lpr2869_Berinert_46:900x340 16.07.2012
`
`09:13 Seitel
`
`CSL Behring
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use Berinert
`safely and effectively. See full prescribing information for Berinert.
`
`FULL PRESCRIBING INFORMATION: CONTENTS’
`
`Recongitution
`
`Administration
`
`_I
`2
`
`U'Ibw
`
`6
`
`“N
`
`The procedures below are provided as general guidelines for the reconstitution and
`administration of 8erinert.
`
`1. Ensure that the Berinen vial and diluent vial are at room temperature.
`2. Place the Berinert vial, diluent vial and Mix2Via| transfer set on a flat surface.
`3. Remove the flip caps from the Berinen and diluent vials. Wipe the vial stoppers with
`the alcohol swab provided. Allow to dry prior to opening the Mix2Via| transfer set
`package.
`4. Open the Mix2Via| transfer set package by peeling away
`the lid (Figure 1). Leave the Mix2Via| transfer set in the
`clear padcage.
`
`(1
`
`0 Do not mix Berinen with other medicinal products. Administer Berinert by a separate
`infusion line.
`- Use aseptic technique when administering Berinen.
`- Follow recommended venipuncture guidelines for initiating intravenous therapy.
`- Administer Berinert by slow intravenous injection at a rate of approximately 4 mL per
`minute. Please refer tothe illustration in step 6 of the self-administration section in the
`Patient Product Information (PPI) section.
`0 For self-administratio n, providethe patient with instructions and training for intravenous
`injection outside of a clinic setting so patients may self-administer Berinen upon
`recognition of symptoms of an HAE attack [see Patient Counseling Information (17)].
`- After administration, immediately discard any unused product and all used disposable
`supplies in accordance with local requirements.
`
`3
`
`DOSAGE FORMS AND STRENGTHS
`
`figure 1
`
`Placebocontrolled Cliniml Study
`In the placebocontrolled clinical study, referred to as the randomized clinical trial (RC1)
`[see Clinical Studies (14)], 124 subjects experiencing an acute moderate to severe
`abdominal or facial HAE attack were treated with Berinert (either a 10 IU per kg body
`weight or a 20 IU per kg body weight dose), or placebo (physiological saline solution).
`
`Table 3: Incidence of Subjects and Attacks with Adverse Reactions (ARs)’
`Starting during Infusion or Within 24 Hours or 72 Hours after End of
`an Infusion (Experienced by 22 Subjects or Associated with 25
`Attacks Overall) by Preferred Term (Safety Subject and Attack
`Populations)
`
`The treatment-emergent serious adverse reactions/events that occurred in 5 subjects in the
`RC1 were laryngeal edema, facial attack with laryngeal edema, swelling (shoulder and
`chest), exacerbation of hereditary angioedema, and laryngospasm.
`
`Table 1: Adverse Reactions" Occurring up to 4 Hours After Initial Infusion in
`More Than 4% of Subjects'
`
`Adverse Reactions
`
`Number (%) of
`Subjects Reporting
`Adverse Reactions
`Berinen 20 lUIkg
`(n=43)
`30%)
`
`Number (%) of
`Subjects Reporting
`Adverse Reactions
`Plaoebo Group
`(n=42)
`5mm
`
`Preferred term
`
`Any preferred term
`
`N umber (%) of
`Subjects
`(n =57)
`
`ARs
`within
`72 hours
`
`ARs
`within
`24 hours
`
`13
`(22.8%)
`
`Number (%) of Attacks
`(n=1085)
`
`ARs
`within
`24 hours
`
`27
`(2.5%)
`
`ARs
`within
`72 hours
`
`41
`(3.8%)
`
`1 (1.8%)
`
`3 (5.3%)
`
`2 (0.2%)
`
`6 (0.6%)
`
`DRUG INTERACTIONS
`
`Thrombotic Events figciated with HAE Treatment
`Thromboembolic events including basilar artery thrombosis, multiple pulmonary micro
`emboli, and thrombosis have been reported with the use of Berinert at the recommended
`dose following treatment of HAE.
`f-Ll
`Thrm 'En
`'
`w‘h
`Thromboembolic events reported with the use of Berinert in patients receiving off-label
`high doses during cardiac surgery include carotid arterythrombosis, cerebral thrombosis,
`myocardial infarction, pulmonary embolism, renal vein thrombosis, sagittal sinus throm-
`bosis, inferior vena cava thrombosis, superior vena cava thrombosis, internal jugular vein
`thrombosis, and peripheral venous thrombosis.
`
`The following adverse reactions, identified by system organ class, have been attributed to
`Berinert during post-approval use outside the US.
`
`0 Immune System Disorder: Hypersensitivity/anaphylactic reactions and shock
`- GeneraVBody as a Whole: Pain on injection, redness atinjection site, chi/ls, and fever
`
`Table 5: Mean Virus Inactivation/Reductions in Berinert
`
`Pasteuri-
`zation
`L|°9rol
`
`Hydrophobic
`Interaction
`Ch '0 matog 'aPhV
`"09101
`
`Virus
`Filtration
`”0910]
`
`Total
`Cumulative
`“0910]
`
`Enveloped Viruses
`
`————-r_
`NorrEnveloped Viruses
`
`This was evaluated in a series of in vitro spiking experiments. The total mean cumulative
`virus inactivation/reduction is shown in Table 5.
`
`Table 7: Pharmacokinetic Parameters of Berinert in Pediatric Subjects with
`HAE by Non-compartmental Analysis (n=5)
`
`Unadjusted for baseline
`
`Adjusted for baseline
`
`AUCM (hr x IU/mL)‘
`
`25.45 1 5.8 (16.8317)
`
`9.78 1 4.37 (4115.2)
`
`CL (mL/hr/kg)
`
`Vis (ml/kg)
`Half-life (hrs)
`
`0.621 0.17 (0.47-0.89)
`
`1.9 1 1.1 (0.98-3.69)
`
`19.8 1 4.0 (16.7-26.1)
`22.4 1 1.5 (20.3-24.4)
`
`38.8 1 8.9 (31954.0)
`16.7 1 5.3 (7422.5)
`
`32.3 1 2.3 (29.3-35.2)
`
`24.0 1 8.3 (10.7-32.4)
`
`
`
`AUC:Area under the curve
`CL: Clearance
`V“: Volume steady state
`MRT: Mean residence time
`‘Based on a 15 lU/kg dose. Numbers in parenthesis are the range.
`
`Berinert [C1 Esterase Inhibitor (Human)]
`For intravenous use. FreezeDried Powder for Reconstitution.
`Initial U.S.Approval: 2009
`MW-«mRECENT MAJOR CHANGES—m-
`Indications and Usage (1)
`Dosage and Administration (2.2)
`Warnings and Precautions (5.2)
`Warnings and Precautions (5.3)
`Warnings and Precautions (5.4)
`“WNW DICATIONS AND USAGEW
`Berinert is a plasmaderived C1 Esterase Inhibitor (Human) indicated for the treatment of
`acute abdominal, facial, or laryngeal attacks of hereditary angioedema (HAE) in adult and
`adolescent patients (1).
`
`-
`12/2011
`12/2011
`09/2011
`08/2011
`12/2011
`
`The safety and efficacy of Berinert for prophylactic therapy have not been established (1).
`
`
`DOSAGE AND ADMIN ISTRATION—-—
`For intravenous use only.
`0 Store the vial in the original carton in order to protect from light. Store at 2-25°C
`(36-77°F). Do not freeze (2).
`0 Administer 20 International Units per kg body weight (2).
`0 Reconstitute Berinen prior to use using the Sterile Water for Injection, USP provided
`(2.1).
`0 Administer at room temperature within 8 hours of reconstitution (2.1).
`- Inject at a rate of approximately 4 mL per minute (2.2).
`0 Do not mix Berinert with other medicinal products or solutions (2.2).
`0 Appropriately trained patients may self-administer upon recognition of an HAE attack
`(2.2).
`
`INDICATIONS AND USAGE
`DOSAGE AND ADMINISTRATION
`2.1 Preparation and Handling
`2.2 Reconstitution andAdministration
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
`5.1 Hypersensitivity
`5.2 Thrombotic Events
`5.3 Transmission of InfectiousAgents
`5.4 LaryngealAttacks
`ADVERSE REACTIONS
`6.1 ClinicalTrials Experience
`6.2 Postmarketing Experience
`DRUG INTERACTIONS
`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
`12
`CLINICAL PHARMACOLOGY
`12.1 Mechanism ofAction
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.2 Animal Toxicology and/or Pharmacology
`14 CLINICAL STUDIES
`REFERENCES
`15
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied
`16.2 Storage and Handling
`PATIENT COUNSELING INFORMATION
`
`17
`
`'Sections or subsections omitted from the full prescrbing information are not listed.
`
`FULL PRESCRIBING INFORMATION
`
`Berinert° [C1 Esterase Inhibitor (Human)]
`Freeze-dried powder
`
`INDICATIONS AND USAGE
`
`5. Place the diluent vial on a flat surface and hold the vial
`tightly. Grip the Mix2Via| transfer set together with the clear
`package and push the plastic spike at the blue end of the
`MixZVial transfer set firmly through the center of the stopper
`
`ofthediluentvial(Figure2).
`
`6. Carefullyremove the dear package from the Mix2Vial
`transfer set. Make sure that you pull up only the clear
`package, and not the Mix2Via| transfer set (Figure 3).
`
`7. With the Berinert vial placed firmly on a flat surface, invert
`the diluent vial with the Mix2Via| transfer set attached
`and push the plastic spike of the transparent adapter firmly
`through the center of the stopper of the Berinen vial
`(Figure 4).
`The diluent will automaticallytransfer into the Berinert vial.
`
`fi
`
`figure 2
`
`figure 3
`
`- Berinen is available in a single-use vial that contains 500 IU of C1 esterase
`inhibitor as a lyophilized concentrate.
`0 Each vial must be reconstituted with 10 mL of Sterile Water for Injection, USP
`provided.
`
`4
`
`CONTRAINDICATIONS
`
`Berinen is contraindicated in individuals who have experienced life-threatening
`hypersensitivity reactions, including anaphylaxis, to C1 esterase inhibitor preparations.
`
`5
`
`WARNINGS AND PRECAUTIONS
`
`5.1 Hypersensitivity
`Severe hypersensitivity reactions may occur. Epinephrine should be immediately available
`for treatment of acute severe hypersensitivity reaction (see Patient Counseling Information
`(17)]. The signs and symptoms of hypersensitivity reactions may include hives. generalized
`urticaria, tightness of the chest, wheezing, hypotension, and/or anaphylaxis during or after
`injection of Berinert.
`
`Because hypersensitivity reactions may have symptoms similar to HAE attacks, treatment
`methods should be carefully considered. In case of suspected hypersensitivity, immediately
`discontinue administration of Berinen and institute appropriate treatment.
`
`
`
`‘ The study protocol specified that adrerse events that began within 72 hours of blinded study
`medication administration, ‘rrespective of the investigator's assessment of causality, were to be
`classified as at least possibly related to study medication (ie, adverse reactions).
`1 The following abdominal synptoms were identified in the protocol as associated with HAE
`abdominal attacks: abdominal pain, bloating, cramps, nausea, vomiting, and diarrhea.
`
`Table 2: Adverse Reactions' Occurring in More Than 4% of Subjects up to
`72 Hours After Infusion of Initial or Rescue Medication1 by Intent-
`to-Treat
`
`Adverse Reactions
`
`Number (%) of
`Subjects Reporting
`Adverse Reactions"
`Berinert 20 lU/kg
`(n=43)
`3.7%.
`30%)
`
`Number (%) of
`Subjects Reporting
`Adverse Reactions"
`Placebo Group
`(n=42)
`nae-2w
`5mm
`
`an»
`
`5......)
`
`Abdominal pain or
`discomfort
`
`Upper respiratory
`tract infection
`
`..r..........r....
`
`0(0)
`
`1 (1.8%)
`
`0(0)
`
`1 (<0.1%)
`
`mew mew
`
`
`
`_ 2.3.5).
`Vulvovaginal mycotic
`0 (O)
`infection
`
`28.5%)
`2 (3.5%)
`
`0(0)
`
`2 (0.2%)
`
`N = total number of objects/attacks
`Data are sorted by decreas'ng frequency by number of stbjects
`" Because of the allowance of rescue medication in both study arms, all listed adverse events were
`considered to be at least potentially related to study medication (eg, adverse reactions), regardless
`of the investigator's opinion concerning causality
`t Hereditary angioedema attacks were only to be reponed as adverse reaction if it vas a worsening
`of symptoms during 3 treated attack. New attacks were not to be reported as adverse reactions.
`Although the adverse reaction of hereditary angioedema in subject 22301 was a new attack that
`started after the previous attack had completely resolved, this attadt was reported as an adverse
`reaction, because the attack was not included in the study and treated outside study site with
`medication other than the study medcation.
`
`Table 4: Summary of Adverse Reactions“ by Type of Attack (Safety Subject
`Population)
`
`7
`
`No drug interaction studies have been conducted.
`
`8
`
`USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`Pregnancy Category C. Animal reproduction studies have not been conducted with
`Berinert. It is not known whether Berinert can cause fetal harm when administered to
`a pregnant woman or can affect reproduction capacity. Berinert should be given to a
`pregnant woman only if clearly needed. In a retrospective case collection study, 20
`pregnant women ranging in age from 20 to 35 years received 8erinert with repeated
`doses up to 3,500 IU per attack; these women reponed no complications during delivery
`and no harmful effects on their 34 neonates.
`
`8.2 Labor and Delivery
`The safety and effectiveness of Berinert administration prior to or during labor and
`delivery have not been established. Use only if dearly needed.
`
`8.3 Nursing Mothers
`It is not known whether Berinen is excreted in human milk. Because many drugs are
`excreted in human milk, use only if clearly needed when treating a nursing woman.
`
`
`
`———-s-m-
`ram—m-
`HIV~1, Human immunodeficiency virus type I, a model for HIV~1 and HIV-2
`BVDV, Bovine v'ral diarrhea virus a model for HCV
`PRV, Pseudorabies virus a model for large enveloped DNA viruses
`WNV, West Nile virus
`HAV, Hepatitis A virus
`CPV, Canine parvovirus
`8191/, Human Parvovirus 819
`ND, Not deternined
`NA, Not applicable
`
`12
`
`CLINICAL PHARMACOLOGY
`
`12.1 Mechanism ofAction
`
`C1 esterase inhibitor is a normal constituent of human plasma and belongs to the group
`of serine protease inhibitors (serpins) that includes antithrombin III, alpharprotease
`inhibitor, alphaz-antiplasmin, and heparin cofactor II. 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
`C1 esterase inhibitor.
`
`Studies have not been conducted to evaluate the pharmacokinetics of Berinen in special
`patient populations identified by gender, race, geriatric age, or the presence of renal or
`hepatic impairment.
`
`13
`
`NONCLIN ICAL TOXICOLOGY
`
`13.1 Carcinogenesis Mutagenesis, Impairment of Fertility
`No animal studies have been completed to evaluate the effects of Berinert on carcino
`genesis, mutagenesis, and impairment of fertility.
`
`13.2 Animal Toxicology and/or Pharmacology
`Acute intravenous toxicity of Berinert was performed in mice at 1500, 3000, and
`6000 IU/kg and in rats at 1000, 2000, and 3000 IU/kg. Berinert was well tolerated and
`no signs of toxicity were observed up to the highest dose administered.
`
`Repeat intravenous dose toxicity was studied in a 14day repeat dose study in rats at
`doses of 20, 60, and 200 IU/kglday. Berinert was well tolerated and no toxicity was
`observed upto the highest dose administered. No antibody response against C1 esterase
`inhibitor could be demonstrated in this study after multiple dosing with Berinen.
`
`In a safety pharmacology study, Berinen was administered to beagle dogs intravenously
`at a cumulative dose of 3500 IU/kg. No adverse effects were seen on the cardiovascular
`and respiratory system. There was a drop in body temperature, reduced coagulation time,
`and a decrease in thrombocyte aggregation.
`
`Local intravenoustolerance of Berinen was evaluated in rabbits at 1500 IU. No pathological
`changes were noted at the time of injection or during the following 24 hours. No
`pathological signs were noted during necropsy.
`
`8.4 Pediatric Use
`Safety and efficacy of Berinert in children (ages 0 through 12) have not been established.
`The clinical studies included an insufficient number of subjects in this age group to
`determine whether they respond differently from older subjects. In the pharmacokinetic
`study [see Clinical Pharmacology(12.3)], the safety and pharmacokinetics of Berinen were
`evaluated in 5 drildren (ages 3 through 12) and in 8 adolescent subjects (ages 13 through
`16). The 5 children less than 12 years had a shorter half—life (16.7 1 5.8 hours) and
`faster clearance (1.9 1 1.1 mUhr/kg) compared to adults (halHife: 18.4 1 3.5 hours,
`clearance 1.44 1 0.67 mUhr/kg).
`
`8.5 Geriatric Use
`Safety and efficacy of Berinen in the geriatric population have not been established.
`Clinical studies with Berinert included four subjects older than 65 years. The clinical
`studies included an insufficient number of subjects in this age group to determine
`whether they respond differently from younger subjects.
`
`10 OVERDOSAGE
`
`The development of thrombosis has been reported after doses exceeding 20 IU/kg body
`weight of Berinert when used off-labell in newboms and young children with congenital
`heart anomalies during or after cardiac surgery under extracorporeal drculation.
`
`The maximum dose administered in clinical studies in hereditary angioedema was 20 lUIkg
`body weight.
`
`11
`
`DESCRIPTION
`
`C1 esterase inhibitor, which is usually activated during the inflammatory process,
`inactivates its substrate by covalently binding to the reactive site. C1 esterase inhibitor is
`the only known inhibitor for the subcomponent of the complement component 1 (Ch),
`Cls, coagulationfactorXIla, and kallikrein. Additionally, C1 esterase inhibitor is the main
`inhibitor for coagulation factor Xla of the intrinsic coagulation cascade.
`
`HAE patients have low levels of endogenousor functional C1 esterase inhibitor.AIthough
`the events that induce attacks of angioedema in HAE patients are not well defined, it has
`been postulated that increased vascular permeability and the clinical manifestation of
`HAE attacks may be primarily mediated through contact system activation. Suppression
`of contact system activation by C1 esterase inhibitor through the inactivation of plasma
`kallikrein and factor Xlla is thought to modulate this vascular permeability by preventing
`the generation of bradykinin.5
`
`Administration of Berinert to patients with C1 esterase inhibitor deficiency replaces the
`missing or malfunctioning protein in patients. The plasma concentration of C1 esterase
`inhibitor in healthy volunteers is approximately 270 mgIL.6
`
`12.3 Pharmacokinetics
`The pharmacokinetics of Berinen were evaluated in an openlabel, uncontrolled, single-
`center study in 40 subjects (35 adults and 5 children under 16 years of age) with either
`mild or severe HAE.A|| subjects received a single intravenous injection of Berinen ranging
`from 500 IU to 1500 IU. Blood samples were taken during an attack-free period at
`baseline and for up to 72 hours after drug administration. Phannacokinetic parameters
`were estimated using noncompartmental analysis (with or without baseline adjustment).
`Table 6 summarizes the pharmacokinetic parameters in 35 adult subjects with HAE.
`
`Thrombotic events have been reported in association with C1 esterase inhibitor products
`when used off-label and at higher than labeled dosesl {see Overdosage (10)]. Animal
`studies have confirmed the risk of thrombosis from intravenous administration of
`C1 esterase inhibitor products.1
`
`14
`
`CLINICAL STUDIES
`
`The safety and efficacy of Berinen in the treatment of acute abdominal or facial attacks
`in subjects with hereditary angioedema were demonstrated in a placebocontrolled,
`doubleblind, prospective, multinational, randomized, parallelgroup, dose-finding, three-
`ann, clinical study, referred to as the randomized clinical trial (RC1). The RC1 assessed
`the efficacy and safety of Berinen in 124 adult and pediatric subjects with C1 esterase
`inhibitor deficiency who were experiencing an acute moderate to severe attack of
`abdominal or facial HAE. Subjects ranged in age from six to 72 years of age; 67.7% were
`female and 32.3% were male; and approximately 90% were Caucasian.
`
`The study objectives were to evaluate whether 8erinert shortens the time to onset of
`relief of symptoms of an abdominal or fadal attadc compared to placebo and to compare
`the efficacy of two different doses of Berinert. The time to onset of relief of symptoms
`was determined by the subject's response to a standard question posed at appropriate
`time intervals for as long as 24 hours after start of treatment, taking into account all
`single HAE symptoms. In addition the severity of individual HAE symptoms was assessed
`over time.
`
`Number (%) of Subjects
`Abdominal Peripheral
`Laryngeal
`(n=51)
`(n=30)
`(n=16)
`mas-3%)
`res-3%)
`
`4 (7.8%)
`
`3 (10.0%)
`
`1 (6.3%)
`
`0(0)
`
`0(0)
`
`Type of AR
`
`Subjects with at least
`possibly related ARs
`Subjects with serious
`ARs
`
`Study medication
`permanently
`discontinued due to
`ARs
`
`1 (2.0%)
`
`1 (2.0%)
`
`0 (0)
`
`0 (0)
`
`0(0)
`
`0(0)
`
`0(0)
`
`0(0)
`
`00 AA99
`
`0(0)
`
`0
`0 AA
`
`9
`8
`
`0(0)
`
`AA89
`
`0 0
`
`0(0)
`
`0(0)
`
`0(0)
`0(0)
`
`Most frequent ARs (23 subjects overall)
`Headache
`5 (9.8%)
`0 (0)
`1 (2.0%)
`2 (6.7%)
`
`Nasopharyngitis
`At least possibly related ARs
`Abdominal
`0(0)
`discomfort
`
`1 (3.3%)
`
`0(0)
`
`wwDOSAGE FORMS AND STRENGTHSNW-
`500 International Units Iyophilized concentrate in a singleuse vial for reconstitution with
`10 ml of Sterile Water for Injection, USP (3).
`m—m—mmmmm—«conrrmmDICArrons—m—mmmmmmm-
`0 Do not use in patients with a history of life-threatening immediate hypersensitivity
`reactions, including anaphylaxis, to C1 esterase inhibitor preparations (4).
`
`
`-WARNINGS AND PRECAUTIONS
`- Hypersensitivity reactions may occur. Epinephrine should be immediately available to
`treat any acute severe hypersensitivity reactions following discontinuation of admin-
`istration (5.1).
`0 Thrombotic events have been reported at the recommended dose of C1 Esterase
`Inhibitor (Human) products, including Berinert, following treatment of HAE. Thrombotic
`events also have been reported in association with Berinen when used off-label and
`at higher than labeled doses.‘ Monitor closely patients with known risk factors for
`thrombotic events (5.2).
`0 Berinert is made from human plasma and may contain infectious agents, eg, viruses
`and, theoretically, the Creutzfeldt—Jakob disease (CID) agent (5.3).
`0 Laryngeal attacks: Following self-administration of Berinert for laryngeal attacks, advise
`patients to immediately seek medical attention (5.4).
`-----—--
`—--~—-—-—-----—-—-—---—ADVERSE REACTIONS
`~ The most serious adverse reaction reported in subjects who received Berinert was an
`increase in the severity of pain associated with HAE (6.1).
`0 The most common adverse reaction reported in greater than 4% of the subjects and
`greater than placebo among subjects who received Berinen in the placebocontrolled
`clinical trial was dysgeusia (6.1).
`
`1
`
`Berinen is a plasmaderived concentrate of C1 Esterase Inhibitor (Human) indicated for
`the treatment of acute abdominal, fao'al, or laryngeal attacks of hereditary angioedema
`(HAE) in adult and adolescent patients.
`
`The safetyand effitacy of Berinert for prophylactic therapy have not been established.
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`For Intravenous Use Only.
`
`Administer Berinert at a dose of 20 International Units (IU) per kg body weight by
`intravenous injection. Doses lowerthan 20 IU/kg body weight should not be administered.
`
`Berinen is provided as a freeze-dried powder for reconstitution with the SterileWater for
`Injection, USP provided. Store the vial in the original carton in order to protect from light.
`Do not freeze.
`
`8. With the diluent and Berinen vial still attached to the
`Mix2Vial transfer set, gently swirl the Berinert vial to
`ensure that the Berinert is fully dissolved (Figure 5).
`Do not shake the vial.
`
`9. With one hand, grasp the Berinen-side of the MixZVial
`transfer set and with the other hand grasp the blue
`diluent-side of the MixZVial transfer set and unscrew
`the set into two pieces (Figure 6).
`
`
`
`C
`
`figrrre 6
`
`5.2 Thrombotic Events
`Thrombotic events have been reported at the recommended dose of C1 Esterase Inhibitor
`(Human) products, induding 8erinert, following treatment of HAE. Thrombotic events also
`have been reported in assodation with Berinert when used off-label and at higher than
`labeled doses.1 Monitor closely patients with known risk factors for thrombotic events.
`
`Animal studies have confirmed the risk of thrombosis from intravenous administration of
`C 1 esterase inhibitor productsl [see Overdosage (10) and Nonclinical Toxicology (13.2)].
`
`5.3 Transmission of Infectious Agents
`it may contain infectious agents (eg,
`Because Berinert is made from human blood,
`viruses and, theoretically, the Creutzfeldt-Jakob disease [CJD] agent) that can cause
`disease. The risk that such products will transmit an infectious agent has been reduced by
`screening plasma donors for prior exposure to certain viruses, by testing for the presence
`of certain current virus infections, and by processes demonstrated to inactivate and/or
`remove certain viruses during manufacturing [see Description( 1 1) and PaIientCounseIing
`Information (17)].
`
`Despite these measures, such products may still potentially transmit disease.There is also
`the possibilitythat unknown infectious agents may be present in such products.
`
`Since 1979, afew suspected cases of viral transmission have been reported with the use
`of Berinert outside the US, including cases of acute hepatitis C. From the incomplete
`information available from these cases, it was not possible to determine with certainty
`if the infections were or were not related to prior administration of 8erinert. With the
`introduction of the pasteurization step (heat treatment in aqueous solution at 60°C
`for 10 hours) in 1985, case reports on suspected transmission of viruses have not
`demonstrated a causal relationship to the administration of Berinert.
`
`r_——
`
`‘ The study protocol specified that adverse events that began within 72 hours of blinded study
`medication administration, 'rrespective of the investigator's assessment of causality, were to be
`classified as at least possibly related to study medication (ie, adverse reactions).
`1 If a subject experienced no relief or insufficient relief of symptoms within 4 hours after 'nfusion,
`investigators had the option to administer a blinded second infusion (‘rescue‘ treatment) of
`Boinen (20 lUIkg for the placebo group or 10 lUIkg for the 10 IU/kg group), or placebo (for the
`20 IU/kg grow).
`t Adverse reactions following either initial treatment and/or blinded "rescue' treatment. Because
`more subjects in the placebo randomization groupthan in the Berinen randomization group received
`rescue treatment, the median observation period in this analysis for subjects randomized to
`placebo was slightly longer than for subjects randomized to receive Berinen.
`
`To report SUSPECTED ADVERSE REACTIONS, contact the CSL Behring
`Pharmacovigilance Department at 1-866-915—6958
`or to the FDA at 1-800—FDA-1088 or www.fda.gov/medwatch.
`
`muse IN SPECIFIC POPULATIONSWW~
`0 Pregnancy: No animal data. Limited human data. Use only if clearly needed (8.1).
`0 Compared to adults, when adjusted for baseline, the half-life of Berinert was shorter
`and clearance (on per kg basis) was faster in children. The clinical implication of this
`difference is not known (12.3).
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient
`labeling.
`
`2.1 Preparation and Handling
`0 Check the expiration date on the product vial label. 00 not use beyond the
`expiration date.
`- Prepare and administer using aseptic techniques [see Dosage andAdministration
`(2.2)]-
`0 After reconstitution and prior to administration, inspect Berinert visually for
`particulate matter and discoloration. The reconstituted solution should be color-
`less, clear, and free from visible particles. 00 not use if the solution is cloudy,
`discolored, or contains particulates.
`0 The Berinert vial is for single use only. Berinert contains no preservative. Any
`product that has been reconstituted should be used promptly. The reconstituted
`solution must be used within 8 hours. Discard partially used vials.
`0 Do not freeze the reconstituted solution.
`
`2.2 Reconstitution and Administration
`Each Berinen vial containing 500 IU ofC1 esterase inhibitor as a Iyophilized concentrate
`for reconstitution with 10 mL of SterileWater for Injection, USP provided.
`
`Revised: July 2012
`
`Use either the Mix2Vial° transfer set provided with Berinert [see HowSupp/ied/Storage
`and Handling (16. 1)] or a commercially available double-ended needle and vented filter
`spike.
`
`10. Carefully look at reconstituted solution in each vial of Berinen. It should be colorless,
`clear, and free from visible particles. Do not use the vial if the liquid looks doudy,
`contains particles, or has changed color. Do not use if the expiration date on the label
`has expired.
`11. Draw air into an empty, sterile syringe.While the Berinert
`vial is upright, screw the syringe to the Mix2Via| transfer set.
`Inject air into the Berinert vial. While keeping the syringe
`plunger pressed, invert the system upside down and draw
`the concentrate into the syringe by pulling the plunger
`back slowly (Figure 7).
`
`12. Now that the concentrate has been transferred into the
`syringe, firmly grasp the barrel of the syringe (keeping the
`plunger facing down) and unscrew the syringe from the
`Mix2Via| transfer set (Figure 8). Attach the syringe to a
`suitable intravenous administration set.
`
`2!in.-Frgure 8
`
`13.
`
`If patient requires more than one vial, pool the contents of multiple vials into one
`syringe. A new unused MixZViaI transfer set should be used for each Berinert vial.
`14. Do not refrigerate after reconstitution.When reconstitution is canied out using aseptic
`technique, administration may begin within 8 hours, provided the solution has been
`stored at up to 25°C (77°F). 00 not refrigerate or freeze the reconstituted solution.
`
`C2869 G46A
`
`1
`
`W
`
`Page 1 of 2
`
`Subjects were tested at baseline and after 3 months for possible exposure to Parvovirus
`B19, hepatitis B, hepatitis C, and HIV-1 and HIV-2. No subject who underwent testing
`evidenced seroconversion or treatment-emergent positive polymerase chain reaction
`testing for these pathogens.
`n
`
`In the safety analysis of the open-label ortension study, 57 subjects with 1085 acute
`moderate to severe abdominal, facial, peripheral, and laryngeal attacks recein a
`20 IU/kg body weight dose of Berinert [see Clinical Studies (14)]. This study provides
`additional safety data in subjects who recein multiple infusions of the product for
`sequential HAE attacks (one infusion per attadt).
`
`Table 3 lists the adverse reactions that occurred in the safety analysis of the open-label
`extension study in 22 subjects orassociatedwith 25 attacks during infusion orwithin 24
`hours or 72 hours after the end of a Berinert infusion.
`
`The physician should disorss the risksand benefits of this productwith the patient before
`prescribing or administering it to the patient [see Paa'ent Counseling Information (17)].
`
`All infections thought by a physician possibly to have been transmitted by Berinert should
`be reported by lot number, by the physician, or other healthcare provider to the
`CSL Behring Pharmacovigilance Department at 1-866-9156958.
`
`5.4 Laryngeal Attadts
`Given the potential for airway obstruction during acute laryngeal HAE attacks, patients
`self-administering Berinert should be advised to immediately seek medical attention in
`an appropriate healthcare facility after treatment with Berinen.
`
`6
`
`ADVERSE REACTIONS
`
`The most serious adverse reaction reported in subjects enrolled in clinical studies who
`received Berinert was an increase in the severity of pain associated with HAE.
`
`The most common adverse reaction reported in greater than 4% of the subjects and
`greater than placebo among subjects who received Berinert in the placebo-controlled
`clinical trial was dysgeusia.
`
`6.1 Clinical Trials Experience
`Because clinical studies are mnducted under widely varying conditions, adverse reaction
`rates obsenred in the clinical trials of a drug cannotbe directly compared to rates in the
`clinical trials of another drug and may not reflect the rates observed in practice.
`
`Dizziness
`3o
`gQ
`ma infediosum
`E
`Headache
`InfusiorHeIated
`reaction
`
`Influenza like illness
`Pruritus
`Rash
`
`1 (2.0%)
`0(0)
`1 (2.0%)
`1 (2.0%)
`1 (2.0%)
`
`1 (2.0%)
`0(0)
`0 (0)
`
`0 (0)
`l (3.3%)
`0 (0)
`0 (0)
`0 (0)
`
`0(0)
`I (3.3%)
`1 (3.3%)
`
`0(0)
`0(0)
`0(0)
`0(0)
`0(0)
`
`1 (6.3%)
`0(0)
`0(0)
`
`N = number of subjects
`OnlyARs associated with attacks of the respective subgroups were included in the analysis
`" Because of the allowance of rescue medication in both study arms. all listed adverse events were
`considered to be at least potentially related to study medication (eg, adverse reactions), regardless
`of the ‘nvestigator's opinion concerning causality.
`
`The inddence and type of adverse reactions with Berinen when administered fortreatrnent
`of multiple consecutive acute HAE attacks of any type was similar to those previously
`observed. As in the placebocontrolled study, no proven cases of infections due to HIV-1/2,
`HAV, HBV, HCV or Parvovirus 819 were observed during the study.
`
`6.2 Postrnarketing Experience
`Because postmarketing reporting ofadverse 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 t