Drug: Cinryze

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 LAlanine, 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 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

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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. 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 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 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 WARNINGS AND PRECAUTIONS, Transmissible Infectious Agents) 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. Read the Cinryze (c1 esterase inhibitor [human] freeze dried powder) Side Effects Center for a complete guide to possible side effectsLearn More »

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For Intravenous Use Only. 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 Infusion rate Routine prophylaxis against HAE attacks 1,000 Units Intravenous every 3 or 4 days 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. 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
  • 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.
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 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.
  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. CINRYZE must be administered at room temperature within 3 hours after reconstitution. Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Administration Two vials of reconstituted CINRYZE are combined for a single dose.
  1. Use Aseptic Technique.
  2. 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.
  3. 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.
  4. Attach the syringe onto the top of the clear end of the Mix2Vial transfer device by turning it clockwise.
  5. Invert the vial and inject air into the solution and then slowly withdraw the reconstituted CINRYZE into the syringe.
  6. Detach the syringe from the vial by turning it counterclockwise and releasing it from the clear end of the Mix2Vial transfer device.
  7. Using the same syringe, repeat steps 3to 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.
  8. 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. Please refer to the illustration in step 3 of the self administration section within the PATIENT INFORMATION Leaflet.
  9. 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.

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No drug interaction studies have been conducted. Read the Cinryze Drug Interactions Center for a complete guide to possible interactions Learn More »

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CINRYZE is a C1 esterase inhibitor indicated for routine prophylaxis against angioedema attacks in adolescent and adult patients with Hereditary Angioedema (HAE).

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CINRYZE is contraindicated in patients who have manifested life-threatening immediate hypersensitivity reactions, including anaphylaxis to the product. Last reviewed on RxList: 12/2/2014
This monograph has been modified to include the generic and brand name in many instances.

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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.

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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.
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 Carton and Vial: NDC 42227-081-05.
Manufactured by: Sanquin Blood Supply Foundation, Amsterdam, The Netherlands. Distributed by: ViroPharma Biologics, Inc., Lexington, MA 02421-2101. Revised: Aug 2014 Last reviewed on RxList: 12/2/2014
This monograph has been modified to include the generic and brand name in many instances.

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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 INFORMATION) 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 offlabel at higher than labeled doses2,3. (see Section titled 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 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. 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. [1-866-888-0660]. 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) 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 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. 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. 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.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility No animal studies have been completed to evaluate the effects of CINRYZE on carcinogenesis, mutagenesis, and impairment of fertility. Use In Specific Populations Pregnancy 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 the randomized, placebo-controlled, crossover, routine prophylaxis trial, were under the age of 18 years (9, 14, and 16 years of age). 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. Last reviewed on RxList: 12/2/2014
This monograph has been modified to include the generic and brand name in many instances.

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