45
5.62 Postmarketing Reports
Berinert
®
has a well-established safety profile. At the
recommended dosages for HAE, it is safe and well tolerated.
Because postmarketing reporting of adverse reactions is
voluntary and from a population of uncertain size, it is
not always possible to reliably estimate the frequency of
these reactions or establish a causal relationship to product
exposure.
The pasteurized C1-INH concentrate Berinert
®
has been
available in certain parts of Europe for nearly 30 years.
1
Over these decades, adverse reactions reported in patients
receiving Berinert
®
for treatment of HAE include allergic/
anaphylactic reactions, injection-site pain, injection-site
redness, chills, and fever.
100
Between January 1985 and June 2011, 95 spontaneous
reports of suspected adverse drug reactions (ADRs) were
collected from the worldwide market. During this time
period, approximately 374 million IU of Berinert
®
were
administered worldwide, corresponding to more than half
a million estimated single standard doses (Table 13).
1
Overall, 61 of the 95 reported ADRs are covered by the
known safety profile of Berinert
®
(allergic/anaphylactic
reactions [n=9]; chills and fever [n=5]; lack of effect [n=26];
suspected virus transmission [n=5]; thrombosis [n=16]).
The suspected virus transmission could not be proven in
any of the 5 cases, and a causal relationship between the
administration of Berinert
®
and the virus infections was
excluded. Of the 16 reports of thrombosis, 14 reports
occurred with high-dose off-label use during cardiac
surgery. In 1 of the remaining 2 cases, causal relationship
could be excluded. In the second case, the patient had a
medical history of thrombotic events and prothrombotic
risk factors.
1
A total of 34 of the 95 reported ADRs were classified as
unexpected (i.e., not covered by the known safety profile
of Berinert
®
). In none of these cases a causal relationship
could be established. These cases included exacerbation
of HAE, suspected inhibitor development against C1-INH,
development of an HAE attack, light-headedness, acidosis,
atrial fibrillation, burning pain upon infusion, elevated
liver function, fatal lung hemorrhage (in a 4-week-old
infant with congenital heart anomaly), headache, possible
interaction with acenocoumarol (Rifampicin
®
), localized
redness at injection site, malaise, nausea, right flank pain,
pain on injection, development of pulmonary microemboli,
rotary vertigo, sinus infection, Steven-Johnson syndrome
(in a 20-month-old child with Morbus Farquhar [familial
hemophagocytic lymphohistiocytosis] who developed
graft-versus-host reaction after a bone marrow transplant),
unspecified cause of death (in a 95-year-old patient), visual
impairment, ventricular tachycardia, vomiting, and weight
gain. Not associated with an angioedema were 1 case of
drug exposure during pregnancy and 1 case of infusion of
expired Berinert
®
.
Efficacy
Table 13 – Overview of the Safety Profile
Between 1985 and 2011
1
ADR=Adverse drug reaction; HIV=Human immunodeficiency virus.
a
Assumes 500 IU treatments until 30 Nov 2008, and 1,500 IU treatments
from 1 Dec 2008 through 30 Jun 2011.
Berinert
®
Safety Profile
Marketing authorization
1 Jan 1985
Estimated number of treatments
a
630,000
ADR reports
95
ADR reporting rate overall
a
1 Jan 1985 to 30 Nov 2008 (500 IU dose)
1 Dec 2008 to 30 Jun 2011 (1,500 IU dose)
1 in 6,632 treatments
1 in 8,967 treatments
1 in 2,052 treatments
Suspected virus transmission (not confirmed)
Cases of seroconversion to HIV
Cases of seroconversion to other blood-bourne viruses
5
0
0
Cases of thrombosis in labeled indication
2
Cases of allergic- or anaphylactic-type reactions
9
