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CINRYZE
(C1 Esterase Inhibitor [Human]) Freeze Dried Powder
CINRYZE (C1 esterase inhibitor [human]) (Freeze-Dried powder for Reconstitution) 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 LValine, 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:
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 log reductions are shown in Table 4.
Table 4 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 is a C1 esterase inhibitor indicated for routine prophylaxis against angioedema attacks in adolescent and adult patients with Hereditary Angioedema (HAE).
For Intravenous Use Only.
Table 1 Routine Prophylaxis Dosing
| Indication | Dose | Infusion rate |
| Routine prophylaxis against HAE attacks | 1,000 Units Intravenous every 3 or 4 days | 1 mL/min (10 min) |
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.
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.
Two vials of reconstituted CINRYZE are combined for a single dose. Sterile Water for Injection, USP, is required and not supplied with 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. CINRYZE must be administered at room temperature within 3 hours after reconstitution.
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Two vials of reconstituted CINRYZE are combined for a single dose.
Manufactured by: Sanquin Plasma Products B.V. Amsterdam, The Netherlands. Revised: June 2016
The only serious adverse reaction observed in clinical studies of CINRYZE was cerebrovascular accident.
The most common adverse reactions observed were headache, nausea, rash, and vomiting.
Because CINRYZE is a therapeutic protein, there is potential for immunogenicity. Using a validated assay there was no evidence of antibody development following administration of CINRYZE. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of anti-C1 Esterase Inhibitor antibody positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibody development across products cannot be made.
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.
Twenty-four subjects were evaluated in the randomized, placebo-controlled, crossover, routine prophylaxis trial.
There were no serious adverse reactions in the randomized, placebo-controlled, crossover, routine prophylaxis trial.
Adverse reactions in the randomized, placebo-controlled, crossover, routine prophylaxis trial (n=24) that occurred in at least two subjects (≥8%) receiving CINRYZE are given in the following table:
Table 2 Adverse Reactions in the Randomized, Placebo-Controlled, Cross over, Routine
Prophylaxis Trial
| Adverse Reaction | Number of Adverse Reactions | Number
of
Subjects (N = 24) |
| Rash | 8 | 5 |
| Headache | 4 | 4 |
| Pruritus | 2 | 2 |
| Vomiting | 2 | 2 |
In an open-label follow-on trial, 146 patients received a median of 243.5 days of CINRYZE (maximum = 959 days). The most common adverse reaction observed was headache. No patients were discontinued due to an adverse reaction.
Adverse reactions in the open-label follow-on trial (n=146) that occurred in at least three subjects (≥2%) receiving CINRYZE, are given in the following table:
Table 3 Adverse Reactions in the Open-Label Follow-On Trial
| Adverse Reaction | Number (%) of Subjects (N=146) with Adverse Reaction |
Number (%) of Infusion Days (N=11,435) with Adverse Reaction |
| Headache | 28 (19) | 62 (0.5) |
| Nausea | 26 (18) | 29 (0.3) |
| Rash | 15 (10) | 30 (0.3) |
| Vomiting | 15 (10) | 17 (0.1) |
| Pyrexia | 7 (5) | 7 (<0.1) |
| Catheter Site Pain | 4 (3) | 5 (<0.1) |
| Dizziness | 3 (2) | 4 (<0.1) |
| Erythema | 3 (2) | 3 (<0.1) |
| Pruritus | 3 (2) | 4 (<0.1) |
More than 14,000 doses of CINRYZE have been administered to over 260 different patients in all completed, controlled and open-label clinical studies. All patients who were evaluated were found negative for seroconversion to parvovirus B19, Hepatitis B, Hepatitis C and HIV. (See Transmissible Infectious Agents)
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 inflammation or hematoma at the infusion site) and hypersensitivity.
Postmarketing thromboembolic events have been reported, including catheter-related and deep venous thromboses, transient ischemic attack, and stroke.
No drug interaction studies have been conducted.
Included as part of the "PRECAUTIONS" Section
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.
Consider treatment methods carefully, because hypersensitivity reactions may have symptoms similar to HAE attacks.
In case of hypersensitivity, discontinue CINRYZE infusion and institute appropriate treatment. Have epinephrine immediately available for treatment of acute severe hypersensitivity reaction. (See Patient Counseling Information)
Serious arterial and venous thromboembolic (TE) events have been reported at the recommended dose of C1 Esterase Inhibitor (Human) products, including CINRYZE, following administration in patients with HAE. Risk factors may include presence of an indwelling venous catheter/access device, prior history of thrombosis, underlying atherosclerosis, use of oral contraceptives, certain androgens, morbid obesity, and immobility. Benefits of CINRYZE for routine prophylaxis of HAE attacks should be weighed against the risks of TE events in patients with underlying risk factors. Monitor patients with known risk factors for TE events during and after CINRYZE administration.
TE events have been reported following administration of a C1 Esterase Inhibitor (Human) product when used off-label at higher than labeled doses2,3. (see Animal Pharmacology)
In an open-label trial further investigating the use of CINRYZE for prevention (n=146) of HAE attacks, 5 serious thromboembolic events (including myocardial infarction, deep vein thrombosis, pulmonary embolism and 2 events of cerebrovascular accident) occurred. Subjects had underlying risk factors for thromboembolic events.
Because CINRYZE is made from human blood, it may carry a risk of transmitting infectious agents, e.g. viruses, and, theoretically, the Creutzfeldt-Jakob disease (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 Shire Medical Information. [1-800-828-2088]. The physician should discuss the risks and benefits of this product with the patient, before prescribing or administering it to the patient. (See PATIENT INFORMATION)
See FDA-approved patient labeling (PATIENT INFORMATION).
No animal studies have been completed to evaluate the effects of CINRYZE on carcinogenesis, mutagenesis, and impairment of fertility.
Background risk (general population)
A review of available data suggests that major birth defects occur in 2-4% of the U.S. general population and that miscarriage occurs in 15-20% of clinically recognized pregnancies, regardless of drug exposure.
Risk in CINRYZE patients
No adequate and well-controlled studies of CINRYZE 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.
The safety and effectiveness of CINRYZE administration prior to or during labor and delivery have not been established. Use only if clearly needed.
Animal data
In an embryofetal development study (C1 inhibitor administered during the period of organogenesis) in rats, there was no maternal or fetal toxicity at doses up to 400 Units/kg/day that provided an exposure similar to that in humans after a 1000 Unit dose.
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.
The safety and effectiveness of CINRYZE have not been established in neonates, infants, or children. Three of the 24 subjects in the randomized, placebo-controlled, crossover, routine prophylaxis trial, were under the age of 18 years (9, 14, and 16 years of age).
The randomized, placebo-controlled, crossover, routine prophylaxis trial did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently from younger subjects.
REFERENCES
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
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.
CINRYZE is contraindicated in patients who have manifested life-threatening immediate hypersensitivity reactions, including anaphylaxis to the product.
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.
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.
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 5 Mean pharmacokinetic parameters of Functional C1 Inhibitor
| 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) |
| 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 |
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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.
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 followed by a pivotal 14-day repeat dose study. The acute and 14-day repeat 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 or repeat dose studies. Repeat dosing in the rat resulted in an antibody response between days 1 and 14 that was not characterized for neutralizing activity. However, there was no change in the functional activity of CINRYZE over the dosing period.
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 with another C1 esterase inhibitor product 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 Thromboembolic Events in WARNINGS AND PRECAUTIONS).
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 6:
Table 6 The Randomized, Placebo-Controlled, Cross over, Routine Prophylaxis Trial 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 7 Summary Statistics on Number of HAE Attacks in the Randomized, Placebo-Controlled,
Cross over, Routine Prophylaxis Trial
| 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 8.
Table 8 The Randomized, Placebo-Controlled, Cross over, Routine Prophylaxis Trial Secondary
Efficacy Outcomes
| CINRYZE N=22 |
Placebo N=22 |
95% Confidence Interval
for Treatment Effect (Placebo minus Cinryze) |
|
| Mean Severity of
HAE Attacks (Score from 1 to 3)1 (SD) |
1.3 (0.85) | 1.9 (0.36) | 0.58** (0.19, 0.97) |
| Mean Duration of
HAE Attacks (Days ) (SD) |
2.1 (1.13) | 3.4 (1.4) | 1.23** (0.49, 1.96) |
| Days of Swelling (SD) |
10.1 (10.73) | 29.6 (16.9) | 19.5** (11.94, 27.06) |
| 1=mild; 2=moderate; and 3=severe **p<0.01 |
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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
CINRYZE®
(SIN-rise)
(C1 Esterase Inhibitor [Human])
Freeze Dried Powder
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
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:
Serious blood clots may occur with CINRYZE. Call your healthcare provider or get emergency support services right away if you have any of the following symptoms:
The most common side effects seen with CINRYZE were headache, nausea, rash, and vomiting.
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 Shire Medical Information at 1-800-828-2088 or 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.
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.
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CINRYZE should be administered at room temperature promptly after preparation in the syringe.
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.
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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.
