Download Tizanidine - NHS Trafford CCG

GREATER MANCHESTER INTERFACE
PRESCRIBING GROUP
On behalf of the
GREATER MANCHESTER MEDICINES MANAGEMENT
GROUP
SHARED CARE GUIDELINE for Tizanidine
Reference Number
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Scope: Tizanidine for the treatment of spasticity associated
Classification
with multiple sclerosis or spinal cord injury or disease
SHARED CARE GUIDELINE
Issue date: 31 August 06
Replaces: No previous version available
Author(s)/Originator(s)
Stockport NHS Foundation Trust
To be read in conjunction with the
following documents
Pharmaceutical company’s patient information
leaflet (PIL)
Summary of product characteristics (SPC)
Interface Prescribing Group
Date: 9/11/06
31 August 08
Authorised by
Review Date
1. Introduction
This protocol has been produced to facilitate shared care between a
secondary or tertiary care specialist and the patient’s GP. Additional
information can be found in the latest summary of product characteristics i
Tizanidine is licensed for the treatment of spasticity associated with
multiple sclerosis (MS) or spinal cord injury or disease. It is not currently
licensed for fibromyalgia, general low back pain, complications for stroke,
prophylactic migraine therapy.
Tizanidine is an α2 adrenergic receptor agonist within the CNS at supraspinal and spinal levels. This effect inhibits spinal polysynaptic reflex
activity. Tizanidine has no direct effect on skeletal muscle, the
neuromuscular junction or on monosynaptic spinal reflexes.
In MS and spinal cord injury tizanidine reduces pathologically increased
muscle tone, reducing resistance to passive movements and alleviates
painful spasms and clonus.
NICE guidance is available on the treatment of MS.
2. Scope
Tizanidine may be considered for shared care arrangements for treatment
of spasticity associated with muscular sclerosis and spinal cord injury or
disease.
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3. Clinical condition being treated
Licensed tizanidine conditions: Spasticity associated with MS and spinal
cord injury and disease.
NICE ii currently recommends baclofen or gabapentin as first line
pharmacological treatment for bothersome regional or global spasticity or
spasms associated with MS.
Baclofen (with or without diazepam) is accepted first line treatment for
spinal cord injury.iii
Tizanidine may be considered for use in a patient by the consultant where
alternative first line treatment has been unsuccessful or side effects cannot
be tolerated.
4. Product information and treatment regimen to be used
The dosage of tizanidine needs to be individually tailored. The starting
dose is usually 2mg, increasing at 2mg increments at no less than half
weekly intervals. The minimum dose needed to produce the desired
therapeutic effect should be used. Most patients will need a dose of no
greater than 24mg in divided doses (over 3 to 4 doses per day) to achieve
this with a maximum daily dosage being set at 36mg.
5. Regimen Management
Prior to initiation with tizanidine, baclofen and gabapentin will typically
have been trialled. Unresponsive patients should be seen by a team
specialising in the management and treatment of spasticity who will
assess suitability for tizanidine.
Consultant responsibilities:
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Assessment of suitability for tizanidine usage in patients with a diagnosis
of: MS or spinal cord injury or disease.
Initiate/recommend treatment with tizanidine.
Advise patient on what necessary monitoring will be needed and discuss
possible interactions with any patients taking oral contraceptives.
Communicate with the GP regarding shared care, and obtain GP
agreement.
Carry out baseline liver function tests (LFTs) where practicable.
Carry out baseline renal function tests where impaired renal function exists
or is suspected.
Measure blood pressure.
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For new patients clinical monitoring occurs in the outpatient clinic, usually
at four months and at six monthly intervals thereafter. GPs can refer
patients back to clinic as necessary.
Communicate with GP regarding protocol and results of monitoring and
dosage recommendations.
Evaluate adverse drug reactions (ADRs) reported by GP or patient. Report
to the Medicines and Healthcare products Regulatory Agency (MHRA) as
necessary.
Advise the patient/carer of common side effects. This may include
discussions regarding lowering the dosage if side effects become
intolerable.
GP responsibilities:
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Notify the consultant of willingness accept shared care.
Prescribe therapy recommended by the consultant with minimum delay.
Treatment may be initiated in clinic, but more often the consultant will
advise treatment with Tizanidine.
Notes on treatment
When treating a patient with normal renal function the dosage will typically
start at 2mg increasing by 2mg every 4 days according to tolerability and
efficacy. A total daily dosage of 14mg to 16mg in divided doses will be
aimed for. Assessment will then take place in clinic at 4 months. The
dosage may then be increased if necessary by 2mg every four days until a
total daily dosage of 20 mg is reached. Normally the aim is not to go
beyond 24mg bearing in mind potential drowsiness problems.
In patients with impaired renal function it would seem prudent to keep the
final dose as low as possible depending on patient response and
tolerability, increasing dosage at weekly intervals. (It is advised to increase
the once a day dose before increasing frequency of administration).
Monitor closely for onset or increase in severity of adverse effects
particularly dry mouth, somnolence, asthenia and dizziness.
(Written information obtained from manufacturers)

Carry out routine monitoring
Article I.
Notes on Monitoring
Baseline liver function tests (LFTs) will be required where they not already
carried out in clinic, repeated after 2 weeks of treatment, then every 4
weeks for the first three months of treatment. Tests should be at three
monthly intervals thereafter.
Additionally carry out LFTS for patients developing unexplained nausea,
anorexia, tiredness as these may suggest liver dysfunction.
If LFTS show an increasing trend then decrease the dosage of tizanidine
and contact the consultant for advice.
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Discontinue treatment and contact the responsible consultant if AST, ALT,
γGT are persistently above three times the upper limit of normal range.
For patients with impaired renal function monitor renal function at the
same time as performing LFTs.
Perform normal BP monitoring.
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Assess the patient for adverse drug reactions/drug interactions. Refer
queries to the consultant and report to MHRA as necessary.
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Inform the consultant of dosage changes made. This is essential
information needed at clinic appointments especially if the patient if the
patient has difficulty communicating this information themselves.
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Supplementary/Independent prescriber responsibilities:
Prescribing must lie within the individual’s competency range.
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Dispensing Pharmacy responsibilities:
Ensure patient receives a manufacturer’s patient information leaflet (PIL)
with dispensed medication.
6. Summary of cautions, contra indications, side-effects
This information should be read in conjunction with the latest SPC.
Doses of tizanidine need to be slowly titrated starting with 2mg daily with
most patients needing no more that 24mg daily with a maximum total daily
dose of 36mg.
Contra-indications
Hypersensitivity to tizanidine
Significantly impaired hepatic function (due to extensive liver metabolism)
Cautions
Renal impairment: – lower doses may be needed.
Liver function: - Baseline LFTs required and at a minimum of monthly
intervals for first 4 months, then if symptoms of liver dysfunction
suspected. Some specialists prefer more frequent monitoring (see under
GP responsibilities)
Use in patients under 18 years is not recommended
Benefit of treatment must outweigh the risk in the elderly and
pregnant/breastfeeding ladies.
Elderly (renal clearance may be decreased)

In renal insufficiency (i.e. creatinine clearance < 25ml/min) treatment
should be started at 2mg daily with slow titration to achieve an effective
dose. Dose increments should be no greater than 2mg according to
tolerability and effectiveness. It is advised to increase the once a day
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dose before increasing frequency of administration. Monitor renal
function.
(Information regarding max single dose in renal impairment removed –
manufacturers will not give written confirmation)

Tizanidine is rapidly absorbed reaching peak plasma concentration in
approximately 1 hour. Elimination half-life is 2 to 4 hours. Tizanidine is
30% bound to plasma proteins. It undergoes extensive first pass
metabolism in the liver mainly by cytochrome P450 isoenzyme and
CYP1A2. It is excreted in the urine as inactive metabolites.
Side effects
Most frequent:- Drowsiness, fatigue, dizziness, dry mouth, nausea, GI
disturbances and a reduction in blood pressure.
Reduction in BP is seen in 7 to 12% of patientsv (these are minimised by
slow upward titration of dose)
Insomnia, bradycardia, hallucinations. (There is no evidence of psychosis
with hallucinations). Hallucinations may be more frequent in patients taking
antidepressants/ potentially hallucinogenic drugs.
Increases in hepatic serum transaminases (reversible on stopping
treatment)
Infrequent: Acute hepatitis
muscle weakness
Rare: allergic reactions (pruritus, rash)
Patients with renal impairment should be closely monitored for
onset or increase in severity of the above side effects
Drug interactions
Interactions classified as potentially hazardous by the BNF (No. 51):
●Procainamide (effects of muscle relaxants enhanced by procainamide)
●Quinidine (effects of muscle relaxants enhanced by quinidine)
●Ciprofloxacin – (plasma concentration of tizanidine increased by
ciprofloxacin (increased risk of toxicity)—avoid concomitant use)
Other interactions – caution needed:
Diuretics – increased hypotensive effect (Tizanidine can produce
hypotension)
Antihypertensives (ACE inhibitors, adrenergic neurone blockers, αblockers, angiotensin II receptor antagonists, calcium channel blockers,
clonidine, methyldopa, monoxidine, nitrates, hydralazine, nitroprusside):
increased hypotensive effect iv
β-blockers: bradycardia or hypotension
Digoxin:- bradycardia or hypotension
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Drugs which prolong QT interval (Drugs which prolong the QT interval
include Astemizole, Clarithromycin, Dolasetron, Erythromycin,
Haloperidol, Lithium, Lofexidine, Lopinavir with Ritonavir, Mizolastine,
Moxifloxacin, Olanzapine, Palonsetron, Phenothiazines, Pimozide,
Quetiapine, Quinupristin with Dalfopristin, Sertindole, Risperidone,
Sotalol, Telithromycin, Terfenadine, Tolterodine, Tricyclic antidepressants,
Tropisetron, Vardenafil, Venlafaxine, Voriconazole, Zotepine, Class 1A or
111 antiarrythmics eg amiodarone, procainamide) . This list is not
comprehensive and the extent to which prolongation occurs varies so
consult the relevant SPC for a particular drug.
Oral contraceptives;- clearance of Tizanidine may be reduced by up to
50%v. Clinical relevance is uncertain,
Alcohol – increased sedative effect.
Anxiolytics and hypnotics: Increased sedative effect
Fluvoxamine – increased side effectsvi
Ciprofloxacin – increased hypotension (CYP1A2 inhibition)vii
Phenytoin – one isolated case of raised serum phenytoin levels.
7. Special considerations
No special handling conditions. Tizanidine is prescribable in the
community on NHS FP10 forms.
8. Back-up care available to GP from Hospital, including emergency
contact procedures and help line numbers
Contact Dr Mag Kadies Consultant in Rehabilitation Stepping Hill Hospital
0161-419-4863
9. Statement of agreement
Shared care is an agreement between the GP and the Consultant. This
form is a request by the consultant to share the suggested care pathway of
your patient. If you are unable to agree to the sharing of care and
initiating/continuing the suggested medication, please make this known to
the consultant within 14 days, ideally stating the nature of your concern.
10. Written information provided to the patient
Manufacturer’s patient information leaflet which should include information
about not driving or operating machinery if affected by drowsiness.
11. Supporting References
i
Available online at http://emc.medicines.org.uk/
NICE Multiple Sclerosis Management of Multiple Sclerosis in primary
and secondary care, Clinical Guideline 8, November 2003
ii
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iii
Pharmacological interventions for spasticity following spinal cord injury
(Review); Taricco M, Adone R, Pagliacci C, Telaro E; The Cochrane
Collaboration 2006 Issue 1
iv BNF edition 51, March 2006-04-28
v Stockley Ivan, Stockleys Drug Interactions 6 th edition 2002.
vi Martindale – The Complete Drug reference
vii Granfors−Marika−T, Backman−Janne−T, Neuvonen−Mikko,
Neuvonen−Pertti−J.;Clinical pharmacology and therapeutics,
{Clin−Pharmacol−Ther}, Dec 2004, vol. 76, no. 6, p. 598−606,
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