Worcestershire Hospitals NHS Trust
Rheumatology And Dermatology
Shared Care Guidelines For Disease Modifying Drugs
March 2009
Jointly developed by: • Dr Ian Rowe, Consultant Rheumatologist • Dr Ashok Rai, Consultant Rheumatologist • Dr Athiveer Prabu, Consultant Rheumatologist • Dr Joanne Hague, Consultant Dermatologist • Ann Wild, Nurse Consultant in Rheumatology
Approved by Area Prescribing Committee: 7th April 2009
To be reviewed: March 2011, or sooner if required
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INDEX
Page
Introduction and Contacts 3
Responsibilities of Speciality Team, General Practitioner Team 4 and Patients
Azathioprine - Shared Care Information 5 - Dosage & Monitoring 7
Ciclosporin - Shared Care Information 8 - Dosage & Monitoring 9
Dapsone - Shared Care Information 10 - Dosage & Monitoring 11
D-Penicillamine - Shared Care Information 12 - Dosage & Monitoring 13
Hydroxycarbamide - Shared Care Information 14 - Dosage & Monitoring 15
Hydroxychloroquine - Shared Care Information 16 - Dosage & Monitoring 17
Leflunomide - Shared Care Information 18 - Dosage & Monitoring 19
Methotrexate - Shared Care Information 21 - Dosage & Monitoring 24
Myocrisin (im Gold) - Shared Care Information 26 - Dosage and administration 27
Sulfasalazine - Shared care information 28 - Dosage & Monitoring 29
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Appendix i - BSR Vaccination guidelines for the 30 immunocompromised person
References 32
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Introduction and Contacts
Introduction Rheumatoid Arthritis (RA) is a chronic, incurable, progressive inflammatory disease of the synovial lining of peripheral joints. The goals of management of RA are to relieve pain and inflammation, to prevent joint destruction and to preserve or improve a patient’s function. First-line treatment starts with simple analgesics and/or non-steroidal anti-inflammatory drugs (NSAIDs) but since they do not affect disease progression, slow-acting disease modifying anti-rheumatic drugs (DMARD’s) are added at increasingly early states of the disease to suppress the processes responsible for the chronic inflammation of RA. Biological (anti TNF) therapy is increasingly used in association with other therapy for highly active RA and treatment is instigated and monitored in Secondary Care. Disease modifying drugs are also used for the treatment of other rheumatoid conditions and in other specialities, including dermatology, respiratory medicine and gastroenterology. This document has been produced for the rheumatology and dermatology specialities but is also of interest to other specialities where DMARD’s are used and monitoring is undertaken. Although the common uses and doses for the drugs have been listed, where they are prescribed for other indications the doses are likely to be different. Please consult the manufacturer’s literature.
Availability of Back-up Advice and Support
Rheumatology Advice Line Worcestershire Royal Hospital……………………………………01905 760461
Ann Wild, Rheumatology Consultant Nurse…………………………………………………….. 01905 760461 Ext 33466
Kirsty Edwards, Rheumatology Nurse Practitioner………… …………………………………. 01905 760461 Worcestershire Royal Hospital Ext 33466
Claire Rochelle, Community Specialist Nurse, Kidderminster Hospital……………………….01562823424 (Wyre Forest and Tenbury Wells Localities)
Julie Cahill Rheumatology Nurse Practitioner …………………………………………………..01527 47914 Alexandra Hospital Ext 47914
Dr I Rowe, Consultant Rheumatologist …………………………………………………………. 01905 760460 Worcestershire Royal Hospital
Dr A Rai, Consultant Rheumatologist Worcestershire Royal Hospital …………………….……………………………………………01905 760460 Kidderminster General Hospital …………………………………………………………………..01562 513093
Dr A Prabu, Consultant Rheumatologist………………………………………………………….01527 44133
Dr C Bertram Consultant Dermatologist………………………………………………………….Ext 39427 Worcestershire Royal Hospital
Pharmaceutical Advisers…………………………………………………………………………...01905 760077 Worcestershire PCT
OUT OF HOURS EMERGENCY CONTACT (5pm until 9am Mon to Sat and all weekend)
Contact the Medical Assessment Unit (MAU) at either Worcester Royal Hospital or the Alexandra Hospital OUT OF HOURS in the event of SEVERE NEUTROPENIA
MAU Worcester Royal Hospital …………………………………….……………………………01905760545
MAU Alexandra Hospital…………………………………………………………………………..01527512091
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Responsibilities of Speciality Team, GP, Patient and Pharmacist in Shared Care Arrangement
SPECIALITY TEAM GP TEAM RESPONSIBILITY PATIENT RESPONSIBILITY PHARMACIST RESPONSIBILITY RESPONSIBILITY
Assessment ∗ Provide patient with information on ∗ Read information provided and give Appointment disease and drug treatment options consent for treatment chosen ∗ Carry out pre-treatment ∗ Inform speciality team of any other assessment, including necessary medication they may be taking, blood tests including OTC products
Prescription ∗ Initiate treatment ∗ GP Team to contact speciality ∗ Safe storage and handling of Appointment ∗ Issue clinic letter to GP with details team only if there are concerns medicine ∗ Ensure appropriate dose of baseline assessments and over shared care arrangement ∗ Safe keeping of patient held notes prescribed with clear directions prescribed dose not 'as directed'. ∗ Issue patient held monitoring booklet ∗ Provide advice on adverse and patient info leaflet effects ∗ Issue patient held letter to GP ∗ Provide advice on drug interactions with prescription ∗ Issues prescription and OTC medicines st 1 Review ∗ Initial monitoring results checked ∗ Carry out monitoring ∗ Request prescription from GP ∗ Issue patient information Appointment ∗ Assess response to treatment, adjust according to guidance in ∗ Report any adverse effects or leaflets dose if necessary shared care agreement problems ∗ Monitor frequency of ∗ Ensure patient held monitoring ∗ Review results against drug- ∗ Ensure patient held monitoring prescription requests and booklet is up-to-date for dose and specific guidelines before booklet is up-to-date for dose contact GP if quantities in monitoring parameters at clinic visit issuing any further excess of the prescribed ∗ Ensure GP aware of any dose prescriptions weekly dose are ordered change ∗ Contact speciality team to discuss anomalous results or potential adverse effects Further Review ∗ Review progress in clinic ∗ Ensure patient held monitoring ∗ Report adverse effects Appointments ∗ Respond to requests for further booklet is up-to-date for dose ∗ Ensure GP is aware of any OTC advice from GP Team and monitoring parameters at medication they may be taking ∗ Ensure patient held monitoring surgery visit ∗ Ensure patient held monitoring booklet is up-to-date for dose and ∗ Ensure patient is aware of any booklet is up-to-date for dose monitoring parameters if reviewed in dose change clinic ∗ ESR & CRP 6 monthly ∗ Ensure GP Team is aware of any desirable ( or as indicated) to dose change aid disease assessment
At each appointment with Speciality or GP Team the prescriber must ensure that the monitoring booklet is up to date for dose and monitoring parameters. Patients should be informed of the importance of the booklet being kept up to date at all times Page 4 of 32
Azathioprine Shared Care Information
Indications Licensed - RA, systemic lupus erythematosus, dermatomyositis & polymyositis, autoimmune and chronic active hepatitis, pemphigus vulgaris. Unlicensed - vasculitides such as polyarteritis and giant cell arteritis, psoriasis & psoriatic arthritis, severe eczema, bullous dermatoses including pemphigoid, inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease.
Time to response 6 -12 weeks
Presentation and Availability Azathioprine 25mg and 50mg tablets available.
Side effects Rarely: Hypersensitivity reaction (including malaise, dizziness, vomiting, diarrhoea, fever, rigors, myalgia, arthralgia, rash, hypotension and interstitial nephritis – calling for immediate withdrawal of drug) Serious effects: Liver impairment, cholestatic jaundice – see monitoring Blood dyscrasias – see monitoring Rash, mouth ulcers – see monitoring.
See BNF
Pregnancy and fertility & breastfeeding Discuss with Specialist (clinical data indicate risk of foetal congenital anomalies following in-utero exposure is small in non-renal transplant recipients, but see manufacturers SPC. Needs specialist supervision). Women of childbearing potential should be advised to use effective contraceptive precautions. Evidence of mutagenicity is equivocal in men. In most cases azathioprine should not be prescribed if there is a possibility of pregnancy, although there may be circumstances where the benefit of continuing treatment outweighs the possibility of risk related to the unborn child. A careful assessment of risk versus benefit is advised. Dose reduction at 32 weeks of gestation may prevent neonatal leucopenia. Women treated with azathioprine should not breastfeed.
Drug Interactions • Allopurinol inhibits the metabolism of azathioprine leading to increased toxicity. Dose of azathioprine should be reduced to 25% of original dose. • Warfarin: inhibition of anticoagulant effect of has been reported. • ACE inhibitors: co-prescription may cause anaemia and leucopenia (if significant consider alternative to ACE or different DMARD. • Co-trimoxazole & Trimethoprim can cause life threatening haemotoxicity • Phenytoin, Sodium Valproate, Carbamazepine: Azathioprine reduces the absorption of these drugs. • Aminosalicylates i.e. Mesalazine, Olsalazine, Balsalazide or Sulphasalazine, may contribute to bone marrow toxicity. See Appendix in BNF for further clarification of drug interactions.
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Contra-indications: • TPMT deficiency (homozygous state) • Aminosalicilates may cause bone marrow suppression • Lesch Nyhan Syndrome – due to congenital HGPRT deficiency • Immunization with live vaccines ( Inactivated polio is available although suboptimal response may be seen)
Thiopurine methyl transferase (TPMT) deficiency TPMT assay provides additional information of risks related to treatment but does replace routine monitoring. In patients with higher levels of serum TPMT, higher doses of TPMT may be required. Homozygous deficiency is associated with serious and fatal toxicity that may occur within six weeks of starting Azathioprine. Heterozygous deficiency is also linked to serious adverse events, although symptoms may not be evident until six months after commencing treatment.
Vaccines See contraindications and Appendix i
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Azathioprine – Dosage & Monitoring
Dosage and Administration: 1mg/kg per day. Increasing after 4-6 weeks to 3mg/kg per day. Lower doses in the elderly or in hepatic or renal impairment
Pre-treatment assessment: FBC, LFTs, U&Es and creatinine plus TPMT assay (TPMT deficiency – (homozygous state) - avoid (can be fatal) During treatment:
See Page 4 ‘Responsibilities of Speciality Team, GP Team, Patient and Pharmacist in Shared Care Arrangement’
Test Frequency Specialist GP FBC & LFT’s Weekly for 6 weeks 9 Continue fortnightly until dose stable. 2 weeks following dose change FBC & LFT’s Monthly. If dose stable 9 for 6 months consider reducing to 3 monthly (In pts heterozygote for TPMT continue monthly monitoring) U&E and Creatinine 6 monthly 9
Action to be taken: WBC< 4.0 x 109/l Withhold until discussed with speciality team
Neutrophil <2.0 x 109/l Withhold until discussed with speciality team
MCV > 105 fl Investigate B12 & folate & TSH, if low, start appropriate supplementation Platelets <150 x 109/l Withhold until discussed with speciality team
AST, ALT, Withhold until discussed with speciality team > 2 fold rise (from upper limit of reference range) U&E (renal impairment)-Creatinine Withhold until discussed with speciality team clearance 10-20 ml/min (moderate) Rash or oral ulceration Withhold until discussed with speciality team
Abnormal bruising or sore throat Withhold until FBC result available & discuss with speciality team CRP/ESR may be done every 3 – 6 months.CRP/ESR is used to monitor disease treatment and progress, please monitor as indicated by specialist team.
Please note that in addition to absolute values for haematological indices a rapid fall or a consistent downward trend in any value should prompt caution and extra vigilance.
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Ciclosporin Shared Care Information
Indications Oral Ciclosporin is licensed for rheumatoid arthritis, psoriasis, atopic dermatitis. Intravenous Ciclosporin is used in acute inflammatory bowel disease (in pt’s under 75 yrs) (unlicensed) Time to response up to 12 weeks
Presentation and Availability Oral preparation only in rheumatology. Available as 10mg, 25mg, 50mg and 100mg capsules in 30 capsule packs. Also available as oral solution, sugar free, 100mg/ml. Ciclosporin injection 50mg / ml
Side effects Common non-life threatening: Burning sensation in hands and feet, usually during the first weeks of treatment. Nausea, tremor, abdominal discomfort – may occur initially but usually subsides. Gum hyperplasia, poor appetite, increased hair growth
Rare: Hypertension – see monitoring Nephrotoxicity – see monitoring Hepatotoxicity – see monitoring
Pregnancy and Breastfeeding Reliable contraception should be prescribed for men and women – consult rheumatologist / dermatologist. Contraindicated in breastfeeding women.
Contraindications 1 Uncontrollable hypertension 2 Renal or liver failure (in RA patients) 3 Severe electrolyte imbalance eg.hyperkalemia 4 Suspected systemic infections or sepsis 5 Patients under 18 years (in RA patients)
Interactions Numerous – (See Appendix in BNF for further clarification of drug interactions) Lipid regulating drugs NSAIDs - increased nephrotoxicity, doses of diclofenac should be decreased by half Digoxin – may increase serum levels of Digoxin Methotrexate – increased toxicity Avoid St Johns Wort – decreases Ciclosporin activity Avoid grapefruit juice 1 hour prior to or after medication Avoid Colchicine Avoid Tacrolimus, Lercanidipine
Vaccines See Appendix i
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Ciclosporin – Dosage & Monitoring
Dosage and Administration 2.5mg/kg per day in 2 divided doses, increasing after 6 weeks by 25mg increments to a maximum of 4mg/kg per day (in rheumatoid arthritis) 2.5 mg/kg for 2 weeks then 5mg/kg per day (in dermatology) Careful monitoring is required when switching between capsules and oral solution as bioequivalencies vary.
Pre-treatment assessment: FBC, LFTs, U&Es and Creatinine on two occasions (to obtain mean value) Fasting lipids, Creatinine clearance, BP should be normal on 2 separate occasions prior to treatment, if greater than 140/90 treat hypertension before starting Ciclosporin. In pts with psoriatic arthritis: assess whether pt has received PUVA. If total dose exceeds 1000 J discuss with dermatologists
During treatment: See Page 4 ‘Responsibilities of Speciality Team, GP Team, Patient and Pharmacist in Shared Care Arrangement’
Investigation Frequency Specialist GP FBC & LFT’s fortnightly till dose 9 stable for 3 months
Then monthly 9 Serum electrolytes Fortnightly till dose 9 including potassium stable for 3 months and creatinine Then monthly 9
Fasting serum lipids 6 monthly 9 Blood pressure Each time pt attends 9 for monitoring CRP/ESR may be done every 3 – 6 months. CRP/ESR is used to monitor disease treatment and progress, please monitor as indicated by specialist team
Action to be taken: Creatinine >30% rise from baseline on 2 Repeat in 1 week if still > 30% above baseline - consecutive occasions Withhold until discussed with speciality team
Potassium rise to above normal range Withhold until discussed with speciality team
Platelets <150 x 109/l Withhold until discussed with speciality team AST, ALT, Alk Phos >2 fold rise (from upper limit of reference range) Withhold until discussed with speciality team. Check any other reasons e.g. alcohol, drug interaction (including over the counter medication) Abnormal bruising Check FBC & withhold until discussed with speciality team BP rise: > 140/90 on 2 consecutive Consider treating hypertension before stopping occasions 2 weeks apart ciclosprin. Also discuss with speciality team. Fasting lipids – significant rise Withhold until discussed with speciality team
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Dapsone, Shared Care Information
Indications An anti-inflammatory sulphonamide drug used in the treatment of dermatitis, herpetiformis and some other inflammatory dermatoses, including neutrophilic vasculitis.
Presentation and Availability Dapsone 50mg and 100mg tablets are available.
Contraindications G6DP deficiency
Side effects Haemolytic anaemia, agranulocytosis, hepatitis, dapsone hypersensitivity syndrome, neuropathy. See BNF.
Drug Interactions Trimethoprim, Probenecid and folic acid antagonists can increase dapsone levels, leading to an increased risk of side-effects. Rifampicin can decrease dapsone levels. Sulphonamide and Hydroxychloroquine can increase the risk of haemolysis. See appendix in BNF.
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Dapsone – Dosage and Monitoring
Dosage and Administration Dermatitis herpetiformis, initially 50mg daily, gradually increased to 300mg then reduced to a usual maintenance dose of 25-50mg daily Multibacillary leprosy in adults, 100mg daily for at least two years. Paucibacillary leprosy in adults, 100mg daily for at least six months. See manufacturer’s information for doses in other conditions.
Pre-treatment assessment: FBC, LFTs G6PD levels in patients of Middle and Far Eastern Origin
During treatment: See Page 4 ‘Responsibilities of Speciality Team, GP Team, Patient and Pharmacist in Shared Care Arrangement’
Investigation Time Interval Specialist GP
FBC Fortnightly for 8 weeks 9
Every 2-3 months 9
Monthly until dose stable 9 LFTs
3 Monthly once dose stabilised 9
Action to be taken: WBC <4.0 x 109/l Withhold until discussed with specialist team
Neutrophils <2.0 x 109/l Withhold until discussed with specialist team
Platelets <150 x 109/l Withhold until discussed with specialist team
AST, ALT, Alk Phos >2 fold rise Withhold until discussed with specialist team (from upper limit of reference range) MCV >105 fl Investigate and if B12 & folate low start supplementation
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D-Penicillamine Shared Care Information
Indications Rheumatoid arthritis. Wilson’s disease Dermatologists generally do not use this drug May take three to six months to start working.
Presentation and Availability Available as 125mg and 250mg tablets in packs of 20.
Side effects Less common: Altered or metallic taste – generally goes away within a few weeks Rash (early or late onset) Nausea, anorexia – reduce dose
Serious effects: Abnormal renal function, proteinuria – see monitoring Blood dyscrasias – see monitoring Myositis, myasthenia gravis, drug induced lupus, thyroiditis – withdraw drug Mouth ulcers – see monitoring
Pregnancy and fertility Avoid in pregnancy – discuss with rheumatologist
Contraindications: Systemic Lupus Erythematosus Moderate to severe renal impairment Pregnancy and lactation
Drug Interactions Antacids, Iron and Zinc – decreased absorption of D Penicillamine – leave 2 hours after a dose of any of these. Caution in patients who have had adverse reactions to gold. Antipsychotic drugs: may increase risk of agranulocytosis Digoxin: levels of Digoxin may be reduced by concurrent use of Penicillamine. Penicillin allergy – use extreme caution Concurrent NSAIDs and other nephrotoxic drugs – increase risk of renal damage
See Appendix in BNF for further clarification of drug interactions.
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D- Penicillamine – Dosage & Monitoring
Dosage and Administration 125mg daily before food, increasing every 4–6 weeks to maximum of 1500mg daily in divided doses. If sustained remission occurs, dose reduction may be considered. Do not give iron or antacids simultaneously.
Pre-treatment assessment: FBC, urinalysis for protein, U & Es and creatinine During treatment: See Page 4 ‘Responsibilities of Speciality Team, GP Team, Patient and Pharmacist in Shared Care Arrangement’
Investigation Time Interval Specialist GP FBC Fortnightly until dose stable 9
FBC Monthly once stabilised 9 LFTs 6 monthly for first 18 months 9
Urinalysis Fortnightly until dose stable 9 monthly thereafter Ask patient about rash At each visit until dose 9 or oral ulceration stabilised At each visit once stabilised 9 CRP/ESR may be done every 3 – 6 months.CRP/ESR is used to monitor disease treatment and progress, please monitor as indicated by specialist team
Action to be taken: WBC <4.0 x 10^9/l Withhold until discussed with specialist team Neutrophil <2.0 x 109/l Withhold until discussed with specialist team Platelets <150 x 109/l Withhold until discussed with specialist team Proteinuria 2+ or more Check MSU: If evidence of infection treat appropriately. If sterile and protein 2+ or more persists withhold until discussed with specialist team Severe rash or oral ulceration ( late Withhold until discussed with specialist team rashes are more serious than early ones)
Alteration of taste Continue treatment (usually settles spontaneously)
Abnormal bruising or sore throat Withhold and review when FBC available Dyspepsia Possibly secondary to concurrent NSAID. Consider dose reduction if severe
Please note that in addition to absolute values for haematological indices a rapid fall or a consistent downward trend in any value should prompt caution and extra vigilance.
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Hydroxycarbamide, Shared Care Information
Indications Cytotoxic drug used off-licence in psoriasis where other drugs have failed or are contra-indicated.
Presentation Hydroxycarbamide 500mg capsules available.
Side effects The major side effect is bone marrow suppression, leucopenia, thrombocytopenia and anaemia may occur. Rarely; leg ulceration, hyper-pigmentation.
See BNF.
Pregnancy and Fertility Hydroxycarbamide affects DNA synthesis and may be a potent mutagenic agent. Clinicians should carefully consider this possibility before administering the drug to male and female patients who may contemplate conception. It has also been shown to decrease spermatogenesis. When appropriate both male and female patients should be counselled concerning the use of contraceptive measures before and during treatment.
It should not normally be given to pregnant patients, or those who are breast-feeding unless the potential benefits outweigh the possible hazards.
Drug Interactions There is an increased risk of toxicity when Hydroxycarbamide is given with Didanosine and Stavudine, and concomitant use should be avoided. The absorption of Phenytoin may possibly be reduced by Hydroxycarbamide. Avoid prescribing in patients taking Clozapine due to an increased risk of agranulocytosis.
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Hydroxycarbamide – Dosage & Monitoring
Dosage and Administration: Dose is generally in the range of 500mg to 2.0g daily, as a single dose or as two divided doses (morning and evening). Usual initial dose in adults is 1g daily which is titrated according to efficacy and toxicity, up to a maximum of 2g daily.
Pre-treatment assessment: FBC (including platelet count and differential white cell count), LFTs
During treatment:
See Page 4 ‘Responsibilities of Speciality Team, GP Team, Patient and Pharmacist in Shared Care Arrangement’
Investigation Time Interval Specialist GP Weekly for 4 weeks FBC & LFTs 9
Monthly thereafter 9
Action to be taken:
WBC <4.0 x 109/l Withhold until discussed with specialist team Neutrophil <2.0 x 109/l Withhold until discussed with specialist team
Platelets <150 x 109/l Withhold until discussed with specialist team
>2-fold rise in AST, ALT, Alk Phos Withhold until discussed with specialist team (from upper limit of reference range) MCV > 105 fl Investigate and if B12 & folate low start appropriate supplementation Reduction in haemoglobin of 3g/dl or more Withdraw therapy
Severe cutaneous reactions Withdraw therapy
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Hydroxychloroquine Shared Care Information
Indications
Licensed - Rheumatoid arthritis and connective tissue diseases (systemic and discoid lupus). It is also used in some photosensitive dermatological conditions.
Presentation and Availability Available as 200mg tablets (Plaquenil) in 60 tablet packs.
Side effects Uncommon: Gastrointestinal side effects - indigestion and diarrhoea (reduce dose) Skin reactions, rashes, pruritis, depigmentation or loss of hair
Rare: Retinopathy, see monitoring, below ECG changes and convulsions Blood disorders, rarely leucopenia Hepatotoxicity Note: very toxic in overdose – seek immediate advice
Pregnancy Discuss with specialist. Hydroxychloroquine has been used in relative safety in pregnancy. The risks of stopping treatment should be weighed against the small possible risk to the unborn child
Breastfeeding Women treated with Hydroxychloroquine should not breast feed
Contra indications Pre-existing maculopathy Known hypersensitivity to 4-aminoquinolone compounds
Caution Hepatic and renal impairment Severe neurological disorders Patients with epilepsy May exacerbate psoriasis
Interactions Avoid antacids within 4 hours of dose Avoid concurrent use of hepatotoxic drugs and nephrotoxic drugs Amiodarone – avoid concomitant use Ciclosporin: concomitant use may increase plasma concentration of ciclosporin Digoxin-increased plasma levels of digoxin, monitor Digoxin levels Moxifloxacin, Ciprofloxacin, Mefloquine and Quinine - avoid concurrent use Methotrexate: concomitant administration may increase plasma concentration of methotrexate although Methotrexate and Hydroxychloroquine are often used in combination
See Appendix in BNF for further clarification of drug interactions
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Hydroxychloroquine – Dosage & Monitoring
Dosage and Administration Usual dose 400mg daily (sometimes taken on 5 days a week only). May later be reduced to 200mg daily and may be further decreased to 200mg 2 – 3 times per week. Response may take 2- 3 months. Discontinue after 6 months if no response.
Pre-treatment assessment: LFTs, U&Es, FBC
• Ask about visual impairment which is not corrected by glasses • Record near visual acuity of each eye (with reading glasses if worn) using a test type or the reading chart • If no abnormality detected, commence treatment • If an abnormality detected refer first to an optometrist or ophthalmologist if required
During treatment:
See Page 4 ‘Responsibilities of Speciality Team, GP Team, Patient and Pharmacist in Shared Care Arrangement’
FBC & ESR, LFT’s U&E’s & CRP may be requested periodically by rheumatology team to aid clinical assessment, or prior to next hospital appointment
The Royal College of Ophthalmologists recommend: Annual review by an optometrist, or enquiring about visual symptoms, rechecking visual acuity and assessing for blurred vision using the reading chart at hospital appointment.
Patients should be advised to report any visual disturbance.
CRP/ESR may be done every 3 – 6 months or as indicated by specialist team
Action to be taken Development of blurred vision or changes in Stop medication and refer as above visual acuity Patients requiring long-term therapy (5 years or Discuss with ophthalmologist more) Severe GI upset Withhold until discussed with speciality team
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Leflunomide Shared Care Information
Indications Licensed - rheumatoid arthritis, psoriatic arthritis. Not used in psoriasis Time to response 8-12 weeks. Presentation and Availability Leflunomide 10mg and 20mg tablets in 30 tablet packs. Leflunomide 100mg in 3 tablet pack.
Side Effects (Numerous - see BNF) includes: Common: Diarrhoea / Nausea Less common Mouth ulcers Weight loss Abdominal pain Headache Dizziness Mild hypertension Alopecia Rash Serious effects: Hepatotoxicity Anaphylaxis Toxic epidermal necrolysis
Contraindications: • .Pregnancy and Breastfeeding Leflunomide MUST NOT be prescribed in pregnancy or women of childbearing potential who might become pregnant. It should also be avoided in women who wish to breast-feed. There should be a two-year period between taking the drug and starting a family to ensure there is full drug elimination. Alternatively patients could be treated with Cholestyramine or activated charcoal and the elimination of the drug will be reduced to a duration of a few weeks. Blood tests should be carried out to confirm there has been drug elimination in view of the theoretical teratogenic effects of Leflunomide metabolites. This service is provided free of charge by Aventis, the drug manufacturer. Men should use effective contraception for 3 months after stopping Leflunomide. See Washout Procedure. • Severe immunodeficiency • Serious infections • Severe unexplained hypoproteinaemia • Moderate to severe renal impairment • Hepatic impairment • Impairment of bone marrow function as indicated by anaemia and cytopenias due to causes other than RA and Psoriatic arthritis
Caution: Evidence of localised or systemic infection such as Hepatitis B or C Infection or tuberculosis Drug potentiation: Haematotoxic or hepatotoxic drugs such as methotrexate Leflunomide SPC states caution if used together with methotrexate although combination therapy with these drugs has been used
Drug Interactions Theoretical drug interaction with Phenytoin, Warfarin and Tolbutamide, whereby the effects of these drugs may be enhanced, although significant interaction unlikely. Cholestyramine should be avoided unless rapid drug elimination is required. Vaccination with live vaccinations is not recommended for patients taking Leflunomide. See Appendix in BNF for further clarification of drug interactions. Vaccination See drug interactions and Appendix i
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Leflunomide – Dosage and Monitoring
Dosage and Administration
Loading dose 100mgs daily for three days may be used to speed onset of effect, but unacceptable GI side effects may occur with loading dose and is often omitted in routine practice.
Dose for RA patient’s is usually 20mg daily.10mg tablets are available for patients requiring a lower dose. Psoriatic arthritis dose is 20mg daily.
Pre-treatment assessment: Baseline blood pressure: BP should be normal on 2 separate occasions prior to treatment, if greater than 140/90 treat hypertension before starting drug.
FBC (including total and differential white cell count and platelets), LFT’s, U&E’s.
Body weight, - to allow assessment of weight loss.
During treatment: See Page 4 ‘Responsibilities of Speciality Team, GP Team, Patient and Pharmacist in Shared Care Arrangement’ Specialist GP Blood pressure At each monitoring visit 3 3 FBC 9 Including differential Fortnightly for 2 months white blood cell count and platelet count & LFTs Monthly thereafter. 9 FBC Including differential white blood cell count and platelet count & LFTs
CRP/ESR may be done every 3 – 6 months. CRP/ESR is used to monitor disease treatment and progress , please monitor as indicated by specialist team
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Action to be taken Increase ALT less than Monitor LFTs every 2 weeks & expect values to 2 X upper limit normalize spontaneously
ALT >2-3 x upper limit Recheck LFT’s within 72 hours, if still 2-3 x ULN reduce dose – monitor LFT’s fortnightly. If still 2- 3x ULN stop – discuss with specialist team
ALT > 3 x upper limit- Recheck LFT’s within 72hours if still >3x ULN stop and discuss with specialist team - consider washout WBC < 4.0X 109/l Withhold until discussed with specialist team
Neutrophils < 2.0 x 109/l Withhold until discussed with specialist team
Withhold until discussed with specialist team Platelets < 150 x 109/l Abnormal bruising Check FBC immediately and withhold until or severe sore throat results available
Rash, itch or hair loss Consider dose reduction. If severe, stop and consider washout
Severe GI upset If severe or persistent stop and consider washout Weight loss Monitor carefully. If > 10% reduce dose or stop. Consider washout Hypertension Consider dosage reduction &/or co-prescription of with conventional anti-hypertensive therapy. If BP remains uncontrolled stop & consider washout.
NB. Simple dose reduction is unlikely to produce a rapid diminution of adverse effects as the half-life of the drug is two weeks ( 1- 4 weeks). If a rapid response is required consider washout.
Washout procedure To aid drug elimination in cases of serious adverse effect or before conception, stop treatment and give either Cholestyramine 8g three times daily for 11 days or activated charcoal 50g four times daily for 11 days. The concentration of active metabolite after washout should be less than 20µg/l (measured on two occasions 14 days apart) in men and women before conception.
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Methotrexate Shared Care Information
Indications Licensed – Rheumatoid arthritis, psoriasis Unlicensed – Psoriatic arthritis, Crohn’s disease, connective tissue disease (SLE, myositis, & vasculitis) Felty’s syndrome
National Patient Safety Agency (NPSA) – Patient safety alert 03 and 13 Oral Methotrexate is a safe and effective medication if taken at the right dose and with appropriate monitoring. However two NPSA patient safety alerts (03 and 13) highlighted problems with taking the medications can cause serious harm and even death. This shared care information has been developed to ensure the safe prescribing and monitoring of Methotrexate treatment.
Presentation and Availability Only the 2.5mg tablets should be prescribed for all patients covered by this shared care guideline. IMPORTANT: The 10mg tablets should NEVER be prescribed or dispensed for the patients covered by this shared care agreement. See section ‘Recommendations to GP’). (NB: Methotrexate is also available as im or s/c injection and is often given by the subcutaneous route if requested by the clinic team for patients unable to tolerate oral methotrexate)
Side-Effects Common non-life threatening: nausea, diarrhoea, and stomatitis
Less commonly: headaches, drowsiness and blurred vision
Serious effects: hepatic, pulmonary, and bone-marrow toxicity, which can occur acutely at any time during therapy. bone-marrow suppression; a low neutrophil count is of most concern and can present with high fever and sore throat.
Serious pulmonary adverse effects with acute breathlessness have been recorded.
If a serious reaction is suspected: stop the drug immediately, check blood tests and contact the speciality team for advice and/or review.
Guidance on Prevention of Teratogenic Effects Methotrexate is teratogenic and female patients of childbearing age should be prescribed or offered contraception. Patients should not become pregnant within 3 to 6 months of stopping methotrexate depending on advice from the physician. Male patients are also advised to use contraception for 3 to 6 months following discontinuation of methotrexate.
Drug Interactions (refer to BNF and SPC) Avoid nephrotoxic / hepatotoxic drugs
Phenytoin: anti folate effect of methotrexate is increased
NSAIDs and salicylates can reduce excretion of methotrexate, and although it is advised not to use these drugs together, clinically significant interaction between NSAID and methotrexate is rare. The Rheumatology department have many years experience of co-prescribing these drugs without additional problems, as some patients will still need an anti-inflammatory agent. Monitoring would continue as normal, with vigilance for any abnormalities in LFT’s
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Tolbutamide: serum concentration of Methotrexate may be increased Probenecid: Methotrexate excretion is reduced Ciclosporin can increase Methotrexate toxicity. The speciality team will provide patient-specific advice on co-prescriptions. Trimethoprim and Co-trimoxazole: antifolate effect of methotrexate is increased and greatly increases the risk of bone marrow aplasia. Concurrent use of these drugs with Methotrexate should be avoided There may be a small risk of increased methotrexate levels with antibiotics e.g. penicillins.
Avoid concurrent use of Acitretin and Methotrexate due to risk of hepatotoxicity. Alcohol should be avoided but small amounts are unlikely to be a problem (ie within the national limits)
Caution • Renal impairment • Systemic infection • Unexplained anaemia
See Appendix in BNF for further clarification of drug interactions.
Vaccination Patients receiving Methotrexate must not receive immunization with live vaccines. Inactivated polio is available although suboptimal response may be seen Annual ‘flu vaccine is recommended Prior to commencing Methotrexate ask about previous exposure to chickenpox or shingles. Patients receiving Methotrexate exposed to chickenpox or shingles, passive immunization should be carried out using VZIG. Also see Appendix i
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Recommendations to GP Team
1. Prescriptions for methotrexate need to be explicit. Use of phrases such as “as directed” should not be used. Community Pharmacists must not dispense prescriptions for methotrexate if they are written “as directed”. Ensure patient knows the number of 2.5mg tablets to take and that it is a WEEKLY dose
2. GPs are responsible for receipt of blood test results and reviewing and actioning such results, when prescribing the drug. For details of actions required, see page 25.
3. Any change in therapy including dosage needs to be recorded in both the patient’s medical record and computer based prescribing systems held by the GP.
4. GP prescribing software systems should be programmed to have a warning prompt that Methotrexate is prescribed weekly. Specific actions should be required to over-ride the warning.
5. Methotrexate should only be prescribed as 2.5mg tablets as this is the only strength licensed for rheumatoid arthritis treatment. (10mg tablets must NEVER be prescribed for patients covered by these shared care guidelines)
6. Repeat prescriptions should be retained separately for prescriber review prior to authorising.
7. Be aware of patients who attend with symptoms such as breathlessness, dry persistent cough, vomiting or diarrhoea, as these can be signs of methotrexate toxicity or intolerance.
Recommendations to other Hospital Specialities who may be involved with the care of a patient who is already taking DMARD’s
1. Remember that the prescriber of a drug has responsibility for ensuring that the dose is correct.
2. It is recommended and good practice that they have a secondary care clinician involved.
Other Specialties Initiating DMARD therapy
Methotrexate may also be initiated by consultants in other specialties, notably respiratory medicine and gastroenterology. These guidelines have also been approved by these consultants. Availability of back up advice is available through their team.
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Methotrexate – Dosage & Monitoring
Dosage and Administration The doses of methotrexate used in rheumatoid arthritis are usually 5mg – 7.5mg orally once weekly initially, increasing by 2.5mg every 6 weeks to 15 – 20mg (usual max 25mg) weekly depending on patient response. Lower doses should be used in the frail elderly or if there is significant renal impairment. All increases and dose adjustments will be done in Out-Patients unless directions have been specified in the medical letter to the GP. The dose used for severe psoriasis is adjusted according to the severity of the condition and haematological and biochemical measurements; the usual dose is 10 to 25mg once weekly, by mouth. It is important to note that the Methotrexate dose is once weekly. Serious/fatal reactions have occurred when this dose regime has not been followed. Folic acid 5 - 10mg once a week (on a different day to methotrexate, usually 3 days later) should be co-prescribed to minimise the risk of minor side-effects. In children, folic acid 5mg is given each day except the day methotrexate is given.
Pre-treatment assessment: FBC, U & Es, creatinine, LFTs Chest X-ray (unless done in the last 6 months). P3NP – dermatology
During treatment:
See Page 4 ‘Responsibilities of Specialist Team, GP Team, Patient and Pharmacist in Shared Care Arrangement’
Investigation Time Interval Specialist GP FBC and LFTs Fortnightly until 6 weeks after (including AST or ALT) last dose increase. Continue if unstable 9 If stable, monthly after last dose 9 increase U & E’s 6-12 monthly (more frequently if 9 there is any reason to suspect deteriorating renal function) CRP/ESR may be done every 3 – 6 months. CRP/ESR is used to monitor disease treatment and progress, please monitor as indicated by specialist team
Notes 1) In patients who have previously been stable, a dose adjustment may warrant altered monitoring frequency recommended by the prescribing physician or nurse consultant / practitioner.
2) There are currently separate arrangements in place for patients in the former Wyre Forest PCT, Kidderminster Hospital and those under the care of the Wyre Forest Community Rheumatology Specialist Nurse, whereby the shared care monitoring booklet acts as a request for blood tests, with results checked by GP’s in the booklet prior to issuing the next prescription. Please refer to Kidderminster protocols for these patients.
3) For patients on anti TNF α therapy, with concomitant methotrexate, follow Methotrexate monitoring schedule.
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Action to be taken:- WBC <4.0x109/l withhold until discussed with speciality team Neutrophils <2.0x109/l withhold until discussed with speciality team
Platelets <150x109/l withhold until discussed with speciality team >2-fold rise in AST, ALT withhold until discussed with speciality team (from upper limit of reference range) Unexplained fall in albumin withhold until discussed with speciality team Rash or oral ulceration withhold until discussed with speciality team New or increasing dyspnoea or cough withhold & discuss urgently with speciality team MCV>105fl investigate B12, folate & TFT if low start appropriate supplementation /discuss with specialist team PNP3 >4.2mcg/l in three samples over a 12 Refer to specialist dermatology team month period PNP3 >8.0mcg/l in 2 consecutive samples Refer to specialist dermatology team Significant deterioration in renal function withhold until discussed with speciality team Abnormal bruising or sore throat withhold until FBC result available & discuss with speciality team
Please note that in addition to absolute values for haematological indices a rapid fall or a consistent downward trend in any value should prompt caution and extra vigilance.
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Myocrisin (sodium aurothiomalate) Gold Intramuscular Injection Shared Care Information
Indications Licensed – Rheumatoid arthritis, juvenile idiopathic arthritis Unlicensed – skin diseases including pemphigus Time to response: at least 12 weeks
Presentation and Availability Injectable gold, sodium aurothiomalate is available in 0.5ml ampoules in the following strengths: 20mg/ml (10mg), 100mg/ml (50mg). (Oral gold, Auranofin, is available as 3mg tablets in a 60 tablet pack, but is rarely used due to high incidence of adverse effects)
Side effects Severe reactions occur in up to 5% of patients. Side effects include; mouth ulcers, skin reactions (including on prolonged parenteral treatment, irreversible pigmentation in sun exposed areas), proteinuria, blood disorders. Rarely anaphylaxis – can occur just a few minutes after injection colitis, peripheral neuropathy, pulmonary fibrosis, hepatotoxicity. See BNF.
Pregnancy and fertility & breastfeeding Avoid in pregnancy and during breastfeeding
Interactions Increased risk of toxicity with other nephrotoxic and myelosuppressive drugs. ACE inhibitors – increased risk of anaphylaxis
Contraindications Severe renal or hepatic impairment History of blood disorders or marrow aplasia Exfoliative dermatitis Systemic lupus erythematosus Necrotising enterocolitis Significant pulmonary fibrosis Porphyria Pregnancy
See Appendix in BNF for further clarification of drug interactions.
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Myocrisin (Gold) Intramuscular Injection – Dosage & Monitoring
Dosage and Administration Gold may be given by intramuscular injection as Sodium Aurothiomalate (or by mouth as Auranofin). Sodium Aurothiomalate must be given by deep intramuscular injection and the area gently massaged. For the injection, a test dose of 10mg is given after which the patient is observed for 30 minutes, for skin rash or hypersensitivity. This is followed by doses of 50 mg at weekly intervals until significant response or a total of 1g has been reached. In patients who do respond the interval between injections is gradually increased to 4 weeks and is continued for up to 5 years after complete remission. After a total dose of 1g has been administered, if no response has occurred, treatment should stop.
Pre-treatment assessment: FBC, LFTs, U&Es and creatinine, urinalysis for protein
During Treatment:
See Page 4 ‘Responsibilities of Speciality Team, GP Team, Patient and Pharmacist in Shared Care Arrangement’
Investigation Time Interval GP FBC At time of each injection 3 (Can work one FBC in arrears) Urinalysis Ask patient about Before each injection 9 abnormal bruising, sore throat, rash or oral ulceration CRP/ESR may be done every 3 – 6 months. CRP/ESR is used to monitor disease treatment and progress, please monitor as indicated by specialist team
Action to be taken: WBC < 4.0 x 109/l Withhold until discussed with speciality team
Neutrophil <2.0 x 109/l Withhold until discussed with speciality team
Eosinophilia >0.5 x 109/l Caution and increased vigilance is required
Platelets <150 x 109/l Withhold until discussed with speciality team
> 2+ proteinuria or more Check MSSU: if infection treat appropriately. If sterile and 2+ proteinuria or more persists withhold until discussed with speciality team Rash or oral ulceration Withhold until discussed with speciality team Abnormal bruising or sore throat Caution and increased vigilance is required
Please note that in addition to absolute values for haematological indices a rapid fall or a consistent downward trend in any value should prompt caution and extra vigilance.
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Sulfasalazine EN Shared Care Information
Indications Licensed – Rheumatoid arthritis, ulcerative colitis, Crohn’s disease. Unlicensed – sero negative spondylo-arthropathy, psoriasis. Contains Sulphapyridine and Salicylate. Time to response: minimum of 12 weeks
Presentation and Availability Available as 500mg tablets in packs of 112. Enteric coated tablets recommended for Rheumatology patients to minimise GI side effects
Side-effects Common non-life threatening: nausea, diarrhoea, abdominal pain, headache
Serious effects: blood dyscrasias (see monitoring) Sensitivity reaction – stop immediately
Miscellaneous: Orange urine, stain soft contact lenses yellow. Tinnitus, fever, photosensitisation
Pregnancy and fertility Sulphasalazine can cause a fall in sperm count reversible on stopping the drug. Pregnancy –stop drug prior to conception and discuss with specialist team. Reliable contraception should be used by males and females.
Drug Interactions Antacids should not be taken at the same time Digoxin and Folic acid – levels of these may be reduced Azathioprine- possible increased risk of haematological toxicity See Appendix in BNF for further clarification of drug interactions
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Sulfasazine EN – Dosage & Monitoring
Dosage and Administration 500mg/day increased at intervals of one week to a maximum of 2-3 grams daily in divided doses. (gastroenterology : start with 1g twice daily increasing up to 4g in divided doses) Time to response 6-12 weeks
Pre-treatment assessment: FBC, LFT, U&Es, creatinine
During treatment:
See Page 4 Responsibilities of Specialist Team, GP Team and Patient and Pharmacist in Shared Care Arrangement’
Investigation Time Interval Specialist GP FBC Monthly for 3 months 9 If stable, 12 weekly in 1st year, 9 6 monthly thereafter LFTs Monthly for 3 months 9 If stable, 12 weekly in 1st year, 9 6 monthly thereafter FBC & LFT One month following dose 9 change Ask patient about rash At each visit 9 or oral ulceration At each visit 9 CRP/ESR may be done every 3 – 6 months. CRP/ESR is used to monitor disease treatment and progress, please monitor as indicated by specialist team
Action to be taken: WBC <4.0 x 109/l Withhold until discussed with specialist team
Neutrophil <2.0 x 109/l Withhold until discussed with specialist team
Platelets <150 x 109/l Withhold until discussed with specialist team
AST, ALT >2 fold rise Withhold until discussed with specialist team (from upper limit of reference range) MCV >105 fl Investigate and if B12 or folate low start supplementation
Nausea/dizziness/headache If possible continue, may have to reduce dose or stop if symptoms severe
Abnormal bruising or sore throat Withhold until FBC result available
Unexplained acute widespread rash Withhold – seek urgent specialist (preferably dermatological) advice
Oral ulceration Withhold until discussed with specialist
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Appendix i
VACCINATIONS IN THE IMMUNOCOMPROMISED PERSON GUIDELINES FOR THE PATIENT TAKING IMMUNOSUPPRESSANTS, STEROIDS AND THE NEW BIOLOGIC THERAPIES
This is the BSR’s most recent guidance and is subject to revision and formal review.
GENERAL INFORMATION • Cytotoxic/immunosuppressant drugs used by Rheumatologists include Azathioprine, Methotrexate, Leflunomide,Chlorambucil, Cyclophosphamide and Cyclosporin. The new biologics are currently considered with this group. • The use of live vaccines is contra-indicated unless immunosuppressives are stopped at least 3 months beforehand. • If use of live vaccines is necessary allow at least 2 weeks, preferably 4 weeks, before immunosuppressive therapy is commenced. • If a patient is vaccinated while taking immunosuppressives they may not mount the appropriate immune response. Consider repeating 3 months after therapy has ceased if viral titres low. • Consider using immunoglobulins if contact risk is significant (e.g. Varicella, Measles).
TRAVEL ADVICE Only 2 live attenuated viruses, yellow fever and polio, are used regularly for foreign travel.
• Yellow fever - this must not be given. Patients should be advised not to travel to countries requiring this e.g. mid-Africa. If the patient has to travel, an exemption statement may be accepted but the patient will be at risk. • Polio vaccine - the live oral vaccine must not be given. Killed inactivated vaccine can be given but may need to be obtained from abroad so adequate notice must be given. • Typhoid - the live form should not be given. Killed vaccine is available but only 70% protective. • Inactive viruses can be given e.g. Rabies, Anthrax, Cholera, Plague.
HOME ADVICE • Oral live Polio Vaccine (OPV) must not be given to patient or household contacts. Inactivated form (IPV) can be used. • Measles, Mumps, Rubella (MMR) - all three live vaccines and must not be given to patient but use is not contraindicated in household contacts. Exposure to measles should be treated with immunoglobulin regardless of prior immunisation. • BCG is contra-indicated in patients on treatment. Consider giving it in juvenile arthritis 4 weeks before immunosuppressives. Patients with juvenile arthritis should be brought up to date with vaccination schedules prior to receiving Methotrexate. • In immunosuppressed patients, the immunological response to inactive virus vaccines may not be as good as in the healthy and more frequent boosters may be required. There is an increased risk in the immunocompromised from secondary bacterial infections following influenza. Immunisation against Pneumococcal, Meningococcal, Haemophilus B, Tetanus and Hepatitis B infection might be indicated. Check Hep B titres 3 months after the 3rd injection. • Check Varicella zoster titres prior to immunisation if appropriate.
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PATIENTS ON STEROIDS Live vaccines must not be given to patients taking moderate or high doses of steroids for longer than 2 weeks.
There is no consensus as to what is a low dose of steroid (10mg per day or below is thought a sensible compromise). A full immunosuppressive dose may be 20mg per day and not 40mg as previously accepted.
There are no contra-indications to using live vaccines if:
• Steroid is for less than 2 weeks • Treatment is alternate day with short acting steroid • By topical application • By intra articular or soft tissue injection • Replacement therapy with physiological doses e.g. adrenal insufficiency • Long term low dose steroids (10mg per day or less)
Moderate or high dose steroid must be stopped 3 months before live vaccines can be administered.
BIOLOGICS No data is available on the effects of vaccination in patients receiving biologics e.g. Infliximab, Etanercept or Anakinra. At present is advised not to give live vaccines concurrently with these drugs.
LEFLUNOMIDE The long half-life of Leflunomide should be considered when contemplating administration of a live vaccine after stopping the drug.
REFERENCES • Immunisation against infectious disease, Salisbury and Begg 1996 HMSO • Vaccination in the Immunocompromised Person Grabosky, Hadler, Chen and Edwards, Bulletin of Rheumatic Disease 1995 44(8) 3-6 • Recommendation of the Advisory Committee on Immunisation Practices - Use of Vaccines an Immune Globulins for Persons with Altered Immunocompetence, Morbidity Weekly Reports 1993 42(RR-4) 1-18
28 January 2002
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References
British National Formulary 56. September 2008. Published by BMJ Group and RPS Publishing. London, UK.
British Society of Rheumatology National Guidelines for monitoring second line drugs 2000
BSR/BHPR guideline for disease-modifying anti-rheumatic drug (DMARD) therapy in consultation with British Association of Dermatologists 2008. Rheumatology. 2008
Electronic Medicines Compendium. Available via www.emc.medicines.org.uk
Vaccinations in the immunocompromised person BSR (2002)
Reducing the harm caused by oral methotrexate. National Patient Safety Agency. 29 July 2004. Available via www.npsa.nhs.uk/health/alerts
Improving compliance with oral methotrexate guidelines. Patient safety alert 13. National Patient Safety Agency. 1 June 2006. Available via www.npsa.nhs.uk/health/alerts
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