarction due to embolism of right vertebral

artery

X X X X

I63.112 Cerebral infarction due to embolism of left vertebral

artery

X X X X

I63.113

Cerebral infarction due to embolism of bilateral

vertebral arteries

X X X X

I63.119 Cerebral infarction due to embolism of unspecified

vertebral artery

X X X X

I63.12 Cerebral infarction due to embolism of basilar artery X X X X

I63.131 Cerebral infarction due to embolism of right carotid

artery

X X X X

I63.132

Cerebral infarction due to embolism of left carotid

artery

X X X X

I63.133 Cerebral infarction due to embolism of bilateral carotid

arteries

X X X X

I63.139

Cerebral infarction due to embolism of unspecified

carotid artery

X X X X

I63.19 Cerebral infarction due to embolism of other

precerebral artery

X X X X

I63.20

Cerebral infarction due to unspecified occlusion or

stenosis of unspecified precerebral arteries

X X X X

I63.211 Cerebral infarction due to unspecified occlusion or

stenosis of right vertebral artery

X X X X

I63.212

Cerebral infarction due to unspecified occlusion or

stenosis of left vertebral artery

X X X X

I63.213 Cerebral infarction due to unspecified occlusion or

stenosis of bilateral vertebral arteries

X X X X

I63.219

Cerebral infarction due to unspecified occlusion or

stenosis of unspecified vertebral artery

X X X X

I63.22 Cerebral infarction due to unspecified occlusion or

stenosis of basilar artery

X X X X

I63.231

Cerebral infarction due to unspecified occlusion or

stenosis of right carotid arteries

X X X X

I63.232 Cerebral infarction due to unspecified occlusion or

stenosis of left carotid arteries

X X X X

I63.233

Cerebral infarction due to unspecified occlusion or

stenosis of bilateral carotid arteries

X X X X

I63.239 Cerebral infarction due to unspecified occlusion or

stenosis of unspecified carotid artery

X X X X

I63.29

Cerebral infarction due to unspecified occlusion or

stenosis of other precerebral arteries

X X X X

I63.30 Cerebral infarction due to thrombosis of unspecified

cerebral artery

X X X X

I63.311

Cerebral infarction due to thrombosis of right middle

cerebral artery

X X X X

Botulinum Toxins A and B

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UnitedHealthcare Commercial Medical Benefit Drug Policy

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Diagnosis Code Description

Applies to HCPCS Code

J0585 J0586 J0587 J0588 J0589

I63.312

Cerebral infarction due to thrombosis of left middle

cerebral artery

X X X X

I63.313 Cerebral infarction due to thrombosis of bilateral

middle cerebral arteries

X X X X

I63.319

Cerebral infarction due to thrombosis of unspecified

middle cerebral artery

X X X X

I63.321 Cerebral infarction due to thrombosis of right anterior

cerebral artery

X X X X

I63.322

Cerebral infarction due to thrombosis of left anterior

cerebral artery

X X X X

I63.323 Cerebral infarction due to thrombosis of bilateral

anterior cerebral arteries

X X X X

I63.329

Cerebral infarction due to thrombosis of unspecified

anterior cerebral artery

X X X X

I63.331 Cerebral infarction due to thrombosis of right posterior

cerebral artery

X X X X

I63.332

Cerebral infarction due to thrombosis of left posterior

cerebral artery

X X X X

I63.333 Cerebral infarction due to thrombosis of bilateral

posterior cerebral arteries

X X X X

I63.339

Cerebral infarction due to thrombosis of unspecified

posterior cerebral artery

X X X X

I63.341 Cerebral infarction due to thrombosis of right

cerebellar artery

X X X X

I63.342

Cerebral infarction due to thrombosis of left cerebellar

artery

X X X X

I63.343 Cerebral infarction due to thrombosis of bilateral

cerebellar arteries

X X X X

I63.349

Cerebral infarction due to thrombosis of unspecified

cerebellar artery

X X X X

I63.39 Cerebral infarction due to thrombosis of other cerebral

artery

X X X X

I63.40

Cerebral infarction due to embolism of unspecified

cerebral artery

X X X X

I63.411 Cerebral infarction due to embolism of right middle

cerebral artery

X X X X

I63.412

Cerebral infarction due to embolism of left middle

cerebral artery

X X X X

I63.413 Cerebral infarction due to embolism of bilateral middle

cerebral arteries

X X X X

I63.419

Cerebral infarction due to embolism of unspecified

middle cerebral artery

X X X X

I63.421 Cerebral infarction due to embolism of right anterior

cerebral artery

X X X X

I63.422

Cerebral infarction due to embolism of left anterior

cerebral artery

X X X X

Botulinum Toxins A and B

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UnitedHealthcare Commercial Medical Benefit Drug Policy

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Diagnosis Code Description

Applies to HCPCS Code

J0585 J0586 J0587 J0588 J0589

I63.423

Cerebral infarction due to embolism of bilateral

anterior cerebral arteries

X X X X

I63.429 Cerebral infarction due to embolism of unspecified

anterior cerebral artery

X X X X

I63.431

Cerebral infarction due to embolism of right posterior

cerebral artery

X X X X

I63.432 Cerebral infarction due to embolism of left posterior

cerebral artery

X X X X

I63.433

Cerebral infarction due to embolism of bilateral

posterior cerebral arteries

X X X X

I63.439 Cerebral infarction due to embolism of unspecified

posterior cerebral artery

X X X X

I63.441

Cerebral infarction due to embolism of right cerebellar

artery

X X X X

I63.442 Cerebral infarction due to embolism of left cerebellar

artery

X X X X

I63.443

Cerebral infarction due to embolism of bilateral

cerebellar arteries

X X X X

I63.449 Cerebral infarction due to embolism of unspecified

cerebellar artery

X X X X

I63.49

Cerebral infarction due to embolism of other cerebral

artery

X X X X

I63.50 Cerebral infarction due to unspecified occlusion or

stenosis of unspecified cerebral artery

X X X X

I63.511

Cerebral infarction due to unspecified occlusion or

stenosis of right middle cerebral artery

X X X X

I63.512 Cerebral infarction due to unspecified occlusion or

stenosis of left middle cerebral artery

X X X X

I63.513

Cerebral infarction due to unspecified occlusion or

stenosis of bilateral middle cerebral arteries

X X X X

I63.519 Cerebral infarction due to unspecified occlusion or

stenosis of unspecified middle cerebral artery

X X X X

I63.521

Cerebral infarction due to unspecified occlusion or

stenosis of right anterior cerebral artery

X X X X

I63.522 Cerebral infarction due to unspecified occlusion or

stenosis of left anterior cerebral artery

X X X X

I63.523

Cerebral infarction due to unspecified occlusion or

stenosis of bilateral anterior cerebral arteries

X X X X

I63.529 Cerebral infarction due to unspecified occlusion or

stenosis of unspecified anterior cerebral artery

X X X X

I63.531

Cerebral infarction due to unspecified occlusion or

stenosis of right posterior cerebral artery

X X X X

I63.532 Cerebral infarction due to unspecified occlusion or

stenosis of left posterior cerebral artery

X X X X

I63.533

Cerebral infarction due to unspecified occlusion or

stenosis of bilateral posterior cerebral arteries

X X X X

Botulinum Toxins A and B

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Diagnosis Code Description

Applies to HCPCS Code

J0585 J0586 J0587 J0588 J0589

I63.539

Cerebral infarction due to unspecified occlusion or

stenosis of unspecified posterior cerebral artery

X X X X

I63.541 Cerebral infarction due to unspecified occlusion or

stenosis of right cerebellar artery

X X X X

I63.542

Cerebral infarction due to unspecified occlusion or

stenosis of left cerebellar artery

X X X X

I63.543 Cerebral infarction due to unspecified occlusion or

stenosis of bilateral cerebellar arteries

X X X X

I63.549

Cerebral infarction due to unspecified occlusion or

stenosis of unspecified cerebellar artery

X X X X

I63.59 Cerebral infarction due to unspecified occlusion or

stenosis of other cerebral artery

X X X X

I63.6

Cerebral infarction due to cerebral venous thrombosis,

nonpyogenic

X X X X

I63.81 Other cerebral infarction due to occlusion or stenosis

of small artery

X X X X

I63.89 Other cerebral infarction X X X X

I63.9 Cerebral infarction, unspecified X X X X

J38.5 Laryngeal spasm X X

K11.7 Disturbances of salivary secretion X X X X

K22.0 Achalasia of cardia X X

K60.1 Chronic anal fissure X X

K60.2 Anal fissure, unspecified X X

L74.510 Primary focal hyperhidrosis, axilla X X

L74.511 Primary focal hyperhidrosis, face X X

L74.512 Primary focal hyperhidrosis, palms X X

L74.513 Primary focal hyperhidrosis, soles X X

L74.519 Primary focal hyperhidrosis, unspecified X X

L74.52 Secondary focal hyperhidrosis X X

N31.0 Uninhibited neuropathic bladder, not elsewhere

classified

X X X

N31.1 Reflex neuropathic bladder, not elsewhere classified X X X

N31.9 Neuromuscular dysfunction of bladder, unspecified X X X

N32.81 Overactive bladder X

N36.44 Muscular disorders of urethra X X X

N39.41 Urge incontinence X

N39.46 Mixed incontinence X

R13.3 Dysphagia, pharyngeal phase X X

R25.0 Abnormal head movements X X

R25.1 Tremor, unspecified X X

R25.2 Cramp and spasm X X

R25.3 Fasciculation X X

R25.8 Other abnormal involuntary movements X X

Botulinum Toxins A and B

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UnitedHealthcare Commercial Medical Benefit Drug Policy

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Diagnosis Code Description

Applies to HCPCS Code

J0585 J0586 J0587 J0588 J0589

R25.9 Unspecified abnormal involuntary movements X X

R29.891 Ocular torticollis X X X X

R49.0 Dysphonia X X

R49.9 Unspecified voice and resonance disorder X X

R61 Generalized hyperhidrosis X X

Background

There are seven serologically distinct forms of botulinum toxin, A through G. All seven neurotoxins share a common structure

consisting of one heavy chain and one light chain. They all inhibit acetylcholine release at the neuromuscular junction via the

enzymatic inactivation of a protein that is required for the docking and fusion process involved in the release of acetylcholine.

Each neurotoxin works at a distinct site. Botulinum toxin type A cleaves the protein SNAP-25 and botulinum toxin type B

cleaves synaptobrevin, both of these proteins are part of a protein complex necessary for proper docking and fusion.

1,2,10,70

The potency units of botulinum toxins are specific to the preparation and assay method utilized. They are not interchangeable

and, therefore, the units of biological activity cannot be compared to nor converted into units of any other botulinum toxin

products assessed with any other specific assay method.

1,2,10,70

Benefit Considerations

Botulinum toxin type A and B are cosmetic when used to improve appearance, or in the absence of physiological functional

impairment that would be improved by their use. Most United Healthcare Certificates of Coverage (COCs) and Summary Plan

Descriptions (SPDs) exclude benefit coverage for cosmetic services. In addition, most Certificates of Coverage and many

Summary Plan Descriptions explicitly exclude benefit coverage for medical and surgical treatment of excessive sweating

(hyperhidrosis). The member specific benefit plan document must be reviewed to determine what benefits, if any, exist for

treatment of hyperhidrosis.

Some Certificates of Coverage allow for coverage of experimental/investigational/unproven treatments for life-threatening

illnesses when certain conditions are met. The member specific benefit plan document must be consulted to make coverage

decisions for this service. Some states mandate benefit coverage for off-label use of medications for some diagnoses or under

some circumstances when certain conditions are met. Where such mandates apply, they supersede language in the benefit

document or in the medical or drug policy. Benefit coverage for an otherwise unproven service for the treatment of serious rare

diseases may occur when certain conditions are met. Refer to the Policy and Procedure addressing the treatment of serious

rare diseases.

Clinical Evidence

Proven

Cervical Dystonia

In a randomized, double-blind, multicenter, non-inferiority, two-period crossover study, Yun et al compared the efficacy and

safety of Dysport and Botox at a 2.5:1 ratio in the treatment of cervical dystonia (CD).

The lower ratio than 3:1 was suggested

as a more appropriate conversion ratio, due to the higher efficacy of Botox and more frequent incidence of adverse effects in

CD and other focal movement disorders. Patients who were over 20 years old and have experienced CD for at least 18 months

were eligible, and were allowed to continue on a stable dose of medications for CD for the duration of the trial. Both products

were diluted so that the 2.5:1 ratio resulted in the same volume to be administered. The patients received either Dysport or

Botox, and were followed monthly for the first 16 weeks. After the 4-week washout period, each group was crossed over to

receive the other product, respectively. Patients were also followed up with monthly for 16 weeks in the second period. Results

from both periods were merged and compared according to the two different products. The primary efficacy outcome was the

change in the Tsui scale between the baseline value and that at 1 month after each injection (peak effect). One hundred and

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two patients enrolled in the study. Patients were allocated 49 and 53 to two different arms of the trial. Arm 1 received Dysport

during the first phase and Botox during the crossover phase. Arm 2 received Botox during the first phase and Dysport during

the second phase. Only 94 of the 102 patients completed the entire study and were included in the final analysis. Mean

changes in the Tsui scale between baseline and 4 weeks after each injection trended to favor Botox, however, this was not

statistically significant (4.0 ±3.9 points Dysport vs. 4.8 ±4.1 points for Botox; 95% CI, -0.1-1.7; p = 0.091). The mean change of

the Toronto western spasmodic torticollis rating scale score, the proportion of improvement in clinical global impression and

patient global impression, and the incidences of adverse events were not significantly different between the two treatments.

The authors concluded that, in terms of efficacy and safety, Dysport at a ratio of 2.5:1 to Botox was not inferior to Botox in

patients with CD.

The efficacy of Daxxify was evaluated in a randomized, double-blind, placebo-controlled, multicenter trial in a total of 301

patients (NCT03608397).

102

At study baseline, 84% of patients had previously received a botulinum toxin as treatment for

cervical dystonia. Patients had a clinical diagnosis of cervical dystonia with baseline Toronto Western Spasmodic Torticollis

Rating Scale (TWSTRS) total score ≥ 20, TWSTRS severity score ≥ 15, TWSTRS disability score ≥ 3, and TWSTRS pain score

≥ 1. For patients who had previously received a botulinum toxin treatment for cervical dystonia, the trial required that ≥ 14

weeks had passed since the most recent botulinum toxin administration. Patients were randomized (3:3:1) to receive a single

administration of 2.5 mL of either Daxxify 125 Units (n = 125), Daxxify 250 Units (n = 130), or placebo (n = 46), divided amongst

the affected muscles as selected by the investigator. The primary efficacy endpoint was the mean change in the TWSTRS total

score from baseline averaged over weeks 4 and 6. TWSTRS evaluates the severity of dystonia, patient-perceived disability from

dystonia, and pain, with a range of possible scores from 0 to 85. The mean change from baseline in the total TWSTRS score

was significantly greater for both dosage groups of Daxxify than for placebo.

Detrusor Overactivity

In a prospective, long-term (3 year), multicenter, open-label extension study following a 52-week, phase III trial of

onabotulinumtoxinA, patients were treated on an “as needed” basis with intradetrusor onabotulinumtoxinA (200U or 300U) for

urinary incontinence (UI) due to neurogenic detrusor overactivity.

Patients received treatment ≥ 12 weeks since the previous

treatment and a UI episode threshold. The primary efficacy endpoint was the change from study baseline in UI episodes/day at

week 6 after each treatment. Additional efficacy measurements included: percent change in UI episodes, the proportions of

patients with ≥ 50% and 100% reductions from baseline in UI episodes/day, changes from baseline in volume/void and

Incontinence Quality of Life (I-QOL) total summary scores, IQOL responder rates (proportion of patients achieving a ≥ 11-point

increase from baseline in I-QOL total score, which is defined as the minimally important difference for I-QOL in NDO), and

duration of treatment effect (time to patient request for retreatment). OnabotulinumtoxinA 200U consistently reduced UI

episodes/day; reductions from baseline ranged from –3.2 to –4.1 across six treatments. Volume/void consistently increased,

nearly doubling after treatment. I-QOL improvements were consistently greater than twice the minimally important difference (+

11 points). Overall median duration of effect was 9.0 months (200U). Results were similar for onabotulinumtoxinA 300U. Most

common AEs were urinary tract infections and urinary retention. De novo CIC rates were 29.5, 3.4, and 6.0% (200U), and 43.0,

15.0, and 4.8% (300U) for treatments 1–3, respectively; de novo CIC rates were 0% for treatments 4–6. The authors concluded

that OnabotulinumtoxinA treatments consistently improve UI, volume/void, and QOL in patients with UI due to NDO in this 4-

year study, with no new safety signals.

Migraine Headache

OnabotulinumtoxinA is beneficial for the prophylaxis of chronic migraine headaches based upon FDA approval, published

practice guidelines, professional society evidence reviews, randomized controlled clinical trials, and smaller randomized

exploratory studies.

15,24,25-6

Aurora et al performed a secondary analysis of the data to assess patients who received all five treatment cycles and completed

the PREEMPT-1 and PREEMPT-2 trials. Both studies were 24 week double-blind, placebo controlled, parallel-group phase, with

a 32-week open-label phase, that evaluated the efficacy and safety of onabotulinumtoxinA (BoNT-A). Out of a total of 1,384 total

patients, 1,005 received all five treatment cycles and were included in the analysis. Of these, 513 received all 5 cycles with BTA,

whereas 492 underwent 2 cycles of placebo followed by 3 cycles of BoNT-A treatment. After 56 weeks of treatment, significant

between group differences were found favoring BoNT-A treatment vs. placebo, even after those receiving placebo switching to

BoNT-A. The following headache symptoms were evaluated: mean change in frequency of headache days (-12.0 vs -11.0, p =

0.035); total migraine days (-11.6 vs -10.7, p = 0.038), and moderate/severe headache days (-11.0 vs -10.1 n = 0.042). There

were also large mean improvements from baseline in the following measures: cumulative hours of headache on headache days,

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frequency of headache episodes, percentage with severe Headache Impact Test (HIT)-6 scores, and total HIT-6 and Migraine-

Specific Quality of Life Questionnaire scores). The percent of patients with a ≥ 50% reduction from baseline in frequency of

headache days was significantly greater for the BoNT-A only group at week 56 (69.6% vs 62.8%, p = 0.023). Treatment-related

adverse event rates were 28.5% for the BoNT-A group vs. 12.4% for the placebo group during the double-blind phase of the

trials. The most frequently reported treatment related adverse events were neck pain (4.3%), muscular weakness (1.6%),

injection site pain (2.1%), and eyelid ptosis (1.9%). This data supports the use of onabotulinumtoxinA for the treatment of

migraine headaches.

In a follow up analysis of the PREEMPT clinical trials, Lipton et al., assessed the effects of treatment with onabotulinumtoxinA

on health-related quality of life (HRQoL) and headache impact in adults with chronic migraine.

In the PREEMPT trials,

Headache Impact Test (HIT)-6 scores were obtained at baseline and every 4 weeks. In terms of change in total HIT-6 scores, a

negative value reflects reduced headache impact and an improvement in the patient’s functionality. HRQoL was measured by

the Migraine-Specific Quality of Life Questionnaire (MSQ v2.1). This score was obtained at baseline and every 12 weeks. A

positive change in MSQ v2.1 scores reflects improvement in HRQoL during the PREEMPT study. An analysis of the combined

data looked at 688 subjects who received treatment with Botox vs. 696 who received saline placebo injections. Baseline mean

total HIT-6 and MSQ v2.1 scores were comparable between groups; 93.1% were severely impacted based on HIT-6 scores ≥ 60.

At 24 weeks, in comparison with placebo, Botox treatment significantly reduced HIT-6 scores at all time periods during the

double-blind phase of the trials (p ≤ 0.014). Additionally, HIT-6 measures of headache impact scores showed significant benefit

for the Botox group at 24 weeks of treatment (p < 0.001). Botox treatment significantly improved all domains of the MSQ v2.1 at

24 weeks (p < 0.001). There was also a significant benefit shown for the Botox group compared to placebo with regard to the

proportion of subjects who received clinically meaningful reduction in the number of headache days at all-time points in the

double-blind study periods (p ≤ 0.025). The authors concluded that Botox treatment reduces headache impact and improves

HRQoL.

The pooled results of two phase 3, randomized, double-blind, multicenter, placebo controlled trials addressing the use of

botulinum toxin for the treatment of chronic migraine headaches were reported by Dodick et al., in 2010.

29-31

These studies were

from the Phase III REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical program, involving a 24 week

randomized, double-blind phase followed by a 32 week open-label phase. Subjects were randomized (1:1) to receive either 155

units of onabotulinumtoxinA (BoNT-A) or placebo injections every 12 weeks. A total of 1384 adult patients were randomized to

onabotulinumtoxinA (n = 688) or placebo (n = 696), with study visits every 4 weeks. Both studies were identical in design, with

the exception being the designation of the primary (mean change from baseline in frequency of headache days for the 28-day

period ending with week 24) and secondary endpoints (frequency of migraine days, number of cumulative hours of headache

on headache days, proportion of patients with severe HIT-6 score, and others). Injections of BoNT-A or placebo were injected

as 31 fixed-sites, fixed-dose injections across 7 specific head/neck muscle areas. A discretionary 40 units could be

administered using a “follow-the-pain” strategy, resulting in 195 units over 39 sites. Pooled analyses demonstrated a large mean

decrease from baseline in frequency of headache days, with statistically significant between-group differences favoring

onabotulinumtoxinA over placebo at week 24 (-8.4 vs. -6.6; p < 0.001) and at all other time points. Significant differences

favoring onabotulinumtoxinA were also observed for all secondary efficacy variables at all time points, including frequency of

headache days, cumulative headache hours, and the proportion of subjects with severe headaches. No significant difference

was noted in the frequency of acute headache pain medication taken. There was a significantly greater proportion of

experimental group subjects that had a greater that 50% decrease from baseline in headache days. Adverse events occurred in

62.4% of experimental group subjects and 51.7% of placebo subjects, with a greater than 5% incidence of neck pain and

muscular weakness in the experimental group. The authors concluded that the use of onabotulinumtoxinA treatment for

chronic migraine was effective, safe, and well tolerated.

Overactive Bladder

Nitti et al examined the efficacy and safety of onabotulinumtoxinA for the treatment of overactive bladder and urinary

incontinence (UI) in a phase 3, randomized, multicenter, placebo controlled trial.

Adult patients (18 years or older) with

idiopathic overactive bladder who experienced 3 or more urgency UI episodes in a 3-day period and an average of 8 or more

micturitions per day were enrolled in the study. Patients were randomized 1:1 to either receive onabotulinumtoxinA 100 U or

placebo over 20 evenly distributed intradetrusor injections. Co-primary end points were the change from baseline in the number

of urinary incontinence episodes per day and the proportion of patients with a positive response on the treatment benefit scale

at posttreatment week 12. Secondary end points included other overactive bladder symptoms and health related quality of life.

OnabotulinumtoxinA significantly decreased the daily frequency of urinary incontinence episodes vs placebo (–2.65 vs –0.87, p

< 0.001) and 22.9% vs 6.5% of patients became completely continent. A larger proportion of onabotulinumtoxinA than placebo

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treated patients reported a positive response on the treatment benefit scale (60.8% vs 29.2%, p < 0.001). All other overactive

bladder symptoms improved vs placebo (p < 0.05). OnabotulinumtoxinA improved patient health related quality of life across

multiple measures (p < 0.001). Uncomplicated urinary tract infection was the most common adverse event. A 5.4% rate of

urinary retention was observed. The authors concluded that OnabotulinumtoxinA showed significant, clinically relevant

improvement in all overactive bladder symptoms and health related quality of life in patients inadequately treated with

anticholinergics and was well tolerated.

Spasticity (Associated with Cerebral Palsy)

In a global, randomized, placebo-controlled study, the efficacy and safety of abobotulinumtoxinA was evaluated for the

treatment of spasticity in cerebral palsy children with dynamic equinus foot deformity.

Two hundred and forty-one patients

were randomized 1:1:1 to receive either abobotulinumtoxinA 10 U/kg/leg, 15 U/kg/leg, or placebo injections into the

gastrocnemius-soleus complex of either one or both legs. The primary endpoint was the demonstration of benefit for each dose

over placebo on the Modified Ashworth Scale from baseline to week 4. Secondary endpoint includes the change of the

Physician’s Global Assessment at week 4 from baseline. Two hundred and twenty-six patients completed the study. At week 4,

Modified Ashworth Scale scores significantly improved with abobotulinumtoxinA; mean (95% confidence interval) treatment

differences versus placebo were –0.49 (–0.75 to –0.23; p = 0.0002) for 15 U/kg/leg and –0.38 (–0.64 to –0.13; p = 0.003) for 10

U/kg/leg. The Physician’s Global Assessment treatment differences versus placebo of 0.77 (0.45 to 1.10) for 15 U/kg/leg and

0.82 (0.50 to 1.14) for 10 U/kg/leg were also significant (both Ps < .0001). The most common treatment-related adverse event

was muscular weakness (10 U/Kg/leg = 2; placebo = 1). The authors concluded that treatment with abobotulinumtoxinA

improves muscle tone in children with dynamic equinus resulting in an improved overall clinical impression and is well

tolerated.

An additional subgroup analysis was conducted on the same two-hundred and forty-one patients examined in the above study.

Delgado et al. found that abobotulinumtoxin A was similarly effective in treating spasticity in cerebral palsy children with

dynamic equinus foot deformity in both children who had not received botulinum toxin before and children who had previously

received botulinum toxin. Of the 241 patients examined, 113 had received botulinum toxin treatment before participating in the

study. Previous botulinum toxin treatment also had no effect on safety outcomes between the two groups.

Unproven

Benign Prostatic Hyperplasia

The efficacy and tolerability of botulinum toxin A (BoNT-A) for the treatment of lower urinary tract symptoms in men with benign

prostatic hyperplasia (LUTS/BPH) was evaluated in a randomized placebo controlled trial involving 315 subjects assigned to

either 200 U of BoNT-A (Botox) (n = 157) or placebo (n = 156).

Patients with International Prostate Symptom Score (I-PSS) 14

or greater, with peak urinary flow rate 4 to 15 ml per second and total prostate volume 30 to 80 ml were randomized 1:1 to a

single intraprostatic injection of BoNT-A or placebo. A single-blind sham procedure, followed by a 4 week run in was included to

minimize potential placebo effect. The primary endpoint from baseline is total I-PSS at week 12. Additional endpoints assessed

at weeks 6, 12, and 24 were peak urinary flow rate (Qmax), total prostate volume (TPV), and post-void residual urine volume

(PVR). At all-time points there was no difference in I-PSS between the BoNT-A and placebo groups, included at the primary time

point at 12 weeks, however both groups experienced a decrease (-6.3 vs -5.6 points, p < 0.001). There were no differences

between treatment groups for TPV, PSA, or PVR at 12 or 24 weeks. The authors concluded that BoNT-A is unlikely to be a

therapy for male LUTS/BPH.

In an additional phase III clinical trial completed in 2018, BoNT-A was tested against optimized oral medications in treating

lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia. Four months after BoNT-A injection, most of the

patients who received BoNT-A were able to interrupt LUTS-related medical treatments, but this study’s design did not allow for

a conclusion that this improvement was related to the study drug rather than a sustained placebo effect.

Chronic Daily Headache

Four studies were published in the American Academy of Neurology's 2008 assessment of botulinum neurotoxin for pain

disorders.

Each of the studies specifically referenced chronic daily headache (CDH) and had a large population of patients

with transformed migraine. The primary outcome measure for all the studies was mean change in headache-free days per

month. The first study, which used a technique of modifying injection site based on location of pain, showed a significant

benefit (11 days vs. 8 days) in the BoNTA treated population. The second study, the largest of patients with CDH, was a

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randomized, double-blind, placebo-controlled, phase II study, enrolling 702 patients. This trial used a fixed-site strategy. Eligible

patients were injected with BoNTA at 225 U, 150 U, 75 U, or placebo and returned for additional masked treatments at day 90

and day 180. Patients were assessed every 30 days for 9 months. The primary efficacy end point was the mean change from

baseline in the frequency of headache-free days at day 180 for the placebo nonresponder group. The primary efficacy end

point was not met. Mean improvements from baseline at day 180 of 6.0, 7.9, 7.9, and 8.0 headache-free days per month were

observed with BoNTA at 225 U, 150 U, 75 U, or placebo, respectively (p = 0.44). However, a priori-defined analysis of headache

change from baseline in headache frequency revealed that the 225 U and 150 U Botox A groups had statistically significant

greater reductions in headache frequency compared with placebo at day 240 (p = 0.03). In conclusion, BoNTA was safe and

well tolerated. Although the primary efficacy end point was not met, all groups responded to treatment. The 225 U and 150 U

groups experienced a greater decrease in headache frequency than the placebo group at day 240, but the placebo response

was higher than expected. The third study was a subgroup of patients not taking prophylactic medications from a larger overall

study. Only this subgroup showed a significant mean increase in headache-free days although there was a decrease in the

frequency per 30 days. An additional study evaluated 82 patients with chronic daily headache treated with botulinum neurotoxin

76.1% of the chronic migraine patients and 36.4% of the chronic tension-type headache patients were considered

responders. Because studies of botulinum A for the prevention of chronic daily headache show mixed results, further studies

are recommended.

Tension Headache

Four studies of patients with tension-type headache were reviewed in the American Academy of Neurology's 2008 assessment

of botulinum neurotoxin for pain disorders.

Patients in these studies were randomized to either botulinum neurotoxin (BoNT)

or placebo. After 6 weeks, the first study (n = 112) showed no significant difference compared to a baseline 6 week period in

the primary outcome measure of area under the headache curve in the subjects' headache diary. In another of the studies, both

the BoNT and the placebo group showed improvement in the primary outcome of mean change from baseline in number of

headache-free days from 30 to 60 after injection, but BoNT was not more beneficial and a power analysis was not provided. A

third study showed no significant benefit of BoNT after 12 weeks for decrease of headache, intensity on visual analog scale,

mean number of headache days, headache hours per day, days on which symptomatic treatment was taken, number of

analgesics taken per day, or patient's assessment of improvement.

The fourth study, a smaller trial, included 16 patients in a

prospective double-blind, placebo-controlled crossover study and thirty patients in an open-label long-term study. These

patients showed reduction in headache severity and pericranial muscle tenderness, and increased headache-free days with

botulinum treatment.

Additional small randomized controlled trials have found conflicting results similar to those presented above.

Until larger

randomized trials are conducting showing a beneficial effect of BTX-A, its use in tension headache is unproven.

Miscellaneous

Botulinum toxin A has been studied in a number of other disorders including: cricopharyngeal dysphagia,

20-23

gustatory

epiphora (crocodile tears), Sphincter of Oddi dysfunction,

pancreas divisum, anismus,

lower urinary tract dysfunction,

11,18

pelvic floor spasticity,

chronic prostatic pain,

severe paradoxical vocal cord movement,

post-parotidectomy sialoceles,

severe bruxism,

41-42

temporomandibular disorders,

43-44,48

myofascial pain syndrome,

45,72,81

brachial plexus palsy,

46,80,81

thyroid

associated ophthalmopathy,

esophageal spasm,

post-thoracotomy pseudoangina, epiphora following salivary gland

transplantation, trigeminal neuralgia,

32,73-4

trismus and stridor in amyotrophic lateral sclerosis, proctalgia fugax,

nasal

hypersecretion,

50,67

gastroparesis (including diabetic gastroparesis),

58-62, 80,90-91

Lichen simplex, lateral epicondylitis,

51,52

Stiff-

person syndrome, traumatic sixth nerve palsy, Tourette's syndrome,

chronic scrotal pain,

and pain and/or wound healing

after hemorrhoidectomy. The studies in these disorders have been small and/or uncontrolled open-label trials. Larger, well-

designed studies must occur to demonstrate the effectiveness of botulinum toxin in the treatment of these conditions.

Technology Assessments

Achalasia

A 2014 Cochrane review was published evaluating and comparing endoscopic pneumatic dilation (PD) versus botulinum toxin

injection in the management of primary achalasia.

Seven studies involving 178 participants were included. Two studies were

excluded from the meta-analysis of remission rates on the basis of clinical heterogeneity of the initial endoscopic protocols.

There was no significant difference between PD or botulinum treatment in remission within four weeks of the initial intervention;

with a risk ratio of remission of 1.11 (95% CI 0.97 to 1.27). There was also no significant difference in the mean esophageal

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pressures between the treatment groups; with a weighted mean difference for PD of -0.77 (95% CI -2.44 to 0.91, p = 0.37). Data

on remission rates following the initial endoscopic treatment were available for three studies at six months and four studies at

12 months. At six months 46 of 57 PD participants were in remission compared to 29 of 56 in the botulinum group, giving a risk

ratio of 1.57 (95% CI 1.19 to 2.08, p = 0.0015); whilst at 12 months 55 of 75 PD participants were in remission compared to 27

of 72 botulinum participants, with a risk ratio of 1.88 (95% CI 1.35 to 2.61, p = 0.0002). No serious adverse outcomes occurred

in participants receiving botulinum, while PD was complicated by perforation in three cases. The authors concluded that PD is

the more effective endoscopic treatment in the long term (greater than six months) for patients with achalasia.

Cervical Dystonia

An update of a Cochrane review from 2005 was published in 2017 to compare the efficacy, safety, and tolerability of botulinum

toxin type A (BtA) versus placebo in people with cervical dystonia.

100

The authors included eight randomized controlled trials

(RCTs) of moderate overall risk of bias, including 1010 participants with cervical dystonia. Six studies excluded participants with

poorer responses to BtA treatment, therefore including an enriched population with a higher probability of benefiting from this

therapy. Only one trial was independently funded. All RCTs evaluated the effect of a single BtA treatment session, using doses

from 150 U to 236 U of onabotulinumtoxinA (Botox), 120 U to 240 U of incobotulinumtoxinA (Xeomin), and 250 U to 1000 U of

abobotulinumtoxinA (Dysport).BtA was associated with a moderate-to-large improvement in the participant's baseline clinical

status as assessed by investigators, with reduction of 8.06 points in the Toronto Western Spasmodic Torticollis Rating Scale

(TWSTRS total score) at week 4 after injection (95% CI 6.08 to 10.05; I2 = 0%) compared to placebo, corresponding on average

to a 18.7% improvement from baseline. The mean difference (MD) in TWSTRS pain subscore at week 4 was 2.11 (95% CI 1.38

to 2.83; I2 = 0%). Overall, both participants and clinicians reported an improvement of subjective clinical status. There were no

differences between groups regarding withdrawals due to adverse events. However, BtA treatment was associated with an

increased risk of experiencing an adverse event (risk ratio (RR) 1.19; 95% CI 1.03 to 1.36; I2 = 16%). Dysphagia (9%) and diffuse

weakness/tiredness (10%) were the most common treatment-related adverse events (dysphagia: RR 3.04; 95% CI 1.68 to 5.50;

I2 = 0%; diffuse weakness/tiredness: RR 1.78; 95% CI 1.08 to 2.94; I2 = 0%). Treatment with BtA was associated with a

decreased risk of participants withdrawing from trials. We have moderate certainty in the evidence across all of the

aforementioned outcomes. The authors found no evidence supporting the existence of a clear dose-response relationship with

BtA, nor a difference between BtA formulations, nor a difference with use of EMG-guided injection. Due to clinical

heterogeneity, the authors did not pool data regarding health-related quality of life, duration of clinical effect, or the

development of secondary non-responsiveness. The authors stated that they have moderate certainty in the evidence that a

single BtA treatment session is associated with a significant and clinically relevant reduction of cervical dystonia-specific

impairment, including severity, disability, and pain, and that it is well tolerated, when compared with placebo. There is also

moderate certainty in the evidence that people treated with BtA are at an increased risk of developing adverse events, most

notably dysphagia and diffuse weakness. There are no data from RCTs evaluating the effectiveness and safety of repeated BtA

injection cycles. There is no evidence from RCTs to allow us to draw definitive conclusions on the optimal treatment intervals

and doses, usefulness of guidance techniques for injection, the impact on quality of life, or the duration of treatment effect.

Chronic and Episodic Migraine Headache

A 2018 Cochrane review was published evaluating the effects of botulinum toxins versus placebo or active treatment for the

prevention or reduction in frequency of chronic or episodic migraine in adults.

Twenty-eight studies involving 4,190

participants were eligible for inclusion. The longest treatment duration was three rounds of injections with three months

between treatments, so the authors could not analyze long-term effects. For the primary analyses, the authors pooled data from

both chronic and episodic participant populations. Where possible, the authors also separated data into chronic migraine,

episodic migraine and 'mixed group' classification subgroups. Most trials (21 out of 28) were small (fewer than 50 participants

per trial arm). The risk of bias for included trials was low or unclear across most domains, with some trials reporting a high risk

of bias for incomplete outcome data and selective outcome reporting. Twenty-three trials compared botulinum toxin with

placebo. Botulinum toxin may reduce the number of migraine days per month in the chronic migraine population by 3.1 days

(95% confidence interval (CI) -4.7 to -1.4, 4 trials, 1497 participants, low-quality evidence). This was reduced to -2 days (95% CI -

2.8 to -1.1, 2 trials, 1384 participants; moderate-quality evidence) when the authors removed small trials. A single trial of people

with episodic migraine (n = 418) showed no difference between groups for this outcome measure (p = 0.49).In the chronic

migraine population, botulinum toxin reduces the number of headache days per month by 1.9 days (95% CI -2.7 to -1.0, 2 trials,

1384 participants, high-quality evidence). The authors did not find evidence of a difference in the number of migraine attacks

for both chronic and episodic migraine participants (6 trials, n = 2004, p = 0.30, low-quality evidence). For the population of

both chronic and episodic migraine participants a reduction in severity of migraine rated during clinical visits, on a 10 cm visual

analog scale (VAS) of 3.3 cm (95% CI -4.2 to -2.5, very low-quality evidence) in favor of botulinum toxin treatment came from

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four small trials (n = 209); better reporting of this outcome measure from the additional eight trials that recorded it may have

improved our confidence in the pooled estimate. Global assessment and quality-of-life measures were poorly reported and it

was not possible to carry out statistical analysis of these outcome measures. Analysis of adverse events showed an increase in

the risk ratio with treatment with botulinum toxin over placebo 30% (RR 1.28, 95% CI 1.12 to 1.47, moderate-quality evidence).

For every 100 participants 60 experienced an adverse event in the botulinum toxin group compared with 47 in the placebo

group. Three trials studied comparisons with alternative oral prophylactic medications. Meta-analyses were not possible for

number of migraine days, number of headache days or number of migraine attacks due to insufficient data, but individually

trials reported no differences between groups for a variety of efficacy measures in the population of both chronic and episodic

migraine participants. The global impression of disease measured using Migraine Disability Assessment (MIDAS) scores were

reported from two trials that showed no difference between groups. Compared with oral treatments, botulinum toxin showed no

between-group difference in the risk of adverse events (2 trials, n = 114, very low-quality evidence). The relative risk reduction

(RRR) for withdrawing from botulinum toxin due to adverse events compared with the alternative prophylactic agent was 72% (p

= 0.02, 2 trials, n = 119). There were insufficient data available for the comparison of different doses. The quality of the evidence

assessed using GRADE methods was varied but mostly very low; the quality of the evidence for the placebo and active control

comparisons was low and very low, respectively for the primary outcome measure. Small trial size, high risk of bias and

unexplained heterogeneity were common reasons for downgrading the quality of the evidence. The authors concluded that for

chronic migraine, botulinum toxin type A may reduce the number of migraine days per month by 2 days compared with placebo

treatment. Non-serious adverse events were probably experienced by 60/100 participants in the treated group compared with

47/100 in the placebo group. For people with episodic migraine, the authors remain uncertain whether or not this treatment is

effective because the quality of this limited evidence is very low. Better reporting of outcome measures in published trials would

provide a more complete evidence base on which to draw conclusions.

Chronic Migraine Headache

Hayes compiled a Medical Technology Directory on botulinum toxin treatment for migraine headache dated September 22,

2011.

Although a relatively large number of well-designed randomized controlled trials (RCTs) have evaluated

onabotulinumtoxinA (onaBTX-A) and abobotulinumtoxinA (aboBTX-A) [BTX-A] for prevention of migraine, the clinical role of this

treatment remains to be established. Many of the available placebo-controlled RCTs found that BTX-A did not provide

statistically significant benefits or found that the benefits obtained were inconsistent, for instance, occurring at some time

points but not at others. In contrast, the largest available RCT and one of the older RCTs found that patients who underwent

treatment with onaBTX-A experienced statistically significant improvements such as reductions in migraine frequency and

severity. This divergence in study results cannot be resolved based solely on differences in study size and a more likely

explanation was that the benefits obtained with onaBTX-A were relatively small, perhaps too small to be clinically significant.

Moreover, due to lack of long-term follow-up, the available RCTs do not provide any data concerning the durability of potential

benefits from treatment with onaBTX-A. In addition, there was insufficient evidence to support conclusions regarding the

efficacy of onaBTX-A relative to other types of medication for prevention of migraine. Likewise, there was very limited evidence

regarding the effectiveness of aboBTX-A, and no evidence regarding other types of BTX, for the management of chronic or

recurrent headache. Therefore, Hayes has assigned a D rating (no proven benefit and/or not safe) to abobotulinumtoxinA for

prevention of migraine and to rimabotulinumtoxinB as a treatment for migraine headache. Overall, onaBTX-A was safe with few

serious complications reported, earning onabotulinumtoxinA a Hayes rating of C (potential but unproven benefit) for prevention

of migraine headache. Further studies are needed to determine the clinical role of BTX-A relative to current treatments for

prevention of migraine. An annual review of the Hayes Directory on August 21, 2019 resulted in no changes to the original

findings.

Chronic Tension Headache

Hayes compiled a Medical Technology Directory on botulinum toxin treatment for chronic tension-type headache dated

December 30, 2011.

A relatively large number of well-designed, randomized, placebo-controlled trials (RCTs) have evaluated

the effects of botulinum toxin A (BTX-A) on patients diagnosed with chronic tension-type headache (CTTH). The majority of

these studies found no benefit of BTX-A relative to placebo. The two studies that did report beneficial effects of BTX on

headache frequency and intensity were very small. Overall, BTX-A was safe. None of the studies compared BTX-A with other

prophylactic treatments for CTTH. An annual review of the Hayes Directory on January 13, 2015 resulted in no changes to the

original findings.

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Detrusor Overactivity

Hayes compiled a Medical Technology Directory on botulinum toxin treatment for detrusor instability, dated December 30,

2011.

The results of the available studies provide some evidence that onabotulinumtoxinA (onaBTX-A) improves outcomes for

patients who have idiopathic or neurogenic detrusor overactivity; however, these studies do not provide sufficient evidence to

establish the clinical role of botulinum toxin type A (BTX-A) for these indications. Although randomized clinical trials (RCTs)

consistently found that BTX-A provided statistically significant improvements in urinary incontinence (UI) compared with

placebo treatment, the largest available RCT of BTX-A for idiopathic detrusor overactivity found a placebo effect that was nearly

as large as the treatment effect when expressed in terms of decrease in number of episodes of UI per week. In the largest

available RCT of BTX-A for neurogenic detrusor overactivity, BTX-A treatment was associated with statistically significant

increases in urinary retention and urinary tract infections. None of the studies that met the criteria for review involved long-term

follow-up of patients who underwent treatment with multiple doses of BTX-A, and none of the studies compared BTX-A with

augmentation cystoplasty or neuromodular implantation. At least six of the studies were sponsored by the manufacturer,

creating the potential for bias. Additional controlled studies are needed to determine the long-term efficacy and safety of BTX-A

relative to other current invasive treatments for idiopathic and neurogenic detrusor overactivity. An annual review of the Hayes

Directory on January 9, 2015 resulted in no changes to the original findings.

Strabismus

A 2017 update to a 2012 Cochrane review was published to examine the efficacy of botulinum toxin therapy in the treatment of

strabismus compared with alternative conservative or surgical treatment options.

The review also sought to determine the

types of strabismus that particular benefit from the use of botulinum toxin as a treatment option. The secondary objectives were

to investigate the dose effect and complication rates associated with botulinum therapy. Six randomized controlled trials were

eligible for inclusion. The authors concluded that the published literature on the use of botulinum toxin in the treatment of

strabismus consists of retrospective studies, cohort studies or case reviews. These provide useful descriptive information,

clarification is required as to the effective use of botulinum toxin as an independent treatment modality. Six RCTs on the

therapeutic use of botulinum toxin in strabismus, graded as low and very low-certainty evidence, have shown varying

responses. These include a lack of evidence for effect of botulinum toxin on reducing visual symptoms in acute sixth nerve

palsy, poor response in people with horizontal strabismus without binocular vision, similar or slightly reduced achievement of

successful ocular alignment in children with esotropia and potential increased achievement of successful ocular alignment

where surgery and botulinum toxin are combined. Further high quality trials using robust methodologies are required to

compare the clinical and cost effectiveness of various forms of botulinum toxin (e.g. Dysport, Xeomin, etc.), to compare

botulinum toxin with and without adjuvant solutions and to compare botulinum toxin to alternative surgical interventions in

strabismus cases with and without potential for binocular vision.

Motor/Phonic Tics

A 2018 Cochrane review was published evaluating the safety and effectiveness of botulinum toxin in treating motor and phonic

tics in people with Tourette’s syndrome, and to analyze the effect of botulinum toxin on premonitory urge and sensory tics.

Only one randomized placebo-controlled, double-blind cross-over study met our selection criteria. In this study, 20 participants

with motor tics were enrolled over a three-year recruitment period; 18 (14 of whom had a diagnosis of Tourette's syndrome)

completed the study; in total, 21 focal motor tics were treated. Although we considered most bias domains to be at low risk of

bias, the study recruited a small number of participants with relatively mild tics and provided limited data for our key outcomes.

The effects of botulinum toxin injections on tic frequency, measured by videotape or rated subjectively, and on premonitory

urge, are uncertain (very low-quality evidence). The quality of evidence for adverse events following botulinum toxin was very

low. Nine people had muscle weakness following the injection, which could have led to unblinding of treatment group

assignment. No data were available to evaluate whether botulinum injections led to immunoresistance to botulinum. The

authors concluded that they are uncertain about botulinum toxin effects in the treatment of focal motor and phonic tics in select

cases, as we assessed the quality of the evidence as very low. Additional randomized controlled studies are needed to

demonstrate the benefits and harms of botulinum toxin therapy for the treatment of motor and phonic tics in patients with

Tourette's syndrome.

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Professional Societies

Spasmodic Dysphonia (Laryngeal Dystonia)

In 2018, the American Academy of Otolaryngology – Head and Neck Surgery published an update of their guideline first

published in 2009.

The organization recommended that clinicians should offer, or refer to a clinician who can offer botulinum

toxin injections for the treatment of dysphonia caused by spasmodic dysphonia and other types of laryngeal dystonia.

A recommendation means that the benefits exceed the harms (or that the harms exceed the benefits, in the case of a negative

recommendation) but that the quality of evidence is not as strong (grade B or C). In some clearly identified circumstances,

recommendations may be made on the basis of lesser evidence when high-quality evidence is impossible to obtain and the

anticipated benefits outweigh the harms. Clinicians should also generally follow a recommendation but should remain alert to

new information and sensitive to patient preferences.

Achalasia

In 2020, the American College of Gastroenterology published an evidence-based clinical guideline for the diagnosis and

management of achalasia based on a comprehensive review of the pertinent evidence and examination of relevant published

data.

The recommendations for the treatment of achalasia from this guideline are as follows:

In patients with achalasia who are candidates for definite therapy:

o Pneumatic dilation (PD), laparoscopic Heller myotomy (LHM), and peroral endoscopic myotomy (POEM) are

comparable effective therapies for type I or type II achalasia.

o POEM would be a better treatment option in those with type III achalasia.

o Botulinum toxin injection is reserved for those who cannot undergo the above definitive therapies.

 Recommend botulinum toxin injection as first-line therapy for patients with achalasia who are unfit for definitive

therapies compared with other less effective pharmacological therapies (Grade quality: Moderate;

Recommendation strength: Strong).

 Previous treatment with botulinum toxin injection does not significantly affect performance and outcomes of

myotomy (Grade quality: Low; Recommendation strength: Conditional).

Autonomic & Movement Disorders, Pain, and Spasticity

In a 2013 update to the 2008 Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology

(AAN) published evidence-based (studies classified as Class I to IV and recommendations classified as levels A to U)

assessments on the use of botulinum neurotoxin in the treatment of autonomic disorders and pain,

movement disorders,

and spasticity.

In addition, in 2013 authors performed an assessment on the use of botulinum neurotoxin in the treatment of

urologic conditions

and secretory disorders

based on the AAN methodology. The Quality Standards Subcommittee of the

American Academy of Neurology and the Practice Committee of the Child Neurology Society also published an evidence-based

review of the pharmacologic treatment of spasticity in children and adolescents with cerebral palsy in 2010.

Recommendations from these reviews are classified as follows:

Level A - Established as effective, ineffective, or harmful for the given condition in the specified population, requiring at

least two consistent Class I studies.

Level B - Probably effective, ineffective, or harmful for the given condition in the specified population, requiring at least one

Class I study or at least two consistent Class II studies.

Level C - Possibly effective, ineffective, or harmful for the given condition in the specified population, requiring at least one

Class II study or two consistent Class III studies.

Level U - Data inadequate or conflicting; given current knowledge, treatment is unproven.

Recommendations from these reviews are:

BoNT should be offered as a treatment option for axillary hyperhidrosis and detrusor overactivity (detrusor hyperreflexia)

(Level A). BoNT should be considered for palmar hyperhidrosis, sialorrhea, and detrusor sphincter dyssynergia after spinal

cord injury (Level B).

BoNT is probably effective for the treatment of benign prostatic hyperplasia induced lower urinary tract symptoms (Level

B).

BoNT may be considered for low back pain (Level C). BoNT is probably ineffective in episodic migraine and chronic

tension-type headache (Level B).

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Evidence does not permit drawing conclusions on BoNT’s efficacy in chronic daily headache (mainly transformed migraine)

(Level U). Evidence does not support BoNT’s efficacy for the treatment of gustatory sweating (Level U).

BoNT should be offered as an option for the treatment of blepharospasm, cervical dystonia (Level A).

BoNT may be offered for , hemifacial spasm, focal upper extremity dystonia, , and upper extremity essential tremor (Level

B).

BoNT may be considered for, adductor laryngeal dystonia, focal lower limb dystonia, oromandibular dystonia, and motor

tics (Level C).

BoNT should be offered as an option for the treatment of spasticity in adults (Level A). Spasticity in adults results from a

variety of causes such as stroke, trauma, multiple sclerosis, and neoplasm involving the central nervous system.

For localized/segmental spasticity that warrants treatment in children and adolescents with cerebral palsy, botulinum toxin

type A should be offered as an effective and generally safe treatment (Level A) and there is insufficient data to support or

refute the use of botulinum toxin type B (Level U).

Tics in People with Tourette’s Syndrome and Chronic Tic Disorder

In 2019, the American Academy of Neurology (AAN) published evidence-based guideline recommendations regarding the use

of botulinum neurotoxins in treating tics in people with Tourette’s Syndrome, as well as treating chronic tic disorder (studies

classified as Class I to IV and recommendations classified as levels A to C).

101

The recommendations for the treatment of tics in

people with Tourette’s Syndrome and chronic tic disorder from this guideline are as follows:

• Physicians may prescribe botulinum toxin injections for the treatment of older adolescents and adults with localized and

bothersome simple motor tics when the benefits of treatment outweigh the risks (Level C).

• Physicians may prescribe botulinum toxin injections for the treatment of older adolescents and adults with severely

disabling or aggressive vocal tics when the benefits of treatment outweigh the risks (Level C).

• Physicians must counsel individuals with tics that botulinum toxin injections may cause weakness and hypophonia, and

that all effects are temporary (Level A).

Blepharospasm, Cervical Dystonia, Adult Spasticity, and Headache

In a 2016 update to the 2008 guidelines, the American Academy of Neurology (AAN) published evidence-based (studies

classified as Class I to IV and recommendations classified as levels A to U)

286

assessments on the use of botulinum neurotoxins

in the treatment of blepharospasm, cervical dystonia, headache, and adult spasticity.

Recommendations from this review are classified as follows:

Level A - Established as effective, ineffective, or harmful for the given condition in the specified population, requiring at

least two consistent Class I studies.

Level B - Probably effective, ineffective, or harmful for the given condition in the specified population, requiring at least one

Class I study or at least two consistent Class II studies.

Level C - Possibly effective, ineffective, or harmful for the given condition in the specified population, requiring at least one

Class II study or two consistent Class III studies.

Level U - Data inadequate or conflicting; given current knowledge, treatment is unproven.

Recommendations from this review for abobotulinumtoxinA (aboBoNT-A, Dysport) are as follows:

AboBoNT-A should be offered as a treatment option for cervical dystonia, focal manifestations of upper limb spasticity, and

focal manifestations of lower limb spasticity that warrant treatment (Level A).

o AboBoNT-A has been established as safe and effective for the reduction of adult upper limb spasticity and

improvement of passive function (multiple Class I studies). AboBoNT-A has also been established as safe and effective

for the reduction of adult lower limb spasticity (multiple Class I studies).

o Data is inadequate to determine the efficacy of aboBoNT-A for improvement of active function associated with adult

upper limb spasticity (Class I studies, inconsistent results dependent on active functional outcomes). Data is also

inadequate to determine the efficacy of aboBoNT-A for improvement of active function associated with adult lower limb

spasticity (no studies available or inconsistent results dependent on specific outcome from multiple Class I studies).

AboBoNT-A may be considered as a treatment option for blepharospasm (Level C).

Recommendations from this review for incobotulinumtoxinA (incoBoNT-A, Xeomin) are as follows:

IncoBoNT-A should be offered as a treatment option for focal manifestations of upper limb spasticity (Level A).

o IncoBoNT-A has been established as safe and effective for the reduction of adult upper limb spasticity and

improvement of passive function (multiple Class I studies).

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o Data is inadequate to determine the efficacy of incoBoNT-A for improvement of active function associated with adult

upper limb spasticity (Class I studies, inconsistent results dependent on active functional outcomes).

IncoBoNT-A should be considered as a treatment option for blepharospasm and cervical dystonia (Level B).

There is insufficient evidence to support or refute the use of incoBoNT-A for the treatment of lower limb spasticity (Level U).

Recommendations from this review for onabotulinumtoxinA (onaBoNT-A, Botox) are as follows:

OnaBoNT-A should be offered as a treatment option for focal manifestations of upper limb spasticity, focal manifestations

of lower limb spasticity that warrant treatment, and chronic migraine (Level A).

o OnaBoNT-A has been established as safe and effective for the reduction of adult upper limb spasticity and

improvement of passive function (multiple Class I studies). OnaBoNT-A has also been established as safe and effective

for the reduction of adult lower limb spasticity (multiple Class I studies).

o Data is inadequate to determine the efficacy of onaBoNT-A for improvement of active function associated with adult

upper limb spasticity (Class I studies, inconsistent results dependent on active functional outcomes). Data is also

inadequate to determine the efficacy of onaBoNT-A for improvement of active function associated with adult lower limb

spasticity (no studies available or inconsistent results dependent on specific outcome from multiple Class I studies).

OnaBoNT-A should be considered as a treatment option for blepharospasm and cervical dystonia (Level B).

OnaBoNT-A should not be offered as a treatment option for episodic migraine (Level A).

OnaBoNT-A should not be considered as a treatment option for tension-type headache (Level B).

Recommendations from this review for rimabotulinumtoxinB (rimaBoNT-B, Myobloc) are as follows:

RimaBoNT-B should be offered as a treatment option for cervical dystonia (Level A).

RimaBoNT-B should be considered as a treatment option for focal manifestations of upper limb spasticity (Level B).

o RimaBoNT-B is probably safe and effective for the reduction of adult upper limb spasticity (1 Class I study).

o Data is inadequate to determine the efficacy of rimaBoNT-B for improvement of active function associated with adult

upper limb spasticity (Class I studies, inconsistent results dependent on active functional outcomes).

There is insufficient evidence to support or refute the use of rimaBoNT-B for the treatment of blepharospasm and lower

limb spasticity (Level U).

U.S. Food and Drug Administration (FDA)

This section is to be used for informational purposes only. FDA approval alone is not a basis for coverage.

For non-cosmetic use, abobotulinumtoxinA (Dysport) is FDA approved for the treatment of adults with cervical dystonia. Dysport

is also indicated for the treatment of spasticity in pediatric patients 2 years of age and older.

IncobotulinumtoxinA (Xeomin) is FDA approved for the treatment of adults with cervical dystonia.. Xeomin is also indicated for

the treatment of adults with blepharospasm, upper limb spasticity in adult patients, and chronic sialorrhea in patients 2 years of

age and older. Xeomin is also indicated for the treatment of upper limb spasticity in pediatric patients 2 to 17 years of age,

excluding spasticity caused by cerebral palsy.

For non-cosmetic use, daxibotulinumtoxinA-lanm (Daxxify) is FDA approved for the treatment of cervical dystonia in adult

patients.

102

For non-cosmetic use, onabotulinumtoxinA (Botox) is FDA approved for the prophylaxis of headaches in adult patients with

chronic migraine (≥ 15 days per month with headache lasting 4 hours a day or longer). Safety and effectiveness of Botox have

not been established for the prophylaxis of episodic migraine (14 headache days or fewer per month).

Botox is also approved for treatment of spasticity in patients 2 years of age and older.

Botox is also indicated for reducing the severity of abnormal head position and neck pain associated with cervical dystonia in

adults; for the treatment of strabismus and blepharospasm associated with dystonia; for the treatment of overactive bladder

with symptoms of urge urinary incontinence, urgency, and frequency in adults who have an inadequate response or are

intolerant to an anticholinergic medication; for the treatment of urinary incontinence due to detrusor overactivity associated with

a neurologic condition [e.g., spinal cord injury (SCI), multiple sclerosis (MS)] in adults who have an inadequate response to or

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are intolerant of an anticholinergic medication; and for the treatment of severe primary axillary hyperhidrosis that is

inadequately managed with topical agents.

Safety and efficacy of Botox for hyperhidrosis in other body areas have not been

established. 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. Safety and effectiveness of Botox have not been established for the treatment of axillary hyperhidrosis in pediatric

patients under age 18.

RimabotulinumtoxinB (Myobloc) is FDA approved for the treatment of adults with cervical dystonia to reduce the severity of

abnormal head position and neck pain associated with cervical dystonia. It is also FDA approved for the treatment of chronic

sialorrhea in adults.

All botulinum toxin products approved by the FDA carry a black box warning regarding the possibility of the distant spread of

toxin effect.

1,2,10,70

The warning states that post marketing reports indicate that the effects of 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, 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 an

underlying condition that would predispose them to these symptoms. In unapproved uses, including 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 upper limb spasticity and at lower doses.

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37. Krause E, Hempel JM, Gürkov R. Botulinum toxin A prolongs functional durability of voice prostheses in laryngectomees

with pharyngoesophageal spasm. Am J Otolaryngol. 2009 Nov-Dec;30(6):371-5.

38. de Bree R, Duyndam JE, Kuik DJ, Leemans CR. Repeated botulinum toxin type A injections to treat patients with Frey

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45. Lew HL, Lee EH, Castaneda A, et al. Therapeutic use of botulinum toxin type A in treating neck and upper-back pain of

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46. Price AE, Ditaranto P, Yaylali I, et al. Botulinum toxin type A as an adjunct to the surgical treatment of the medial rotation

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47. Wutthiphan S. Role of botulinum toxin A in diplopia following orbital decompression. Strabismus. 2008;16(3): 112-5.

48. Fu KY, Chen HM, Sun ZP, et al. Long-term efficacy of botulinum toxin type A for the treatment of habitual dislocation of the

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50. Sapci T, Yazici S, Evcimik MF, et al. Investigation of the effects of intranasal botulinum toxin type A and ipratropium

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51. Oskarsson E, Piehl AK, Gustafsson BE, Pettersson K. Improved intramuscular blood flow and normalized metabolism in

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52. Placzek R, Drescher W, Deuretzbacher G, et al. Treatment of chronic radial epicondylitis with botulinum toxin A. A double-

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53. Akbar M, Abel, R, Seyler-Thorsten M, et al. Repeated botulinum-A toxin injections in the treatment of myelodysplastic

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54. Del Popolo G, Filocamo MT, Li Marzi V, et al. Neurogenic Detrusor Overactivity Treated with English Botulinum Toxin A: 8-

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55. Aguirregomozcorta M, Pagonabarraga J, Diza-Manera J, et al. Efficacy of botulinum toxin in severe Tourette syndrome with

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56. Lagalla G, Millevolte M, Capecci M, et al. Long-lasting benefits of botulinum toxin type B in Parkinson's disease-related

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57. Wilken B, Aslami B, Backes H. Successful treatment of drooling in children with neurological disorders with botulinum toxin

A or B. Neuropediatrics. 2008;39(4):200-4.

58. Coleski R, Anderson MA, Hasler WL. Factors Associated with Symptom Response to Pyloric Injection of Botulinum Toxin in

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59. Reddymasu SC, Singh S, Sankula R, et al. Endoscopic pyloric injection of botulinum toxin-A for the treatment of

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60. Mirbaheri SA, Sadeghi A, Amouie M, et al. Pyloric injection of botulinum toxin for the treatment of refractory GERD

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62. Arts J, Holvoet L, Caenepeel P, et al. Clinical trial: a randomized-controlled crossover study of intrapyloric injection of

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63. Ehren I, Volz D, Farrelly E, et al. Efficacy and impact of botulinum toxin A on quality of life in patients with neurogenic

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64. Shuhendler AJ, Lee S, Se B, et al. Efficacy of Botulinum Toxin Type A for the Prophylaxis of Episodic Migraine Headaches:

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65. Kanovsky P, Slawek J, Denes Z, et al. Efficacy and Safety of Botulinum Neurotoxin NT 201 in Poststroke Upper Limb

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66. Barnes M, Schnitzler A, Medeiros L, et al. Efficacy and safety of NT 201 for upper limb spasticity of various etiologies – a

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68. Kuo HC, Liu HT. Therapeutic effects of add-on botulinum toxin A on patients with large benign prostatic hyperplasia and

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72. Soares A, Andriolo RB, Atallah AN, da Silva EM. Botulinum toxin for myofascial pain syndromes in adults. Cochrane

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73. Bohluli B, Motamedi MH, Bagheri SC, et al. Use of botulinum toxin A for drug-refractory trigeminal neuralgia: preliminary

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74. Zuniga C, Diaz S, Piedimonte F, et al. Beneficial effects of botulinum type A in trigeminal neuralgia. Arq Neuropsiquiatr.

2008 Sep;66(3A):500-3.

75. Herd CP, Tomlinson CL, Rick C, et al. Botulinum toxins for the prevention of migraine in adults. Cochrane Database Syst

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77. Waseem Z, Boulias C, Gordon A, Ismail F, Sheean G, Furlan AD. Botulinum toxin injections for low-back pain and sciatica.

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81. MCG

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82. MCG

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84. Novak I, Campbell L, Boyce M, et al. Botulinum toxin assessment, intervention and aftercare for cervical dystonia and other

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85. Vaezi MF, Pandolfino JE, Vela MF. ACG clinical guideline: diagnosis and management of achalasia. Am J Gastroenterol.

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89. Simpson DM, Hallett M, Ashman EJ, et al. Practice guideline update summary: Botulinum neurotoxin for the treatment of

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92. Nitti VW, Dmochowski R, Herschorn S, et al. OnabotulinumtoxinA for the Treatment of Patients with Overactive Bladder and

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Botulinum Toxins A and B

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Policy History/Revision Information

Date

Summary of Changes

04/01/2024

Applicable Codes

Updated list of applicable HCPCS codes to reflect quarterly edits:

o Removed C9160

o Replaced J3490 and J3590 with J0589

Supporting Information

Archived previous policy version 2024D0017AJ

Instructions for Use

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