`
`PRODUCT
`
`PROFILER
`
`
`
`Berinert®
`
`C1 Esterase Inhibitor (Human)
`
`For Treatment of Acute Abdominal or Facial Attacks
`
`of Hereditary Angioedema
`
`Contents
`
`0
`
`Introduction
`
`0 Epidemiologic Burden
`
`0 Current Treatment Options
`
`0 Product Information
`
`0 Dosage and Administration
`
`0 Storage and Handling
`
`0 Clinical Trial Summary
`
`0 Safety
`
`0 P&T Committee Considerations
`
`0 The Berinert" Expert Network (B.E.N.T”')
`
`0 Conclusion
`
`0 References
`
`0 Full Prescribing Information
`
`SECTION TWO
`
`Vol. 35, Issue 7/July 2010
`
`Page 1 of 48
`
`CSL EXHIBIT 1097
`
`

`

`
`
` THE PRODUCT PROFILER
`The Product Profiler provides P&T committee members with current, detailed
`
`information about a specific therapeutic agent to help them manage their formula-
`
`ries and establish medication-related policies. The Profiler provides information
`
`about pharmacology, clinical studies and FDA-approved indications, safety, efiicacy,
`
`acquisition costs, and other pharmacoeconomic variables, along with additional P&T
`
`committee considerations, in a convenient package. Articles are written by experts
`
`in the field.
`
`
`
`
`Editorial Director: Alan Caspi, PhD,
`PharmD, MBA
`
`Editor, P&T”: Sonja Sherritze
`(267) 685-2779
`ssherritze@medimediacom
`
`Associate Editor: Carol Robins
`
`Design Director: Philip Denlinger
`
`Chief Medical Editor:
`Michele Reed, PharmD
`
`Editor of this Product Profiler:
`Amy Krajacic
`Assistant Editor:
`Alina Nar‘done
`
`President and Group Publisher:
`Timothy P. Search, RPh
`
`Director of New
`Product Development:
`Timothy J. Stezzi
`Director of Production Services:
`Waneta Peart
`
`Ofi‘ice fax: (267) 685-2966
`
`Trademark: P&T° is a registered trade-
`mark of MediMedia USA, Inc.
`Publisher: P&T° is a peer-reviewed journal
`for managed care and hospital forrnulary
`management (ISSN 1052-1372) (GST
`#128741063) (1PM #0608025) and is published
`monthly by MediMedia USA, Inc., with busi-
`ness offices at 780 Township Line Road, Yard-
`ley, PA 19067; telephone: (267) 685-2788; fax:
`(267) 685-2966.
`Copyright: Copyright 2010 by MediMedia
`USA, Inc. All rights reserved under the United
`States, International, and Pan-American
`Copyright Conventions. No part of this publi-
`cation may be reproduced, stored in a
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`POSTMASTER: Send address changes to
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`odicals postage paid at Morrisville Pa_, and at
`additional mailing offices
`
`ABOUT THE AUTHORS
`Carole Alison Chrvala, PhD, is president of Health Matters, Inc., an independ-
`ent medical writing and research consulting company in Hillsborough, North Car-
`olina.
`Trained as an epidemiologist at the University of Colorado, Dr. Chrvala is a sea-
`soned researcher and medical writer with 22 years experience in chronic disease
`screening, diagnosis, treatment, and evaluation. Highlighting a career that spanned
`the public and private health sectors, Dr. Chrvala was director of Cancer Prevention
`and Control for the Colorado Department of Public Health and Environment
`(CDPHE). During her tenure at CDPHE, she was a principal investigator or co-prin-
`cipal investigator on more than 10 grants, contracts, and cooperative agreements with
`a cumulative total award exceeding $100 million. Dr. Chrvala also served as invited
`reviewer for several National Institutes of Health (NIH) grant review panels, and
`has had the honor of participating on a variety of advisory boards and steering com-
`mittees on cancer, diabetes, cardiovascular disease, HIV/AIDS, and women‘s health.
`Dr. Chrvala was also employed as a senior program officer at the National Acad-
`emies of Sciences, in Washington, D.C., and as a senior scientist with the U.S. Food
`and Drug Administration, in Bethesda, Md Dr. Chrvala is a member of the American
`Heart Association, American Medical Writers Association, American Society of Clin-
`ical Oncology, American University Women’s Association, Healthcare Business
`Women’s Association, National Association of Medical Communicators, National
`Breast Cancer Coalition, and the Society for Epidemiologic Research. Dr. Chrvala has
`served as the chair of the National Breast Cancer Screening Surveillance Consortium
`and chaired a review panel on the final Mammography Quality Standards Act. She
`provided training and technical assistance to the US. Centers for Disease Control
`and Prevention and served as a consultant to numerous state agencies to support
`implementation of the National Breast and Cervical Cancer Early Detection Pro-
`gram. Dr. Chrvala has written and presented on a wide variety of health topics to more
`than 75 professional audiences and organizations.
`In 2005, Dr. Chrvala founded Health Matters, Inc., to support the development of
`scientifically rigorous medical publications tailored to meet the unique informa-
`tional and educational needs of physicians and other healthcare professionals. Cur-
`rent writing and research activities include manuscripts for peer-reviewed journals,
`continuing medical education, and summaries of key findings presented at profes
`sional conferences, advisory boards, and syrnposia In addition, Dr. Chrvala also pro-
`vides epidemiologic consulting services to a number of federal, state, and local health
`agencies, academic irstitrrtions, pharmaceutical companies, medical education organ-
`izations, and medical communication organizations.
`
`Alan Caspi, PhD, PharmD, MBA, is president of Caspi & Associates in New
`York, New York. Dr. Caspi was formerly director of pharmacy at Ienox Hill Hospi-
`tal in New York for 20 years. Among his many honors, he has received the Merck
`Sharp & Dohme Award for Outstanding Achievement in Pharmacy and the Presi-
`dent‘s Award from the New York State Council of Hospital Pharmacists.
`He served as affiliate associate clinical professor at St. John's University College
`of Pharmacy and as adjunct clinical instructor at the Arnold and Marie Schwartz
`College of Pharmacy and Health Sciences of Long Island University.
`His memberships have included the New York State Council of Hospital Pharma-
`cists and the American Pharmaceutical Association. He also has been recognized as
`a Fellow of the American Society of Hospital Pharmacists.
`Dr. Caspi has served on the editorial advisory boards of The Pharmaceutical
`Biotechnology Monitor. Biotechnology Issues for the Pharmacist and Global Med-
`ical Communications. He currently serves on the editorial board of P&T and coor-
`dinates the journal's Drug Forecast department.
`
`DISCLOSURES
`Carole Alison Chrvala, PhD, and Alan Caspi, PhD, PharmD, MBA, both report that
`they have no financial arrangements or afiiliations that might constitute a conflict
`of interest with respectto this publication. CSL Behring provided funding for this pub-
`lication.
`
`
`
`Page 2 of 48
`
`

`

`PRODUCT PROFILER
`
`Berinerfi
`Cl Esterase Inhibitor (Human)
`
`INTRODUCTION ...................................................................................................................... 2
`
`EPIDENIIOLOGIC BURDEN ....................................................................................................... 2
`
`3
`
`PRODUCT INFORMATION ......................................................................................................... 4
`Indications and Usage ............................................................................................................. 4
`Description .......................................................................................................................... 4
`Clinical Pharmacology ............................................................................................................ 5
`6
`
`STORAGEAND HANDLING ........................................................................................................ 6
`
`CLINICAL-TRIAL SUMMARY
`
`...7
`
`Efficacy of Human Cl Esterase Inhibitor Concentrate Compared with Placebo in Acute Hereditary
`Angioedema Attacks ............................................................................................................... 1
`SAFETY"...
`...12
`Contraindications .................................................................................................................
`12
`12
`13
`
`Warnings and Precautions ......................................................................................................
`Adverse Reactions ................................................................................................................
`
`THE BERINER'I'm EXPERT NETWORK(BENW)
`
`14
`
`16
`
`11
`
`11
`
`19
`
`This section of P&T Is supported by CSL Behring.
`
`Page 3 0f 48
`
`

`

`PRODUCT PROFILER: Berinert"
`
`Berinerif
`Cl Esterase Inhibitor (Human)
`
`INTRODUCTION
`Type I and II hereditary angioedema (HAE) are auto-
`somal dominant inherited disorders caused by a qualita-
`tive or quantitative deficiency of the serine protease
`inhibitor, Cl esterase inhibitor (Cl-INH) (Agostini 2004,
`Frank 1976). Estimates suggest that 80% to 85% of patients
`are affected With type I HAE characterized by antigenic
`and functional plasma Cl-INH levels that are 5% to 30%
`below normal levels (Table 1) (Frank 1976, Nzeako 2001).
`Among the remaining 10% to 1.5% of patients with type II
`HAE, normal or increased levels of Cl-INH are produced
`with decreased C1 inhibitor activity attributed to secre—
`tion of a dysfunctional C1 inhibitor protein (Nzeako 2001).
`Deficiencies in C l-INH activate various systems including
`the contact system, also known as the kallikrein—kinin
`system (Nzeako 2001). Reduced levels of Cl-INH and dys-
`functional Cl-INH prevent autoactivation of the Cl com-
`plement system and impair production of coagulation fac-
`tors XIIa, XIIf, and Xla (Nzeako 2001). CI-INH is a direct
`inhibitor of activated kallikrein (Figure 1) (Agostini 2004).
`Cl-INH deficiencies also affect the complement pathway,
`fibrinolytic system, and the intrinsic coagulation path-
`way (Frank 1976). Activation of each of these systems
`results in the release of vasoactive peptides, such as
`bradykinin, and this release of bradykinin increases the
`permeability of vascular tissue, resulting in angioedema
`(Davis 2006, Zuraw 2008). HAE typically manifests as
`acute attacks with nonpruritic, nonpitting, sub cutaneous,
`or submucosal edema, with the most frequently affected
`areas including the arms, legs, hands, feet, bowels, geni-
`talia, trunk, face, tongue, and larynx (Zuraw 2008).
`
`TABLE 1
`
`Features of HAE by Type
`
`Type
`of HAE
`
`Type |
`
`Type II
`
`Percentage of
`patients
`80-85%
`
`10-15%
`
`Antigenic
`C1 levels
`
`Functional
`C1 levels
`
`Low
`
`Low
`
`
`
`Type I”
`
`<1% m Low
`
`Epidemiologic Burden
`Prevalence estimates for HAE are difficult to determine
`due to a low awareness of the condition and the resem-
`
`blance of symptoms to other disorders resulting in
`delayed or incorrect diagnoses (Agostini 2004). The aver-
`age time between onset of first symptoms and diagnosis
`in 1976 was 21 years, with a recent survey of 457 patients
`with HAE reporting an average of 8.3 years between symp-
`tom onset and diagnosis (Frank 1976, Lunn 2010). It is
`currently estimated that HAE occurs in 1 in 10,000 to 1 in
`50,000 individuals with no known predominance for spe-
`cific ethnic groups (Bowen 2008). HAE is believed to be
`associated with increased risk of autoimmune disorders,
`particularly glomerulonephritis (Brickman 1986).
`The initial symptoms of HAE usually present in child-
`hood with exacerbations associated with the onset of
`
`puberty (Zuraw 2008). HAE persists with anywhere from
`fewer than one attack to more than 26 attacks per year
`occurring among untreated patients, although the fre-
`quency and severity of HAE events vary considerably
`between individuals (Agostini 2004, Winnewisser 1997).
`
`FIGURE 1
`
`Role of Cl-INH in Production of Bradykinin
`
`Factor Xlla
`Plasmin
`
`High-Molecular-Weight Kininogen
`
`Prekallikrein
`
`Kallikrein "—>
`
`.
`
`.
`
`Vasodilation, Nonvascular Smooth
`Muscle Contraction, and Edema
`
`Source: Adapted from Nzeako 2001.
`
`Page 4 of 48
`
`

`

`Acute respiratory attacks and abdominal distress are the
`most serious, life-threatening symptoms and leading
`causes of HAE-related morbidity and mortality (Craig
`2009a, Nzeako 2001). Laryngeal edema can progress from
`mild discomfort to complete obstruction of the airway,
`requiring intubation and/or tracheotomy, while abdomi-
`nal attacks can cause severe abdominal pain, nausea, diar-
`rhea, and vomiting (Bork 2005, Winnewisser 1997). It is
`estimated that approximately 52% of patients experience
`laryngeal attacks at some point in their lives while recur-
`rent abdominal attacks due to gastrointestinal (GI) wall
`edema are reported to affect up to 94% of patients (Bork
`2006). Among untreated patients, mortality rates as high
`as 30% have been associated with laryngeal edema (Frank
`1976).
`Although there is a lack of comprehensive information,
`factors associated with the onset of HAE episodes include
`emotional stress, mechanical stress, infections, minor
`trauma, and minor surgical and dental procedures (Agos-
`tini 2004, Davis 1988, Zuraw 2008). Certain medications,
`such as angiotensin-converting-enzyme (ACE) inhibitors
`and exogenous estrogens, are known to increase risk of
`HAE although the mechanisms underlying these effects
`are not well understood (Agostini 2004, Frank 1976, Frank
`1979).
`The recurrent nature, varying severity of attacks, and
`the need for long-term care imposes a significant eco-
`nomic burden on patients and the healthcare delivery sys-
`tem. Recent research shows that patients with HAE incur
`upwards of $40,000 in direct and indirect medical costs
`associated with the disease with costs increasing con-
`siderably with increasing attack severity (Wilson 2010).
`Additionally, many patients with HAE reported signifi-
`cant work impairments as well as an inability to main-
`tain full-time employment due to HAE (Wilson 2010).
`
`PRODUCT PROFILER: Berinert®
`
`Current Treatment Options
`Therapeutic management of patients with HAE
`includes prompt treatment of acute attacks, short-term
`prophylactic interventions to prevent attacks, and long-
`term preventive interventions to decrease the frequency
`and severity of recurrent attacks. Epinephrine can slow
`progression of edema during acute attacks but its effects
`are transient and do not alter the course of an attack
`(Agostini 2004, Frank 1976, Zuraw 2008). Respiratory sup-
`port should be provided as clinically needed as well as
`aggressive fluid replacement, antiemetics, and pain man-
`agement for symptoms associated with GI edema (Agos-
`tini 2004, Craig 2009a).
`Short-term prophylactic interventions are recom-
`mended for patients undergoing elective dental or surgi-
`cal procedures. These rely on attenuated androgen ther-
`apy (e.g., danazol, stanozolol, and oxandrolone) at least
`2 to 3 days before the procedure (Craig 2009a). However,
`androgens are associated with side effects including vir-
`ilization, weight gain, amenorrhea, decreased libido, myal-
`gia, fatigue, headache, hemorrhagic cystitis, arterial
`hypertension, lipid abnormalities, liver cell adenoma,
`hepatocellular cancer, and hepatic necrosis (Craig 2009a,
`Epstein 2008, Zuraw 2008). Antifibrinolytics, such as
`tranexamic acid and ε-aminocaproic acid, have not been
`approved by the U.S. Food and Drug Administration
`(FDA) to prevent acute episodes of HAE (Craig 2009a,
`Zuraw 2008). Berinert® is a C1 esterase inhibitor approved
`by the FDA for the treatment of acute facial and abdom-
`inal HAE attacks (Berinert® Prescribing Information
`2009). In addition, a kallikrein inhibitor, Kalbitor®, has
`been approved by the FDA for treatment of acute attacks
`in patients 16 years and older (Kalbitor® Package Insert
`2009). The FDA also has approved Cinryze™, a C1 esterase
`inhibitor, for routine prophylaxis of HAE in adolescent
`and adult patients (Cinryze™ Package Insert 2009).
`
`3
`
`Page 5 of 48
`
`

`

`PRODUCT PROFILER: Berinert"
`
`Product Information
`
`INDICATIONS AND USAGE
`Berinert‘” is a plasma-derived concentrate of C1
`Esterase Inhibitor (Hiunan) indicated for the treatment of
`acute abdominal or facial attacks of hereditary
`angioedema (HAE) in adult and adolescent patients. The
`safety and efficacy of Berinert‘m for prophylactic therapy
`have not been established.
`
`Description
`Berinert® is a human plasma-derived, purified, pas-
`teurized, lyophilized concentrate of C1 esterase inhibitor
`to be reconstituted for intravenous administration.
`
`Berinert® is prepared from large pools of human plasma
`from US. donors. One standard unit of C1 esterase
`
`inhibitor concentrate is equal to the amount of C 1 esterase
`inhibitor in 1 mL of fresh citrated human plasma, which
`is equivalent to 270 mg/L or 2.5 ML. There is no interna-
`tional laboratory standard for quantifying Cl esterase
`inhibitor. An in—house standard is used to assure lot-to-lot
`
`consistency with regards to product potency.
`Cl esterase inhibitor is a soluble, single-chain glyco-
`
`TABLE 2
`Mean Virus Inactivation/Reductions in Berinert"
`
`protein containing 478 amino acid residues organized into
`three beta-sheets and eight or nine alpha-helices. The
`heavily glycosylated molecule has an apparent molecular
`weight of 105 kD, of which the carbohydrate chains com-
`pn'se 26% to 35%.
`Each vial of Berinert® contains 500 units of C1 esterase
`inhibitor, 50 to 80 mg of total protein, 85 to 115 mg of
`glycine, 70 to 100 mg of sodiiun chloride, and 25 to 35 mg
`of sodium citrate.
`
`All plasma used in the manufacture of Berinert® is
`obtained from US. donors and is tested using serological
`assays for hepatitis B surface antigen and antibodies to
`I-IIV—1/2 and HCV. Additionally, the plasma is tested with
`Nucleic Acid Testing (NAT) for HCV and HIV-1 and found
`to be non-reactive (negative). In addition, the plasma is
`tested by NAT for HAV and Human Parvovirus B19. Only
`plasma that has passed virus screening is used for pro-
`duction, and the limit for Parvovirus B19 in the fraction-
`ation pool is set not to exceed 104 IU of Parvovirus B19
`DNA per mL.
`The manufacturing process for Berinert‘” includes mul-
`
`Virus studied
`
`Pasteurization [logm]
`
`Hydrophobic interaction
`chromatography [loglo]
`
`DEAE-sephadex A50
`chromatography QAE-
`sephadex chromatogra-
`phy and ammonium
`sulphate precipitation
`[logm]
`
`Total cumulative [Iogm]
`
`Source: Berinert° Prescribing Information 2009.
`
`Enveloped viruses
`
`HIV 1
`>6 6
`>4 5
`>15.4
`
`BVDV
`>9. 2
`>4. 6
`>13. 8
`
`6. 3
`>6. 5
`>7. 7
`>20. 5
`
`>7.0
`
`
`Non-HAenveloped viruses
`
`>6.4
`4.5
`>10.9
`
`1.4
`6.1
`7.5
`
`
`
`Bl9V=Human Parvovirus 819; BVDV=Bovine viral diarrhea virus, a model for HCV; CPV=Canine parvovirus; HAV=Hepatitis A virus; HIV-1=Human immun-
`odeficiency virus type 1, a model for HIV-1 and HIV-2; NA=not applicable; ND=not determined; PRV=Pseudorabies virus, a model for large enveloped DNA
`viruses (eg, herpes virus); WNV=West Nile virus
`
`Page 6 0f 48
`
`

`

`tiple steps that reduce the risk of virus transmission. The
`virus inactivation/reduction capacity of three steps (pas-
`teurization in aqueous solution at 60°C for 10 hours,
`hydrophobic interaction chromatography, and the com-
`bination of ion exchange chromatography and ammo-
`nium sulphate precipitation) was evaluated in a series of
`in vitro spiking experiments. The total mean cumulative
`virus inactivation/reduction is shown in Table 2.
`
`CLINICAL PHARMACOLOGY
`Mechanism of Action
`C1 esterase inhibitor is a normal constituent of human
`
`plasma and belongs to the group of serine protease
`inhibitors (serpins) that includes antithrombin 111, alpha,-
`protease inhibitor, alphaQ-antiplasmin, and heparin cofac-
`tor 11. As with the other inhibitors in this group, C1
`esterase inhibitor has an important inhibiting potential
`on several of the major cascade systems of the human
`body, including the complement system, the intrinsic
`coagulation (contact) system, the fibrinolytic system, and
`the coagulation cascade. Regulation of these systems is
`performed through the formation of complexes between
`the proteinase and the inhibitor, resulting in inactivation
`of both and consumption of the Cl esterase inhibitor.
`C1 esterase inhibitor, which is usually activated dur-
`ing the inflammatory process, inactivates its substrate by
`covalently binding to the reactive site. Cl esterase
`inhibitor is the only known inhibitor for the subcompo-
`
`TABLE 3
`
`PRODUCT PROFILER: Berinert"
`
`nent of the complement component 1 (Clr), Cls, coagu-
`lation factor X1121, and kallikrein. Additionally, Cl esterase
`inhibitor is the main inhibitor for coagulation factor Xla
`in the intrinsic coagulation cascade.
`HAE patients have low levels of endogenous or func-
`tional C1 esterase inhibitor. Although the events that
`induce attacks of angioedema in HAE patients are not
`well defined, it has been postulated that increased vas-
`cular permeability and the clinical manifestation of HAE
`attacks may be primarily mediated through contact sys-
`tem activation. Suppression of contact system activation
`by Cl esterase inhibitor through the inactivation of
`plasma kallikrein and factor XIIa is thought to modulate
`this vascular permeability by preventing the generation of
`bradykinin.
`Administration of Berinert® to patients with C 1 esterase
`inhibitor deficiency replaces the missing or malfunction-
`ing protein in patients. The plasma concentration of C1
`esterase inhibitor in healthy volunteers is approximately
`270 mg/L.
`
`Pharmacoki netics
`
`The pharmacokinetics of Berinert® were evaluated in
`an open—label, uncontrolled, single—center study in 40 sub—
`jects (35 adults and 5 children under 16 years of age) with
`either mild or severe HAE. All subjects received a single
`intravenous injection of Berinert® ranging from 500 units
`to 1,500 units. Blood samples were taken during an attack-
`
`Pharmacokinetic Parameters of Berinertt9 in Adult Subjects with HAE by Non-compartmental Analysis (n=35)
`Parameters
`
`Unadjusted for baseline
`27.5 :i: 8.5 (15.7-44.7)
`
`Adjusted for baseline
`12.8 :1: 6.7 (3.9-34.7)
`
`31.5 :i: 2.4 (23.7-35.2)
`
`AUCM (hr x |U/mL)*
`
`CL (mL/hr/kg)
`
`V,s (mL/kg)
`Half-life (hrs)
`
`MRT (hrs)
`
`0.60 :l: 0.17 (0.34-0.96)
`
`18.6 :i: 4.9 (11.1-27.6)
`
`21.9 i 1.7 (16.5-24.4)
`
`1.44 :l: 0.67 (0.43-3.85)
`
`35.4 110.5(14.1-56.1)
`
`18.4 :1: 3.5 (7.4-22.8)
`
`26.4 :i: 5.0 (10.7-33.0)
`
`AUC=area under the curve; CL=clearance; MRT=mean residence time; V§,=volume steady state
`
`*Based on a 15 unit/kg dose. Numbers in parentheses are the range.
`
`Source: Berinert° Prescribing Information 2009.
`
`TABLE 4
`Pharmacokinetic Parameters of Berinerto in Pediatric Subjects with HAE by Non-compartmental Analysis (n=5)
`Parameters
`Unadjusted for baseline
`
`32.3 :i: 2.3 (29.3-35.2) Adjusted for baseline
`
`25.45 :l: 5.8 (16.8-31.7)
`
`0.62 :l: 0.17 (0.47-0.89)
`
`19.8 :i: 4.0 (16.7-26.1)
`
`22.4 i 1.6 (20.3-24.4)
`
`9.78 :i: 4.37 (4.1-15.2)
`
`1.9 :l:1.1(0.98-3.69)
`
`38.8 :i: 8.9 (31.9-54.0)
`
`16.7 :1: 5.8 (7.4-22.5)
`
`24.0 :i: 8.3 (10.7-32.4)
`
`AUCM, (hr x |U/mL)*
`
`CL (mL/hr/kg)
`
`V,s (mng)
`
`Half-life (hrs)
`
`MRT (hrs)
`
`Source: Berinerte Prescribing Information 2009.
`
`Page 7 0f 48
`
`

`

`Administer Berinert® by slow intravenous injection at
`a rate of approximately 4 mL per minute.
`
`HOW SUPPLIED/STORAGE AND HANDLING
`How Supplied
`Berinert® is supplied in a single-use vial. Each carton
`contains a 500 unit vial of Berinert® for reconstitution
`with 10 mL of diluent containing sterile water (meets USP
`chemistry requirements except for pH; pH 4.5-8.5). The
`components used in the packaging for Berinert® are latex-
`free.
`Each product package consists of the following:
`
`NDC Number
`63833-825-02
`
`Component
`Carton (kit) containing one 500 unit vial of
`Berinert® [NDC 63833-835-01], one 10 mL vial
`of diluent (sterile water) [NDC 63833-765-15],
`one Mix2Vial filter transfer set, and one alco-
`hol swab.
`
`PRODUCT PROFILER: Berinert®
`
`free period at baseline and for up to 72 hours after drug
`administration. Pharmacokinetic parameters were esti-
`mated using non-compartmental analysis (with or with-
`out baseline adjustment). Table 3 summarizes the phar-
`macokinetic parameters in 35 adult subjects with HAE.
`Table 4 summarizes the pharmacokinetic parameters in
`5 pediatric subjects (ages 6 through 13) with HAE. Based
`on adjusted baseline, compared to adults, the half-life of
`Berinert® was shorter and clearance was faster in this
`limited cohort of children. However, the clinical implica-
`tion of this difference is not known.
`
`DOSAGE AND ADMINISTRATION
`For Intravenous Use Only.
`Administer Berinert® at a dose of 20 units per kg body
`weight by intravenous injection.
`Berinert® is provided as a freeze-dried powder for
`reconstitution with the diluent (sterile water) provided.
`Store the vial in the original carton in order to protect
`from light. Do not freeze.
`
`Preparation and Handling
`Check the expiration date on the product vial label. Do
`not use beyond the expiration date.
`Use aseptic technique when preparing and adminis-
`tering Berinert®.
`After reconstitution and prior to administration, inspect
`Berinert® visually for particulate matter and discoloration.
`The reconstituted solution should be colorless, clear, and
`free from visible particles. Do not use if the solution is
`cloudy, discolored, or contains particulates.
`The Berinert® vial is for single use only. Berinert® con-
`tains no preservative. Any product that has been recon-
`stituted should be used promptly. The reconstituted solu-
`tion must be used within 8 hours. Discard partially used
`vials.
`Do not freeze the reconstituted solution.
`
`Reconstitution and Administration
`Each Berinert® kit consists of one carton containing
`one single-use vial of Berinert®, one 10 mL vial of diluent
`(sterile water), one Mix2Vial™ transfer set, and one alco-
`hol swab.
`Use either the Mix2Vial transfer set provided with
`Berinert® or a commercially available double-ended nee-
`dle and vented filter spike.
`
`Reconstitution
`The procedures below are provided as general guide-
`lines for the reconstitution and administration of
`Berinert®.
`
`Administration
`Do not mix Berinert® with other medicinal products
`and administer by a separate infusion line.
`Use aseptic technique when administering Berinert®.
`
`6
`
`Page 8 of 48
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`

`

`PRODUCT PROFILER: Berinert"
`
`Clinical Trial Summary
`
`Efficacy of Human Cl Esterase Inhibitor Concen-
`trate Compared with Placebo in Acute Hereditary
`Angioedema Attacks
`The International Multi-centre Prospective
`Angioedema Cl-Inhibitor Trial (IMPACT-l) was a multi-
`national, parallel-group, double-blind, randomized,
`placebo-controlled, 3-arm, phase 2/3 trial conducted at 36
`sites in 15 countries between August 2005 and December
`2007 (Craig 2009b). The primary study objective was to
`compare the efficacy and safety of Berinert®, a Cl
`esterase inhibitor (C 1-INH), 20 U/kg with placebo for the
`treatment of acute facial or abdominal attack of HAE.
`
`The efficacy of Berinert®10 U/kg also was compared with
`placebo as a secondary trial objective.
`Study eligibility criteria included patients 6 years of
`age or older with either type I or II HAE who had labora-
`tory-confirmed Cl-INH deficiency. Treatment of eligible
`patients was administered at the time of occurrence of an
`acute moderate-to—severe abdominal or facial attack of
`
`HAE within 5 hours of the attack attaining moderate inten-
`sity according to patient evaluation and confirmation by
`the investigators. Patients were excluded from the trial if
`they had a history of hypersensitivity to Cl-INH concen-
`trates, a diagnosis of acquired angioedema, all other types
`of angioedema, and abdominal pain not associated with
`
`FIGURE 2
`
`Cl-INH deficiency. Additional exclusion criteria included
`a history of routine use of narcotics or pain medications
`during a current HAE attack, treatment with any Cl-INH
`concentrate or any other drug for acute angioedema, and
`treatment with fresh frozen or native plasma in the 7 days
`preceding enrollment in the IMPACT-1 trial.
`
`Methods
`Patients were randomized to intravenous infusion with
`
`Cl-INH 20 U/kg, Cl-INH 10 U/kg, or placebo and each
`patient was treated for only one abdominal or facial
`attack during the course of the trial. Figure 2 presents the
`disposition of patients by the three treatment groups for
`IMPACT-1. Patients were observed for at least 4 hotus fol—
`
`lowing initiation of treatment and discharged thereafter
`if their symptoms resolved. A second dose of double-
`blind treatment was administered as rescue medication
`
`to patients who failed to obtain relief of their symptoms
`within 4 hours following their initial treatment. Rescue
`study medications included Cl-INH 20 U/kg for patients
`randomized to placebo, a second dose of Cl-INH 10 U/kg
`to those randomized to the Cl-INH 10 U/kg group, and
`treatment with placebo for patients randomized to treat-
`ment with Cl-INH 20 U/kg. Viral safety assessments were
`performed before randomization and for up to 12 weeks
`following treatment.
`
`Study Design and Patient Disposition for IMPACT-1 Trial
`
`126 patients
`enrolled
`
`125 patients
`randomized
`
`1 patient not
`randomized
`but treated
`
`from Elsevier.
`
`Randomized
`
`Placebo
`42 patients
`
`Cl-INH 10 U/kg
`40 patients
`
`Cl-INH 20 U/kg
`43 patients
`
`Intention-to- -
`treat population
`(as randomized)
`
`Placebo
`
`42 Patients
`
`Cl-INH 10 U/kg
`39 patients
`
`Cl-INH 20 U/kg
`43 patients
`
`1 patient
`
`1 patient
`
`Safety
`population
`(as treated)
`
`Placebo
`41 patients
`
`Cl-INH 10 U/kg
`39 patients
`
`Cl-l N H 20 U/kg
`46 patients
`
`Source: Craig 2009b. Reprinted from Efficacy of human C1 esterase inhibitor concentrate compared with placebo in
`acute hereditary angioedema attacks. JA/Ierg/ Clin Immunol. 2009; 124:801-806. Copyright 2009, with permiSion
`
`Study endpoints
`The primary endpoint was time to
`symptom relief following initiation of
`treatment assessed by patient
`responses to a standardized ques-
`tionnaire conducted at appropriate
`time intervals for up to 24 hours fol-
`lowing treatment initiation. Second-
`ary efficacy endpoints included time
`to complete resolution of all syrnp—
`toms of HAE, the proportion of
`patients who experienced worsening
`of HAE symptoms between 2 and 4
`hours after treatment initiation com-
`
`pared with baseline with at least one
`HAE symptom reported at baseline,
`and the munber of episodes of vom-
`iting within 4 hours of treatment ini-
`tiation.
`
`Four primary safety endpoints
`were monitored. These included: the
`
`number and type of adverse events
`(AE5) that occtu'red up to 9 days fol-
`
`Page 9 0f 48
`
`

`

`PRODUCT PROFILER: Berinert"
`
`lowing initial treatment, serious adverse events (SAEs) up
`to 12 weeks after treatment, vital signs (blood pressure,
`heart rate, respiratory rate, and body temperature) prior
`to treatment and up to 24 hours following initiation of
`therapy, and assessments of viral safety up to 12 weeks
`following treatment including rates of HIV 1 and 2, hepa-
`titis, and the human B19 virus.
`All efficacy analyses were based on the intention-to—
`treat (ITT) population defined as all patients who were
`treated with any blinded dose of study medication while
`the safety analyses included all patients who received any
`treatments. A Wllcoxon l-sided, 2—samp1e test was per-
`fomied to analyze the primary efficacy endpoint of time
`to onset of symptom relief by treatment group. Time to
`onset of symptom relief was set at 24 hours if patients
`required treatment With rescue medications to achieve
`symptom relief or were treated with analgesics, antiemet-
`ics, open—label Cl-INH, or fresh frozen plasma during the
`
`fi1st4 to 5 hours following the start of their initial treat-
`ment. Wilcoxon l-sided, 2—sample tests also were con-
`ducted to evaluate time to complete symptom resolution
`and number of vomiting episodes while a l-sided Fischer
`exact test yielded the statistical comparison between the
`three treatment groups for the proportion of patients
`experiencing exacerbations in the intensity of symptoms
`occurring 2 and 4 hours following treatment initiation.
`Safety analyses included assessment of AEs that occtu'red
`in the 4 hours following initiation of treatment to provide
`an unbiased assessment of Cl-INH compared with
`placebo dining maximum exposure to therapy during the
`acute phase of each attack, which preceded administra-
`tion of any rescue medications. AEs also were evaluated
`for all patients who received any dose of Cl-INH includ-
`ing patients in the placebo group who required rescue
`therapy with C 1-INH 10 U/kg. Descriptive statistics char-
`acterized vital signs and viral safety assessments.
`
`TABLE 5
`
`Baseline Demographic and Clinical Characteristics of lntention-to-Treat Population
`
`Cl-INH 20 Ulkg
`Cl-INH 10 Ulkg
`
`(n=39) (n=43)
`
`Treatment Group
`
`Gender. n (‘36)
`
`Female
`
`Age. years
`
`Mean (SD)
`
`Range
`
`Race/ethnic group, n (%
`
`)
`
`28 (66.7)
`
`14 (33.3)
`
`26 (66.7)
`
`30 (69.8)
`
`84 (67.7)
`
`40 (32.3)
`
`31.5 (13.57)
`
`33.1 (12.77)
`
`34.6 (14.91)
`
`33.1 (13.76)
`
`1 (2.4