Protocol for use of Botulinum toxin A in Unlicensed Indications in Pathological Muscle Hypertonia (614)

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A guideline is intended to assist healthcare professionals in the choice of disease-specific treatments.

Clinical judgement should be exercised on the applicability of any guideline, influenced by individual patient characteristics. Clinicians should be mindful of the potential for harmful polypharmacy and increased susceptibility to adverse drug reactions in patients with multiple morbidities or frailty.

If, after discussion with the patient or carer, there are good reasons for not following a guideline, it is good practice to record these and communicate them to others involved in the care of the patient.

Background

Pathological Muscle Hypertonia as part of disordered motor control, like Spasticity and Dystonia, is common in conditions affecting the brain and spinal cord such as cerebral palsy (CP), acquired brain injury (ABI), stroke (CVA), multiple sclerosis (MS), hereditary spastic paraparesis (HSP), spinal cord injury (SCI) and others. Botulinum toxin A is a recognised treatment for focal spasticity and dystonia. It may be required to gain or prevent loss of function, help manage pain and prevent secondary complications of spasticity. Botulinum toxin A injection is part of a rehabilitation programme involving physical management and/or rehabilitation to achieve an optimal clinical effect.

Spend on botulinum toxin A in PDRU was:
• £60,488 in 2017/2018
• £88,678 in 2018/2019
• £121,953 in 2019/2020
Expenditure is monitored on a regular basis.

Agent and route

Three preparations are available:
• IncobotulinumtoxinA – Xeomin®
• AbobotulinumtoxinA – Dysport®
• OnabotulinumtoxinA – Botox®


Botulinum toxin A is given via an intramuscular injection using electromyographic guidance, electrical muscle stimulation, ultrasound or clinical anatomy.

License status

This protocol has been devised to cover use of Botulinum toxin A in unlicensed indications in PDRU. Approval of this protocol removes the requirement for individual Unlicensed Medicine (ULM) forms for each patient.

Botulinum toxin A is not licensed for upper or lower limb spasticity in non-stroke spasticity in adults and therefore use is “off label” or unlicensed.

Summary of licensed indications for “focal spasticity” in upper and lower limbs

 

 

Licensed status

Licensed status

Preparation

Upper Limb

Lower Limb

Dysport

Post Stroke & TBI

Post stroke and TBI but:

IPTR form required see below

Xeomin

Post stroke

Unlicensed

Botox

Post stroke

Post stroke but:

IPTR form required see below

When used for a licensed indication the ULM protocol is not required, however it should be noted that the administration of Dysport and Botox for lower limb use post stroke has not been approved for use by the Scottish Medicines Consortium (SMC) and requires completion of an Individual Patient Treatment Request (IPTR) form.

Indications for use

Treatment with botulinum toxin A should be considered in patients with focal or multi-focal spasticity / dystonia.


Patients should be selected for Botulinum toxin A injections on the basis of:
• focal or multi-focal clinical problems due to spasticity/dystonia
• clearly identified goals for treatment and anticipated clinical gains (taking into account the risks of any negative impact where patients rely on their spasticity for function).

Treatment goals

Common treatment goals for intervention include:


• reduction of pathological muscle hypertonia
• pain relief
• reduction of involuntary movements (e.g. associated reactions, spasms)
• prevention of contractures and deformity
• passive function (making it easier to care for the affected limb)
• active function (using the affected limb)
• mobility.


Patients will have a thorough and detailed assessment documented prior to receiving treatment.
Outcome measure and SMART goals are recorded and reviewed within a month of treatment.

Future treatment will be planned in accordance to goals.

Treatment will be discontinued if goals are not achieved or if no response (as below).

Authorised and designated areas applicable to

Patients may be treated within inpatient or outpatient settings in NHS GGC under the umbrella of Regional Services Directorate.

Dose, duration, dilution and administration

The total maximum dose, as suggested by RCP guidelines or SPC for each preparation per treatment session in is as follows:

Xeomin:
Upper limb: 500 units
Lower limb: 500 units

Botox:
Upper limb: Botox 360 units
Lower limb: 400 units

Dysport:
Upper limb: 1000 units
Lower limb: 1500 units


Treatment should be started at a low dose of the therapeutic range for the specific muscle to minimise side effects. If an inadequate response is observed, consider a higher dose at next treatment. If a higher dose fails to produce an adequate response, consider switching to alternative brand if treatment is still appropriate. If there are 2 failed responses then the failure protocol as described by Kessler et al (1997) or Hanna et al (1999) should be used (See under references).


All new patients requiring botulinum toxin A for an unlicensed indication will receive the most cost-effective brand (currently Dysport and Xeomin).
Patients under existing treatment will continue with regular/previously used brand.


Injections should be given in one session and re-injections should occur no sooner than 12 weeks after the previous session.

Refer to RCP guidelines (see under references and Appendix 1) or Delphi Panel guidance for suggested muscle dosing regimes (see under references and Appendix 2).

Potential side effects

Local and distant spread of toxin effect

Spread of toxin distant from the site of administration has been reported, sometimes resulting in death, which in some cases was associated with dysphagia, pneumonia and/or significant debility.

Patients treated with therapeutic doses may also experience exaggerated muscle weakness.

Dysphagia has also been reported following injection to sites other than the cervical musculature.

Patients with pre-existing neuromuscular disorders


May have an increased sensitivity to agents such as Botulinum Toxin A, which may result in excessive muscle weakness and an increased risk of clinically significant systemic effects including severe dysphagia and respiratory compromise.

 

 

Hypersensitivity reactions


If serious (e.g. anaphylactic reactions) and/or immediate hypersensitivity reactions occur, appropriate medical therapy should be instituted.

 

 

Antibody formation


Too frequent doses may increase the risk of antibody formation, which can result in treatment failure.

The potential for antibody formation may be minimised by injecting with the lowest effective dose at the longest intervals between injections as clinically indicated

 

 

Procedure-related injury


Could occur such as localised infection, pain, inflammation, paraesthesia, hypoesthesia, tenderness, swelling, erythema, and/or bleeding/bruising.


Needle-related pain and/or anxiety may result in vasovagal responses, e.g. syncope, hypotension, etc.


Flu like symptoms have also been reported in some patients.

Contraindications for use

•The presence of infection or inflammation at the proposed injection site.


• Under active treatment with antibiotic therapy due to infection.


• Avoid use in patients with subclinical or clinical evidence of defective neuromuscular transmission e.g. Myasthenia Gravis or Lambert-Eaton Syndrome.


• Patients who are currently breast feeding.

Cautions for use

General

Should be used with caution:


• in pregnancy (the benefit must outweigh the risks). Note that Botox is not recommended in pregnancy or in women of childbearing potential not using contraception

• if bleeding disorders of any type occur

• in patients receiving anticoagulant therapy or taking other substances that could have an anticoagulant effect.


NB If the patient is taking warfarin then the INR should be taken prior to the treatment and be ≤2.5 on day of injection. If patients target INR needs to be higher than this then liaise with anticoagulation clinic/Haematology.

If the patient is taking other anticoagulants (such as apixaban, edoxaban, rivaroxaban, dabigatran), they would continue to take their normal dose. Half the volume of saline should be used to dilute the mixture i.e. 100 units mixed with 1 ml saline and the minimal number of injection sites used.

Pre existing neurological conditions

Should only be used with extreme caution and under close supervision in patients with lower motor neurone syndromes (e.g. amyotrophic lateral sclerosis, post-polio syndrome or motor neuropathy).


Patients with a history of dysphagia, aspiration or breathing difficulties should be treated with extreme caution. In these patients, treatment must be administered only if the benefit of treatment outweighs the risk.


Caution is warranted when injecting in proximity to the lung (particularly the apices) or other vulnerable anatomic structures.


Elderly and debilitated patients should be treated with caution.


Careful consideration should be given before the injection of patients who have experienced a previous allergic reaction to a product containing botulinum toxin type A. The risk of a further allergic reaction must be considered in relation to the benefit of treatment.

Authorised users

Dedicated Consultants
Approved Specialist Registrars
Approved Physiotherapists

Authorised for storage in clinical areas

Botulinum toxin A should be signed out via the toxin register stored within the controlled drugs cupboard in PDRU.

References

ROYAL COLLEGE OF PHYSICIANS 2018. Spasticity in adults: management using botulinum toxin. London. [viewed 28 August 2019]. Available from: http://www.rcplondon.ac.uk


ESQUENAZI, A., ALFARO, A., AYYOUB, Z., CHARLES, D., DASHTIPOUR, K., GRAHAM, G., McGUIRE, J., ODDERSON, I., PATEL, A. & SIMPSON, D., 2017. OnabotulinumtoxinA Injections for Lower Limb Spasticity: Guidance From a Delphi Panel Approach. American Academy of Physical Medicine and Rehabilitation. 9, pp. 960-968. [viewed 15 July 2020]. Available from:
http://dx.doi.org/10.1016/j.pmrj.2016.06.016


SIMPSON, D., PATEL, A., ALFARO, A., AYYOUB, Z., CHARLES, D., DASHTIPOUR, K., ESQUENAZI, A., GRAHAM, G., McGUIRE, J. & ODDERSON, I., 2017. OnabotulinumtoxinA Injection for Poststroke Upper-Limb Spasticity: Guidance forEarly Injectors From a Delphi Panel Process. American Academy of Physical
Medicine and Rehabilitation. 9, pp. 136-148. [viewed 15 July 2020]. Available
from: http://dx.doi.org/10.1016/j.pmrj.2017.02.014

TRUONG, D., HALLETT, M., ZACHARY, C. & DRESSLER, D., 2014. Manual of
Botulinum Toxin Therapy second edition. Cambridge: Cambridge University
Press.

HARDING, P., HICKLIN, D., LINDSAY, C., MAYBURY, M., JONES, C., MASON, S.
2013. Botulinum Toxin injections workbook. Edition 1, First Printing, UK.

WOLFGANG, J., 2012. Pictorial Atlas of Botulinum Toxin injection: dosage,
localisation , application. Second edition, Quintessence Publishing Co. Ltd, UK.

HANNA, P., JANKOVIC, J., & VINCENT, A.,1999. Comparison of mouse bioassay
and immunoprecipitation assay for botulinum toxin antibodies. Journal of
Neurology and Neurosurgical Psychiatry. 66, pp. 612-616.

KESSLER, K. & BENECKE, R., 1997. The EBD test- a clinical test for detection of
antibodies to Botulinum Toxin type A. Movement Disorders. 12(1), pp.95-99.
Botox, Xeomin and Dysport SPC https://www.medicines.org.uk/emc/

Appendix 1 - RCP guidelines dosing

Upper Limb

Botox/Xeomin* (U)

Dysport (U)

Pectoral girdle

Trapezius

50-75

200-300

Rhomboid

50-60

200-250

Supraspinatus

40-50

160-200

Infraspinatus

50-60

200-200

Subscapularis

50-80 (B)

15-100 (X)

200-320

Deltoid

50-75 (B)

20-150 (X)

200-300

Shoulder

Pectoralis major

75-100 (B)

20-200 (X)

300-400

Pectoralis minor

40

150-160

Latissimus dorsi

60-80 (B)

25-150 (X)

240-320

Teres major

30-50 (B)

20-100 (X)

120-200

Teres minor

30-50

120-200

Serratus anterior

60-70

250-270

Coracobrachialis

30-50

120-200

Elbow flexors

Biceps brachii

75-100

100-300

Brachialis

50-75

200-400

Brachioradialis

50-60

200-240

Forearm

Pronator quadratus

20-30

75-120

Pronator teres

30-40

120-160

Supinator

30-40

120-160

Wrist flexors

Flexor carpi radialis

30-40

120-160

Flexor carpi ulnaris

30-40

120-160

Finger flexors

Flexor digitorum superficialis

25-30

100-120

Flexor digitorum profundus

30-40

120-160

Thumb flexors

Flexor pollicus longus

20-30

75-120

Flexor pollicus brevis

(SPC 5-30)

-

Opponens pollicis

(SPC 5-30)

-

Adductor pollicis

20-40

75-100

Elbow extensors

Triceps

75-100

300-400

Wrist extensors

Extensor carpi ulnaris

30-40

120-160

Extensor carpi radialis longus

30-40

120-160

Extensor carpi radialis brevis

20-30

75-120

Finger extensors

Extensor digitorum communis

30-40

120-160

Extensor digiti minimi

30-40

120-160

Extensor indicis

20-30

75-120

Thumb extensors

Extensor pollicis longus

20-30

75-120

Extensor pollicis brevis

20-25

75-100

 

 

Lower limb

Botox/Xeomin* (U)

Dysport (U)

Hip flexors

Psoas major

100-200

600-800

Iliacus

75-150

200-400

Lateral verterbral column flexion

Quadratus lumborum

100

400

Hip adductors

Adductor magnus,

100-200

400-750

Adductor longus,

(between whole Adductor group)

(between whole Adductor group)

Adductor brevis

(between whole Adductor group)

(between whole Adductor group)

Gracilis

80-120

300-400

Pectineus

50-100

200-400

Internal rotation of hip

Gluteus maximus

-

-

Gluteus medius

100

400

Gluteus minimis

-

-

Knee flexors

Semitendinosus,

100-150

400-600

Semimembranosus

100-150

400-500

Biceps femoris long head and short

head

100-150

400-600

Popliteus

25-30

100-120

Knee extensors

Rectus femoris

100-150

400-500

Vastus medialis, intermedius and

vastus lateralis

100-150

400-500

Sartorius

-

-

Plantar flexors

Gastrocnemius medial head

50-100

200-400

Gastrocnemius lateral head

50-100

200-400

Soleus

75-100

300-400

Tibialis posterior

50-80

200-320

Foot

Tibialis anterior

75-120

300-400

Peroneus tertius

30-40

120-150

Peroneus longus

50-80

200-320

Peroneus brevis

30-40

120-160

Extensor digitorum longus

50-75 (B)

50-80 (X)

200-300

Extensor hallucis longus

50-60

200-250

Flexor digitorum longus

40-60

160-200

Flexor digitorum brevis

10-20

40-80

Flexor hallucis longus

40-60

160-240

Flexor hallucis brevis

10-20

40-80

Adductor Hallucis

10-20

40-80

* Xeomin doses same as Botox unless stated

Appendix 2 Delphi panel approach to treating most common UL and LL postures:

Delphi panel approach to treating most common UL postures:

UL posture;

Muscles

Dose range (U)

Total dose used (U)

Adducted and IR shoulder

Pectoral complex

75-100

100-200

 

Latissimus Dorsi

75

 

 

Teres Major

50-75

 

 

Deltoid

20

 

 

Brachialis

75

 

 

Levator scapulae

30

 

 

 

 

 

Flexed elbow

Brachioradialis

25-50

100-150

 

Biceps

0-50

 

 

Brachialis

50-100

 

 

Pronator teres

38-100

 

 

 

 

 

Pronated forearm

Pronator quadratus

0-25

50-100

 

Pronator teres

45-60

 

 

 

Flexor carpi radialis

20

 

 

Brachialis

100

 

 

Brachioradialis

25

 

 

 

 

 

Flexed wrist

Flexor carpi radialis

50-75

60-100

 

Flexor carpi ulnaris

25-50

 

 

Palmaris longus

13-50

 

 

Flexor pollicis longus

20-75

 

 

Flexor digit superficialis

25-75

 

 

Flexor digit profundus

25-75

 

 

 

 

 

Flexed fingers

Flexor digit superficialis

20-60

50-100

 

Flexor digit profundus

 

25-75

 

 

Flexor carpi radialis

30

 

 

Flexor carpi ulnaris

30

 

 

Lumbricals

30

 

 

 

 

 

Thumb-in-palm

Flexor pollicis longus

40-50

50-75

 

Adductor pollicis

10-20

 

 

Flexor pollicis brevis

12.5-20

 

 

Flexor digit profundus

35

 

 

Delphi panel approach to treating most common LL postures:

LL posture;

Muscle

Dose range (U)

Total dose (U)

Adducted thigh

Adductor magnus  

75-150

150-200

 

Adductor longus

75-80

 

 

Adductor brevis

20-25

 

 

Gracilis

25-40

 

 

Iliopsoas

25-150

 

 

Medial hamstrings

50

 

 

 

 

 

Flexed knee

Medial hamstrings  

125

100-200

 

Lateral hamstrings

75

 

 

Gastrocnemius

50-200

 

 

Iliopsoas

40-150

 

 

Tensor fascia lata

25-150

 

 

Medial Hamstrings

50

 

 

 

 

 

Extended knee

Rectus femoris

80-125

125-200

 

Vastus lateralis

50-70

 

 

Vastus medialis

50

 

 

Vastus intermedialis

35-75

 

 

Gluteus maximus

40

 

 

 

 

 

Equinovarus foot

Tibialis posterior  

100

250-300

 

Gastrocnemius

125

 

 

Soleus

75-100

 

 

Tibialis anterior

75

 

 

Flexor digitorum longus

20-75

 

 

Flexor digitorum brevis

13-38

 

 

Flexor hallucis longus

25-38

 

 

Extensor hallucis longus

13-50

 

 

 

 

 

Plantar flexed foot

Gastrocnemius

125

200

 

Soleus

75

 

 

Tibialis posterior

25-75

 

 

Long toe flexors

20

 

 

 

 

 

Striated toe

Extensor hallucis longus

50

50

 

Extensor hallucis longus

38

 

 

(motor point)

 

 

 

Flex digitorum longus

25-30

 

 

 

 

 

Flexed toes

Flexor digitorum longus

50-80

100-125

 

Flexor digitorum brevis

25

 

 

Flexor hallucis longus

40-50

 

 

Flexor hallucis brevis

13

 

Last reviewed: 16 March 2021

Next review: 01 January 2023

Author(s): Alison Barclay

Version: 2

Author Email(s): [email protected], [email protected]

Co-Author(s): Angela Lindsay

Approved By: Institute of Neurological Sciences Medical Clinical Governance Group

Document Id: 614