Dimethyl Fumarate (Tecfidera) pathway for Walton Centre MS patients Author and Contact details: Responsible Director: Ian Pomeroy Service lead for MS. Tel: (0151) 529 5715 Email: ian.pomeroy@thewaltoncentre.nhs.uk Dr Enevoldson Approved by and date: Drug and Therapeutics Committee October 2014 Document Type: CLINICAL GUIDELINE Version 1.0 Scope: Document Approval, History/Changes All trust employees. For further information contact the Governance Department on Tel: (0151) 529 5436 Think of the environment Do you have to print this out this document? You can always view the most up to date version electronically on the Trust intranet. Page 1 of 10
Table of Contents 1. Pathway... 3 1.1. Initial appointment with Neurologist... 3 1.2. MS Nurse Clinic... 4 1.3. MS nurse follow up Appointment at 3 and 6 months... 5 1.4. Annual Neurologist Review... 5 2. Appendix... 6 2.1. Indications and Guidelines... 6 2.1.1 Licensed Indication... 6 2.1.2 NICE Guidelines... 6 2.1.3 Specialist Commissioning Guidelines... 6 2.2. Licensed Dose... 6 2.3. Mechanism of Action... 6 2.4. Effectiveness... 6 2.5. Contra Indications... 7 2.6. Cautions... 7 2.7. Side Effects... 7 2.7.1 Flushing... 7 2.7.2 Gastrointestinal Symptoms... 8 2.7.3 Infection... 8 2.7.4 Abnormal LFTs... 8 2.7.5 Renal Impairment... 8 2.7.6 Haematological Effects... 9 2.8. Interactions... 9 2.9. Vaccination... 9 2.10. Reproduction Issues... 9 2.10.1 Contraception... 9 2.10.2 Pregnancy... 9 2.10.3 Breast-feeding... 9 2.11. Switching Treatments... 9 2.12. Monitoring... 10 2.12.1 Pre treatment... 10 2.12.2 During treatment... 10 Page 2 of 10
1. Pathway 1.1. Initial appointment with Neurologist Neurologist will: Consider treatment options with the patient. If dimethyl fumarate is considered the neurologist should confirm eligibility according to current licensed indication, NICE guidelines and specialist commissioning guidelines. Review for presence of contraindications, consider interactions, and cautions. Information to Patient Discuss evidence base and potential benefits. Discuss potential side effects. Discuss Monitoring. For women of childbearing potential, discuss issues surrounding contraception, pregnancy and breast feeding, Agree stopping criteria. Following consideration, assessment and discussion as above, if patient and neurologist consider dimethyl fumarate treatment is appropriate the patient should be referred to the MS nurse with a letter confirming eligibility for treatment. Page 3 of 10
1.2. MS Nurse Clinic MS Nurse Will: Discuss with patient aims of treatment and side effects and check patient s understanding of these issues. Discuss side effect profile flushing, GI events (diarrhoea, nausea, abdominal pain), infections and abnormal haematological, renal and liver tests. Discuss common symptoms of infection which should be reported to a physician. Discuss issues surrounding flushing take with food, temporary aspirin treatment and temporary dose reduction where required. Make the patient aware of any signs that mean the should stop taking Tecfidera and call a doctor - patients receiving Dimethyl fumarate should be instructed to report symptoms of infections to their GP. Discuss need to consider suspending treatment with serious infections. Full discussion with women of child bearing age with regard to need for effective contraception. Counsel regarding risks of oral contraception failure if significant diarrhoea should occur. Discuss risks of teratogenicity and potential risk of breast feeding. Discuss if pregnancy suspected MS Consultant/MS Nurse should be informed and tecfidera should be suspended. Discuss need to avoid live vaccines. Discuss need for adherence daily to therapy. Discuss need for adherence to monitoring protocol. Arrange monitoring with pre-treatment FBC, U&E, LFT. Discuss stopping criteria. Discuss pack sizes with the patient (Tecfidera starter pack 120mg bd for 7 days, Tecfidera Standard Pack 240mg bd thereafter) Discuss delivery options (home delivery, Boots pharmacy collection, hospital pharmacy collection) Inform the patient they will receive a Tecfidera patient support pack from Alcura Ltd. Send registration form and prescription to Alcura (Signed copy to be faxed to: Alcura Ltd, Selborne House, Mill Lane, Alton, Hampshire,GU34 2QJ. Tel: 01420 543400 Freephone: 0800 9800 686 Fax: 01420 544588. Original signed copy to be posted using pre-paid envelopes) Answer any questions from patient/family. Ensure contact details for MS Nurses given. Ensure 3 and 6 monthly MS Nurse appointment is made and patient has annual neurologist appointment. Letter to be sent to GP and Consultant to inform of response. Page 4 of 10
1.3. MS nurse follow up Appointment at 3 and 6 months MS nurse will Record any side effects of drug. Document any relapses. Inform GP and neurologist in writing of progress. Arrange monitoring tests with U&E, LFT, and FBC at 3 and 6 months. 1.4. Annual Neurologist Review Neurologist will: Document the patient s EDSS and any locally agreed objective measures. Review the number of relapses in the last 12 months. Document side effects and the patient s tolerance of dimethyl fumarate in the last 12 months. Record any changes of treatment. Ensure the patient has a 6 month follow up with MS Nurse and for 12 months with consultant. Arrange U&E, LFT and FBC at 12 months and decide on 6 monthly or 12 monthly ongoing monitoring as clinically indicated Page 5 of 10
2. Appendix Data predominately derived from Summary of product Characteristics: 2.1. Indications and Guidelines 2.1.1 Licensed Indication Tecfidera is indicated for the treatment of adult patients with relapsing remitting multiple sclerosis. 2.1.2 NICE Guidelines (TA320 http://guidance.nice.org.uk/ta320) Dimethyl fumarate is recommended as an option for treating adults with active relapsing-remitting multiple sclerosis (normally defined as 2 clinically significant relapses in the previous 2 years), only if: They do not have highly active or rapidly evolving severe relapsing-remitting multiple sclerosis, as defined by NICE and The manufacturer provides dimethyl fumarate with the discount agreed in the patient access scheme. 2.1.3 Specialist Commissioning Guidelines (SSC1451) All MS patients who meet the NICE criteria for dimethyl fumarate will receive funding from November 27 2014. Patients who start on dimethyl fumarate and progress and/or unable to continue will be eligible for other MS disease modifying treatments if they meet the criteria within either a published NICE Guidance and/or the NHS England Clinical Commissioning Policy: Disease Modifying Therapies for Patients with Multiple Sclerosis (MS) which can be found at: http://www.england.nhs.uk/ourwork/commissioning/spec-services/policies/ This will include fingolimod as a second line therapy. 2.2. Licensed Dose The starting dose is 120 mg twice a day for 7 days After 7 days, the dose is increased to the recommended dose of 240 mg twice a day. 2.3. Mechanism of Action The mechanism by which dimethyl fumarate exerts therapeutic effects in multiple sclerosis is not fully understood. Preclinical studies indicate that pharmacodynamic responses appear to be primarily mediated through activation of the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) transcriptional pathway. Dimethyl fumarate has been shown to up regulate Nrf2-dependent antioxidant genes in patients (e.g. NAD(P)H dehydrogenase, quinone 1; [NQO1]). 2.4. Effectiveness (Data from DEFINE and CONFIRM studies, - note CONFIRM included single blinded glatiramer acetate comparator group, both studies had placebo controlled groups and treatment groups Page 6 of 10
with dimethyl fumarate 240bd or 240tds, figures quoted below are 240mg bd group vs. placebo from both studies). Eligibility Criteria - EDSS 0-5, 1 relapse in 1year or MRI with 1 enhancing lesion 6 weeks prior to randomization. Baseline characteristics mean age 37-39y, annualized relapse rate 1.3-1.4 mean disease duration 6.0-7.0y, mean EDSS 2.0-2.5. Clinical Outcomes Relative reduction of 44-53% in annual relapse rate vs placebo Absolute reduction of 0.18-0.19 relapses/year Relative reduction of 3 month sustained progression over 2 years of 17-38% (lower figure not significant) Absolute reduction of 3 month sustained progression over 2 years of 4-11% 2.5. Contra Indications Hypersensitivity 2.6. Cautions Patients with low lymphocyte counts Severe active gastrointestinal disease Severe renal impairment Severe hepatic impairment 2.7. Side Effects 2.7.1 Flushing Experienced in 34% of trial patients vs. 4% of placebos. Can include hot flush, warmth, redness, itching and burning sensation. Flushing events tend to begin early in the course of treatment (primarily during the first month) and in patients who experience flushing, these events may continue to occur intermittently throughout treatment with dimethyl fumarate. In the majority of patients flushing was mild or moderate in severity, 3% of patients discontinued treatment due to flushing. 3/2560 trial patients experienced serious flushing thought to be hypersensitivity or anaphylactic reactions. Temporary dose reduction to 120 mg twice a day may reduce the occurrence of flushing and gastrointestinal adverse reactions. Within 1 month, the recommended dose of 240 mg twice a day should be resumed. Dimethyl Fumarate should be taken with food which may improve tolerability. Administration of 325 mg (or equivalent) non-enteric coated acetylsalicylic acid, 30 minutes prior to Dimethyl fumarate, over 4 days of dosing, did not alter the pharmacokinetic profile of Dimethyl fumarate and reduced the occurrence and severity of flushing in a healthy volunteer study. However, long term use of acetylsalicylic acid is not recommended for the management of flushing. Potential risks associated with acetylsalicylic acid therapy should be considered prior to co-administration with Dimethyl fumarate. Page 7 of 10
2.7.2 Gastrointestinal Symptoms The incidence of a variety of gastrointestinal events was higher in treated patients vs. placebo in the trials (diarrhoea 14% vs. 10%, nausea 12% vs.9%, upper abdominal pain 10% vs.6%, abdominal pain 9% vs.4%, vomiting 8% vs.5% and dyspepsia 5% vs.3%). Gastrointestinal events tend to begin early in the course of treatment (primarily during the first month) and in patients who experience gastrointestinal events, these events may continue to occur intermittently throughout treatment. In the majority of patients who experienced gastrointestinal events, symptoms were mild or moderate in severity. 4% of patients discontinued due to gastrointestinal events. The incidence of serious gastrointestinal events, including gastroenteritis and gastritis, was seen in 1% of patients treated with dimethyl fumarate. 2.7.3 Infection The incidence of infections (60% vs 58%) and serious infections (2% vs 2%) was similar in patients treated with dimethyl fumarate or placebo, respectively in phase 3 trials. There was no increased incidence of serious infections observed in patients with lymphocyte counts <0.8x109/L or <0.5x109/L. If a patient develops a serious infection, suspending treatment with dimethyl fumarate should be considered and the benefits and risks should be reassessed prior to re-initiation of therapy. Patients receiving dimethyl fumarate should be instructed to report symptoms of infections to a physician. Patients with serious infections should not start treatment with dimethyl fumarate until the infection(s) is resolved. 2.7.4 Abnormal LFTs The majority of patients with elevations had hepatic transaminases that were <3 times the upper limit of normal (ULN). The increased incidence in patients treated with Dimethyl fumarate relative to placebo was primarily seen during the first 6 months of treatment. Elevations of alanine aminotransferase and aspartate aminotransferase 3 times ULN, respectively, were seen in 5% and 2% of patients treated with placebo and 6% and 2% of patients treated with Dimethyl fumarate. There were no elevations in transaminases 3 times ULN with concomitant elevations in total bilirubin >2 times ULN. Discontinuations due to elevated hepatic transaminases were <1% and similar in patients treated with Dimethyl fumarate or placebo. 2.7.5 Renal Impairment In placebo-controlled studies, the incidence of proteinuria was higher in patients treated with dimethyl fumarate (9%) compared to placebo (7%). The overall incidence of renal and urinary adverse events was similar for dimethyl fumarate and placebo-treated patients. There were no reports of serious renal failure. On urinalysis, the percentage of patients with protein values of 1+ or greater was similar for Dimethyl fumarate (43%) and placebo-treated patients (40%). Typically, laboratory observations of proteinuria were not progressive. Compared to patients treated with placebo, estimated glomerular filtration rate was observed to increase in patients treated with Dimethyl fumarate, including those patients with 2 consecutive occurrences of proteinuria ( 1+). Page 8 of 10
2.7.6 Haematological Effects In the placebo-controlled studies, most patients (>98%) had normal lymphocyte values prior to initiating treatment. Upon treatment with Dimethyl fumarate, mean lymphocyte counts decreased over the first year by approximately 30% of baseline value with a subsequent plateau. Mean and median lymphocyte counts remained within normal limits. Lymphocyte counts <0.5x109/l were observed in <1% of patients treated with placebo and 6% of patients treated with Dimethyl fumarate. A lymphocyte count <0.2x109/l was observed in 1 patient treated with Dimethyl fumarate and in no patients treated with placebo. A transient increase in mean eosinophil counts was seen during the first 2 months of therapy. 2.8. Interactions During treatment with dimethyl fumarate, simultaneous use of other fumaric acid derivatives (topical or systemic) should be avoided. As of August 2014 there are no licensed fumaric acid derivatives available in the UK (a small number of dermatology patients may be taking Fumaderm for severe psoriasis). Concurrent therapy with nephrotoxic medicinal products (such as aminoglycosides, diuretics, NSAIDs or lithium) may increase the potential of renal adverse reactions (e.g. proteinuria) in patients taking dimethyl fumarate (see section 4.8). 2.9. Vaccination Live vaccines might carry an increased risk of clinical infection and should not be given to patients treated with Dimethyl fumarate unless, in exceptional cases, this potential risk is considered to be outweighed by the risk to the individual of not vaccinating. 2.10. Reproduction Issues 2.10.1 Contraception In vitro CYP induction studies did not demonstrate an interaction between dimethyl fumarate and oral contraceptives. In vivo interaction studies have not been performed with oral contraceptives. Even though an interaction is not expected, non-hormonal contraceptive measures should be considered with dimethyl fumarate. 2.10.2 Pregnancy There are no or limited amount of data from the use of dimethyl fumarate in pregnant women. Animal studies have shown reproductive toxicity. Dimethyl fumarate is not recommended during pregnancy and in women of childbearing potential not using appropriate contraception. Dimethyl fumarate should be used during pregnancy only if clearly needed and if the potential benefit justifies the potential risk to the foetus. 2.10.3 Breast-feeding It is unknown whether dimethyl fumarate or its metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue dimethyl fumarate therapy. The benefit of breast-feeding for the child and the benefit of therapy for the woman should be taken into account. 2.11. Switching Treatments As of August 2014 Biogen state there is no known reason why patients cannot be directly switched from Tecfidera onto other DMFs without a washout period. Page 9 of 10
2.12. Monitoring 2.12.1 Pre treatment FBC, U&E, LFT 2.12.2 During treatment U&E, LFT after 3 months U&E, LFT, FBC after 6 months U&E, LFT and FBC repeated 6 to 12 months thereafter as clinically indicated. Page 10 of 10