HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use CINRYZE®
`safely and effectively. See full prescribing information for CINRYZE.
`CINRYZE® (C1 Esterase Inhibitor [Human])
`For Intravenous Use, Freeze-Dried Powder for Reconstitution
`Initial U.S. Approval: 2008
`RECENT MAJOR CHANGES
`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).
`DOSAGE AND ADMINISTRATION
`• Intravenous Use Only
`• Prior to reconstitution, protect from light.
`• A silicone-free syringe is recommended
`• Store at 2 C - 25 C (36 F - 77 F). Do not freeze.
`• To obtain the required dose, reconstitute two CINRYZE vials with two vials Sterile
`Water for Injection, USP (5 mL each) using aseptic sterile technique.
`• Administer at room temperature within 3 hours of reconstitution.
`
`Routine Prophylaxis Dosing
`
`Indication
`
`Dose
`
` Infusion rate
`
`1 mL/min
`(10 min)
`
`1,000 Units Intravenous
`Routine prophylaxis
`every 3 or 4 days
`against HAE attacks
`DOSAGE FORMS AND STRENGTHS
`Approximately 500 Units (lyophilized) in an 8 mL vial.
`CONTRAINDICATIONS
`Patients who have manifested life-threatening immediate hypersensitivity reactions,
`including anaphylaxis, to the product (4).
`WARNINGS/PRECAUTIONS
`• Hypersensitivity reactions may occur. Have epinephrine immediately available
`for treatment of acute severe hypersensitivity reaction (5.1).
`• Thrombotic events have been reported in patients receiving CINRYZE for routine
`prophylaxis. Thrombotic events also have been reported in patients receiving off-label
`high dose C1 esterase inhibitor therapy (5.2). Monitor closely patients with known risk
`factors for thrombotic events.
`
`• CINRYZE is made from human plasma and may contain infectious agents, e.g.
`viruses and, theoretically, the Creutzfeldt-Jakob disease agent. (5.3)
`ADVERSE REACTIONS
`The most common adverse reactions observed were headache, nausea, rash, and
`vomiting. (5.1, 6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact ViroPharma Medical
`Information at (866) 331-5637 or the FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`
`USE IN SPECIFIC POPULATIONS
`Pregnancy: No human or animal data. Use only if clearly needed. (8.1)
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-approved
`patient labeling.
`
`Revised: November 2012
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1 INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`2.1 Routine Prophylaxis against HAE attacks
`2.2 Instructions for use
`2.3 Preparation and Handling
`2.4 Administration
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Hypersensitivity Reactions
`5.2 Thrombotic Events
`5.3 Transmissible Infectious Agents
`
`FULL PRESCRIBING INFORMATION
`CINRYZE® (C1 Esterase Inhibitor [Human])
`Freeze-Dried Powder for Reconstitution
`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 Dosing
`
`Indication
`
`Dose
`
`Infusion rate
`
`1 mL/min
`(10 min)
`
`1,000 Units Intravenous
`every 3 or 4 days
`
`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.
`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.
`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 5
`
`Figure 4
`2.4 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 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.
`
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience
`7 DRUG INTERACTIONS
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Labor and Delivery
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`10 OVERDOSAGE
`11 DESCRIPTION
`
`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.
`(See DOSAGE AND ADMINISTRATION [2]) 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.
`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 WARNINGS AND PRECAUTIONS
`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 Thrombotic Events
`Thrombotic events have been reported following administration of 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. Monitor closely patients with known risk factors for thrombotic
`events.
`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
`ViroPharma Medical Information [(866) 331-5637]. 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.
`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.
`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.
`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
`Number of
`Number of
`Adverse Reaction
`Subjects (N = 24)
`Adverse Reactions
`5
`8
`Rash
`4
`4
`Headache
`2
`2
`Pruritus
`2
`2
`Vomiting
`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
`Number (%) of
`Number (%) of
`Infusion Days
`Subjects (N=146)
`(N=11,435) with
`with Adverse
`Adverse Reaction
`Reaction
`28 (19)
`62 (0.5)
`Headache
`26 (18)
`29 (0.3)
`Nausea
`15 (10)
`30 (0.3)
`Rash
`15 (10)
`17 (0.1)
`Vomiting
`7 (5)
`7 (<0.1)
`Pyrexia
`4 (3)
`5 (<0.1)
`Catheter Site Pain
`3 (2)
`4 (<0.1)
`Dizziness
`3 (2)
`3 (<0.1)
`Erythema
`3 (2)
`4 (<0.1)
`Pruritus
`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 Section 5 3 Transmissible Infectious Agents)
`
`Adverse Reaction
`
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.2 Animal Toxicology and/or Pharmacology
`14 CLINICAL STUDIES
`15 REFERENCES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`*Sections or subsections omitted from the full prescribing information are not listed
`
`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).
`Postmarketing thrombotic 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 USE IN SPECIFIC POPULATIONS
`8.1 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.
`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 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 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 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 Section 13.2
`Animal Toxicology and/or Pharmacology and Section 5.2 Thrombotic events in
`WARNINGS AND PRECAUTIONS)
`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 Viruses
`Log10 Virus Reduction
`Enveloped viruses
`Non-enveloped viruses
`PRV
`BVDV
`HAV
`CPV
`HIV
`PEG
`6.0 ± 0.3
`4.5 ± 0.3
`2.8 ± 0.2
`4.2 ± 0.2
`5.1 ± 0.2
`precipitation
`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
`> 16.8
`> 16.7
`> 19.1
`> 10.5
`> 8.7
`reduction
`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 bradykinin.1 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.
`
`Process step
`
`Page 1 of 2
`
`CSL EXHIBIT 1010
`
`

`

`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
`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 parentheses 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
`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
`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 Subject
`Percent Reduction
`Subject
`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, Crossover, Routine Prophylaxis Trial
`Statistic
`CINRYZE N=22
`Placebo N=22
`Mean
`6.1
`12.7
`SD
`5.4
`4.8
`Median
`6
`13.5
`Min
`0
`6
`Max
`17
`22
`GEE Analysis Results
`
`Number
`of Attacks
`
`p-value
`Effect Assessed
`<0.0001
`Treatment Effect
`0.3347
`Sequence Effect
`0.3494
`Period Effect
`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, Crossover, Routine
` Prophylaxis Trial: Secondary Efficacy Outcomes
`
`CINRYZE
`N=22
`
`Placebo
`N=22
`
`1.3 (0.85)
`
`1 9 (0.36)
`
`95% Confidence
`Interval for
`Treatment Effect
`(Placebo minus
`CINRYZE)
`0.58**
`(0.19, 0.97)
`
`1.23**
`(0.49, 1.96)
`19.5**
`(11.94, 27.06)
`
`2.1 (1.13)
`
`3.4 (1.4)
`
`10.1 (10.73)
`
`29.6 (16.9)
`
`Mean Severity of
`HAE Attacks (Score
`from 1 to 3)1 (SD)
`Mean Duration of
`HAE Attacks (Days)
`(SD)
`Days of Swelling
`(SD)
`1 1=mild; 2=moderate; and 3=severe
`**p<0.01
`15 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
`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 Carton and Vial: NDC 42227-081-05.
`
`17 PATIENT COUNSELING INFORMATION
`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.
`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.
`FDA-Approved Patient Labeling
`Information for the Patient
`CINRYZE® (SIN-rise)
`(C1 Esterase Inhibitor [Human])
`This leaflet summarizes important information about CINRYZE. Please read it
`carefully before using CINRYZE and each time you get a refill. There may be new
`information. This information does not take the place of talking with your healthcare
`provider, and it does not include all of the important information about CINRYZE.
`If you have any questions after reading this, ask your healthcare provider.
`Do not attempt to self-administer unless you have been taught how by your
`healthcare provider.
`What is CINRYZE?
`CINRYZE is an injectable medicine that is used to help prevent swelling and/or
`painful attacks in teenagers and adults with Hereditary Angioedema (HAE). HAE is
`caused by the decreased functioning of a protein called C1 esterase inhibitor that is
`present in your blood and helps control inflammation (swelling) and parts of the
`immune system. CINRYZE contains C1 esterase inhibitor. Before you can inject
`CINRYZE into your vein (intravenous injection), you must dissolve the CINRYZE
`powder using Sterile Water for Injection, USP. You can get supplies, including
`Sterile Water for Injection, USP from your pharmacist.
`Who should not use CINRYZE?
`You should not use CINRYZE if you have had life-threatening immediate
`hypersensitivity reactions, including anaphylaxis to the product.
`What should I tell my healthcare provider before using CINRYZE?
`Tell your healthcare provider about all of your medical conditions, including if you
`• are pregnant or planning to become pregnant. It is not known if CINRYZE can
`harm your unborn baby.
`• are breastfeeding or plan to breastfeed. It is not known if CINRYZE passes into
`your milk and if it can harm your baby.
`• have a history of blood clotting problems. Very high doses of C1 esterase inhibitor
`could increase the risk of blood clots.
`Tell your healthcare provider and pharmacist about all of the medicines you take,
`including all prescription and non-prescription medicines such as over-the-counter
`medicines, supplements, or herbal remedies.
`What are the possible side effects of CINRYZE?
`Allergic reactions may occur with