WC500165698

Summary of recommendation(s)
The MAH for Stivarga (regorafenib) should submit to the EMA within the next PSUR (DLP
26/03/2014), a cumulative review of all cases suggestive of this suspected adverse drug
reaction, from spontaneous reports, from clinical trials as well as from the literature.
4.1.4. Tacrolimus - ADVAGRAF (CAP), MODIGRAF (CAP), NAP
Febuxostat – ADENURIC (CAP)
Signal of potential drug-drug interaction between systemic tacrolimus and febuxostat
Regulatory details:
PRAC Rapporteur: Almath Spooner (IE)
Administrative details:
EPITT 17809 – New signal
MAH(s): Astellas Pharma Europe B.V. (Advagraf, Modigraf), Menarini International Operations
Luxembourg S.A. (Adenuric), various
Background
Tacrolimus is a calcineurin inhibitor used in the prophylaxis of transplant rejection in adult kidney or
liver allograft recipients and for the treatment of allograft rejection resistant to treatment with other
immunosuppressive medicinal products in adult patients. Febuxostat is a xanthine oxidase inhibitor
authorised for the treatment of chronic hyperuricaemia in conditions where urate deposition has
already occurred (including a history, or presence, of tophus and/or gouty arthritis).
During routine signal detection activities, a signal of drug-drug interaction between systemic tacrolimus
and febuxostat was identified by the UK, based on an individual case reported in the United Kingdom
and further cases retrieved from EudraVigilance. The Rapporteur confirmed that the signal needed
initial analysis and prioritisation by the PRAC.
Discussion
The PRAC discussed the information on the cases of suspected interaction between tacrolimus and
febuxostat leading to an increase in tacrolimus blood concentrations. The PRAC commented that a
particular underlying mechanism was not obvious, the number of cases was small in absolute terms
and the detail provided was quite limited.
However, the identified time to interaction seemed plausible and positive dechallenge information
(further normalisation of blood levels after febuxostat dechallenge or tacrolimus dose reduction) was
present. The suspected interaction, if confirmed, could be potentially medically important as tacrolimus
is a medicine with a narrow therapeutic index and maintenance of whole blood tacrolimus
concentrations within the therapeutic range is required to avoid toxicity and graft rejection linked to
overdosing and under dosing, respectively. The consequences of overdose are primarily renal
impairment; however other manifestations of toxicity include nausea, vomiting, tremor and elevated
liver enzymes. Investigation of the potential for an interaction is also clinically relevant in the context
of real world use as gout is a common problem among the population of renal transplant patients with
a prevalence of 2 to 13% 5 (although the use of febuxostat in organ transplant recipients is not
recommended in section 4.2 of the Summary of Product Characteristic (SmPC) of Adenuric as there is
no experience with febuxostat in this patients population).
5 JASN 2000 vol.11 no. 5 974-979
Pharmacovigilance Risk Assessment Committee (PRAC)
EMA/PRAC/253432/2014 Page 17/64