A guide to the accelerated elimination procedure

Transcription

1 A guide to the accelerated elimination procedure Prescribing information and information on adverse event reporting can be found on the last page.

2 What is the accelerated elimination procedure? An accelerated elimination procedure is available for AUBAGIO, indicated for the treatment of adult patients with relapsing-remitting multiple sclerosis (RRMS), to allow more rapid elimination of the drug when treatment is discontinued. Teriflunomide is eliminated slowly from the plasma; drug elimination processes can be used in certain situations to reduce plasma concentrations of some drugs. The elimination of AUBAGIO from the circulation can be accelerated by administration of cholestyramine or activated charcoal. The availability of this procedure provides added flexibility during treatment with AUBAGIO. When might the accelerated elimination procedure be used? An accelerated elimination procedure can be used at any time after discontinuation of AUBAGIO. 1 It is recommended that the accelerated elimination procedure should be used after discontinuation of AUBAGIO in the following situations: When a woman taking AUBAGIO wants to become pregnant In the event of clinically significant overdose or toxicity If severe generalised major skin reactions are suspected (Steven-Johnson Syndrome, or toxic epidermal necrolysis - Lyell s Syndrome) The procedure can also be considered in the following situations: When pregnancy occurs during AUBAGIO treatment If a patient receiving AUBAGIO develops a serious infection and treatment is suspended In cases of severe haematological reactions, including pancytopenia If the patient receiving AUBAGIO develops a confirmed peripheral neuropathy

3 Why is the accelerated elimination procedure required in these cases? AUBAGIO is eliminated slowly from the plasma. 1 Without an accelerated elimination procedure, on average it takes 8 months to reach plasma concentrations less than 0.02 mg/l, although due to individual variation in drug clearance it may take up to 2 years. 1 An accelerated elimination procedure can be used at any time after discontinuation of AUBAGIO. 1 In pregnancy AUBAGIO may cause serious birth defects when administered during pregnancy. Use of the accelerated elimination procedure to rapidly lower the blood level of AUBAGIO below 0.02 mg/l at the first delay of menses may decrease the risk to the foetus. 1 If female patients wish to become pregnant, treatment with AUBAGIO should be stopped. The accelerated elimination procedure is recommended to more rapidly achieve concentrations below 0.02 mg/l.

4 What is the accelerated elimination procedure for AUBAGIO? If drug discontinuation is necessary, such as in the case of pregnancy or an adverse event, AUBAGIO can be rapidly removed from the body using one of the following procedures: 1 Cholestyramine Activated charcoal Administration of cholestyramine 8 g Administration of oral activated powdered charcoal 50 g Well tolerated? Repeat every 12 hours for 11 days* Yes No Repeat 8 g 3 times daily for 11 days* Reduce to cholestyramine 4 g 3 times daily for 11 days* *Days do not need to be consecutive unless there is a need to lower AUBAGIO plasma concentration rapidly. 1 On average, the procedure takes 11 days, but may take longer in some cases. At the end of 11 days, both regimens successfully accelerated AUBAGIO elimination, leading to >98% reduction in AUBAGIO plasma concentrations following treatment cessation. The choice between the elimination procedures should depend on the patient s tolerability. 1 In patients who are pregnant or wish to become pregnant, a blood sample should be taken to confirm that blood levels are below 0.02 mg/l. 1 Verification by 2 separate tests at an interval of at least 14 days and a waiting period of one-and-a-half months between the first occurrence of a plasma concentration below 0.02 mg/l and fertilisation is also required. 1

5 How does the accelerated elimination procedure of AUBAGIO work? AUBAGIO normally undergoes enterohepatic recycling, a process in which bile acids and other substances excreted by the liver are absorbed by the intestinal mucosa and returned to the liver via the portal vein. Cholestyramine and activated charcoal bind and sequester teriflunomide in the small intestine and prevent it from being reabsorbed, thus accelerating its elimination. 2 Plasma Liver Reabsorption AUBAGIO (teriflunomide) Excretion Gut Bile Faeces Cholestyramine and activated charcoal sequester teriflunomide in the small intestine, preventing reabsorption and enterohepatic recirculation 2 Are there any adverse events associated with the accelerated elimination procedure? Four phase I trials have been undertaken, in which healthy volunteers were administered teriflunomide and subsequently the accelerated elimination procedure with cholestyramine or activated charcoal was applied. The most common adverse events (86%) experienced during the elimination procedure in these trials were mild to moderate gastrointestinal events. 2 Please consult the Summary of Product Characteristics for cholestyramine or activated charcoal for more information.

6 Prescribing information AUBAGIO 14 mg (teriflunomide) film-coated tablets. Please refer to the Summary of Product Characteristics (SmPC) before prescribing. PRODUCT COMPOSITION: Each film-coated tablet contains 14 mg of teriflunomide. INDICATIONS: AUBAGIO is indicated for the treatment of adult patients with relapsing remitting multiple sclerosis (MS). DOSAGE AND ADMINISTRATION: The treatment should be initiated and supervised by a physician experienced in the management of multiple sclerosis. The recommended dose of teriflunomide is 14 mg once daily. The film-coated tablets are for oral use. The tablets should be swallowed whole with some water. AUBAGIO can be taken with or without food. Elderly population: AUBAGIO should be used with caution in patients aged 65 years and over due to insufficient data on safety and efficacy. Renal impairment: No dosage adjustment is necessary for patients with mild, moderate or severe renal impairment not undergoing dialysis. Hepatic impairment: No dosage adjustment is necessary for patients with mild and moderate hepatic impairment. Paediatric population: The safety and efficacy of AUBAGIO in children aged from 10 to less than 18 years has not yet been established. CONTRAINDICATIONS: Hypersensitivity to the active ingredient or excipients. Severe hepatic impairment (Child-Pugh class C). Pregnant women, or women of childbearing potential not using reliable contraception during treatment with teriflunomide and thereafter as long as its plasma levels are above 0.02 mg/l. Breast-feeding women. Severe immunodeficiency states, e.g. AIDS. Significantly impaired bone marrow function or significant anaemia, leucopenia, neutropenia or thrombocytopenia. Severe active infection until resolution. Severe renal impairment undergoing dialysis, because insufficient clinical experience is available in this patient group. Severe hypoproteinaemia, e.g. in nephrotic syndrome. EDUCATIONAL GUIDANCE: Prior to prescribing AUBAGIO, physicians must familiarise themselves with educational materials which consist of a Healthcare Professional Education/Discussion guide and they should provide their patients with a Patient Card and Patient Leaflet. WARNINGS AND PRECAUTIONS: Monitoring: Before starting treatment the following should be assessed: blood pressure, alanine aminotransferase (ALT/SGPT), complete blood cell count (CBC) including differential white blood cell (WBC) and platelet count. Exclude pregnancy. During treatment the following should be monitored: blood pressure, ALT/SGPT. A CBC should be performed based on signs and symptoms. Accelerated elimination procedure: Without an accelerated elimination procedure, it takes an average of 8 months to reach plasma concentrations less than 0.02 mg/l, although due to individual variation in substance clearance it may take up to 2 years. An accelerated elimination procedure can be used at any time after discontinuation of teriflunomide. (For further information, please refer to the SmPC). Hepatic effects: Assess liver enzymes before initiation of teriflunomide therapy - every two weeks during the first 6 months of treatment, and every 8 weeks thereafter or as indicated by clinical signs and symptoms. For ALT (SGPT) elevations between 2- and 3-fold the upper limit of normal, monitoring must be performed weekly. Teriflunomide therapy should be discontinued if liver injury is suspected and discontinuation should be considered if liver enzymes are confirmed as >3x ULN. Patients with pre-existing liver disease may be at increased risk of developing elevated liver enzymes when taking teriflunomide and should be closely monitored for signals of liver disease. AUBAGIO should be used with caution in patients who consume substantial quantities of alcohol. Blood pressure: Must be checked before the start of teriflunomide treatment and periodically thereafter. Infections: Patients receiving AUBAGIO should be instructed to report symptoms of infections to a physician. Patients with active acute or chronic infections should not start treatment with AUBAGIO until the infection(s) is resolved. For patients testing positive in tuberculosis screening, treat by standard medical practice prior to therapy with teriflunomide. Haematological effects: A mean decrease of less than 15% from baseline affecting white blood cell counts have been observed. Obtain complete blood count with differential prior to initiation of treatment, thereafter CBC should be assessed as indicated by clinical signs and symptoms. In patients with pre-existing cytopenias there might be a higher risk of haematological disorders with teriflunomide. In cases of severe haematological reactions, including pancytopenia, AUBAGIO and all concomitant myelosuppressive treatment must be discontinued and the accelerated elimination procedure be considered. Respiratory reactions: Due to the potential risk of interstitial lung disease, pulmonary symptoms, such as persistent cough and dyspnoea, may be a reason for discontinuation of the therapy and for further investigation, as appropriate. Skin reactions: In case of ulcerative stomatitis, or if skin and /or mucosal reactions are observed which raise the suspicion of severe generalised major skin reactions, teriflunomide must be discontinued and an accelerated procedure initiated immediately. Immunosuppressive/Immunomodulating therapies: Co-administration with leflunomide is not recommended. Co-administration with antineoplastic or immunosuppressive therapies has not been evaluated. Peripheral neuropathy: Confirmed peripheral neuropathy, consider discontinuing AUBAGIO therapy and performing the accelerated elimination procedure. Vaccination: Live attenuated vaccines should be avoided. SWITCHING to or from AUBAGIO: No waiting period is required when initiating teriflunomide after interferon beta or glatiramer acetate. Due to the risk of concomitant immune effects for up to 2-3 months, caution is required when switching patients immediately from natalizumab to teriflunomide. To avoid concomitant immune effects when switching from fingolimod, weeks is needed for lymphocytes to return to the normal range. If a decision is made to stop treatment with AUBAGIO, during the interval of 5 half-lives (approximately 3.5 months, although may be longer in some patients), starting other therapies will result in concomitant exposure to AUBAGIO. This may lead to an additive effect on the immune system and caution is, therefore, indicated. CONCOMITANT USE AND DRUG INTERACTION: Co-administration of teriflunomide with leflunomide is not recommended. Co-administration with antineoplastic or immunosuppressive therapies has not been evaluated. Rifampicin and other known potent CYP and transporter inducers, medicinal products metabolised by CYP2C8, medicinal products metabolised by CYP1A2, OAT3 substrates, BCRP substrates and OATP substrates should be used with caution during treatment with teriflunomide. Coadministration with oral contraceptives; interaction observed with repeated doses of teriflunomide. Whilst the interaction of teriflunomide is not expected to adversely impact the efficacy of oral contraceptives, it should be considered when selecting or adjusting oral contraceptive treatment. For patients receiving teriflunomide, treatment with cholestyramine or activated charcoal is not recommended. For co-administration of warfarin with teriflunomide, close INR follow-up and monitoring is recommended. PREGNANCY AND LACTATION: Pregnancy: Women of childbearing potential have to use effective contraception during treatment and after treatment as long as teriflunomide plasma concentration is above 0.02 mg/l. In case of suspicion of pregnancy, patient must notify the physician. In case of pregnancy, the physician and patient must discuss the risk to the pregnancy and the accelerated elimination procedure. In women wishing to become pregnant, teriflunomide should be stopped and an accelerated elimination procedure is recommended (Please refer to the SmPC for further information). Both cholestyramine and activated powdered charcoal may influence the absorption of oestrogens and progestogens during the accelerated elimination procedure. Use of alternative contraceptive methods is recommended. Lactation: Breast-feeding women must not receive teriflunomide. UNDESIRABLE EFFECTS: Based on placebo-controlled studies the most commonly reported adverse reactions in the teriflunomide treated patients were: Diarrhoea, increased ALT, nausea, and alopecia. Very common ( 1/10); Diarrhoea, nausea, alopecia and ALT increase. Common ( 1/100 to < 1/10); Influenza, upper respiratory tract infection, urinary tract infection, bronchitis, sinusitis, pharyngitis, cystitis, gastroenteritis viral, oral herpes, tooth infection, laryngitis, tinea pedis, neutropenia, anaemia, mild allergic reactions, anxiety, paraesthesia, sciatica, carpal tunnel syndrome, hypertension, upper abdominal pain, vomiting, toothache, rash, acne, musculoskeletal pain, myalgia, pollakiuria, menorrhagia, pain, GGT increase, AST increase, weight decrease, neutrophil count decrease and WBC decrease. Uncommon ( 1/1000 to < 1/100); Mild thrombocytopenia (platelets <100G/l), hyperaesthesia, neuralgia, peripheral neuropathy and post-traumatic pain. For listings and further information on adverse reactions, please refer to the SmPC. Legal Classification: POM (Prescription Only Medicine) List Price: per 28 day pack MARKETING AUTHORISATION NUMBER: EU/1/13/838/ MARKETING AUTHORISATION HOLDER: Sanofi-Aventis Groupe. 54, Rue La Boétie. F Paris. France. FULL PRESCRIBING INFORMATION AVAILABLE FROM Genzyme Therapeutics Ltd, 4620 Kingsgate, Cascade Way, Oxford Business Park South, Oxford OX4 2SU. DATE OF PREPARATION: October 2014 AUBAGIO is subject to additional monitoring. This will allow quick identification of new safety information. Adverse Events should be reported. Reporting forms and information can be found at: Adverse events should also be reported to Genzyme Tel: AUBA-UK-9/ r(1). Date of preparation: November References: 1. AUBAGIO Summary of Product Characteristics. November Miller A, Turpault S, Menguy-Vacheron F. Rapid elimination procedure of teriflunomide with cholestyramine or activated charcoal. Poster presented at: 17th Annual Meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS); June 1-2, 2012; San Diego, California.