67
The following standard categories of frequency are used:
Very common:
≥
1/10
Common:
≥
1/100 and < 1/10
Uncommon:
≥
1/1,000 and < 1/100
Rare:
≥
1/10,000 and < 1/1,000
Very rare:
< 1/10,000 (including reported single cases)
Undesired reactions with Berinert are rare.
For safety with respect to transmissible agents, see section 4.4.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the
medicinal product is important. It allows continued monitoring
of the benefit/risk balance of the medicinal product. Healthcare
professionals are asked to report any suspected adverse reactions
via the national reporting system listed in Appendix V.
4.9 Overdose
No case of overdose has been reported.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: C1-inhibitor, plasma derived
ATC code: B06AC01
C1-esterase inhibitor is a plasma glycoprotein with a molecular
weight of 105 kD and a carbohydrate moiety of 40%. Its con-
centration in human plasma ranges around 240 mg/l. Besides its
occurrence in human plasma, also the placenta, the liver cells,
monocytes and platelets contain C1-esterase inhibitor.
C1-esterase inhibitor belongs to the serine-protease-inhibitor-
(serpin)-system of human plasma as do also other proteins like
antithrombin III, alpha-2-antiplasmin, alpha-1-antitrypsin and
others.
Under physiological conditions C1-esterase inhibitor blocks the
classical pathway of the complement system by inactivating the
enzymatic active components C1s and C1r. The active enzyme
forms a complex with the inhibitor in a stoichiometry of 1 : 1.
Furthermore, C1-esterase inhibitor represents the most important
inhibitor of the contact activation of coagulation by inhibiting
factor XIIa and its fragments. In addition, it serves, besides alpha-
2-macroglobulin, as the main inhibitor of plasma kallikrein.
The therapeutic effect of Berinert in hereditary angioedema is
induced by the substitution of the deficient C1-esterase inhibitor
activity.
5.2 Pharmacokinetic properties
The product is to be administered intravenously and is
immediately available in the plasma with a plasma concentration
corresponding to the administered dose.
Pharmacokinetic properties have been investigated in 40 patients
(6 patients <18 years) with hereditary angioedema. These
included 15 patients under prophylactic treatment (with frequent/
severe attacks), as well as 25 patients with less frequent/mild
attacks and “on demand” treatment. The data were generated
in an attack-free interval.
The median
in vivo
recovery (IVR) was 86.7% (range: 54.0 –
254.1%). The IVR for children was slightly higher (98.2%, range:
69.2 – 106.8%) than for adults (82.5%, range: 54.0 – 254.1%).
Patients with severe attacks had a higher IVR (101.4%) compared
to patients with mild attacks (75.8 %, range: 57.2 – 195.9%).
The median increase in activity was 2.3%/IU/kg b.w. (range: 1.4
– 6.9%/IU/kg b.w.). No significant differences were seen between
adults and children. Patients with severe attacks showed a slightly
higher increase in activity than patients with mild attacks (2.9,
range: 1.4 – 6.9 vs 2.1, range: 1.5 – 5.1%/IU/kg b.w.).
The maximum concentration of C1-esterase inhibitor activity
in plasma was reached within 0.8 hours after administration
of Berinert without significant differences between the patient
groups.
The median half-life was 36.1 hours. It was slightly shorter in
children than in adults (32.9 vs 36.1 hours) and in patients with
severe attacks than in patients with mild attacks (30.9 vs 37.0).
5.3 Preclinical safety data
Berinert contains as active ingredient C1-esterase inhibitor. It
is derived from human plasma and acts like an endogenous
constituent of plasma. Single-dose application of Berinert in rats
and mice and repeated-dose application in rats did not show any
evidence of toxicity.
Preclinical studies with repeated-dose application to investigate
carcinogenicity and reproductive toxicity have not been conducted
because they cannot be reasonably performed in conventional
animal models due to the development of antibodies following
the application of heterologous human proteins.
The
in vitro
Ouchterlony test and the
in vivo
PCA model in
guinea pigs did not show any evidence of newly arising antigenic
determinants in Berinert following pasteurization.
Product Information
