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|ROYAL FREE LONDON NHS FOUNDATION TRUST |

|CHILDREN 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 services |

| |In 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 Chodhari |

|Clinical Director |Tim Wickham |

|Director of Midwifery/ Nursing |Mai Buckley |

|For Review: |Month Year or in response to practice developments |

Contents

1. Overview 2

2. Pre-treatment testing 2

3. Contraindications and Drug Interactions 3

4. Prescription/Dosage/Administration 3

5. Side Effects 4

6. Ongoing mangement & Blood Monitoring 4

7. Vaccinations and Exposure to Infectious Diseases 6

8. Repeat Prescriptions 6

9. Prescribing for Patients admitted to Hospital 6

10. Transition to adult services 7

Monitoring compliance 7

References 7

EQUALITY STATEMENT 8

APPENDIX 1: MONITORING TOOL 0

|1. Overview |

Low 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 testing |

Before 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.

| |

|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.

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 acid

Dose 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 Effects |

The 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 hours

3) Mouth ulceration. If minor, dose of folic acid can be increased

4) Photosensitivity. Use sunscreen.

5) Injection site reaction e.g. mild erythema

6) 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) Rashes

9) Hair loss

10) Adolescent issues – if sexually active must use contraception as teratogen, discuss alcohol intake

11) 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

|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 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 |Action |

|Liver function test* |Omit dose and repeat test prior to next dose |

|ALT: 3 x upper limit of normal | |

|or unexplained fall in albumin | |

| |Repeat LFTs in 2-3 weeks |

|ALT: raised but less than 3x ULN | |

| |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 rising |Omit dose and repeat blood test before restarting – discuss with |

|Dehydration/acute renal failure |specialist team/nephrology |

|MCV>105fl |Withhold and check serum B12, folate and TFT and discuss with |

| |specialist team if necessary |

|Unexplained or persistent cough or |Omit dose and arrange urgent review by Consultant/paediatric team|

|breathlessness or abnormal chest x-ray |Consider CXR |

| | |

|Fever >38.5 C, severe sore throat or suspected bacterial |Omit dose and arrange medical review by GP/paediatric team |

|Illness | |

| | |

|Rash or unexplained bruising |Omit dose and arrange medical review |

| | |

|Jaundice, RUQ abdominal pain |Omit dose and arrange medical review |

*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 |

Vaccinations

Live 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 Diseases

If 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 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 services |

Young 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 treatment

Ensure 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 Rheumatology



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 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.

|APPENDIX 1: MONITORING TOOL |

|Element to be monitored |Lead |

|Briefly 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 2004 |

|Directorate 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) |

|Equality Group |Column 1 Identify |Column 2 What evidence, |Column 3 How will you |Column 4 Identifies who will lead|Column 5 Please list positive|

| |negative impacts |engagement or audit has been|address the issues identified? |the work for the changes required|impacts and existing support |

| | |used? | |and when? |structures |

|Disability |Patients with rheumatology|N/A |N/A |N/A |Management at local centre reduces |

|Think outside the box, you may not be able to see the |conditions may have | | | |travel to specialist centre for |

|disability. It could be physical (hearing, seeing) or a |reduced mobility | | | |appointments |

|learning disability (Autism), mental health, long term | | | | |Monitoring may be managed closer to|

|illness etc | | | | |home through GP or children’s |

|Accessibility – venue, location, signage, furniture, | | | | |community nursing team. |

|getting around | | | | |Self/carer administration |

| | | | | |encourages independence & need to |

|Disability awareness training for staff | | | | |attend. |

|Actively involve staff and patients ask what their | | | | | |

|needs are do not assume. | | | | | |

|Gender Reassignment |No impact |N/A |N/A |N/A |N/A |

|Think about creating an environment 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 Partnership |N/A in this age group |N/A |N/A |N/A |N/A |

|Think about access and confidentiality | | | | | |

|Direct discrimination only. | | | | | |

|Pregnancy and maternity |N/A in this age group. |N/A |N/A |N/A |Patients managed through paediatric|

|The policy / function / service must be accessible for | | | | |service where breastfeeding and |

|all for example opening hours. ( do they clash with | | | | |other family issues are expressly |

|school times) | | | | |supported. |

| | | | | | |

|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 |N/A |N/A |N/A |N/A |

|Race | | | | | |

|You 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 Belief | | | | | |

|As above think about local population and what religion | | | | | |

|or belief they may have. | | | | | |

|Think about: | | | | | |

|Staff training on respecting differences, religious | | | | | |

|beliefs | | | | | |

|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 | | | | | |

|Sex |N/A |N/A |N/A |N/A |N/A |

|This 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 Orientation | | | | | |

|Don’t make assumptions and this protected characteristic| | | | | |

|may not be 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 |N/A |N/A |N/A |N/A |Patients treated in children’s |

|Does your policy / function / service impact on carers? | | | | |services where family issues are |

|Ask them. | | | | |expressly supported. |

|What support will you be offering? | | | | |Management at local centre reduces |

| | | | | |travel to specialist centre for |

| | | | | |appointments |

| | | | | |Monitoring may be managed closer to|

| | | | | |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 |Organisation |Date |

|and approval committee(s). Add more lines if necessary) | | |

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

| |Royal Free London | |

| |Royal Free London | |

| | | |

| | | |

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