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

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.

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.

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.

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).

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).

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

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).

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.

•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.

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.

Dedicated Consultants
Approved Specialist Registrars
Approved Physiotherapists

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

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/

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

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