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human c1-esterase inhibitor injection, powder, lyophilized, for solution
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
CINRYZE is a C1 esterase inhibitor indicated for routine prophylaxis against angioedema attacks in adolescent and adult patients with Hereditary Angioedema (HAE).
2 DOSAGE AND ADMINISTRATION
For Intravenous Use, Freeze-Dried powder for Reconstitution.
2.1 Routine prophylaxis against HAE Attacks
2.2 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.
2.3 Preparation and Handling
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.
Two vials of reconstituted CINRYZE are combined for a single dose.
3. DOSAGE FORMS AND STRENGTHS
CINRYZE is contraindicated in patients who have manifested life-threatening immediate hypersensitivity reactions, including anaphylaxis to the product.
5 WARNINGS AND PRECAUTIONS
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 )
5.2 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.
5.3 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 . 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 )
6 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.
6.1 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.
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:
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.
6.2 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)
8 USE IN SPECIFIC POPULATIONS
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.
8.2 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.
8.3 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.
8.4 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).
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 (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:
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.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism 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.
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:
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.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No animal studies have been completed to evaluate the effects of CINRYZE on carcinogenesis, mutagenesis, and impairment of fertility.
13.2 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).
14 CLINICAL STUDIES
14.1 Routine 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:
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.
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Allergic-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.
Advise female patients to notify their physician if they become pregnant or intend to become pregnant during their routine prevention with CINRYZE.
Advise patients to notify their physician if they are breastfeeding or plan to breastfeed.
17.4 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.
17.5 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
(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
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:
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.
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.
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
Distributed by: ViroPharma Biologics, Inc.
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.
FOR INTRAVENOUS INJECTION
C1 esterase inhibitor (human)
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
FOR INTRAVENOUS INJECTION
C1 esterase inhibitor (human)
Contains 1 single-use vial.
Recommended dose is 1000 U
See package insert for full prescribing
information and administration.
ViroPharma Biologics, Inc.
Revised: 11/2010 ViroPharma Biologics
Reproduced with permission of U.S. National Library of Medicine
Copyright © 2020
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