Cinryze
Generic Name: c1
esterase inhibitor (human)
Dosage Form: injection, powder, lyophilized, for solution
Cinryze™ (C1
Esterase Inhibitor [Human])
Freeze dried powder
Indications and Usage for Cinryze
Cinryze is a C1 esterase
inhibitor indicated for routine prophylaxis against angioedema attacks in
adolescent and adult patients with Hereditary Angioedema (HAE).
Cinryze Dosage and Administration
For
Intravenous Use, Freeze-Dried powder for Reconstitution.
Routine
prophylaxis against HAE Attacks
·
A dose of 1,000 Units Cinryze
can be administered every 3 or 4 days for routine prophylaxis against angioedema
attacks in HAE patients.
·
Cinryze is administered at an
injection rate of 1 mL per minute.
Table 1 Routine Prophylaxis Dosing
|
|
Indication
|
Dose
|
Initial Infusion
rate
|
Maintenance
infusion rate
(if tolerated)
|
|
Routine
prophylaxis against HAE attacks
|
1,000 Units
Intravenous
every 3 or 4 days
|
1 mL/min
(10 min)
|
1 mL/min
(10 min)
|
Instructions
for Use
The procedures below are
provided as general guidelines for the reconstitution and administration of
Cinryze. Use either the Mix2Vial® transfer device or a commercially available double-ended
needle.
Cinryze IS A
LYOPHILIZED POWDER THAT IS SUPPLIED IN A VACUUM-SEALED VIAL.
Always work on a clean surface
and wash your hands before performing the following procedures.
Reconstitution, product
administration, and handling of the administration set and needles must be done
with caution. Percutaneous puncture with a needle contaminated with blood can
transmit infectious viruses including HIV (AIDS) and hepatitis. Obtain immediate
medical attention if injury occurs. Place needles in a sharps container after
single use. Discard all equipment, including any reconstituted Cinryze in an
appropriate container.
Preparation
and Handling
· Prior
to reconstitution, Cinryze should be protected from light.
·
Cinryze should be inspected
visually for particulate matter and discoloration prior to administration,
whenever solution and container permit. The reconstituted solution should be
colorless to slightly blue, and free from visible particles. Do not use if
turbid or discolored.
·
The Cinryze vial is for single
use only. Cinryze contains no preservative. Any vial that has been entered
should be used promptly. Partially used vials should be discarded in accordance
with biohazard procedures.
·
Do not mix Cinryze with other
materials.
·
Do not use if frozen.
·
Do not use after expiration
date.
Reconstitution:
Two vials of
reconstituted Cinryze are combined for a single dose. Sterile Water for
Injection, USP, is required and not supplied with Cinryze.
1.
Aseptic technique should be
used during the reconstitution procedure.
2.
Bring the Cinryze (powder) and
Sterile Water for Injection, USP (diluent) (not supplied) to room temperature
if refrigerated.
3.
Remove caps from the Cinryze
and diluent vials.
4.
Cleanse stoppers with an
alcohol wipe or swab, and allow them to dry prior to use.
5.
Remove protective covering
from the top of the Mix2Vial transfer device package. Do not remove the device
from the package.
6. Note:
Diluent vial must be accessed prior to Cinryze vial to prevent loss of vacuum. Place diluent on a flat surface and insert the blue end of
the device into the diluent vial, pushing down until the spike penetrates
through the center of the diluent vial stopper and the device snaps in place (Figure
1). The Mix2Vial transfer device must be
positioned completely vertical prior to penetrating the stopper closure.
7.
Remove the plastic package and
discard it (Figure 2). Take care not to touch the exposed end of the device.
8.
Place vial of Cinryze on a
flat surface. Invert diluent vial containing 5 mL Sterile Water for Injection,
USP, and insert the clear end into the Cinryze vial, pushing down until the
spike penetrates the rubber stopper and the device snaps into place. The
Mix2Vial transfer device must be positioned completely vertical prior to
penetrating the stopper closure. The Sterile Water for Injection, USP will
automatically flow into the vial of Cinryze (Figure 3), because the vacuum in the vial will draw in the
diluent. If there is no vacuum in the vial, do not use
the product.
9.
Gently swirl (do not shake)
the Cinryze vial until all powder is dissolved. Be sure that Cinryze is
completely dissolved (Figure 4). Disconnect the Sterile Water for Injection, USP vial by turning
it counterclockwise (Figure 5). Do not remove the clear end of the
Mix2Vial transfer device from the vial of Cinryze.
One vial of reconstituted
Cinryze contains 5 mL of C1 esterase inhibitor at a concentration of 100
Units/mL. Reconstitute two vials of Cinryze for one dose. Repeat steps 1 to 9
above using an additional package containing a Mix2Vial transfer device to
reconstitute the second of two vials of Cinryze. Do not
reuse the Mix2Vial transfer device.
Administration
Two
vials of reconstituted Cinryze are combined for a single dose.
1.
Use Aseptic Technique.
2.
After reconstitution, the
solutions are colorless to slightly blue and clear. Do not use the product if
the solutions are turbid or discolored.
3.
Cinryze must be administered
at room temperature within 3 hours after reconstitution.
4.
Please refer to the
illustrations in steps 7 to 9 included within the Patient Information Leaflet.
Utilizing a sterile, disposable 10 mL syringe, draw back the plunger to admit 5
mL air into the syringe.
5.
Attach the syringe onto the
top of the clear end of the Mix2Vial transfer device by turning it clockwise.
6.
Invert the vial and inject air
into the solution and then slowly withdraw the reconstituted Cinryze into the
syringe.
7.
Detach the syringe from the
vial by turning it counterclockwise and releasing it from the clear end of the
Mix2Vial transfer device.
8.
Using the same syringe, repeat
steps 4 to 7 with a second vial of Cinryze to make the complete dose.
9.
Attach a suitable needle or
infusion set with winged adapter, and inject intravenously. As a guideline,
administer 1,000 Units (reconstituted in 10 mL) of Cinryze by intravenous
injection at a rate of 1 mL per minute over 10 minutes. (see Clinical Studies, [14]) Please refer to the
illustration in step 3 of the self administration section within the Patient
Information Leaflet.
10.
Dispose of all unused
solution, the empty vial(s), and the used needles and syringes in an
appropriate container for throwing away waste that might hurt others if not
handled properly.
3. DOSAGE FORMS AND STRENGTHS
·
Cinryze is a lyophilized
preparation available in a single-use vial that contains 500 Units (U) human C1
esterase inhibitor.
·
Each vial must be
reconstituted with 5 mL Sterile Water for Injection, USP (diluent) (not
supplied).
·
Two reconstituted vials must
be used to make a single, 1,000 Units, dose.
Contraindications
Cinryze is contraindicated in
patients who have manifested life-threatening immediate hypersensitivity
reactions, including anaphylaxis to the product.
Warnings and PrecautionsSensitivity
Severe hypersensitivity
reactions may occur. The signs and symptoms of hypersensitivity reactions may
include the appearance of hives, urticaria, tightness of the chest, wheezing,
hypotension and/or anaphylaxis experienced during or after injection of
Cinryze.
Because hypersensitivity
reactions may have symptoms similar to HAE attacks, treatment methods should be
carefully considered.
In case of hypersensitivity,
Cinryze infusion should be discontinued and appropriate treatment instituted.
Epinephrine should be immediately available for treatment of acute severe
hypersensitivity reaction. (See Patient Counseling
Information [17])
Thrombotic
Events
Thrombotic events have been
reported in association with C1 esterase inhibitor products when used off-label
at high doses.2 Animal studies have supported a concern about the risk of
thrombosis from intravenous administration of C1 esterase inhibitor
products. 3 (see Sections 10
OVERDOSAGE and 13.2
Animal Toxicology and/or Pharmacology)
In an open label trial further
investigating the use of Cinryze for prevention (n=146) of HAE attacks, 5
serious thrombotic events (including myocardial infarction, deep vein
thrombosis, pulmonary embolism and 2 events of cerebrovascular accident)
occurred. Subjects had underlying risk factors for thrombotic events. Patients
with known risk factors for thrombotic events should be monitored closely while
taking Cinryze.
Transmissible
Infectious Agents
Because Cinryze is made from
human blood, it may carry a risk of transmitting infectious agents, e.g.
viruses, and, theoretically, the Creutzfeldt-Jakob (CJD) agent [11]. ALL infections thought by a physician possibly to have been
transmitted by Cinryze should be reported by the physician or other healthcare
provider to ViroPharma Biologics, Inc. [(877) 945-1000]. The physician should
discuss the risks and benefits of this product with the patient, before
prescribing or administering it to the patient. (See
Patient Counseling Information [17])
Adverse Reactions
The most serious adverse
events observed in clinical studies of Cinryze have been death due to
non-catheter related foreign body embolus, pre-eclampsia resulting in emergency
C-section, stroke, and exacerbation of HAE attacks, none of which have been
considered drug related.
The most common drug related
adverse reactions observed at a rate ≥ 5% were upper respiratory tract
infection, sinusitis, rash, and headache.
Clinical
Trials Experience
Because clinical studies are conducted under widely varying
conditions, adverse reaction rates observed in the clinical trials of a drug
cannot be directly compared to rates in the clinical trials of another drug and
may not reflect the rates observed in practice.
Routine Prophylaxis
Twenty-four subjects were
evaluated in study LEVP2005-1/B for routine prophylaxis.
There were no
treatment-emergent serious adverse reactions in study LEVP2005-1/B.
Adverse reactions in trial
LEVP2005-1/B that occurred in at least two subjects during Cinryze prophylaxis,
irrespective of the causality assessment, are given in the following table:
Table 2 Adverse Reactions in Routine
Prophylaxis Study LEVP2005-1/B Irrespective of Causality
|
|
Adverse Reaction
|
Number of
Adverse
Events
|
Number of
Subjects
(N = 24)
|
|
Sinusitis
|
8
|
5
|
|
Rash
|
7
|
5
|
|
Headache
|
4
|
4
|
|
Upper respiratory tract infection
|
3
|
3
|
|
Viral upper respiratory tract infection
|
5
|
3
|
|
Bronchitis
|
2
|
2
|
|
Limb injury
|
2
|
2
|
|
Back pain
|
2
|
2
|
|
Pain in extremity
|
2
|
2
|
|
Pruritus
|
2
|
2
|
More than 9000 doses of
Cinryze have been administered to over 180 patients in all controlled and open
label clinical studies. All patients were evaluated and found negative for
seroconversion to parvovirus B19, Hepatitis B, Hepatitis C and HIV.
No clinically relevant
antibody formation was seen in clinical trials of prophylaxis.
Postmarketing
Experience
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.
Postmarketing adverse
reactions include local infusion site reactions (including pain, rash,
erythema, inflammation or hematoma at the infusion site).
Postmarketing thrombotic
events have been reported, including catheter-related and deep venous
thromboses, transient ischemic attack, and stroke. Patients with known risk
factors for thrombotic events should be monitored closely. (See Section 5.2 Thrombotic events in WARNINGS AND PRECAUTIONS)
Drug Interactions
No drug interaction studies
have been conducted.
USE IN SPECIFIC POPULATIONSPregnancy
Pregnancy Category C. No
animal data are available. No adequate and well-controlled studies were
conducted in pregnant women. It is not known whether Cinryze can cause fetal
harm when administered to a pregnant woman or can affect reproduction capacity.
Cinryze should be given to a pregnant woman only if clearly needed.
Labor and
Delivery
The safety and effectiveness
of Cinryze administration prior to or during labor and delivery have not been
established. Use only if clearly needed.
Nursing
Mothers
It is not known whether
Cinryze is excreted in human milk. Because many drugs are excreted in human
milk, caution should be exercised when Cinryze is administered to a nursing
woman.
Pediatric Use
The safety and effectiveness
of Cinryze have not been established in neonates, infants, or children. Three
of the 24 subjects in Study LEVP2005-1/B were under the age of 18 years (9, 14,
and 16 years of age).
Geriatric Use
The clinical study
LEVP2005-1/B did not include sufficient numbers of subjects 65 years of age and
older to determine whether they respond differently from younger subjects.
Overdosage
The maximum dose administered
in clinical studies was 4000 Units given over approximately 5 hours (an average
dose of 57 Units/kg) and 9000 Units given over a 7 day period. There have been
no overdosages of Cinryze reported during clinical studies.
In
vitro and in
vivo animal thrombogenicity studies with Cinryze showed a
potential for clot formation when Cinryze was administered at doses 14 times
the recommended clinical dose (greater than 200U/kg). Thrombotic events have
been reported in association with C1 esterase inhibitor products when used
off-label at high doses.2 Animal studies have supported a concern about the risk of
thrombosis from intravenous administration of C1 esterase inhibitor products.3 (see
Section 13.2 Animal Toxicology
and/or Pharmacology and Section 5.2 Thrombotic events in WARNINGS AND PRECAUTIONS).
Cinryze Description
Cinryze (C1 esterase inhibitor
[human]) is a sterile, stable, lyophilized preparation of C1 esterase inhibitor
derived from human plasma. Cinryze is manufactured from human plasma purified
by a combination of filtration and chromatographic procedures. The specific
activity of Cinryze is 4.0 – 9.0 units/mg protein. The purity is ≥ 90% human C1
esterase inhibitor. Following reconstitution with 5 mL of Sterile Water for
Injection, USP, each vial contains approximately 500 units of functionally
active C1 esterase inhibitor, pH 6.6 - 7.4, and an osmolality between 200 – 400
mosmol/kg. One Unit (U) of Cinryze corresponds to the mean quantity of C1
esterase inhibitor present in 1 mL of normal fresh plasma.
Cinryze, when reconstituted
with 5 mL of Sterile Water for Injection, USP contains the following
excipients: 4.1 mg/mL sodium chloride, 21 mg/mL sucrose, 2.6 mg/mL trisodium
citrate, 2.0 mg/mL L-Valine, 1.2 mg/mL L-Alanine, and 4.5 mg/mL L-Threonine.
The following manufacturing
steps are designed to reduce the risk of viral transmission:
·
Screening donors at U.S.
licensed blood collection centers to rule out infection with Human Immunodeficiency
Virus (HIV-1/HIV-2), Hepatitis B Virus, or Hepatitis C Virus.
·
Testing plasma pools by
in-process NAT for parvovirus B19 via minipool testing and the limit of B19 in
the manufacturing pool is set not to exceed 104 IU of B19 DNA per mL.
·
Use of two independent viral
reduction steps in the manufacture of Cinryze: pasteurization (heat treatment
at 60°C for 10 hours in solution with stabilizers) and nanofiltration through
two sequential 15 nm filters.
These viral reduction steps,
along with a step in the manufacturing process, PEG precipitation, have been
validated in a series of in vitro experiments
for their capacity to inactivate/remove a wide range of viruses of diverse
physicochemical characteristics including: Human Immunodeficiency Virus (HIV),
Hepatitis A Virus (HAV), and the following model viruses: Bovine Viral Diarrhea
Virus (BVDV) as a model virus for HCV, Canine Parvovirus (CPV) as a model virus
for Parvovirus B19, Pseudorabies Virus (PRV) as a model virus for large
enveloped DNA viruses (e.g. herpes virus). Total mean log10 reductions are shown
in Table 3.
Table 3 Log10 Virus Reduction Factor for Selected
Viruses
|
|
|
Process step
|
Log10 Virus Reduction
|
|
|
Enveloped viruses
|
Non-enveloped viruses
|
|
|
HIV
|
BVDV
|
PRV
|
HAV
|
CPV
|
|
|
PEG
precipitation
|
5.1 ± 0.2
|
4.5 ± 0.3
|
6.0 ± 0.3
|
2.8 ± 0.2
|
4.2 ± 0.2
|
|
|
Pasteurization
|
> 6.1 ± 0.2
|
> 6.7 ± 0.3
|
> 6.7 ± 0.2
|
2.8 ± 0.3
|
0.1 ± 0.3
|
|
|
Nanofiltration
|
> 5.6 ± 0.2
|
> 5.5 ± 0.2
|
> 6.4 ± 0.3
|
> 4.9 ± 0.2
|
> 4.5 ± 0.3
|
|
|
Total reduction
|
> 16.8
|
> 16.7
|
> 19.1
|
> 10.5
|
> 8.7
|
|
Cinryze - Clinical PharmacologyMechanism of
Action
C1 inhibitor is a normal
constituent of human blood and is one of the serine proteinase inhibitors
(serpins). The primary function of C1 inhibitor is to regulate the activation
of the complement and intrinsic coagulation (contact system) pathway. C1
inhibitor also regulates the fibrinolytic system. Regulation of these systems
is performed through the formation of complexes between the proteinases and the
inhibitor, resulting in inactivation of both and consumption of the C1
inhibitor.
HAE patients have low levels
of endogenous or functional C1 inhibitor. Although the events that induce
attacks of angioedema in HAE patients are not well defined, it is thought by
some that increased vascular permeability and the clinical manifestation of HAE
attacks are primarily mediated through contact system activation. Suppression
of contact system activation by C1 inhibitor through the inactivation of plasma
kallikrein and factor XIIa is thought to modulate this vascular permeability by
preventing the generation of bradykinin1. Administration of Cinryze increases plasma levels of C1
inhibitor activity.
Pharmacodynamics
In clinical studies, the
intravenous administration of Cinryze demonstrated an increase in plasma levels
of C1 inhibitor within approximately one hour or less of administration.
Biological activity of Cinryze
was shown in 35 subjects by the subsequent increase in plasma C4 levels from an
average of C4 8.1 mg/mL at baseline to C4 8.6 mg/mL 12 hours after infusion of
Cinryze.
Pharmacokinetics
A randomized, parallel group,
open label pharmacokinetics (PK) study of Cinryze was performed in patients
with non-symptomatic hereditary angioedema (HAE). The patients received either
a single dose of 1,000 Units or 1,000 Units followed by a second 1,000 Units 60
minutes later. The PK results for functional C1 inhibitor are presented the
following table:
Table 4 Mean pharmacokinetic parameters
of Functional C1 Inhibitor
|
|
Numbers in parenthesis are number of
subjects evaluated
|
|
Single dose = 1,000 Units
|
|
Double dose = 1,000 Units followed by a
second 1,000 Units 60 minutes later
|
|
* One Unit is equal to the mean C1
inhibitor concentration of 1 mL of normal human plasma
|
|
Parameters
|
Single Dose
|
Double Dose
|
|
Cbaseline (units/mL)
|
0.31 ± 0.20 (n = 12)
|
0.33 ± 0.20 (n = 12)
|
|
Cmax (units/mL)
|
0.68 ± 0.08 (n = 12)
|
0.85 ± 0.12 (n = 13)
|
|
Tmax (hrs)
|
3.9 ± 7.3 (n = 12)
|
2.7 ± 1.9 (n = 13)
|
|
AUC(0-t) (units*hr/mL)
|
74.5 ± 30.3 (n = 12)
|
95.9 ± 19.6 (n = 13)
|
|
CL (mL/min)
|
0.85 ± 1.07 (n = 7)
|
1.17 ± 0.78 (n = 9)
|
|
Half-life
(hours)
|
56 ± 36 (n = 7)
|
62 ± 38 (n = 9)
|
The maximum plasma
concentrations (Cmax) and area under the plasma concentration-time curve (AUC)
increased from the single to double dose, although the increase was not dose
proportional. The mean half-lives of Cinryze were 56 hours (range 11 to 108
hours) for a single dose and 62 hours (range 16 to 152 hours) for the double
dose.
Studies have not been
conducted to evaluate the PK of Cinryze in special patient populations
identified by gender, race, age (pediatric or geriatric), or the presence of
renal or hepatic impairment.
Nonclinical ToxicologyCarcinogenesis,
Mutagenesis, Impairment of Fertility
No animal studies have been
completed to evaluate the effects of Cinryze on carcinogenesis, mutagenesis,
and impairment of fertility.
Animal
Toxicology and/or Pharmacology
Acute toxicity of Cinryze was
studied in a combined acute toxicity and 7-day repeat dose/ dose range finding
(DRF) study in Sprague Dawley rats. Repeat dose toxicity was studied in a 7-day
repeat dose follow up to the acute dose study. The acute and repeated dose
toxicity studies were performed with intravenous administration of Cinryze at
dose levels of 1, 7 and 28 times normal dose. No signs of toxicity were
observed in the single dose study. In the repeated dose study, no signs of
toxicity were observed in the two lower doses. Repeat dosing in the rat
resulted in a robust neutralizing antibody response between days 1 and 14.
Therefore, toxicity in animals dosed repeatedly is difficult to interpret.
In
vitro and in
vivo thrombogenicity studies showed a potential for clot
formation when Cinryze was administered at doses 14 times the recommended
clinical dose (greater than 200U/kg).
Clinical StudiesRoutine
Prophylaxis Trial LEVP2005-1/B
The safety and efficacy of
Cinryze prophylaxis therapy to reduce the incidence, severity, and duration of
HAE attacks was demonstrated in a single randomized, double blind, placebo
controlled multi-center cross-over study of 24 patients. Patients were screened
to confirm a diagnosis of HAE and a history of at least two HAE attacks per
month. 24 patients (mean age 38.1 years with a range of 9 to 73 years) were
randomized to one of two treatment groups: either Cinryze prophylaxis for 12
weeks followed by 12 weeks of placebo prophylaxis; or randomized to placebo
prophylaxis for 12 weeks followed by 12 weeks of Cinryze prophylaxis. Two
subjects dropped out (one in each arm); 22 patients crossed over into period 2
and were included in the efficacy analysis. Patients were given blinded
injections (Cinryze or placebo) every 3 to 4 days, approximately 2 times per
week. Patients recorded all angioedema symptoms daily. An attack was defined as
the subject-reported indication of swelling at any location following a report
of no swelling on the previous day.
The efficacy determination was
based on the number of attacks during the 12 week period while receiving
Cinryze as compared to the number of attacks during the placebo treatment
period. The effectiveness of C1 esterase inhibitor prophylaxis in reducing the
number of HAE attacks was variable among the subjects as shown in table
5:
Table 5 LEVP2005-1/B Prevention of HAE
Attacks Clinical Trial Results by Subject
|
|
Subject
|
Percent
Reduction in
Attack
Frequency
|
|
1
|
100%
|
|
2
|
100%
|
|
3
|
100%
|
|
4
|
100%
|
|
5
|
90%
|
|
6
|
88%
|
|
7
|
84%
|
|
8
|
83%
|
|
9
|
78%
|
|
10
|
76%
|
|
11
|
60%
|
|
12
|
47%
|
|
13
|
43%
|
|
14
|
43%
|
|
15
|
32%
|
|
16
|
31%
|
|
17
|
25%
|
|
18
|
21%
|
|
19
|
10%
|
|
20
|
1%
|
|
21
|
-8%
|
|
22
|
-85%
|
Table 6 Summary Statistics on Number of
HAE Attacks in LEVP2005-1/B
|
|
|
Statistic
|
Cinryze N=22
|
Placebo
N=22
|
|
Number of Attacks
|
Mean
|
6.1
|
12.7
|
|
SD
|
5.4
|
4.8
|
|
Median
|
6
|
13.5
|
|
Min
|
0
|
6
|
|
Max
|
17
|
22
|
|
GEE Analysis Results
|
|
Effect Assessed
|
p-value
|
|
Treatment Effect
|
<0.0001
|
|
Sequence Effect
|
0.3347
|
|
Period Effect
|
0.3494
|
|
|
|
|
|
|
Patients treated with Cinryze
had a 66% reduction in days of swelling (p<0.0001), and decreases in the
average severity of attacks (p=0.0006) and the average duration of attacks
(p=0.0023), as shown in table 7.
Table 7 LEVP2005-1/B Clinical Trial
Secondary Efficacy Outcomes
|
|
|
Cinryze
N=22
|
Placebo
N=22
|
Treatment Effect
p-value
|
|
Mean Severity of
HAE Attacks
(Score from 1 to 3)
(SD)
|
1.3 (0.85)
|
1.9 (0.36)
|
0.0006
|
|
Mean Duration of
HAE Attacks (Days)
(SD)
|
2.1 (1.13)
|
3.4 (1.4)
|
0.0023
|
|
Days of Swelling
(SD)
|
10.1 (10.73)
|
29.6 (16.9)
|
<0.0001
|
REFERENCES
1.
Davis AE, The pathophysiology
of hereditary angioedema. Clin Immunol. 2005;
114:3-9.
2.
Arzneimittelkommission der
Deutschen Aertzteschaft. Schwerwiegende Thrombenbildung nach Berinert HS. Dtsch Aerztebl. 2000; 97:B-864
3.
Horstick, G et al, 2001. Circulation 104:3125-3131
How Supplied/Storage and Handling
·
Cinryze is available in
single-use vials that contain 500 Units per vial.
·
Cinryze is supplied as a
single glass vial of Cinryze powder to be reconstituted with 5 mL Sterile Water
for Injection, USP (Not supplied).
·
Cinryze, packaged for sale, is
stable for 18 months when stored at 2°C–25°C (36°F-77°F).
·
Do not freeze.
·
Store the vial in the original
carton to protect it from light.
·
The reconstituted solution
must be used within 3 hours of reconstitution.
·
Do not use beyond the
expiration date on the Cinryze vial.
Patient Counseling InformationAllergic-type
Hypersensitivity Reactions
Allergic-type hypersensitivity
reactions are possible [5.1]. Inform patients of the early signs of hypersensitivity
reactions [including hives (itchy white elevated patches), tightness of the
chest, wheezing, hypotension] and anaphylaxis. Advise patients to discontinue
use of Cinryze and contact their physicians if these symptoms occur.
Pregnancy
Advise female patients to
notify their physician if they become pregnant or intend to become pregnant during
their routine prevention with Cinryze.
Nursing
Advise patients to notify
their physician if they are breastfeeding or plan to breastfeed.
Usage While
Traveling
Based on their current
regimen, advise patients to bring an adequate supply of Cinryze for routine
prevention when traveling. Advise patients to consult with their healthcare
professional prior to travel.
Transmissible
Infectious Agents
Advise patient that, because
Cinryze is made from human blood, it may carry a risk of transmitting
infectious agents, e.g. viruses, and, theoretically, the Creutzfeldt-Jakob
(CJD) agent [5.3, 11]. The risk of transmitting disease has been reduced, but not
eliminated, by carefully selecting blood donors, testing donors for infections,
and inactivating or removing most viruses during the manufacturing process.
Inform patients of the risks and benefits of Cinryze before prescribing or
administering to the patient.
FDA-Approved
Patient Labeling
Information for the
Patient
Cinryze™ (SIN-rise)
(C1 Esterase Inhibitor
[Human])
This leaflet summarizes
important information about Cinryze. Please read it carefully before using
Cinryze and each time you get a refill. There may be new information. This
information does not take the place of talking with your healthcare provider,
and it does not include all of the important information about Cinryze. If you
have any questions after reading this, ask your healthcare provider.
Do not attempt to
self-administer unless you have been taught how by your healthcare provider.
What is Cinryze?
Cinryze is an injectable
medicine that is used to help prevent swelling and/or painful attacks in
teenagers and adults with Hereditary Angioedema (HAE). HAE is caused by the
decreased functioning of a protein called C1 esterase inhibitor, that is
present in your blood and helps control inflammation (swelling) and parts of
the immune system. Cinryze contains C1 esterase inhibitor. Before you can
inject Cinryze into your vein (intravenous injection), you must dissolve the
Cinryze powder using Sterile Water for Injection, USP. You can get supplies,
including Sterile Water for Injection, USP from your pharmacist.
Who should not use
Cinryze?
You should not use Cinryze if
you have had life-threatening immediate hypersensitivity reactions, including
anaphylaxis to the product.
What should I tell my
healthcare provider before using Cinryze?
Tell your healthcare provider
about all of your medical conditions, including if you
·
are pregnant or planning to
become pregnant. It is not known if Cinryze can harm your unborn baby.
·
are breastfeeding or plan to
breastfeed. It is not known if Cinryze passes into your milk and if it can harm
your baby.
·
have a history of blood
clotting problems. Very high doses of C1 esterase inhibitor could increase the
risk of blood clots.
Tell your healthcare provider
and pharmacist about all of the medicines you take, including all prescription
and non-prescription medicines such as over-the-counter medicines, supplements,
or herbal remedies.
What are the possible
side effects of Cinryze?
Allergic reactions may
occur with Cinryze. Call your healthcare provider or get emergency support
services right away if you have any of the following symptoms:
· wheezing
· difficulty
breathing
· chest
tightness
· turning
blue (look at lips and gums)
· fast
heartbeat
· swelling
of the face
· faintness
· rash
· hives
In clinical studies, the most
common side effects seen with Cinryze were upper respiratory tract infection,
sinusitis, rash, and headache.
These are not all the possible
side effects of Cinryze.
Tell your healthcare provider
about any side effect that bothers you or that does not go away. You can also
report side effects to the FDA at 1-800-FDA-1088.
You can ask your healthcare
provider for information that is written for healthcare providers.
How should I store
Cinryze?
Do not freeze Cinryze.
Store Cinryze in a
refrigerator or at room temperature between 36° to 77°F (2° to 25°C).
Keep Cinryze in the original
carton to protect it from light.
Do not use Cinryze after the
expiration date on the vial.
After preparing Cinryze, you
can store it at room temperature for up to 3 hours. If you have not used it
within 3 hours, throw it away.
Only use the dissolved Cinryze
if it is colorless to slightly blue, clear and free from visible particles.
What else should I know
about Cinryze?
Medicines are sometimes
prescribed for purposes other than those listed here. Do not use Cinryze for a
condition for which it is not prescribed. Do not share Cinryze with other
people, even if they have the same symptoms that you have.
Because Cinryze is made from
human blood, it may carry a risk of transmitting infectious agents, e.g.
viruses, and, theoretically, the Creutzfeldt-Jakob (CJD) agent.
This leaflet summarizes the
most important information about Cinryze. If you would like more information,
talk to your healthcare provider. You can ask your healthcare provider or
pharmacist for information about Cinryze that was written for healthcare
professionals.
Instructions for Use
Do not attempt to
self-administer unless you have been taught how by your healthcare provider.
See the step-by-step
instructions for injecting Cinryze at the end of this leaflet. You should always follow the specific instructions given
by your healthcare provider. The steps listed below are general guidelines for
using Cinryze. If you are unsure of the steps, please call your healthcare
provider or pharmacist before using.
Call your healthcare
provider right away if swelling is not controlled after using Cinryze.
Your healthcare provider will
prescribe the dose that you should take.
Call your healthcare provider
if you take too much Cinryze.
Call your healthcare provider
if you miss a dose of Cinryze.
Talk to your healthcare
provider before traveling. You should plan to bring enough Cinryze for your
treatment during this time.
Preparation of Cinryze
Always wash your hands before
doing the following steps. Try to keep everything clean and germ-free while you
are reconstituting Cinryze. Once you open the vials, you should finish
preparing Cinryze as soon as possible. This will help to keep them germ-free.
Cinryze IS A FREEZE-DRIED POWDER THAT IS SUPPLIED
IN A VACUUM-SEALED VIAL.
Note: Two vials of Cinryze are
required for each dose. You should reconstitute both vials according to steps 1
through 6.
1.
Let the vial of Cinryze and
the vial of Sterile Water for Injection, USP (diluent) reach room temperature.
2.
Remove the cap from the Cinryze
vial and Sterile Water for Injection, USP (diluent) vial to show the center
part of the rubber stopper.
3.
Wipe the top of each vial with
an alcohol wipe or swab, and allow it to dry. Do not blow on the stopper to dry
it faster. Place each vial on a flat surface. After cleaning, do not touch the
rubber stopper with your hand or allow it to touch any surface.
4. Note:
Diluent vial must be penetrated before the Cinryze vial to prevent loss of
vacuum. Remove the protective covering from the top of the Mix2Vial
transfer device package. Do not remove the device from the package. Place the
Sterile Water for Injection, USP (diluent) vial on a flat surface, and place
the blue end of the Mix2Vial transfer device over it, pushing down until the
spike penetrates the rubber stopper and the device snaps in place. Mix2Vial
must be positioned completely upright before penetrating the rubber stopper.
Remove the plastic package and discard it. Take care not to touch the exposed
end of the device.
5.
Place the vial of Cinryze on a
flat surface. Turn the diluent vial containing 5 mL Sterile Water for
Injection, USP, upside-down and insert the clear end of the Mix2Vial transfer
device into the Cinryze vial, pushing down until the spike penetrates the
rubber stopper and the device snaps in place. The Mix2Vial must be positioned
completely upright before penetrating the rubber stopper. The Sterile Water for
Injection, USP, will automatically flow into the Cinryze vial because the
vacuum in the vial will draw the Sterile Water for Injection, USP, into the
Cinryze vial. If this does not happen, do not use the
product.
6. Once all the Sterile Water for Injection, USP, is in the Cinryze
vial, gently swirl (do not shake) the Cinryze vial until all the powder is
dissolved. Disconnect the Sterile Water for Injection, USP vial by turning it
counterclockwise. Do not remove the clear end of the
Mix2Vial device from the vial of Cinryze.
Look
at the final solution before using it to make sure that Cinryze is completely
dissolved. Once dissolved, the solution in the Cinryze vial should be colorless
to slightly blue and clear. Do not use the product if the solution is cloudy,
discolored or contains any particles. Throw it away and prepare a new vial of
Cinryze.
One
vial of dissolved Cinryze contains 5 mL of C1 esterase inhibitor at a
concentration of 100 Units/mL. Prepare two vials of Cinryze for one dose.
Repeat steps 1-6 using a new Mix2Vial transfer device. Do
not reuse the Mix2Vial transfer device.
7.
Utilizing a sterile,
disposable 10mL syringe, draw back the plunger to allow approximately 5mL of
air into the syringe.
8.
Attach the syringe onto the
clear end of the Mix2Vial transfer device by turning it clockwise.
9. Turn the vial of Cinryze upside down, inject air into the vial.
Slowly pull as much dissolved Cinryze as possible into the syringe. While
holding the vial upside down, detach the syringe from the vial by turning it
counterclockwise and releasing it from the Mix2Vial transfer device. Remove any
air bubbles by gently tapping the syringe with your finger and slowly pushing
the air out of the syringe.
Repeat
steps 7-9 above with a second vial of Cinryze to make one complete dose of 10
mL.
10.
Dispose of the vials with the
Mix2Vial transfer device attached to them.
Cinryze should be administered
within 3 hours after preparation. The dissolved Cinryze solution may be stored
at room temperature prior to administration. If not used within 3 hours after
preparation, throw away the Cinryze solution.
SELF ADMINISTRATION
(Intravenous Injection)
Your healthcare provider will
teach you how to safely administer Cinryze. It is important that Cinryze is
injected directly into a superficial vein and not injected into surrounding
tissues and not injected into an artery. Once you learn how to self-administer,
you can follow the instructions in this insert.
1.
Attach a needle or infusion
set with a winged adapter to the syringe containing the dissolved Cinryze
solution. Fill the tubing with dissolved Cinryze by gently pushing the plunger
of the syringe. Be careful not to spill the dissolved Cinryze. This process
replaces the air in the tubing with dissolved Cinryze.
2.
Apply a tourniquet and prepare
the injection site by wiping the skin well with an alcohol swab.
3.
As instructed by your
healthcare provider:
o Insert the butterfly needle of the infusion set tubing into your
vein.
o Remove the tourniquet.
o Make sure that the needle is in a vein.
o Inject the dissolved Cinryze product slowly over ten minutes
(approximately 1mL/min).
4.
After infusing Cinryze, remove
the infusion set and discard. Cover infusion site with an adhesive bandage. The
amount of drug product left in the infusion set will not affect your treatment.
Dispose of all unused solution, the empty vials, and the used needles and
syringe in an appropriate container used for throwing away waste that might
hurt others if not handled properly.
It is a good idea to record
the lot number from the Cinryze vial label every time you use Cinryze.
This Patient Package
Insert has been approved by the U.S. Food and Drug Administration.
Manufactured by:
Sanquin Blood Supply Foundation
Amsterdam, The
Netherlands
Distributed by:
ViroPharma Biologics, Inc.
Exton, PA 19341
U.S. License Number 1833
Mix2Vial® is a registered
trademark of Medimop Medical Projects, Ltd. in the United States and other jurisdictions.
Cinryze™ is a trademark of
ViroPharma Incorporated or its subsidiaries.
©2010 ViroPharma Incorporated.
All rights reserved.
Vial
Label
FOR INTRAVENOUS
INJECTION
49-226
C1
esterase inhibitor (human)
ClNRYZETM
500 u
NDC 42227-081-05
Reconstitute with 5 mL Sterile
Water for Injection, USP.
Use entire contents within 3
hours of reconstitution.
Single-use vial • Rx only • US License No. 1833
Manufactured by Sanquin Blood
Supply Foundation, Amsterdam,
Netherlands 1006 AD, for ViroPharma Biologics, Inc., Exton, PA 19341
Carton
Label
FOR INTRAVENOUS
INJECTION
C1
esterase inhibitor (human)
ClNRYZETM
500 U
Contains 1 single-use vial.
Recommended dose is 1000 U
(2 vials).
Rx only
NDC 42227-081-05
See package insert for full
prescribing
information and
administration.
ViroPharma Biologics,
Inc.
|
Cinryze c1 esterase inhibitor
(human) injection, powder, lyophilized, for solution
|
|
Product
Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:42227-081
|
|
Route of Administration
|
INTRAVENOUS
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
human c1-esterase inhibitor (human c1-esterase inhibitor)
|
human
c1-esterase inhibitor
|
500 [iU]
in 5 mL
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
sodium chloride
|
|
|
sucrose
|
|
|
trisodium citrate dihydrate
|
|
|
Valine
|
|
|
Alanine
|
|
|
Threonine
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:42227-081-05
|
1 VIAL (1 VIAL)
in 1 CARTON
|
|
|
1
|
|
5 mL in 1 VIAL
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
BLA
|
BLA125267
|
12/01/2008
|
|
|
|
Labeler - ViroPharma Biologics (832763085)
|
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Sanquin Blood
Products Foundation, Plasma Products Division
|
|
387373046
|
MANUFACTURE
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
C.A.F.-D.C.F.
cvba-scrl: Centrale Afdeling voor Fractionering van het Rode Kruis cvba -
Departement Central de Fractionnement de la Croix-Rouge S.C.R.L
|
|
375250156
|
MANUFACTURE
|
|
|
|
|
|
|
|
Revised:
11/2010
ViroPharma Biologics
