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ROYAL FREE LONDON NHS FOUNDATION TRUSTCHILDREN SERVICES GUIDELINES

METHOTREXATE FOR PAEDIATRIC RHEUMATOLOGY

Author(s): Dr Austin Isaacs, Consultant Paediatrician

Contact author: Dr Austin Isaacs, Consultant Paediatrician

Other contributors: Chloe Benn Principal pharmacist Women’s & Children’s servicesIn discussion with consultant Paediatricians

Previous authors: N/A

Related guidelines or documents:

Trust Medicines Policy (2016)

Cytotoxic chemotherapy for non-cancer indications –

guideline for the prescribing, supply and administration

(2014)

Approved by: Children’s Directorate Group March 2016

on behalf of the Women and Children Services Division

Issue no (Version): Mar 2016 (version no.1)

File name: Methotrexate for Paediatric Rheumatology

Key words: (up to 10) Methotrexate, Paediatric, Rheumatology

Supercedes: N/A

Significant change in practice:

Implementation plan: Available on Freenet, monitoring annual audit cycle

Service Line Lead Rahul ChodhariClinical Director Tim WickhamDirector of Midwifery/ Nursing

Mai Buckley

For Review: Month Year or in response to practice developments

Contents1. Overview...................................................................................................................22. Pre-treatment testing................................................................................................23. Contraindications and Drug Interactions..................................................................34. Prescription/Dosage/Administration.........................................................................35. Side Effects..............................................................................................................46. Ongoing mangement & Blood Monitoring................................................................47. Vaccinations and Exposure to Infectious Diseases..................................................68. Repeat Prescriptions................................................................................................69. Prescribing for Patients admitted to Hospital...........................................................610. Transition to adult services.....................................................................................7Monitoring compliance..................................................................................................7References...................................................................................................................7EQUALITY STATEMENT.............................................................................................8APPENDIX 1: MONITORING TOOL............................................................................0

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1. OVERVIEWLow dose methotrexate is used in various disorders e.g. rheumatology, gastroenterology, dermatology. It is used in Juvenile Idiopathic Arthritis, Uveitis and Systemic Lupus.

Methotrexate (MTX) is given ONCE WEEKLY, orally or subcutaneously. Methotrexate takes up to 6-12 weeks to be effective.

The current model is a shared care arrangement between The Royal Free Trust and Great Ormond Street Hospital Rheumatology (GOSH). There are currently two lead Paediatric Consultants for the three sites who are supported by Paediatric Community Nursing teams. It is the current agreement that the decision to start treatment, pre-treatment testing, discussion of need for regular blood tests, side effects and consideration of contra-indications is undertaken at the specialist centre (GOSH). This should include information about dose, frequency, need for regular blood tests including written information and blood monitoring booklet. The information below in those sections is for reference purposes only and is based on the current GOSH guideline. The local Paediatrician should ensure the patient/family has been seen at GOSH by the specialist nurse and blood tests reviewed prior to prescribing Methotrexate.

Children on methotrexate will be managed by specialist or secondary care, GPs will not be asked to take on prescribing or monitoring of Methotrexate

2. PRE-TREATMENT TESTINGBefore commencing methotrexate the specialist centre (GOSH) will perform:

Full blood count ESR and CRP ALT Creatinine Varicella immunity status. If negative consider pre-treatment vaccination if

immunosuppression can be delayed Check Measles status. If negative consider pre-treatment vaccination if

immunosuppression can be delayed. Discuss lifestyle issues such as alcohol Advise contraception if sexually active and for 6 months post treatment Ensure child will have regular blood tests Ensure patient/family are aware of side effects Consider teaching family how to administer own injections.

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3. CONTRAINDICATIONS AND DRUG INTERACTIONS

Before initiation the specialist centre will consider the following:

3.1 Contraindications - Absolute Active bacterial infection Active TB Active herpes-zoster infection Active serious fungal infections Acute hepatitis (A, B, C) Pregnancy/breastfeeding

3.2 Contraindications - Relative Chronic hepatitis B or C Hepatic disease Renal disease/impairment

3.3 Drug interactions Other anti-folate drugs e.g. trimethoprim Salicylates and some other NSAIDs delay the excretion of methotrexate

but usually tolerated (ensure regular monitoring)

4. PRESCRIPTION/DOSAGE/ADMINISTRATION

Initial dose & route will be advised by the specialist centre:

Usual starting dose is 10-15mg/m2 once weekly (max 25mg/m2)

There is little evidence that dose greater than 15mg/m2 is effective

The dose is the same for all routes of administration.

Subcutaneous route gives higher bioavailability than oral and less gastrointestinal effects.

Do not use IM in children as painful.

Medication supply:

o The strength of medication supplied to the patient should remain consistent to prevent any confusion for the patient over volume or the number of tablets they need to take.

o Oral methotrexate is dispensed in 2.5mg tablets (10mg tablets are not dispensed for non-oncology indications to avoid confusion)

o Oral solution 10mg/5ml is the recommended strength, however a variety of (unlicensed) strengths may be manufactured- check what the patient is using.

o Patients should be reminded of the need to check the dose and strength of the tablets/ liquid with each prescription.

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Subcutaneous There are pre-filled, pre-dosed syringes Metoject: 7.5 mg in increments of 2.5mg up to 30mg. This is the preferred formulation from GOSH and should be continued.

Folic acidDose 5mg orally weekly (given on different day to methotrexate, preferably day after). Reduces toxic effects MTX.

Prescriptions must be complete and legible and include in full the form, strength, dose and directions (not ‘as directed’) including the day of the week the methotrexate & folic acid are taken. Usually for 3 months prescription.

5. SIDE EFFECTSThe incidence of serious side effects is low. Side effects must be discussed with the patient and carers before starting treatment (and documented within the notes).Side effects should be reviewed and discussed at all outpatient appointments.

1) Nausea, vomiting, decreased appetite including anticipatory nausea. Consider:

Give Anti-emetics before and after methotrexate Increasing dose of folic acid Administering at night Change route of administration Some patients benefit by taking their NSAID (if they are on one) a

few hours before or after, rather than at the same time as their methotrexate dose.

2) Post dose reaction, feeling unwell for 24 hours3) Mouth ulceration. If minor, dose of folic acid can be increased4) Photosensitivity. Use sunscreen.5) Injection site reaction e.g. mild erythema6) Transient elevation of liver enzymes is common. Severe liver damage in

children very rare. (see below)7) Immunosuppression. Fever/bacterial infection may require omission and

review.(see below)8) Rashes9) Hair loss10) Adolescent issues – if sexually active must use contraception as teratogen,

discuss alcohol intake11) Pneumonitis, very rare (see below). Patient/family should be told to arrange

medical review if unexplained cough or breathlessness.

All side effects in children should be reported on a yellow card to the MHRA https://yellowcard.mhra.gov.uk/

6. ONGOING MANGEMENT & BLOOD MONITORING

Patients and families must have a clear monitoring plan and know how to arrange local blood tests and how to obtain methotrexate prescriptions. The local blood tests will be reviewed by the lead Paediatric Consultant/community specialist nurse (under supervision). Any abnormalities, change in dose or need for more frequent blood

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https://yellowcard.mhra.gov.uk/

tests should be communicated to patient. Blood results should be recorded in a patient held monitoring booklet (GOSH Rheumatology have monitoring card which should be used)

Regular blood test monitoring is recommended with the aim to detect early signs of toxicity and therefore reduce the risk of serious adverse effects.After starting methotrexate bloods should be performed as follows for standard monitoring:

2, 4, 8 & 12 weeks after starting then every 8 weeks (FBC, LFTs, Creatinine)

Parameter ActionLiver function test*ALT: 3 x upper limit of normal or unexplained fall in albumin

ALT: raised but less than 3x ULN

Omit dose and repeat test prior to next dose

Repeat LFTs in 2-3 weeks

If frequent abnormal LFTs eg 50% of time discuss with specialist team

WCC falling

Neutrophils fall to 1.0- 1.5 Repeat after 1-2 weeks

Omit if < 1 and repeat test before restarting

Lymphocytes < 0.5 Omit dose and repeat blood test before restarting

Platelets < 150 Omit dose and repeat blood test before restarting

Haemoglobin < 80 Omit dose and repeat blood test before restarting

Creatinine – abnormal or risingDehydration/acute renal failure

Omit dose and repeat blood test before restarting – discuss with specialist team/nephrology

MCV>105fl Withhold and check serum B12, folate and TFT and discuss with specialist team if necessary

Unexplained or persistent cough orbreathlessness or abnormal chest x-ray

Fever >38.5 C, severe sore throat or suspected bacterial Illness

Rash or unexplained bruising

Jaundice, RUQ abdominal pain

Omit dose and arrange urgent review by Consultant/paediatric teamConsider CXR

Omit dose and arrange medical review by GP/paediatric team

Omit dose and arrange medical review

Omit dose and arrange medical review

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*Raised liver enzymes or mild neutropenia may be caused by intercurrent infection. Omitting doses of methotrexate unnecessarily may lead to disease flares. Therefore when interpreting blood results, consider possible causes.

7. VACCINATIONS AND EXPOSURE TO INFECTIOUS DISEASES

VaccinationsLive vaccines should not be given while on methotrexate or for six months after finishing treatment. Inactivated vaccines can be given as normal. Annual influenza vaccination is recommended (with the inactivated flu vaccine injection).

Exposure to Infectious DiseasesIf a patient who is seronegative has a significant chickenpox/varicella contact treatment should be given with VZIG ideally within 72 hours (or consider prophylactic acyclovir protocol as alternative).Patients developing chickenpox or shingles should omit the methotrexate and be treated with aciclovir, usually intravenous initially.

If a child who has not been vaccinated with MMR has been in close contact with someone who develops a rash, which could be measles, they should contact their doctor for advice.

TB: consider need for chemoprophylaxis if in contact with active TB

8. REPEAT PRESCRIPTIONS Check the most recent blood results. Ask to see the patient’s monitoring

booklet & update results

Check if patient experienced any signs/symptoms of MTX toxicity/intolerance

Check for drug interactions (focus on new/acute prescriptions & OTC medication) eg trimethoprim, co-trimoxazole increases risk of bone marrow side effects

Confirm dose (strength & volume or number of tablets)

Confirm what day of the week MTX taken

Prescribe folic acid

9. PRESCRIBING FOR PATIENTS ADMITTED TO HOSPITAL

Methotrexate should not be prescribed to a child admitted for any reason (elective or emergency) until discussed with & authorised by attending or specialist Consultant after clinical review.

Patients may present with symptoms and signs of methotrexate toxicity for example breathlessness, vomiting and diarrhoea. Methotrexate should not be given if the patient has a significant infection particularly acute bacterial illness, respiratory illness or suspected/proven sepsis. Also omit if significant dehydration, renal or liver

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abnormalities or dysfunction. All patients presenting with respiratory illness should have a chest x-ray.

Check relevant haematological, renal and liver function tests & compare with previous results (on Trust system or in handheld monitoring booklet).

Only FY2 or above may prescribe Methotrexate. It is the prescriber’s responsibility to record the correct dosage and frequency

(weekly) on the hospital drug administration chart, and to strike out the six days of the week when a dose must not be administered in the administration section on the chart.

Do not prescribe until it is confirmed what day of the week the dose is due.

Prescriptions and discharge summary information must be complete and legible and include in full the form, strength, dose and directions.

A maximum of one week supply will be made for inpatients (this will equate to a single, once weekly dose).

10. TRANSITION TO ADULT SERVICESYoung people require specialist transitional care into adult rheumatology care. Current arrangements for transition are in discussion and children may be referred to RF site clinic or UCH Rheumatology team.Ensure issues including smoking, contraception, pregnancy are discussed.Avoid conception/pregnancy male and female , for at least 6 months post treatmentEnsure immunisations are up to date.

MONITORING COMPLIANCE

This guideline will be subject to annual audit and multidisciplinary review as described in the monitoring table in Appendix 1.

REFERENCES Adapted from BSPAR and GOSH guidelines.

METHOTREXATE USE IN PAEDIATRIC RHEUMATOLOGY Information for health professionals. The British Society for Paediatric and Adolescent Rheumatologyhttps://www.bspar.org.uk/DocStore/FileLibrary/PDFs/BSPAR%20Guideline%20for%20Methotrexate%202013.pdf

Towards the safer use of oral methotrexate NPSA alert 0102 2004

BSR/BHPR guideline for disease-modifying anti-rheumatic drug (DMARD) therapy in consultation with the British Association of Dermatologists. Rheumatology 2008; Chakravarty K et al; on behalf of the British Society for Rheumatology, British Health

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https://www.bspar.org.uk/DocStore/FileLibrary/PDFs/BSPAR%20Guideline%20for%20Methotrexate%202013.pdf

https://www.bspar.org.uk/DocStore/FileLibrary/PDFs/BSPAR%20Guideline%20for%20Methotrexate%202013.pdf

Professionals in Rheumatology Standards, Guidelines and Audit Working Group in consultation with the British Association of Dermatologists

EQUALITY STATEMENT The equality analysis for this guideline is in Appendix 2.

The Royal Free London NHS Foundation Trust is committed to creating a positive

culture of respect for all individuals, including job applicants, employees, patients,

their families and carers as well as community partners. The intention is, as required

by the Equality Act 2010, to identify, remove or minimise discriminatory practice in

the nine named protected characteristics of age, disability (including HIV status),

gender reassignment, marriage and civil partnership, pregnancy and maternity, race,

religion or belief, sex or sexual orientation. It is also intended to use the Human

Rights Act 1998 to treat fairly and value equality of opportunity regardless of socio-

economic status, domestic circumstances, employment status, political affiliation or

trade union membership, and to promote positive practice and value the diversity of

all individuals and communities.

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APPENDIX 1: MONITORING TOOL Element to be monitored Lead Tool Frequency Reporting

arrangementsActing on recommendations and Lead(s)

Change in practice and lessons to be shared

Pre-treatment tests

Dosage and Administration

Blood Monitoring

Repeat Prescriptions

Prescribing for patients admitted to hospital

Consultant Paediatrician – Guideline Author

Audit Proforma

Annual Report presented to Children’s Services Directorate meeting and Audit meeting to review results and recommendations

Children’s Services Audit meeting will undertake recommendations

Consultant Paediatrician – Guideline Author / Service Line Lead will take each change forward.

Lessons will be shared with the relevant staff groups

Report will be circulated to all relevant clinical areas

Email to all relevant staff groups

Required changes to practice will be identified and actioned within a specific time frame, at the Children’s Services Directorate/Audit Meetings.

Lessons will be shared with all the relevant stakeholders.

Monitoring related incidents Consultant Paediatrician – Guideline Author

Datix report

Annual Report presented to Children’s Services Directorate meeting and Audit meeting to review results and recommendations

Apendix 2 Equality AssessmentName of the policy / function / service development being assessed

Methotrexate for paediatric rheumatogyBriefly describe its aims and objectives:

To ensure safe and effective prescribing, administration and monitoring of methotrexate in the paediatric population

Evidence sources: DH, legislation. JSNA, audits, patient and staff feedback

METHOTREXATE USE IN PAEDIATRIC RHEUMATOLOGY Information for health professionals. The British Society for Paediatric and Adolescent Rheumatology

Towards the safer use of oral methotrexate NPSA alert 0102 2004Directorate lead: Womens & Childrens

Dr Rahul Chodhari; Service Line Lead General & Acute paediatrics

Is the Trust Equality Statement situated in the first three sections of the document? *(where?)

Yes No if no do not proceed with Equality Analysis (EA)

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Equality Group Column 1 Identify negative impacts

Column 2 What evidence, engagement or audit has been used?

Column 3 How will you address the issues identified?

Column 4 Identifies who will lead the work for the changes required and when?

Column 5 Please list positive impacts and existing support structures

AgeThink about different age groups and think about the policy / function / service and the way the user would access, is it user friendly for that age?

N/A N/A The guidance supports safe use of this drug in this age group

DisabilityThink outside the box, you may not be able to see the disability. It could be physical (hearing, seeing) or a learning disability (Autism), mental health, long term illness etc

Accessibility – venue, location, signage, furniture, getting around

Disability awareness training for staff

Actively involve staff and patients ask what their needs are do not assume.

Patients with rheumatology conditions may have reduced mobility

N/A N/A N/A Management at local centre reduces travel to specialist centre for appointmentsMonitoring may be managed closer to home through GP or children’s community nursing team.Self/carer administration encourages independence & need to attend.

Gender ReassignmentThink about creating an environment

No impact N/A N/A N/A N/A

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within the service / policy or function that is user friendly and non judgemental.

If the policy / function / service are specifically targeting this protected characteristic, think carefully about training, confidentiality and communication skills.

Marriage and Civil PartnershipThink about access and confidentialityDirect discrimination only.

N/A in this age group

N/A N/A N/A N/A

Pregnancy and maternityThe policy / function / service must be accessible for all for example opening hours. ( do they clash with school times)

Are the chairs appropriate for breast feeding is there a private area? Are there baby changing facilities and is there space for buggies?

N/A in this age group.

N/A N/A N/A Patients managed through paediatric service where breastfeeding and other family issues are expressly supported.

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RaceYou need to think carefully about the local demographics of the population who will be accessing the policy / function / service. Talk to public health within the local authority(JSNA)

Think about: Cultural issues (gender,

clothing etc) Languages Support to access Staff training on cultural

awareness, interpreting

N/A N/A N/A N/A N/A

Religion or BeliefAs above think about local population and what religion or belief they may have.Think about:

Staff training on respecting differences, religious beliefs

N/A N/A N/A N/A N/A

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Are you trying to implement during a time of religious festivals e.g. Ramadan

Are there designated prayer areas?

Are there known issues for some religions or beliefs around this area of service or service delivery

SexThis is simply the impact on males / females.For example same sex accommodation, are their areas for privacy?

Is it accessible for both taking into account working service users / is it accessible would it be a venue they would go to?

N/A N/A N/A N/A N/A

Sexual OrientationDon’t make assumptions and this protected characteristic may not be

N/A N/A N/A N/A N/A

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visibly obvious.

Providing an environment that is welcoming for example visual aids, posters, leaflets.

Using language that respects LGB&T people.

Staff training on how to ask LGB&T people to disclose their sexual orientation without fear or prejudice.

Carers Does your policy / function /

service impact on carers? Ask them.

What support will you be offering?

N/A N/A N/A N/A Patients treated in children’s services where family issues are expressly supported.Management at local centre reduces travel to specialist centre for appointmentsMonitoring may be managed closer to

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home through GP or children’s community nursing team.Self/carer administration encourages independence & need to attend.

Equality Analysis completed by: (please include every person who has read or commented and approval committee(s). Add more lines if necessary)

Organisation Date

Chloe Benn Royal Free London, Pharmacy 23/03/2016

Royal Free LondonRoyal Free London

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