WC500169468

4.3.6. Sitagliptin – JANUVIA (CAP), RISTABEN (CAP), TESAVEL (CAP), XELEVIA (CAP);
Sitagliptin, metformin – EFFICIB (CAP), JANUMET (CAP), RISTFOR (CAP), VELMETIA (CAP);
Angiotensin-converting enzyme (ACE) inhibitors (NAP)
Signal of angioedema due to interaction between sitagliptin and ACE inhibitors
Regulatory details:
PRAC Rapporteur: Menno van der Elst (NL)
Administrative details:
EPITT 17608 – Follow up December 2013
MAH(s): Merck Sharp & Dohme Ltd, various
Background
For background information, see PRAC minutes of 2-5 December 2013. The MAH replied to the request
for information on the signal of angioedema due to an interaction between sitagliptin and ACE
inhibitors and the responses were assessed by the Rapporteur.
Discussion
Regarding the methodology of the meta-analysis of clinical trials previously discussed by the PRAC,
information was provided regarding the exclusion criteria and sensitivity analyses performed.
Angioedema is a known adverse drug reaction of both sitagliptin and ACE-inhibitors. The incidence
rates observed following sensitivity analyses were comparable with those reported in the initial analysis
and did not show any increased risk of angioedema during concomitant administration of sitagliptin
and ACE inhibitors.
The analysis of these data showed similar incidence rates of angioedema in patients treated with
sitagliptin with or without concomitant treatment with an ACE inhibitor.
Regarding a further review of the post-marketing spontaneous case reports, a diagnosis of angioedema
cannot be inferred from the limited information available in the cases. Regarding the pharmacokinetic
mechanism of interaction it was explained that there is no relevant potential for sitagliptin to increase
ACE inhibitors levels through an interaction via human Organic Anion Transporter 3 (OAT3), as
previously hypothesised. Furthermore, a PK interaction through OAT3 is unlikely to be causally linked
to an increased risk of angioedema.
Summary of recommendation(s)
Current evidence does not indicate an increased risk of angioedema for patients due to
concomitant use of sitagliptin and ACE inhibitors. No other regulatory action except routine
pharmacovigilance is necessary at the moment.
4.3.7. Tiotropium bromide (NAP)
Signal of increased mortality from cardiovascular disease and all-cause mortality – results of
TIOSPIR 8 trial
Regulatory details:
PRAC Rapporteur: Sabine Straus (NL)
Administrative details:
EPITT 17406 – Follow up December 2013
MAH(s): Boehringer Ingelheim Limited, various
8 Tiotropium Safety and Performance in Respimat
Pharmacovigilance Risk Assessment Committee (PRAC)
EMA/PRAC/324055/2014 Page 26/73