Doncaster Area Prescribing Committee s2

Doncaster & Bassetlaw Area Prescribing Committee October 2009 V2.0

Shared Care Protocol for the Management of Inflammatory Arthritis & Connective Tissue Disease for Adult services, over 16

1.0 INTRODUCTION

The use of disease modifying antirheumatic drugs (DMARDs) in treating early and established stages of Inflammatory Arthritis (IA) and in managing Connective Tissue diseases (CTD) is accepted practice. General Practitioners (GPs) are becoming more involved in active management of these conditions with the recognition that patients should be referred early for specialist advice and initiation of disease modifying drugs.

This protocol sets out guidelines for treatment of CTD & IA and delineated responsibilities when care is to be shared between Primary Care and Rheumatology Specialist services.

Shared Care Protocols are intended to provide clear guidance to General Practitioners (GPs) and hospital prescribers regarding the procedures to be adopted when clinical (and therefore prescribing and financial) responsibility for a patient’s treatment with a shared-care disease is transferred from secondary to primary care.

GPs, as independent contractors, have the right to decline to take clinical and prescribing responsibilities for a patient on their medical list who is being treated elsewhere. However the reason for this action must be documented. In the view of the Doncaster & Bassetlaw APC, it would be the exception for a GP to refuse to take clinical and prescribing responsibilities for an individual drug, where shared care guidelines for that drug have become common practice and where shared care guidelines include adequate support, education, and information as approved by the Doncaster & Bassetlaw APC.

If a specialist asks a GP to prescribe these drugs in relation to this disease, the GP should reply to this request as soon as practicable. The doctor who prescribes the medication legally assumes clinical responsibility for the drug and the consequence of its use.

The Doncaster & Bassetlaw Hospitals NHS Foundation Trust is a multi-site trust covering 2 PCT areas (Doncaster and Bassetlaw), with the Rheumatology department split over the two main hospitals. The process of shared care traditionally occurs for the DRI Rheumatology patients treated at Doncaster Royal

1 This Document will be reviewed in the light of new or emerging evidence or by October 2014 Doncaster & Bassetlaw Area Prescribing Committee October 2009 V2.0

Infirmary. and for Bassetlaw patients primary care normally monitor DMARDs. The reason for the difference dates back before the two hospitals merged as one trust. This protocol should allow GPs to undertake either method.

While this document looks to medications used in the treatment of CT & IA diseases, not all drugs will be covered by a shared care protocol for prescribing.

Traffic Light System Classification Drug Class Grey Amber-G Amber Red Drugs that Gold (injectable suppress the & oral) rheumatic Penicillamine disease Sulfasalazine process Antimalarials Hydroxychloroquine Drugs Azathioprine Ciclosporin affecting the Leflunomide Methotrexate immune Methotrexate (injectable) response (oral) Mycophenolate Alkylating Cyclophosphamide drugs Cytokine Abatacept1 Adalimumab modulators Anakinra2 Etanercept Infliximab Rituximab

Grey - These medicines are not recommended for initiation in the Doncaster and Bassetlaw Health Care Communities Amber G – Drug must be initiated and titrated to stable dosage by specialist before GPs take over prescribing responsibility. Once medical condition and drug dosage is stable, there is no specific requirement for ongoing monitoring Amber - Initiation and continued prescribing should only be undertaken under auspices of an agreed shared care protocol Red – Prescribing initiated and retained by specialist – Prescribing monitoring performed in secondary care

1 Abatacept - Abatacept is not recommended (within its marketing authorisation) for the treatment of people with rheumatoid arthritis. Patients currently receiving abatacept for the treatment of rheumatoid arthritis should have the option to continue therapy until they and their clinicians consider it appropriate to stop. NICE TA 141 Abatacept for the treatment of rheumatoid arthritis April 2008 2 Anakinra: On the balance of its clinical benefits and cost effectiveness, anakinra is not recommended for the treatment of RA, except in the context of a controlled, long-term clinical study. NICE CG79 The management of rheumatoid arthritis in adults February 2009

2.0 Background Information

This shared care agreement includes, but is not restricted to, the treatment of patients with any inflammatory arthritis or spondyloarthropathy and connective tissue diseases such as SLE, discoid lupus, myositis, vasculitis as examples.

2.1 RheMOS System General

Doncaster Rheumatology unit use a monitoring system aided by a nationally recognised program called RheMOS. This essentially is a software package that can assess trends in a patient’s blood test parameters. It then highlights when a patient deviates outside set parameters and has not had a blood test according to their drugs’ protocol. This is then actioned by the Rheumatology team as appropriate depending on the clinical situation. Patients are sent the regular blood forms by the support staff in the post, which have a bar code on which highlights to the Trust’s PAS system that it is a RheMOS patient. Recently, the Trust has gone paperless for RheMOS blood results as they were not needed. The forms are sent out each time the patient reaches the end of their group of forms and then ring in on a dedicated phone line extension, which each patient is given. This system also allows for tracking when patients do not attend for blood tests and the departments own protocol for this is followed.

2.2 RheMOS DNA Protocol

If patents DNA blood tests, they are sent a reminder letter as soon as is practicable, asking them to either attend for the blood test or contact on nurses help line if there are problems. They are warned in the letter that it is dangerous to continue the drug unmonitored and if they fail to have the blood test performed treatment might need to be stopped. If the patient fails following this to have a blood test performed or contact the department then a letter is sent to the patient, their GP and whoever is prescribing the DMARD (ie hospital pharmacy) asking them to stop the treatment and that if they continue to take the DMARD after this then that is at their own risk. Contact numbers are again provided on the letter.

2.3 Pregnancy and Breast Feeding

When a patient is prescribed a DMARD there are significant issues regarding pregnancy and family planning posed by the potency and potential teratogenic potential of these drugs. The decision about when and what drugs should be stopped is a decision that needs to be taken in secondary care. The decisions potentially affect both male and female patients depending on the drugs being used. Please see Appendix for specific advice on each drug. Overall the principle is to use the least level of treatment to control the disease but in certain conditions such as SLE, stopping some DMARD therapies has been shown to increase risk of flare and consequent risk to mother and baby. Please refer to Appendix 1.

Breastfeeding should not be advised if a mother is on any DMARD, even those felt to be safe during pregnancy, as small amounts are excreted in the breast milk.

2.4 Chicken Pox

Immunosuppressd Varicella Zoster Virus (VZV) naïve patients have a significant risk of disseminated infection if exposed or contract infection. Therefore, information is passed to all patients in secondary care on DMARD / steroid therapy as what to do if they are exposed or contract chicken pox.

 Exposed to VZV and within incubation period o Previous history of chicken pox Only treat if develop active infection; usually aciclovir o No history of chicken pox . Urgent assessment of VZV antibodies . If antibody status negative: treatment with pooled immunoglobulin . If antibody status positive: only treat with acyclovir if develop infection  Active VZV Infection o Previous history of infection – treat with acyclovir o No history of chicken pox . Urgent assessment of antibodies . Detailed clinical assessment and anti-viral treatment dependent on clinical presentation

2.5 Immunizations

No live vaccine should be given to any immunosuppressed patient. All patients on methotrexate, azathioprine, ciclosporin, lefluonamide, mycophenolate and cyclophosphamide should be offered annual flu vaccination and the one off pneumococcal vaccine unless contraindicated.

3.0 Drug treatment

For contraindications or further information please see the current BNF http://www.bnf.org.uk/bnf/bnf/current/index.htm or summary of product characteristics for the individual drug http://www.medicines.org.uk/

Drug, dose & TLS listing Adverse effects Therapeutic Monitoring Consultant Clinically relevant drug GP interactions 1. Drugs that suppress the rheumatic disease process 1.1 Auranofin – Oral Gold (Amber)  6 mg daily (initially in 2 divided  Diarrhoea Baseline:  None doses then if tolerated as a  Rashes - FBC, WBC, platelets, urinalysis, U&Es, LFT, single dose)  Bone marrow urinalysis for proteinuria and blood  If response inadequate after 6 suppression* Routine: months, increase to 9 mg daily  Oral ulceration Every 4 weeks (in 3 divided doses), discontinue  Proteinuria - FBC, & urinalysis if no response after a further 3  Permanent greyish skin months discolouration  Side effects (chrysiasis) with  Symptom control prolonged use

1.2 Sodium Aurothiomalate – Injectable Gold (Amber)  10mg test dose followed by  Diarrhoea Baseline:  None 50mg once weekly given by  Rashes - FBC, WBC, urinalysis, U&Es, LFT, urinalysis for deep IM injection  Bone marrow proteinuria and blood  After significant response with suppression* Routine: 50mg weekly dose can be  Oral ulceration Before each injection reduced to every 2 weeks to  Proteinuria  FBC, WBC, monthly  Permanent greyish skin  Urinalysis discolouration When stable for 8 weeks it is permissible to work one week in arrears for FBC.

 If a total dose of 1 gram has (chrysiasis) with  Side effects been given & there has been no prolonged use  Symptom control response, treatment should stop.  Vasomotor reaction -  If relapse occurs revert to 50mg flushing erythema, weekly until control re- weakness, hypertension. established  Rarely – enterocolitis, intra hepatic cholstasis, pneumonitis.

1.2 Penicillamine (Amber)  Initially 125mg-250mg daily  Nausea Baseline:  Clozapine increases risk before food for 1 month  Bone marrow  FBC, differential WBC, U&E’s, creatinine & of agranulocytosis. increased by similar amounts at suppression* urinalysis for proteinuria and blood intervals of not less than 4  Rashes Routine: weeks to usual maintenance  Oral ulceration Every 2 weeks for the first 3 months dose of 500-750mg daily in  Alteration of taste  FBC, U&E & urinalysis divided doses.  Proteinuria Every 4 weeks  Maximum dose of 1.5 gram  FBC, U&E’s & urinalysis daily, if remission sustained for 6  Side effects months, reduction of daily dose  Symptom control by 125mg-250mg every 12 weeks may be attempted

1.3 Sulfasalazine (Amber)  Enteric coated tablets only  Orange tears and urine Baseline:  None (Salazopyrin –EN  Nausea  FBC, WBC, creatinine, LFT  500mg per day increasing by  Headache Routine 500mg per day each week to a  Abdominal pain Fortnightly for 12 weeks usual maintenance dose of 2  Diarrhoea  FBC, WBC, LFT. grams per day in divided doses.  Oral ulceration After 12 weeks at 3 monthly intervals for the first year  If no response after 3 months  Rashes  FBC, WBC, LFT. the dose may be increased to a  Oral ulceration After 12 months at 6 monthly intervals (or 1 month maximum of 3g/day (1.5g bd)  Bone marrow after dose increase) suppression*  FBC, WBC,LFT  Hepatitis  Oligospermia  Side effects  Symptom control

2. Antimalarials 2.1 Hydroxychloroquine (Amber-G)  Initially 400mg in divided doses.  Indigestion, nausea, abdominal Baseline  Amiodarone- increase risk of ventricular Can be reduced to 200mg after cramps  FBC, U&E, LFTs arrhythmias. Avoid concomitant use 6 months depending on clinical  Headache,  Ask about visual response.  Tinnitus impairment (eye  Maximum dose is 6.5mg/kg lean  Rashes acuity)

body weight per day or 400mg  Photosensitivity (sunblock  Side effects per day, whichever is lower. advised)  Symptom control  Smaller doses are needed in  Retinopathy can occur after  Annual Visual patients weighing 60kg or less. prolonged treatment symptomatology  Review needed if no clinical  Otoxicity effect after 6 – 12 months of treatment. 3. Drugs affecting the immune response 3.1 Azathioprine (Amber)  1 to 3mg/kg day adjusted for  Nausea, vomiting, diarrhoea Baseline:  Allopurinol-enhanced effects and clinical response  Bone marrow suppression*  FBC,LFT,U&E,TPMT increased toxicity  Check TPMT if possible to  Rashes Routine:  Clozapine- avoid concomitant use starting  Hepatic dysfunction Weekly for 6 weeks potential for causing agranulocytosis  Often started 1mg/kg initially for  FBC, LFT’s  Coumarins- anticoagulant effect 2-4 weeks until TPMT known After 6 weeks at monthly reduced and then increase to 2mg/kg intervals  Sulfamethoxazole -increased risk of  Larger doses used under  FBC, LFT’s haematological toxicity secondary care supervision At 6 monthly intervals  Trimethoprim (also with co-  U&E’s trimoxazole)-increased risk of  haematological toxicity Dose changes: FBC and LFT fortnightly for 6 weeks after any dose increase  Side effects  Symptom control

3.3 Leflunomide (Amber)  Start on 10 -20mg od  Gastrointestinal disturbance Baseline:  Colestyramine significantly  Occasional  Abdominal pain  LFTs, U&Es, creatinine and BP decreases the effect. Avoid circumstances larger  Weight loss  FBC including differential WBC count concomitant use unless doses have been  Oral ulceration Routine: used to quickly discreet used.  Headache Monthly for the first 6 months then every 8 weeks Leflunomide from body in  Increase in blood pressure  FBC, differential WBC cases such as overdose or  Rashes  LFT & BP unexpected pregnancy  Bone marrow suppression*  Hepatitis  Side effects  Symptom control

Drug, dose & TLS Adverse effects Therapeutic Consultant Clinical relevant drug interactions listing Monitoring GP Lead Monitoring# GP 3.4 Methotrexate -oral (Amber)  Initially be given at a  Gastrointestinal disturbance Baseline:  Acitretin increases plasma concentration dose between 2.5 to  Rashes  U&E, creatinine, LFTs, FBC, differential  Ciclosporin risk of toxicity 7.5mg once weekly,  Oral ulceration WBC, platelets and chest x-ray  Clozapine increases risk of increase to a  Hepatic dysfunction Routine: agranulocytosis concomitant use should maintenance dose of  Bone marrow suppression* Every 2 weeks for the first 6 weeks and then be avoided 10 to 25mg once per  Alopecia monthly thereafter:  NSAID’s reduce excretion week.  Headaches  FBC, WBC, U&E’s, LFT’s  Probenecid reduces excretion  Folic acid 5mg given 2  Rarely Pneumonitis Dose changes:  Pyrimethamine increases antifolate days after each dose FBC, LFT’s and U&E’s fortnightly for 6 weeks  Rarely Pulmonary Fibrosis effect may reduce the after any dose increase  Sulfamethoxazole (as Co-trimoxazole) incidence of toxicity increases risk of haematological toxicity  Folic acid can be Ask about respiratory symptoms at monitoring  Trimethoprim increases risk of increased up to 5mg haematological toxicity every day except on Routine: Methotrexate day to  FBC, & LFT’s monthly help control side  U&E every 6 months effects Ask about respiratory symptoms at monitoring #Doncaster PCT Local Enhanced Service The vast majority of patients take Methotrexate  Side effects on a once weekly dosage.  Symptom control For the minority that need to take a twice weekly dose, there is no evidence that suggests that this is more hazardous than a once weekly dose

* Bone Marrow Suppression may present with bruising, bleeding, fever, sore throat or any other signs of sepsis

4.0 SHARED CARE ARRANGEMENTS

Once a stable medication regime has been established (usually 3 months), physical monitoring and prescribing of amber category drugs can be transferred to primary care with agreement.

4.1 Aspects of care for which Secondary Care Team is responsible

 Diagnosis and assessment  Initiation and stabilisation of drug therapy, usually but not exceptionally, a period of 3 months.  Patient/ family education  Ensure patient is fully informed of potential benefits and side effects of treatment  Ensure patient’s guardian/carer is fully informed of the treatment.  Provide a comprehensive treatment package in addition to medications including appropriate information/monitoring sheet(s)  Ensure that shared care arrangements are in place before transfer of treatment . That the patient/carer is clear what is being monitored and by whom . That the patient knows what significant adverse effects/events to report urgently and to whom they should report (specialist or GP)  Any dose changes once the patient is established on treatment will be conveyed in writing to the GP for the GP to prescribe.  Extra monitoring needed for dose changes will be organised by Rheumatology team and conveyed to patient  Monitor side effects of medication via routine out-patient visits or nurse telephone help line.  Report adverse events to the CSM  Monitor patient’s response to treatment  If patients are being monitored using RheMOS system, patients will be sent blood forms and have the results analysed using the already established system (see section 2.1)  If blood abnormalities occur secondary to DMARD picked up using RheMOS, action appropriate to the abnormality will be organised via the Rheumatology team.  If patients DNA their blood test monitoring as picked up on RheMOS, the Rheumatology units protocol will followed (see appendix)

4.2 Aspects of care for which Primary Care Team is responsible

 Ensure that shared care arrangements are in place before transfer of treatment . That the patient/carer is clear what is being monitored and by whom . That the patient knows what significant adverse effects/events to report urgently and to whom they should report (specialist or GP)

 When the specialist initiates treatment, reply to the request for shared care as soon as practicable  Confirm that proposed therapy is not contra-indicated because of concurrent therapy for other conditions the patient may be suffering from e.g. check drug-contraindications and drug-interactions. Contact specialist team if possible interactions found and discuss with rheumatologist  Confirm the specialists have provided the patient/carer with appropriate information sheet(s) for monitoring and/or to alert other clinical staff to the treatment they are receiving. If appropriate information has not been provided by the specialist, the GP must ensure the information is provided  Ensure patient’s guardian/carer is fully informed of the treatment  Monitor treatment as stated in the shared care protocol  Amend prescription as per requests from secondary care for dose changes in patients on established treatment  Confirm with specialist which changes in these or other parameters should trigger urgent referral back to the specialist  Seek specialist advice promptly as advised in the shared care protocol or if signs/symptoms of changes occur consistent with DMARD adverse event  Report adverse events to the CSM  If the drug has a black triangle status or is unlicensed, all events should be reported even if casual relationship is not known or if the adverse event is already known about  Report adverse events to the consultant sharing the care of the patient  Stop treatment on advice of specialist, or immediately if intolerable side effects occur provided that it is safer to do so than to continue this therapy

4.3 Patient (or Carer’s) Responsibilities

 Discuss potential benefits and side effects of treatment with the specialist and GP. Identify whether they have a clear picture of these from the specialist and to raise any outstanding queries  Check that where possible the specialists have provided a patient-held record or information sheet for monitoring and/or to alert other clinical staff to the treatment they are receiving  Share any concerns they have in relation to treatment with the medicine  Report any adverse effects to their specialist or GP whilst taking the medicine  Report to the specialist or GP if they do not have a clear understanding of their treatment  Participate in the monitoring of therapy and the assessment of outcomes, to assist health professionals to provide safe, appropriate treatment

5.0 PROCEDURE FOR ADOPTING SHARED CARE

5.1 General Procedure:

The specialist will send to the GP a diagnostic assessment report, a copy of the shared care protocol and a shared care referral specifying who is responsible for monitoring. Both the specialist and GP should sign the proforma with a record kept in the GP and specialist records. Full details will be given of the prescribing regime (brand, form, strength and dose of medication) and follow-up plan.

The patient will be asked to make arrangements with their GP for continued supply.

6.0 REFERENCES

 British National Formulary 56, September 2008  Arava Summary Product Characteristics  Auranofin Summary Product Characteristics  Distamine Summary Product Characteristics  Imuran Summary Product Characteristics  Maxtrex Summary Product Characteristics  Myocrisin Summary Product Characteristics.  Neoral Summary Product Characteristics  Plaquenil Summary Product Characteristics  Salazopyrin EN Summary Product Characteristics  NICE Technology Appraisal Guidance 141: Abatacept for the treatment of rheumatoid arthritis April 2008  NICE Clinical Guidance 79: The management of rheumatoid arthritis in adults February 2009  BSR/BHPR guideline for disease-modifying anti-rheumatic drug (DMARD) therapy in consultation with the British Dermatologists, K Chakravarty et al. Rheumatology 2008  NPSA Patient safety alert 13; Improving compliance with oral methotrexate guidelines June 2006

7.0 SHARED CARE DEVELOPMENT

Written April 2009 By: Clare Wilkinson, Consultant Rheumatologist Doncaster Royal Infirmary Robert Stevens, Consultant Rheumatologist Doncaster Royal Infirmary Roger Hancocks, Deputy Director of Pharmacy Doncaster Royal Infirmary Joanna Hallatt, Head of Medicines Assurance Doncaster Primary Care Trust Annabelle Coote, Consultant Rheumatologist Doncaster Royal Infirmary Lesley Geddes, Rheumatology Nurse Prescriber Doncaster Royal Infirmary

Reviewed October 2009 By:

Doncaster & Bassetlaw Area prescribing Committee

Appendix 1 - Pregnancy Auranofin  Contraindicated  Omit 3 - 6 months prior to first attempting to conceive Azathioprine  Can be used during pregnancy  Physicians should weigh up risk of treatment versus risk  Certain clinical scenarios such as SLE, evidence suggests reducing/withdrawing treatment can lead to significant flare of disease Ciclosporin  Can be used in pregnancy with caution  Will need close monitoring by physician  If hypertension develops will need assessment to see if drug or pregnancy related D-Penicillamine  Contraindicated  Omit 3 - 6 months prior to first attempting to conceive Hydroxychloroquine  Can be used during pregnancy Leflunomide  Known to be teratogenic  Should be avoided in women of child bearing age unless reliable contraception is used  If children are planned, women should discontinue for 2 years prior to conception or have active metabolite removed rapidly by washout procedures such as cholestyramine  Men should not try for conception till 3 months after cessation of drug Methotrexate  Contraindicated in pregnancy  Known to be teratogenic and abortifacient  Both men and women advised to omit 3-6 months prior to trying to conceive Mycophenolate Mofetil  Contraindicated in pregnancy  Need at least 6 weeks of discontinuation before trying to conceive Sodium Aurothiomalate (injectable gold)  Contraindicated in pregnancy  Omit 3 – 6 months prior to trying to conceive Sulfasalazine  Caution if used during pregnancy  Risk to unborn child vs benefit to mother needs to be assessed by physicians involved  Dose should not exceed 2g/day during pregnancy  Daily supplement of folic acid should be given to those trying to conceive and whilst pregnant when on sulfasalazine  In men of child bearing potential may cause reversible oligospermia

With each patient, it is vital that discussion about the usage of reliable contraception to be used whilst contraindicated drugs are omitted prior to trying to conceive is had.

15 This Document will be reviewed in the light of new or emerging evidence or by October 2014