NDC 42227-083 Cinryze

Human C1-esterase Inhibitor

NDC Product Code 42227-083

NDC 42227-083-01

Package Description: 1 KIT in 1 CARTON * 5 mL in 1 VIAL, SINGLE-USE (42227-081-01) * 5 mL in 1 VIAL, GLASS (64764-515-50)

NDC Product Information

Cinryze with NDC 42227-083 is a a plasma derivative product labeled by Viropharma Biologics Llc. The generic name of Cinryze is human c1-esterase inhibitor. The product's dosage form is kit and is administered via form.

Labeler Name: Viropharma Biologics Llc

Dosage Form: Kit - A packaged collection of related material.

Product Type: Plasma Derivative What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Viropharma Biologics Llc
Labeler Code: 42227
FDA Application Number: BLA125267 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: BLA - A product marketed under an approved Biologic License Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 01-15-2021 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2022 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

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Cinryze Product Label Images

Cinryze Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

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 Only.

2.1 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 DosingIndicationDoseInfusion rateRoutine prophylaxis against HAE attacks1,000 UnitsIntravenousevery 3 or 4 days1 mL/min(10 min)For patients who have not responded adequately to 1,000 U of CINRYZE every 3 or 4 days, doses up to 2,500 U (not exceeding 100 U/kg) every 3 or 4 days may be considered based on individual patient response

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.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

  • Protect CINRYZE from light prior to reconstitution.A silicone-free syringe is recommended for reconstitution and administration of CINRYZE.Inspect the reconstituted product for particulate matter prior to administration; do not use if particles are observed or if solution is turbid. The reconstituted solution is colorless to slightly blue.Each vial of CINRYZE is for single use only. Promptly use any vial that has been entered and discard partially used vials in accordance with biohazard procedures. CINRYZE contains no preservative.Do not mix CINRYZE with other materials.Do not use if frozen.Do not use after expiration date.

Other

  • Reconstitution:Two vials of reconstituted CINRYZE are combined for a single 1,000 U dose. Sterile Water for Injection, USP, is required and not supplied with CINRYZE.Aseptic technique should be used during the reconstitution procedure.Bring the CINRYZE (powder) and Sterile Water for Injection, USP (diluent) (not supplied) to room temperature if refrigerated.Remove caps from the CINRYZE and diluent vials.Cleanse stoppers with an alcohol wipe or swab, and allow them to dry prior to use.Remove protective covering from the top of the Mix2Vial transfer device package. Do not remove the device from the package.Note: Diluent vial must be accessed prior to the vial of CINRYZE 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.Remove the plastic package and discard it (Figure 2). Take care not to touch the exposed end of the device.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.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 1,000 U 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. For higher doses up to 2,500 U (not exceeding 100 U/kg) additional vial(s) will need to be reconstituted.

Routine ProphylaxisTwenty-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, Crossover, Routine Prophylaxis TrialAdverse ReactionNumber ofAdverseReactionsNumberofSubjects(N = 24)Rash85Headache44Pruritus22Vomiting22In 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 TrialAdverse ReactionNumber (%) of Subjects(N=146) with Adverse ReactionNumber (%) of Infusion Days(N=11,435) with AdverseReactionHeadache28 (19)62 (0.5)Nausea26 (18)29 (0.3)Rash15 (10)30 (0.3)Vomiting15 (10)17 (0.1)Pyrexia7 (5)7 (<0.1)Catheter Site Pain4 (3)5 (<0.1)Dizziness3 (2)4 (<0.1)Erythema3 (2)3 (<0.1)Pruritus3 (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 [5.3])A post-approval open-label study assessed escalating doses of CINRYZE (1,500 U, 2,000 U, 2,500 U every 3 or 4 days) as prophylactic therapy in 20 subjects who had an inadequate response (> 1.0 HAE attack/month, regardless of severity) to 1,000 U every 3 or 4 days. The safety profile of doses up to 2,500 U was consistent with previous clinical trial experience at lower doses.

Risk Summary

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 patientsNo 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.

Data

Animal dataIn 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.

Risk SummaryIt 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.

2.4 Administration

  • Two vials of reconstituted CINRYZE are combined for a single 1,000 U dose.Use Aseptic Technique.After reconstitution, the solution should be clear with no evidence of turbidity. Reconstituted solution should be colorless to slightly blue. Do not use if solution is turbid or otherwise discolored.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.Attach the syringe onto the top of the clear end of the Mix2Vial transfer device by turning it clockwise.Invert the vial and inject air into the solution and then slowly withdraw the reconstituted CINRYZE into the syringe.Detach the syringe from the vial by turning it counterclockwise and releasing it from the clear end of the Mix2Vial transfer device.Using the same syringe, repeat steps 3 to 6 with a second vial of CINRYZE to make the complete dose. CINRYZE should be administered promptly after preparation in the syringe and should not be used if particles are observed or if the solution is turbid.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 Dosage and Administration [2].) Please refer to the illustration in step 3 of the self administration section within the Patient Information Leaflet.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.For higher doses of up to 2,500 U, combine the content of the relevant number of vials.

3 Dosage Forms And Strengths

  • CINRYZE (Freeze-Dried powder for Reconstitution) 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.

4 Contraindications

CINRYZE is contraindicated in patients who have manifested life-threatening immediate hypersensitivity reactions, including anaphylaxis, to the product.

5.1 Hypersensitivity Reactions

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 [17])

5.2 Thromboembolic Events

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 Toxicology and/or Pharmacology [13.2])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.In the post-approval open-label study (n=20) there were no systemic thromboembolic events in subjects who received CINRYZE up to 2.500 U (not exceeding 100 U/kg) every 3 or 4 days for up to 12 months. One subject developed a blood clot in an intravenous central catheter, which was treated without systemic complication. (see Clinical Trials Experience [6.1]).

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 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 Counseling Information [17])

6 Adverse Reactions

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. 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.

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.

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 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.

7 Drug Interactions

No drug interaction studies have been conducted.

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 the randomized, placebo-controlled, crossover, routine prophylaxis trial, were under the age of 18 years (9, 14, and 16 years of age).

8.5 Geriatric Use

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.

10 Overdosage

The maximum dose administered in clinical studies was 4000 Units given over approximately 4 hours and 10,000 Units given over a 7 day period. There have been no overdosages of CINRYZE reported during clinical studies.

11 Description

  • 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 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 4.Table 4 Log10 Virus Reduction Factor for Selected VirusesProcess stepLog10 Virus ReductionEnveloped virusesNon-enveloped virusesHIVBVDVPRVHAVCPVPEG precipitation5.1 ± 0.24.5 ± 0.36.0 ± 0.32.8 ± 0.24.2 ± 0.2Pasteurization> 6.1 ± 0.2> 6.7 ± 0.3> 6.7 ± 0.22.8 ± 0.30.1 ± 0.3Nanofiltration> 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

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.

12.2 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.

12.3 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 in the following table:Table 5 Mean pharmacokinetic parameters of Functional C1 Inhibitor         Numbers in parentheses are number of subjects evaluatedSingle dose = 1,000 UnitsDouble 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 plasmaParametersSingle DoseDouble DoseCbaseline (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 concentration (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.

13.1 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 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 [5.2]).

14 Clinical Studies

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, Crossover, Routine Prophylaxis Trial Prevention of HAE Attacks Clinical Trial Results by SubjectSubjectPercentReduction inAttackFrequency1100%2100%3100%4100%590%688%784%883%978%1076%1160%1247%1343%1443%1532%1631%1725%1821%1910%201%21-8%22-85%Table 7 Summary Statistics on Number of HAE Attacks in the Randomized, Placebo-Controlled, Crossover, Routine Prophylaxis TrialStatisticCINRYZEN=22PlaceboN=22NumberofAttacksMean6.112.7SD5.44.8Median613.5Min06Max1722GEE=GEE: Generalized Estimating Equation Analysis ResultsEffect Assessedp-valueTreatment Effect<0.0001Sequence Effect0.3347Period Effect0.3494Patients 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, Crossover, Routine Prophylaxis Trial Secondary Efficacy Outcomes1 1=mild; 2=moderate; and 3=severe**p<0.01CINRYZEN=22PlaceboN=2295% Confidence Intervalfor Treatment Effect(Placebo minus Cinryze)Mean Severity ofHAE Attacks(Score from 1 to 3)1(SD)1.3 (0.85)1.9 (0.36)0.58**(0.19, 0.97)Mean Duration ofHAE 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)

15 References

  • Davis AE, The pathophysiology of hereditary angioedema. Clin Immunol. 2005; 114:3-9.Arzneimittelkommission der Deutschen Aertzteschaft. Schwerwiegende Thrombenbildung nach Berinert HS. Dtsch Aerztebl. 2000; 97:B-864Horstick, G et al, 2001. Circulation 104:3125-3131

16 How Supplied/Storage And Handling

  • CINRYZE is a lyophilized powder that is supplied in a vacuum-sealed single-use glass vial that contains 500 Units per vial to be reconstituted with 5 mL Sterile Water for Injection, USP (Not supplied). It is packaged for sale, and is stable for the period stated on the vial and carton label 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.Do not use beyond the expiration date on the vial of CINRYZE.NDC Number for the Vial: NDC 42227-081-01.NDC Number for the Carton: NDC 42227-081-05.

17 Patient Counseling Information

  • See FDA-approved patient labeling (Information for the Patient).Inform patients to immediately report the following to their physician:Signs of allergic-type hypersensitivity reactions including hives (itchy white elevated patches), tightness of the chest, wheezing, hypotension and anaphylaxis [5.1]. Advise patients to discontinue use of CINRYZE and contact their physicians if these symptoms occur.Signs of a thromboembolic event including pain and/or swelling of an arm or leg with warmth over the affected area, discoloration of an arm or leg, unexplained shortness of breath, chest pain or discomfort that worsens on deep breathing, unexplained rapid pulse, numbness or weakness on one side of the body.Advise patients with known risk factors for thromboembolic events that they may be at increased risk for these events.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.Based on their current regimen, advise patients to bring an adequate supply of CINRYZE for routine prevention when traveling.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 disease (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.

Spl Patient Package Insert

  • FDA-Approved Patient LabelingInformation for the PatientCINRYZE® (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 youhave an indwelling catheter/access device in one of your veins.have a history of blood clots, heart disease, or stroke.are taking birth control pills or androgens.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.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:wheezingdifficulty breathingchest tightnessturning blue (look at lips and gums)fast heartbeatswelling of the facefaintnessrashhivesSerious 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: pain and/or swelling of an arm or leg with warmth over the affected areadiscoloration of an arm or legunexplained shortness of breathchest pain or discomfort that worsens on deep breathingunexplained rapid heart ratenumbness or weakness on one side of the bodyThe 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 UseDo 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 CINRYZEAlways 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 1,000 U dose. You should reconstitute both vials according to steps 1 through 6. Your healthcare provider may decide you require higher doses of CINRYZE. You should always follow the specific instructions given by your healthcare provider.Let the vial of CINRYZE and the vial of Sterile Water for Injection, USP (diluent) reach room temperature.Remove the cap from the vial of CINRYZE and Sterile Water for Injection, USP (diluent) vial to show the center part of the rubber stopper.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. 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 transfer device 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.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 vial of CINRYZE, pushing down until the spike penetrates the rubber stopper and the device snaps in place. The Mix2Vial transfer device must be positioned completely upright before penetrating the rubber stopper. The Sterile Water for Injection, USP, will automatically flow into the vial of CINRYZE because the vacuum in the vial will draw the Sterile Water for Injection, USP, into the vial of CINRYZE. If this does not happen, do not use the product.Once all the Sterile Water for Injection, USP, is in the CINRYZE vial, gently swirl (do not shake) the vial of CINRYZE 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 transfer device from the vial of CINRYZE.Look at the final solution before using it to make sure that CINRYZE is completely dissolved. The solution should be clear with no evidence of cloudiness. Reconstituted solution should be colorless to slightly blue. Do not use if solution is cloudy or otherwise discolored and call Shire Medical Information at 1-800-828-2088 for further instructions.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 1,000 U dose. Repeat steps 1-6 using a new Mix2Vial transfer device. Do not reuse the Mix2Vial transfer device. CINRYZE should be administered within 3 hours of reconstitution.Utilizing a sterile, disposable 10mL syringe, draw back the plunger to allow approximately 5mL of air into the syringe. Use of a silicone-free syringe is recommended.Attach the syringe onto the clear end of the Mix2Vial transfer device by turning it clockwise.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.Dispose of the vials with the Mix2Vial transfer device attached to them.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.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.Apply a tourniquet and prepare the injection site by wiping the skin well with an alcohol swab.As instructed by your healthcare provider:Insert the butterfly needle of the infusion set tubing into your vein.Remove the tourniquet.Make sure that the needle is in a vein.Inject the dissolved CINRYZE product slowly over ten minutes (approximately 1mL/min).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 for: Shire ViroPharma IncorporatedLexington, MA 02421-2101Mix2Vial® is a registered trademark of Medimop Medical Projects, Ltd. in the United States and other jurisdictions.CINRYZE® is a trademark of Shire ViroPharma Incorporated or its subsidiaries.U.S. License Number 1833©2017 Shire ViroPharma Incorporated. All rights reserved.

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