Subcutaneous methotrexate: Shared care protocol


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  • Highland HSCP
  • Primary and Secondary Care.

Drug and indication 

Generic drug name  Methotrexate 
Formulation  Metoject® pre-filled pen 50mg/ml for subcutaneous injection. Available as 7·5mg, 10mg, 12·5mg, 15mg, 17·5mg, 20mg, 22·5mg, 25mg, 27·5mg and 30mg pens. 
Intended indication  Adult patients with rheumatoid arthritis. 
Status of medicine  Licensed

Cautions and contra-indications


  • Renal impairment (reduce dose to 50% if eGFR stable at 30 to 59mL/min and avoid if<30mL/min
  • Hepatic impairment 
  • Patients with third distribution space (eg pleural effusion, ascites) 



  • Liver insufficiency 
  • Alcohol abuse 
  • Pre-existing blood dyscrasia 
  • Pre-existing ulcers of oral cavity or active gastrointestinal ulcer disease 


  • Hypersensitivity to methotrexate 
  • Serious acute or chronic infection 
  • Pregnancy and breast feeding - adequate contraception should be used by females during treatment and for at least 3 months after discontinuation.  There is no need to stop treatment in males prior to conception.  
  • Concurrent vaccination with live vaccines - see the Rheumatology home page on the intranet (vaccinations in the immunocompromised person) 
  • Severe renal insufficiency (eGFR<30mL/min) 


Typical dosage regimen

Route of administration  Subcutaneous injection 
Recommended starting dose  Will vary as directed by rheumatologist – normal starting dose for any route of methotrexate is 15mg per WEEK but may be lower if there is a history of intolerance, renal or hepatic impairment, frailty or low BMI. 
Maximum dose  Generally 25mg per WEEK 
Adjunctive treatment  Folic acid should be prescribed for all patients – usually 5mg per week (the day after the methotrexate) but can be increased to 6 days per week, excluding the day of the methotrexate. Previous NSAIDs can be continued. Anti-emetics can be co-prescribed. 
Usual response time  May take up to 12 weeks to show signs of response 
Duration of treatment  Indefinite 

Adverse drug reactions

ADR details  Management 
Nausea (very common)  Use of anti-emetics where necessary, increase of folic acid intake (see above) switch to subcut formulation +/- dose reduction 
Stomatitis (very common and oral ulcers (common)  Folic acid dose can be increased up to 5 or 6 days per week (avoid on day of methotrexate) 
Elevated transaminases (very common)  If ALT and/or AST >100units/L then withhold and discuss with specialist team.
Blood cell dyscrasia (common) If WCC <3.5x109/L, neutrophils <2.0x109/L or platelets <140x109 /L or MCV >105fl then withhold and discuss with specialist team. A drop in haemoglobin is very rare with methotrexate and other reasons for an isolated drop in haemoglobin should be considered.
Pneumonitis (uncommon) – dry cough or increasing breathlessness  Withhold and discuss urgently with specialist team or if patient unwell or hypoxic and no specialist team available then with acute medical receiving. 
Severe sore throat or abnormal bruising 
Withhold and check FBC. If normal then methotrexate is not the cause. 
Rash, diarrhoea (rare) 
Usually has another cause but withhold and discuss with specialist team if no other cause apparent. 

Drug Interactions (please see BNF/SPC for Metoject® for full list)

Drug Interaction
Trimethoprim or cotrimoxazole Increased risk of blood cell dyscrasia.
NSAIDs Avoid over the counter NSAIDs but when prescribed at low or stable dose then it would be rare to have issues at the doses of methotrexate used for rheumatological conditions.
Clozapine Increased risk of blood cell dyscasia.
Probenecid Excretion of methotrexate reduced.
Acitretin Plasma methotrexate levels increased with increased risk of liver toxicity.
Pyrimethamine Increased risk of blood cell dyscrasia.
Leflunomide/ciclosporin Increased risk of blood cell dyscrasias but still sometimes used when enhanced clinical effect required
Cisplatin Increased pulmonary toxicity.
Antibiotics Unpredictable effect on methotrexate levels and we generally advise that if an antibiotic course is going to be over 1 week in duration then methotrexate is temporarily withheld.


Baseline investigations

  • Please see responsibilities of secondary care service, which outlines the information given to the patient.
  • FBC, U&Es, LFTs within 3 months of initiation.
  • PFTs and CXR are not done routinely, but might be requested by the team in the presence of respiratory symptoms and/or pre-existing respiratory disease (eg COPD, ILD, etc)

Monitoring (Primary Care)

  • See resources for DMARD monitoring guideline. 

Monitoring parameter


Laboratory Results

Action to be taken

Also note: trends in values and any abnormal trends should provoke extra vigilance.

Full Blood Count (FBC)

For those switching from oral methotrexate then monitoring will be the same as previously.

Initiation: 2 weekly for first 12 weeks then monthly for next 9 months and, assuming that results remain normal, then on to every 2 to 3 months depending on clinical judgement.

For those on combination DMARDs: weekly for first 12 weeks then monthly for next 9 months and then, assuming that results remain normal, then on to every 2 months.

  • WCC <3.5x109/L
  • Neutrophils<1.6x109/L
  • Platelets <140x109/L
  • MCV >105 fl.
  • Unexplained eosinophilia >0.5 x 109L

Withhold and discuss with specialist team.

Urea & Electrolytes (U&Es)

Worsening renal function (creatine increase >30% over 12 months, AKI whilst on treatment)

Withhold all nephrotoxins and temporarily suspend methotrexate.

Liver function test (LFTs)

  • ALT (or AST if available) >100 units/L
  • Albumin: unexplained drop <30g/L

Withhold and discuss with specialist team.

C-reactive protein (CRP)

CRP can be checked prior to a clinic visit or when there is a flare in symptoms. It is not a safety blood test but helps assess effectiveness of therapy.

Sudden unexpected rise in CRP.

Continue therapy and inform specialist team.

Severe sore throat, unexpected bruising or bleeding

Withhold all DMARDs.

Check FBC and, if no abnormalities, then look for other non-drug related causes.

New dry cough or worsening breathlessness

Withhold all DMARDs.

If hypoxic or unwell then admit to acute medical receiving, otherwise inform specialist team.


Responsibilities of secondary care (Consultant)

  • To organise baseline investigations (bloods and, if appropriate, PFTs  and CXR). Consultant will act on results of abnormal baseline investigations, including PFTs.
  • To clearly detail starting dose and any planned increments in dose to primary care with recommendation on monitoring.
  • To provide patient with patient information leaflet relevant to DMARDs being commenced and to discuss with patient requirement for blood monitoring and side effects.
  • To provide GP with GP information leaflet on DMARDs being prescribed by both electronic letter to GP either via letter handed to patient or by printed letter, ideally within 14 days of clinic appointment.
  • To provide details on frequency of monitoring covering the first year, then can be at discretion of primary care team according to protocol.
  • To provide advice to primary care on abnormalities in monitoring bloods or clinical side effects.
  • To provide the first prescription of subcutaneous methotrexate for administration by specialist nurse.
  • To provide all purple topped sharps bins to patients, and receive full bins from patients.

Responsibilities of Secondary Care (Specialist Nurse)

  • Training of patient in the administration of methotrexate by the subcutaneous route and supervision of first injection. If not practical then this has to be negotiated with nurse closer to home location and deviation from protocol documented in case notes.
  • Education of patient on importance of monitoring.
  • To explain risks of varicella in non-immune individuals and if uncertainty to organise baseline varicella serology.
  • To provide advice to primary care on abnormalities in monitoring bloods or clinical side effects including appropriate referral back to consultant when it is likely to involve a significant long-term change in treatment plan.
  • Training of patient to deal with spillage and disposal of injections.

Responsibilities of primary care (General Practitioner) 

  • To monitor and prescribe (after first injection) in collaboration with the specialist according to this protocol. Prescriptions should normally be for 12 weeks duration, dispensed monthly.
  • To ensure that the monitoring is kept up to date and consider withdrawing treatment if patient doesn’t comply with monitoring requirements.
  • Symptoms or results are appropriately actioned, recorded and communicated to acute care when necessary and where there is suspension of treatment (except where methotrexate being withheld for temporary antibiotic course).
  • Provision of pneumococcal and influenza vaccination.
  • Avoiding co-prescription of interacting drugs, except leflunomide, ciclosporin, where advised by secondary care.
  • To follow guidance on exposure to varicella in non-immune individuals (see resources)
  • GP queries should be submitted to duty rheumatologist via clinical dialogue

Responsibilities of patient 

  • To report adverse effects to their GP or specialist.
  • To attend for GP visits and blood monitoring visits.
  • To attend hospital appointments for specialist review. Failure of the patient to attend hospital or GP visits will result in medication being stopped.

Contact details

Specialist Rheumatology Nurse: 01463 704019.

GP queries should be submitted to duty rheumatologist via clinical dialogue.


Abbreviation  Meaning
ALT/AST  alanine aminotransferase/asparate aminotransferase
CXR chest x-ray
eGFR  estimated glomerular filtration rate 
FBC  full blood count 
HIV  human immunodeficiency virus 
LFTs  liver function tests 
MCV  mean corpuscular volume 
NSAIDs non steroidal anti-inflammatory drugs
PETs  pulmonary function tests
TB tuberculosis 
TLCO  transfer factor for carbon monoxide
U&Es  urea and electrolytes 
ULN  upper limits of normal 
WCC  white cell count 
Related guidelines
Related resources

Further resources for Healthcare Professionals 



Further information for patients

Self-management information 

Last reviewed: 14 November 2022

Next review: 30 November 2025

Author(s): Department of Rheumatology

Version: 2

Approved By: TAMSG of the ADTC

Reviewer Name(s): Alex Morrison, Specialist Clinical Pharmacist

Document Id: TAM354

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