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Berinert® Monograph Page 1 of 13 THE UNIVERSITY HOSPITALS AND CLINICS
THE UNIVERSITY OF MISSISSIPPI MEDICAL CENTER
JACKSON, MS
Pharmacy and Therapeutics Committee
Drug Monograph
C1 esterase inhibitor (human) (Berinert®)
February 2013
Generic Name
- C1 esterase inhibitor (human) [C1-INH]
- Plasma derived (pdC1-INH)
- Pasteurized
Brand Name (Manufacturer)
- Berinert™ (CSL Behring GmbH: Marburg, Germany)
Therapeutic class
- C1-INH
Similar Drugs
- C1 esterase inhibitor (human) (Cinryze®) (NF)
- Approved for prophylaxis only
- Nano-filtered (nfC1-INH)
- Will not be stocked
- Icatibant (Firazyr) – selective bradykinin B2 receptor inhibitor (NF)
- Ecallantide (Kalbitor) – kallikrein inhibitor (NF)
- Fresh Frozen Plasma (Formulary)
Available Formulations
- 500 international units (units) of pdC1-INH as lyophilized concentrate per
vial (latex free)
FDA Approved Indication(s)
- Treatment of acute abdominal, facial, or laryngeal attacks of hereditary
angioedema (HAE) in adult and adolescent patients
Pharmacology
- C1-INH inhibits kallikrein, complement component 1, and anticoagulation
factor XIIa. Kallikrein is responsible for catalyzing the formation of
bradykinin. Bradykinin is thought to be responsible for increased
vascular permeability that results in angioedema in patients with HAE.
By inhibiting kallikrein, bradykinin production is decreased leading to
decreased vascular permeability and possibly resolution of
angioedema.
Pharmacokinetics
- Onset of Action: 1 h or less
- Duration: no data
- Elimination half-life: 56 ± 36 h
- Clearance: 0.85 ± 1.07 mL/min after a single dose of 1000 units
- Vd: 35-38 mL/kg
- Protein binding: no data
- Metabolism: Inactivation and consumption through formation of
complexes with serine proteinases
- Excretion: not renal or fecal
Contraindications
- Hypersensitivity, including anaphylaxis, to C1-INH preparations
Warnings/Precautions
- Severe hypersensitivity reactions
- Thrombotic events (at recommended and higher than recommended
doses)
Berinert Monograph Page 2 of 13 - Transmission of infectious agents
- Seek medical care with acute, laryngeal HAE attacks even if pdC1-INH
has been administered.
Adverse Effects
Table 1: Adverse reactions occurring up to 4 hours after initial infusion in
more than 4% of subjects
pdC1-INH® 20 units/kg
Placebo
Adverse Reactions
N (%)
N (%)
(n = 43)
(n = 42)
Nausea
3 (7%)
5 (11.9%)
Dysgeusia
2 (4.7%)
0 (0%)
Abdominal pain
2 (4.7%)
3 (7.1%)
Vomiting
1 (2.3%)
3 (7.1%)
Diarrhea
0 (0%)
4 (9.5%)
Headache
0 (0%)
2 (4.8%)
Table 2: Adverse reactions occurring in more than 4% of subjects up to 72
hours after initial or rescue infusion
pdC1-INH® 20 units/kg
Placebo
Adverse Reactions
N (%)
N (%)
(n = 43)
(n = 42)
Nausea
3 (7%)
11 (26.2%)
Headache
3 (7%)
5 (11.9%)
Abdominal pain
3 (7%)
5 (11.9%)
Dysgeusia
2 (4.7%)
1 (2.4%)
Vomiting
1 (2.3%)
7 (16.7%)
Pain
1 (2.3%)
4 (9.5%)
Muscle spasms
1 (2.3%)
4 (9.5%)
Diarrhea
0 (0%)
8 (19%)
Back Pain
0 (0%)
2 (4.8%)
Facial Pain
0 (0%)
2 (4.8%)
Drug Interactions
- None noted
Use in Children and Other
Special Populations
- Geriatrics: safety and efficacy not established
- Pediatric (0-12 years): safety and efficacy not established
- Renal Impairment: no data
- Hepatic impairment: no data
Pregnancy/Lactation
- Pregnancy Category C
Has been used in pregnancy with no harmful effects to 34 neonates
Dosing
- Initial dose: 20 units/kg actual body weight
- Rate of infusion: approx. 4 mL/min
- Repeat dosing: May repeat dose in approximately 2-4 hours after the first
May repeat dose in 30 minutes if HAE is worsening
Administration
- For IV use only
- Warm Berinert® vial and diluents vial to room temperature before mixing.
- Reconstitute each 500 units vial with 10 mL of sterile water for injection.
- Administer at room temperature within 8 hours of reconstitution.
Berinert Monograph Page 3 of 13 - Do not mix Berinert® with other medications. Use a separate infusion line.
Storage
- Store at 36-77°F; Do not freeze.
- Protect from light.
- Store at room temperature after reconstitution.
- Discard if not used 8 hours after reconstitution.
Medication Error
& Sentinel Event
C1-INH (Cinryze) – approved for prophylaxis only
Berinert® Monograph Page 4 of 13 Table 3. Clinical Trial for FDA Approval: pdC1-INH vs. Placebo (IMPACT 1)
Study Design
Results
*Primary Endpoint
Phase II / III study
Intention-to-treat Patients
IMPACT-1 Randomized
Statistic
P-value
pdC1-INH
20 units/kg
Placebo
Double-blind
(n
=
43)
(n
=
42)
2009,
Placebo-controlled
Time to onset of symptom relief (h)*
Craig, et
al.
Purpose: To
0.5
1.42
determine if pdC1-INH
Median (range)
.0025 †
∆
∆
(0.17-24.00)
(0.20-24.00)
is safe and effective
when compared to
Number of patients with individual average time of onset of symptom relief
placebo
<1 h
30 (69.8%) ‡
16 (38.1%)
N/a
Inclusion Criteria:
<4 h
37 (86.0%)
26 (61.9%)
N/a
 ≥ 6 years of age
Time to complete resolution of all HAE symptoms (h)
 Abdominal or facial
HAE attack
7.79
4.92
.0237 †
Median (range)
∂
∂
 Laboratory
(0.47-1486)
(0.33-1486)
confirmed C1-INH
Proportion of patients with worsened HAE symptoms 2-4h after treatment
deficiency (I or II)
 Treated within 5h of
N (%)
2 (4.7%)
13 (31.0%)
.0014 †
acute attack
Trial
Exclusion Criteria:
 Angioedema and
pain not related to
C1-INH deficiency
 Habitual use of
narcotics or use of
pain medications
during an acute
attack
 Treatment of an
acute attack in the 7
days prior to
treatment
 Peripheral or
laryngeal attack
Number of vomiting episodes within 4h after treatment
N(episodes)
6
35
0.033 †
Number of patients requiring rescue medication after treatment and before symptom
onset ∞
N (%)
13 (30.2%)
23 (54.8%)
N/a
N/a = not applicable
†
Statistically significant
‡
See Figure A on next page.
∞Rescue med: placebo for 20 units/kg, 10 units/kg for 10 units/kg and 20 units/kg for placebo
∆
24h for those that received rescue medication, analgesics, antiemetics, open label C1-INH
or FFP (17/42 placebo; 6/43 C1-INH)
∂
Missing values were set to maximum time to complete resolution (i.e. 1486h)
Comments
A 10 units/kg dose was
also administered to 39
patients, but its efficacy
was only slightly better
than placebo with no
improved adverse effect
profile.
Median time to onset of
symptom relief
- Abdominal attacks
C1-INH, 0.5 h
Placebo, 1.3 h
- Facial attacks
C1-INH, 0.9 h
Placebo, 14.0 h
Median time to onset of
symptom relief
- Severe attacks
C1-INH, 0.5 h
Placebo, 13.5 h
- Moderate attacks
C1-INH, 0.8 h
Placebo, 1.3 h
The 20 units/kg dose was
efficacious irrespective of
the body location or
severity of the attack.
Figure 1: Percentage of patients with time to onset of symptom relief at 1 hour
75%
pdC1-INH
Placebo
40%
Berinert Monograph Page 5 of 13 Berinert Monograph Page 6 of 13 Table 4. Clinical Trial for FDA Approval: pdC1-INH extension trial (IMPACT 2)
Trial
Study Design
Results
*Primary Endpoint
IMPACT-2
2011,
Craig, et
al.
Comments
Open-label extension trial
of IMPACT-1
Summary of 1085 attacks in 57 individuals over an average of 2 years:
Purpose: To evaluate the
long-term safety and
efficacy of pdC1-INH for
successive HAE attacks at
any body location
pdC1-INH 20 units/kg
Statistic
All Patients
With Attacks
(n = 57)
Abdominal
(n = 51)
Peripheral
(n = 30)
Facial
(n = 21)
Laryngeal
(n = 16)
Time to onset of symptom relief (h)*
Inclusion Criteria:
 Participant of IMPACT-1
 Treatment in IMPACT-1
had to be at least 24h
before enrollment into
IMPACT-2
Exclusion Criteria:
 Hx of hypersensitivity to
C1-INH
 Use of any C1-INH in the
past 24h
 Use of any FFP within 7
days before treatment
start
 Acquired angioedema
Median
(range)
0.46 †
(0.17-497) ∞
0.39
0.43
0.48
0.44
(0.17-497)
(0.17-27.16)
(0.10-5.61)
(0.20-1.3)
Number of patients with individual average time of onset of symptom relief
<1 h
51 (89.5%)
<4 h
55 (96.5%) ‡
49 (96.1%)
27 (90.0%)
18 (85.7%)
14 (87.5%)
50 (98.0%
29 (96.7%)
20 (95.2%)
16 (100%)
Time to complete resolution of all HAE symptoms (h)
Median
(range)
15.48
12.75
22.73
26.63
5.79 #
(0.64-497)
(0.64-497)
(5.07-497)
(0.95-61.83)
(0.63-48.25)
No statistical analyses performed
The median time to onset of symptoms relief was < 30 minutes for all patients with
attacks
‡
Greater than 96% of patients had onset of symptom relief within 4 hours, with 100% in
the laryngeal attacks
#
The median time to complete resolution of HAE symptoms was shortest for laryngeal
attacks.
∞One patient d/c’d from the study after being treated for an abdominal HAE attack. A
missing value of 497 h was used for this patient
†
The individual average
time to complete
resolution of HAE
symptoms was <24 h in
71.9% of patients.
A single dose of 20
units/kg of pdC1-INH
was sufficient to
effectively treat 1073 of
1085 HAE attacks
(99%).
Additional doses of
pdC1-INH (up to a total
dose of 60 units/kg bw
per attack) were
administered for 12
abdominal attacks in six
patients for worsening
of the HAE attacks.
Trial
Table 5. Analysis of Laryngeal Attacks from IMPACT-2 Study
Study Design
Results
IMPACT 2
2010,
Craig, et
al.
Open-label extension
trial of IMPACT-1
Berinert Monograph Page 7 of 13 *Primary Endpoint
Comments
pcC1-INH 20 units/kg
Statistic
Analysis of laryngeal
attacks of IMPACT-2
Time (h)
Patients (N = 16)
Attacks (N = 39)
Within 1 hour of treatment
start, the onset of
symptom relief was
reported in 95% of all
attacks.
Time to onset of symptom relief (h)*
14 female
2 male
Median (range)
Two-sided 95% CI
for median
0.44
(0.2-1.3)
0.25
(0.1-1.3)
[0.32; 0.72]
[0.25; 0.50]
Time to complete resolution of all HAE symptoms (h)
Median (range)
Two-sided 95% CI
for median
5.87
(0.6-48.3)
8.25
(0.6-48.9)
[2.05; 18.26]
[4.10; 21.50]
For by-patient analyses, the mean times for all attacks in a given patient were used.
One patient had a flu-like illness that was assess as possibly being related to study drug.
The onset of symptom
relief occurred within 4
hours after infusion in all
16 patients with all attacks.
There were no deaths in
these patients.
Table 6. Self-administration of pdC1-INH at home
Trial
Study Design
Results
C1-INH
vs.
Placebo
2006,
Levi, et
al.
*Primary Endpoint
Patients:
HAE – diagnosed
AAE – C1-INH
deficiency diagnosed
by an attack after age
25 (with or without)
antibodies to C1-INH
Treatment:
- C1-INH (1000 units)
by self-administration
at home after three 1
hour teaching
sessions
- Patients received
either
- Every 5-7 day
prophylaxis with
C1-INH
OR
- On-demand
treatment with
C1-INH
Comments
On-Demand
Treatment
Prophylaxis
Total
31
12
HAE
28
10
AAE
3
2
1 per 16.6 days (±4.1)
1 per 7.9 days (± 2.0)
15%
2%
31%
8%
44%
18%
1%
37%
10%
34%
94%
16%
58%
50%
Open-label
Purpose: To determine
if self-administration of
pdC1-INH was possible
and safe and effective
in patients with HAE
Berinert Monograph Page 8 of 13 Frequency of
Attacks
Site of Attacks
Orofacial
Laryngeal
Abdominal
Genitourinary
Extremities
Medication
Danazol
Tranexamic acid
See Figure 2 & 3 for results data
Control refers to the period
before self-administration, when
patients received C1-INH
infusions prepared and
administered by medical
professionals.
Results:
Attack-to-treatment time
Self-administration: 1.4 ± 1.0 h
Before self-admin: 3.4 ± 2.1 h
P = 0.01
Pts AAE had similar results to
pts with HAE (see figure 3).
Pts with AAE did not require
more frequent “on-demand”
injections or higher doses of
C1-INH to treat attacks (did not
report exact doses or number of
on-demand doses given/ did not
report the number of patients
with antibodies to C1 inhibitor).
Figure 2: Onset of Relief and Complete Resolution in All Pts
Berinert Monograph Page 9 of 13 Figure 3: Onset of Relief and Complete Resolution Stratified
by HAE or AAE
Berinert Monograph Page 10 of 13 Berinert Monograph Page 11 of 13 Long-term treatment
with ACE inhibitor
Berinert® Monograph Page 12 of 13 Table 7. Cost
How supplied
Cost per vial
Cost per units
$1573.58
$3.15
500 units per vial
75 kg person
100 kg person
75 * 20 = 1500
units
$4720.74
100 * 20 = 2000
units
$6294.32
Table 8. Summary of C1-INH
Category
C1-INH
Metabolism
Inactivation and consumption through formation of
complexes with serine proteinases
Dosage adjustment
No need for renal or hepatic dosage adjustment
Onset of Effect
1 h or less
Duration of Effect
No data
Elimination Half Life
56 ± 36 h
Drug interactions
None


Administration




Warm vials to room temperature before mixing
Reconstitute each 500 units vial with 10 mL of
sterile water for injection
Only good for 8 hours after reconstitution
Do not shake vial to mix
Administer at rate of approximately 4 mL/min
Do not mix with other medicines (use separate IV
line)
Contraindications
Hypersensitivity to C1-INH preparations
Generic availability
No
Potential Advantages
- Fast onset of symptom relief
- Effective for all types of HAE attacks
- Possibly efficacious for AAE attacks
Potential Disadvantages
- Cost
Formulary Eligibility Criteria
Established efficacy superior to
formulary agents
Established safety superior to
formulary agents
Significant cost/budget
advantage versus formulary
options
Yes
No
No
Berinert Monograph Page 13 of 13 Summary
Berinert® is an intravenous C1-INH that produces symptom relief quickly in most patients with HAE. Berinert®
is approved to treat acute abdominal, facial, or laryngeal attacks of HAE in adult and adolescent patients.
Berinert® has also been shown to be effective for all types of HAE attacks with a tolerable safety profile.
Limited data is available supporting the use of C1-INH in patients with acquired angioedema or ACE inhibitor
induced angioedema at this time. Berinert® is dosed based on actual body weight and does not require any
dosage adjustments for special populations. Berinert® does not provide a potential cost savings when
compared to other options.
Recommendations
The Department of Pharmacy recommends the addition of C1-IHN (Berinert®) to the formulary for all FDA
approved indications for all ages.
References
1. Bernert™ [package insert]. CSL Behring LLC. Marburg, Germany; 2012.
2. Craig TJ, Levy RJ, Wasserman RL, et al. Efficacy of human C1 esterase inhibitor concentrate
compound with placebo in acute hereditary angioedema attacks. J Allergy Clin Immunol
2009;124(4):801-8.
3. Craig TJ, Bewtra AK, Bahna SL, et al. C1 esterase inhibitor concentrate in 1085 hereditary
angioedema attacks--final results of the I.M.P.A.C.T.2 study. Allergy 2011;66(12):1604-11.
4. Craig TJ, Wasserman RL, Levy RJ, et al. Prospective study of rapid relief provided by C1 esterase
inhibitor in emergency treatment of acute laryngeal attacks in hereditary angioedema. J Clin Immunol
2010;30(6):823-9.
5. Levi M, Choi G, Picavet C, et al. Self-administration of C1-esterase inhibitor concentrate in patients
with hereditary and acquired angioedema caused by C1-esterase inhibitor deficiency. J Allergy Clin
Immunol 2006;117(4):904-8.