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Gwent Shared Care Protocol MYCOPHENOLATE MOFETIL (MMF) 500mg Tablets for the treatment of connective tissue disease (UNLICENSED USE) Protocol No. 30 General guidance PLEASE CHECK http://www.wales.nhs.uk/sites3/page.cfm?orgid=814&pid=38180 FOR THE LATEST VERSION OF THIS PROTOCOL ABUHB’s Medicines and Therapeutics Committee has agreed this protocol. It outlines the shared care arrangements for patients initiated on mycophenolate for the treatment of connective tissue disease and should be read in conjunction with the: 1. Shared Care Agreement Form (see Page 6). 2. Summary of Product Characteristics for mycophenolate mofetil – available at: http://www.medicines.org.uk/emc/medicine/1680 This Shared Care Protocol does NOT cover use of 1. Mycophenolate capsules, 250mg tablets or oral suspension. 2. Mycophenolate for post transplant immunosuppression. 3. Mycophenolic acid (Myfortic®). 1. Therapeutic use & Background information Mycophenolate mofetil is a pro-drug of mycophenolic acid. It is a suppressor of T and B cell proliferation and adhesion and inhibits inosine monophosphate dehydrogenase and eventually blocks the progression to DNA synthesis and proliferation. It is used ‘off-label’ as a disease modifying drug in connective tissue disease responding to immunosuppressive therapy when other standard treatments (e.g. azathioprine) have failed or are not tolerated. Such conditions include; rheumatoid arthritis, systemic lupus erythematosus and lupus nephritis and inflammatory myopathy such as dermatomyositis and polymyositis. It is also used in scleroderma, vasculitis and Behçet’s disease. 2. Contra-indications / Cautions Contra-indications: 1. Pregnancy – mycophenolate should not be given to women of childbearing potential who are not using highly effective contraception. Mycophenolate should not be initiated in women of child bearing potential without providing a pregnancy test result to rule out unintended use in pregnancy and it should not be used in pregnancy unless there is no suitable alternative treatment.. 2. Breastfeeding. 3. Live vaccines (e.g. Zostavax®) should be avoided in patients with an impaired immune response. 4. Known hypersensivity to mycophenolate mofetil (CellCept®) or mycophenolic acid (Myfortic®). Cautions: Patients with suspected lymphoproliferative disorder or unexplained anaemia, leucopenia and thrombocytopenia. To reduce the risk of skin malignancies patients should be told to avoid exposure to strong sunlight and to use a high-factor sunscreen. Patients with active gastro-intestinal disease (due to risk of haemorrhage, ulceration and perforation). Localized or systemic infection (e.g. hepatitis B or C). Very frail and elderly. 3. Typical dosage regimen (adults) Starting dose: 500mg daily for first week, 500mg twice daily for second week and increase gradually by 500mg each week until the optimal or maximally tolerated dose is reached. Maximum dose: 3g daily (as 1.5mg twice daily). Mycophenolate is now available in generic form. To be prescribed as mycophenolate mofetil 500mg tablets and not as a brand e.g. CellCept®. 4. Drug interactions Check BNF Appendix 1 Aciclovir (not topical mycophenolate increases plasma concentration of aciclovir, also plasma This Shared Care Protocol should be read in conjunction with the Summary of Product Characteristics Status: APPROVED Issue Date: May 2015 (Update Feb.2016) Approved by: ABUHB MTC Page 1 of 6 Review Date: May 2017 before co-prescribing any other drug. aciclovir) Antacids Colestyramine Ganciclovir Iron (oral) Metronidazole (not topical metronidazole) Norfloxacin Rifampicin Sevelamer 5. Adverse drug reactions All healthcare professionals have a responsibility to patients in advising/acting on suspected adverse drug reactions concentration of inactive metabolite of mycophenolate increased Only significant in renal impairment absorption of mycophenolate reduced – antacids should not be taken at the same time of day. absorption of mycophenolate reduced – take at least 1 hour before or 4–6 hours after colestyramine mycophenolate possibly increases plasma concentration of ganciclovir, also plasma concentration of inactive metabolite of mycophenolate possibly increased absorption of mycophenolate reduced bioavailability of mycophenolate possibly reduced bioavailability of mycophenolate possibly reduced plasma concentration of active metabolite of mycophenolate reduced plasma concentration of mycophenolate possibly reduced Clinical condition (reported frequency) Diarrhoea, nausea, vomiting, abdominal cramps and dyspepsia. (Very Common >10%) Abnormal bruising with or without sore throat - may indicate bone marrow failure. (Severe neutropenia occurs in 0.5% patients receiving mycophenolate in the full dose). Recurrent infections associated with hypogammaglobulinaemia (frequency not known) Development of persistent respiratory symptoms, such as cough and dyspnoea (frequency not known) Skin malignancies. (Common ≥1/100 to <1/10) Hepatitis, jaundice, hyperbilirubinaemia and raised LFTs (Common ≥1/100 to <1/10) Note LFTs are not a monitoring requirement for mycophenolate and the frequency of these reactions was from patients treated with mycophenolate in renal, cardiac and hepatic clinical trials when used in combination with ciclosporin and corticosteroids. Action Discuss with specialist if severe or persistant STOP the drug. Check FBC immediately and also discuss with specialist team. Discuss with specialist – serum immunoglobulin levels should be measured. Discuss with specialist patients should be told to avoid exposure to strong sunlight and to use a high-factor sunscreen Discuss with specialist if there is a particular concern Discuss with specialist Patients should be particularly warned to report any signs or symptoms of bone marrow suppression e.g. infection or unexplained bruising or bleeding. All serious adverse events should be reported to MHRA. 6. Baseline investigations To be undertaken by specialist centre: 7. Monitoring Ongoing Monitoring by GP: FBC, LFTs, U&Es and chest x-ray (within last 6 months) Pregnancy test if appropriate – see contraindications in Section 2 of this protocol. Monitoring FBC weekly until dose stable for 4 weeks then fortnightly for 2 months Result WBC < 3.5 x 109/L Neutrophils < 1.7x109/L Action Stop drug and discuss with specialist This Shared Care Protocol should be read in conjunction with the Summary of Product Characteristics Status: APPROVED Issue Date: May 2015 (Update Feb.2016) Approved by: ABUHB MTC Page 2 of 6 Review Date: May 2017 then monthly thereafter Platelets < 150x109/L Abnormal bruising with or without sore throat Check FBC immediately and withhold drug until results are available. Discuss with specialist Please note that in addition to absolute values for haematological indices, a rapid fall or consistent downward trend in any values should prompt caution and extra vigilance. 8. Specialist centre contact information If stopping the medication or needing advice please contact: 01873 732046 (Rheumatology Helpline) In an emergency a Rheumatology Clinical Nurse can be bleeped via the Nevill Hall Hospital Switchboard on the number 432. Further information on use and monitoring of DMARDs Rheumatology - Frequently Asked Questions for Health Professionals http://howis.wales.nhs.uk/sitesplus/866/page/57539 Vaccination advice for patients with Autoimmune Inflammatory Rheumatic Disease is available for ABUHB Rheumatology at: http://howis.wales.nhs.uk/sitesplus/866/page/57540 9. Criteria for shared care All Wales criteria for Shared Care can be found at: http://www.awmsg.org/docs/awmsg/medman/Criteria%20for%20Shared%20Care.pdf GMC guidance on Shared Care (2013) states: Decisions about who should take responsibility for continuing care or treatment after initial diagnosis or assessment should be based on the patient’s best interests, rather than on convenience or the cost of the medicine and associated monitoring or follow-up. Shared care requires the agreement of all parties, including the patient. Effective communication and continuing liaison between all parties to a shared care agreement are essential. 10. Responsibilities of initiating consultant i. ii. iii. iv. v. To consider initiating mycophenolate 500mg tablets, where azathioprine is contraindicated or not tolerated. To undertake the baseline clinical investigations (see Section 6). To provide a patient information leaflet indicating the risks and benefits associated with mycophenolate, and to discuss these with the patient or carer. The importance of regular monthly blood monitoring should be made clear to the patient/carer. The advice to the patient/carer should cover: a. The potential side effects and the action to be taken should they occur (particularly in relation to reporting any infection, unexplained bruising/bleeding or persistent cough or breathlessness). b. The possible effect of mycophenolate on live vaccines – this is available at: http://howis.wales.nhs.uk/sitesplus/866/page/57540 (Note NHS net connection required). c. The need for women (and female partners of male patients treated with mycophenolate) to use highly effective contraception during treatment and for 90 days after the last dose. Men (including those who have had a vasectomy) should use condoms during treatment and for 90 days after stopping treatment. Record in GP referral letter that contraceptive advice has been given. d. That mycophenolate is being prescribed outside the manufacturer’s product licence (off-label). To confirm patient/carer understanding and consent to treatment. Informed consent for This Shared Care Protocol should be read in conjunction with the Summary of Product Characteristics Status: APPROVED Issue Date: May 2015 (Update Feb.2016) Approved by: ABUHB MTC Page 3 of 6 Review Date: May 2017 ‘off-label’ use should be obtained and documented. See the GMC's Good practice in prescribing and managing medicines and devices1 for further information. This consent should be communicated to the GP on the Shared Care Agreement Form (see Page 5). vi. To write the first prescription for 6 weeks of mycophenolate 500mg tablets and to inform the patient/carer of the dose titration regime and target maintenance dose (usually 1g twice daily) – this information should be communicated to the GP on the Shared Care Agreement Form (see Page 6). vii. To fax the Shared Care Agreement Form (see Page 6) to the GP once the 4th blood test has been reviewed. viii. To provide the patient with FOUR blood sample request forms for the initial monitoring at 1, 2, 3 and 4 weeks post initiation (see detail in Section 7 above). These should allow the patient the option to return to hospital or to attend their GP surgery for the blood samples to be taken. The blood forms should specify that the results should go back to Secondary Care, with copies to the GP surgery. FOLLOWING ANY SUBSEQUENT DECISION TO FURTHER INCREASE THE DOSE (FROM THE INITIAL TARGET DOSE) TO PROVIDE: a. ONE BLOOD SAMPLE REQUEST FORM FOR A WEEK TWO TEST FOLLOWING THE DOSE INCREASE. b. A FUTHER 4 WEEK PRESCRIPTION FOR MYCOPHENOLATE. ix. To keep GP fully informed of any dose adjustments and non attendance following subsequent specialist appointments. 11. Responsibilities of Primary Care i. To prescribe mycophenolate 500mg tablets (generically) from week 6 and monitor the patient in accordance with the schedule above (see Section 7). ii. To inform specialist of any non attendance for ongoing blood tests. Patients should be informed of the consequences to their safety (and that their mycophenolate may be stopped) if they fail to attend for blood tests. iii. To administer annual flu vaccination. Vaccination advice for patients with Autoimmune Inflammatory Rheumatic Disease is available for ABUHB Rheumatology at: http://howis.wales.nhs.uk/sitesplus/866/page/57540 iv. Whenever practicable, to reaffirm with the patient the importance of reporting any infection unexplained bruising/bleeding or persistent cough or breathlessness). 12. Responsibilities of patients/carer To attend hospital and GP practice blood test/monitoring appointments. Significant failure to attend (which affects patient safety) will result in medication being stopped. To report adverse effects to their specialist or GP (particularly any infection, unexplained bruising/bleeding or persistent cough or breathlessness). 13. Responsibilities of all prescribers Any suspected serious adverse reaction to an established drug should be reported to MHRA via the “yellow card scheme.” http://yellowcard.mhra.gov.uk/ 14. Responsibilities of pharmacists Whenever practicable, to reaffirm with the patient the importance of reporting any infection, unexplained bruising/bleeding or persistent cough or breathlessness). 15. Supporting documentation / information Patient information leaflet at: http://beta.medicines.org.uk/emc/PIL.4075.19.pdf/Cellcept%20500mg%20Tablets.pdf or at: http://xpil.medicines.org.uk/viewpil.aspx?docid=4075 2008 BSR/BHPR guideline for disease-modifying anti-rheumatic drug (DMARD) therapy http://www.rheumatology.org.uk/includes/documents/cm_docs/2009/d/diseasemodifying _antirheumatic_drug_dmard_therapy.pdf 2015 Mycophenolate mofetil (CellCept) and mycophenolic acid: risk of hypogammaglobulinaemia and risk of bronchiectasis: 1 http://www.gmc-uk.org/guidance/ethical_guidance/14316.asp This Shared Care Protocol should be read in conjunction with the Summary of Product Characteristics Status: APPROVED Issue Date: May 2015 (Update Feb.2016) Approved by: ABUHB MTC Page 4 of 6 Review Date: May 2017 https://www.gov.uk/drug-safety-update/mycophenolate-mofetil-cellcept-andmycophenolic-acid-risk-of-hypogammaglobulinaemia-and-risk-of-bronchiectasis 2015 Mycophenolate mofetil, mycophenolic acid: new pregnancy-prevention advice for women and men: https://www.gov.uk/drug-safety-update/mycophenolate-mofetil-mycophenolic-acid-newpregnancy-prevention-advice-for-women-and-men This Shared Care Protocol should be read in conjunction with the Summary of Product Characteristics Status: APPROVED Issue Date: May 2015 (Update Feb.2016) Approved by: ABUHB MTC Page 5 of 6 Review Date: May 2017 Shared Care Agreement Form – Accredited CONSULTANT REQUEST To: Dr. Your patient: NHS No. (10digit): was seen on: with a diagnosis of: I recommend that the following drug is continued: This drug has been accepted as suitable for shared care by the ABUHB’s MTC. I agree to the responsibilities set out in the protocol SCP No. 30 (copy attached and also at: http://www.wales.nhs.uk/sites3/page.cfm?orgid=814&pid=38180) Your practice is accredited to provide near patient testing for DMARDs as a National Enhanced Service. I am therefore requesting your agreement to share the care of this patient. The preliminary tests set out in the protocol have been carried out. I am currently prescribing the stabilising treatment. Treatment START DATE (agreed with GP practice): The initial dose regime will be: Patient consented to ‘off-label’ use confirmed: Yes The baseline tests are: If you undertake treatment I will reassess the patient in ____ weeks. You will be sent a written summary within 14 days. I will accept referral for reassessment at your request. The medical staff of the department are available at all times to give you advice. Consultant Name: Signature: Department: Hospital: Date: Contact Telephone Nos: NOTE FOR GENERAL PRACTITIONER AS THE PRACTICE IS ACCREDITED TO UNDERTAKE NEAR PATIENT TESTING, IT WILL BE ASSUMED THAT THE PRACTICE WILL WISH TO ACCEPT REFERRALS FOR SHARED CARE. IF FOR ANY REASON THIS IS NOT THE CASE, PLEASE CONTACT THE CONSULTANT URGENTLY SO THAT ARRANGEMENTS CAN BE MADE TO UNDERTAKE THE NECESSARY MONITORING FOLLOWING INITIATION OF THE DRUG. This Shared Care Protocol should be read in conjunction with the Summary of Product Characteristics Status: APPROVED Issue Date: May 2015 (Update Feb.2016) Approved by: ABUHB MTC Page 6 of 6 Review Date: May 2017