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Administrative details:
EPITT 17760 – Follow-up February 2014
MAH(s): Roche Registration Ltd
Background
For background information, see PRAC minutes of 3-6 February 2014.
The MAH replied to the request for information on the signal of bronchiectasis and
hypogammaglobulinaemia and the responses were assessed by the Rapporteur.
Discussion
The PRAC discussed the assessment of the review of the suspected cases of both bronchiectasis and
hypogammaglobulinaemia (occurring both individually and concurrently) reported in association with
mycophenolate mofetil (MMF). There were several cases of bronchiectasis in patients receiving an
MMF-containing immunosuppressive regimen for which a causal relationship was likely. The majority of
these were published cases (Boddana et al, Pijnenburg et al, Rook et al), which provide particularly
strong evidence of a causal association. Three retrospective studies of renal transplant patients who
received an MMF-containing regimen (n= 93, 96 and 289) found that an unusually high percentage (2–
5%) of them subsequently developed bronchiectasis. There were no cases of bronchiectasis in patients
who had not received MMF; although it was recognised that the retrospective nature of these three
studies may have under-estimated the true incidence in these patients.
The review identified several cases where hypogammaglobulinaemia was likely to be causally related to
MMF given in combination with other immunosuppressants (including MMF combined with ciclosporin
and corticosteroids). The direct effect of MMF on B lymphocytes (as well T cells) seemed to provide a
plausible biological mechanism to explain the reaction. Also, studies showed that the addition of MMF
to prednisolone and ciclosporin profoundly decreased humoral (IgG) responsiveness in renal transplant
recipients (Rentenaar et al 2002; Smith et al 1998).
Based on the evidence presented, the PRAC agreed that there was a reasonable possibility that MMF,
as part of an immunosuppression regimen, was causally related to bronchiectasis. This should be
reflected in the product information so that clinicians and patients are aware of this risk and, more
importantly, can detect it at an early stage. Similarly, PRAC concluded that use of MMF, in combination
with other immunosuppressants, was causally related to hypogammaglobulinaemia. As with
bronchiectasis, the product information should be updated so that clinicians are aware of this risk and
advised to test for it in patients with recurrent infections. Appropriate communications should be
issued to inform prescribers of these changes.
Summary of recommendation(s)
The MAH for the centrally authorised 14 mycophenolate mofetil containing medicines should be
requested to submit to the EMA within 60 days a variation to include information on
bronchiectasis and hypogammaglobulinaemia in the product information 15 and include a Direct
Healthcare Professional Communication (DHPC) as an additional risk minimisation measure.
14 In line with Article 16(3) of Regulation No (EU) 726/2004 and Article 23(3) of Directive 2001/83/EC, the marketing
authorisation holder shall ensure that the product information is kept up to date with the current scientific knowledge
including the conclusions of the assessment and recommendations made public by means of the European medicines webportal
established in accordance with Article 26 of Regulation (EC) No 726/2004 (EMA website). For nationally authorised
medicines, it is the responsibility of the National Competent Authorities of the Member States to oversee that these
recommendations are adhered to
15 Section 4.4 and 4.8 of the Summary of Product Characteristics and package leaflet.
Pharmacovigilance Risk Assessment Committee (PRAC)
EMA/PRAC/438418/2014 Page 22/75