FEBRUARY 2015
HPRA DRUG SAFETY 66TH NEWSLETTER EDITION
3 Mycophenolate mofetil (CellCept) and 4 Direct Healthcare Professional In this Edition Mycophenolic acid (Myfortic) - New warnings Communications published on about the risks of hypogammaglobulinaemia the HPRA website since the last 1 Eligard (leuprorelin acetate depot injection) and bronchiectasis Drug Safety Newsletter - Risk of lack of efficacy due to incorrect reconstitution and administration process 4 Tecfidera (dimethyl fumarate) - Progressive Multifocal Leukoencephalopathy (PML) has 2 Beta interferons – Risk of thrombotic occurred in a patient with severe microangiopathy and nephrotic syndrome and prolonged lymphopenia
Eligard (leuprorelin acetate depot injection) - Risk of lack of efficacy due to incorrect reconstitution and administration process
Following identification of a signal and safe treatment of patients with It is available in six-monthly (45mg), of administration errors with Eligard prostate cancer. Lack of efficacy may three-monthly (22.5mg) and one- and concerns that such errors may occur due to incorrect reconstitution monthly (7.5mg) formulations. In impact on clinical efficacy, this issue of Eligard. the majority of patients, androgen was reviewed at EU level by the deprivation therapy (ADT) with Eligard Eligard is indicated for the treatment Pharmacovigilance Risk Assessment results in testosterone levels below the of hormone dependent advanced Committee (PRAC). A cumulative standard castration threshold (<50ng/ prostate cancer and for the treatment review of reported global cases dL; <1.7 nmol/L); and in most cases, of high risk localised and locally identified errors related to storage, patients reach testosterone levels advanced hormone dependent preparation and reconstitution of below <20ng/dL. prostate cancer in combination Eligard. Appropriate reconstitution with radiotherapy. Healthcare professionals are is a critical step in the administration reminded of the following: of the product to ensure the effective
Advice to Healthcare Professionals • Appropriate reconstitution of • The storage conditions for the • A Direct Healthcare Professional Eligard is a critical step in the product have been updated and Communication (DHPC) was administration of the product. the product information reflecting circulated to relevant healthcare this update is available on the professionals in December 2014 • It is important that all staff HPRA website (www.hpra.ie). The and is available on the HPRA involved in the reconstitution and syringe will be modified to simplify website (www.hpra.ie). administration of Eligard are familiar reconstitution and administration. with and adhere to the instructions • All cases of incorrect storage, The modified syringe (the blue for appropriate methods of reconstitution and administration plunger rod design is changing) reconstitution and administration of Eligard should be reported to will be made available as soon as before using the product. the HPRA. possible. • Testosterone levels should be measured in suspected cases of maladministration of Eligard.
• There have been global • Lack of clinical efficacy • Reconstitution Key Message reports of medication may occur due to instructions in section errors related to incorrect reconstitution 6.6 of the SmPC for * Further details on Eligard are storage, preparation and of Eligard. Eligard must be followed available at www.hpra.ie reconstitution of Eligard. exactly. Beta interferons - Risk of thrombotic microangiopathy and nephrotic syndrome
Interferon beta-1a and interferon beta- In July 2014, a European review thrombocytopenic purpura or 1b are indicated for the treatment of of interferon beta products* and haemolytic uraemic syndrome. Cases relapsing multiple sclerosis* and in associated reports of thrombotic of nephrotic syndrome with different patients with a single demyelinating microangiopathy (TMA) and nephrotic underlying nephropathies have also event with an active inflammatory syndrome was concluded. Cases of been reported in association with these process. Interferon beta-1b products thrombotic microangiopathy (TMA), products. The review could not rule out may also be used in patients with including fatal cases, had been a causal association between interferon secondary progressive multiple reported during treatment of multiple beta products and TMA or nephrotic sclerosis with active disease evidenced sclerosis with interferon beta. Most syndrome. by relapses. TMA cases presented as thrombotic
Advice to Healthcare Professionals
Thrombotic microangiopathy Nephrotic Syndrome • TMA may develop several weeks to several years after • Nephrotic syndrome may develop several weeks to starting treatment with interferon beta. several years after starting treatment with interferon beta. • Be vigilant for signs and symptoms of TMA and manage it promptly in line with the advice below. • Be vigilant for the development of this condition and manage it promptly in line with the advice below. • Clinical features of TMA include thrombocytopenia, new onset hypertension, fever, impaired renal function • Renal function should be monitored periodically and and central nervous system symptoms (e.g. confusion early signs or symptoms of nephrotic syndrome (e.g. and paresis). oedema, proteinuria and impaired renal function, especially in high risk groups) should be noted. • If clinical features of TMA are observed, platelet levels, serum lactate dehydrogenase levels, renal function and • If nephrotic syndrome occurs, it should be treated red blood cell fragments on a blood film should be promptly and consideration should be given to performed. stopping treatment with interferon beta. • If TMA is diagnosed, prompt treatment (e.g. plasma The product information (Summary of Product exchange should be considered) is required and Characteristics (SmPC) and package leaflet (PL)) for all immediate discontinuation of interferon beta is interferon beta products has been updated and will be recommended. fully harmonised with information on TMA and nephrotic syndrome.
Key Message • Cases of TMA including fatal • Cases of nephrotic syndrome with • Be vigilant for the development cases have been reported during different underlying nephropathies of these conditions and manage treatment of multiple sclerosis with have also been reported. them promptly if they occur. interferon beta products. • Both TMA and nephrotic • Most TMA cases presented as syndrome may develop several thrombotic thrombocytopenic weeks to several years after purpura or haemolytic uraemic starting treatment with interferon syndrome. beta.
* The following interferon beta products are authorised for the treatment of multiple sclerosis. Further details available at www.hpra.ie: Avonex (interferon beta-1a), Rebif (interferon beta-1a), Betaferon (interferon beta-1b), Extavia (interferon beta-1b), Plegridy (peginterferon beta-1a).
2 HPRA Drug Safety Newsletter – February 2015 – Edition 66 Beta interferons - Risk of thrombotic microangiopathy Mycophenolate mofetil (CellCept) and Mycophenolic and nephrotic syndrome acid (Myfortic) - New warnings about the risks of hypogammaglobulinaemia and bronchiectasis
The Pharmacovigilance Risk Assessment Committee The active pharmacological form of mycophenolate mofetil (PRAC) of the EMA concluded a review of case reports and is mycophenolic acid and therefore the warnings regarding published studies which showed that mycophenolate mofetil these risks applies to all products that contain mycophenolic in combination with other immunosuppressants can cause acid as their active ingredient such as CellCept and Myfortic. hypogammaglobulinaemia and bronchiectasis.
Advice to Healthcare Professionals
Hypogammaglobulinaemia Bronchiectasis • Hypogammaglobulinaemia associated with recurrent • There have been published reports of bronchiectasis infections has been reported in patients receiving in patients receiving mycophenolate mofetil in mycophenolate mofetil in combination with other combination with other immunosuppressants. immunosuppressants. • Patients who develop persistent pulmonary symptoms, • Patients who develop recurrent infections should have such as cough and dyspnoea, should be investigated their serum immunoglobulins measured. promptly. • In cases of sustained, clinically relevant • In some of the confirmed cases of bronchiectasis, hypogammaglobulinaemia, appropriate clinical action switching mycophenolate mofetil to an alternative should be considered. In some of the reported cases, immunosuppressant resulted in an improvement in switching mycophenolate mofetil to an alternative respiratory symptoms. immunosuppressant resulted in serum IgG levels returning to normal.
Key Message • A review of case reports and • In some of the confirmed cases • The product information (SmPC published studies showed of hypogammaglobulinaemia and PL) for these products will be that mycophenolate mofetil and bronchiectasis, switching updated shortly with the respective (as the active mycophenolic mycophenolate mofetil to an warnings. acid) in combination with other alternative immunosuppressant • Healthcare professionals should immunosuppressants can cause resulted in improvement in report any suspected adverse hypogammaglobulinaemia and symptoms. reactions associated with bronchiectasis. • A Direct Healthcare Professional mycophenolate mofetil and • Patients who experience recurrent Communication (DHPC) was mycophenolic acid to the HPRA. infections should have their serum circulated by the Marketing immunoglobulins measured and Authorisation Holders (MAHs) patients who develop persistent for CellCept and Myfortic to * Further details on CellCept pulmonary symptoms, such as relevant healthcare professionals and Myfortic are available cough and dyspnoea, should be in December 2014 and is available at www.hpra.ie and investigated properly. from the HPRA website www.ema.europa.eu/ema/ (www.hpra.ie).
3 HPRA Drug Safety Newsletter – February 2015 – Edition 66 Tecfidera (dimethyl fumarate)- Progressive Multifocal Leukoencephalopathy (PML) in a patient with severe and prolonged lymphopenia
The European Medicines Agency’s in the setting of severe prolonged Tecfidera is authorised in the EU Pharmacovigilance Risk Assessment lymphopenia, was reported in a for treatment of adult patients with Committee (PRAC) recently advised patient receiving Tecfidera for 4.5 relapsing remitting multiple sclerosis. that Healthcare Professionals and years. Lymphopenia is a known Based on this new information, Patients should be informed about adverse drug reaction of Tecfidera healthcare professionals should be the first case of progressive multifocal and patients undergoing treatment aware of the following: leukoencephalopathy (PML) in a should be monitored regularly, with patient treated with Tecfidera (dimethyl regular complete blood counts (CBC), fumarate). This fatal case of PML, including lymphocytes.
Advice to Healthcare Professionals • Lymphopenia is a known adverse • Prolonged lymphopenia may be • Patients receiving Tecfidera who reaction of Tecfidera and patients associated with an increased risk experience lymphopenia should be undergoing treatment should be of PML. monitored closely and frequently monitored regularly. Complete for signs and symptoms of • Patients should be appropriately blood counts (CBC), including neurological dysfunction. informed about the risk of PML. lymphocyctes, should be checked • When PML is suspected, regularly and at close intervals, as Tecfidera should be discontinued clinically indicated. immediately.
Key Message • A fatal case of PML, in the setting • Patients should have complete • Tecfidera should be stopped of severe prolonged lymphopenia blood counts, including immediately if PML is suspected. has been reported in a patient lymphocytes, monitored regularly • All suspected adverse reactions receiving Tecfidera for 4.5 years. and at close intervals, as clinically associated with Tecfidera should be This is the first case of PML indicated. reported to the HPRA associated with Tecfidera and has • Patients experiencing lymphopenia (www.hpra.ie). been reviewed by PRAC. while being treated with Tecfidera should be monitored closely and * Further details on Tecfidera are frequently for signs and symptoms available at www.hpra.ie and of neurological dysfunction. www.ema.europa.eu/ema/
Direct Healthcare Professional Communications published on the HPRA website since the last Drug Safety Newsletter PRODUCT SAFETY ISSUE Procoralan New contraindication and recommendations to minimise the risk of cardiovascular events (ivabradine hydrochloride) and severe bradycardia.
Cellcept (mycophenolate New warnings about the risks of hypogammaglobulinaemia and bronchiectasis. mofetil) and Myfortic (mycophenolic acid)
Correspondence/Comments should be sent to the Pharmacovigilance Section, Health Products Regulatory Authority, contact details below.
4 Kevin O’Malley House, Earlsfort Centre, Earlsfort Terrace, Dublin 2, Ireland T: +353 1 676 4971 E: [email protected] www.hpra.ie