------------------------------ WARNINGS AND PRECAUTIONS ---------------------
`• Severe hypersensitivity reactions may occur. In case of severe
`hypersensitivity, discontinue HAEGARDA administration and institute
`appropriate treatment. Epinephrine should be immediately available for
`treatment of severe hypersensitivity reaction. (5.1)
`• At the recommended subcutaneous (S.C.) dose, a causal relationship between
`thromboembolic events (TEEs) and the use of HAEGARDA has not been
`established. However, thrombosis has occurred in treatment attempts with
`high doses of C1-INH intravenous (I.V.) for prevention or therapy of
`capillary leak syndrome before, during or after cardiac surgery (unapproved
`indication and dose). (5.2)
`• Because HAEGARDA is made from human blood, it may carry a risk of
`transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob
`disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD)
`agent. (5.3)
`
`--------------------------------- ADVERSE REACTIONS --------------------------------
`• Adverse reactions occurring in more than 4% of subjects treated with
`HAEGARDA were injection site reaction, hypersensitivity, nasopharyngitis
`and dizziness. (6.1)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact the CSL Behring
`Pharmacovigilance Department at 1-866-915-6958 or FDA at 1-800-FDA-1088
`or www.fda.gov/medwatch.
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-approved
`patient labeling.
`
`
`Issued: 06/2017
`
`8
`
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Lactation
`8.4 Pediatric Use
`8.5 Geriatric Use
`10 OVERDOSAGE
`11 DESCRIPTION
`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.
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`HAEGARDA safely and effectively. See full prescribing information for
`HAEGARDA.
`
`HAEGARDA® (C1 Esterase Inhibitor Subcutaneous [Human])
`For Subcutaneous Injection, Freeze-Dried Powder for Reconstitution
`Initial U.S. Approval: 2017
`
`------------------------------- INDICATIONS AND USAGE ----------------------------
`HAEGARDA is a plasma-derived concentrate of C1 Esterase Inhibitor (Human)
`(C1-INH) indicated for routine prophylaxis to prevent Hereditary Angioedema
`(HAE) attacks in adolescent and adult patients. (1)
`
`--------------------------- DOSAGE AND ADMINISTRATION -----------------------
`For subcutaneous use after reconstitution only.
`• Administer 60 International Units per kg body weight twice weekly (every 3
`or 4 days). (2)
`• Reconstitute HAEGARDA prior to use using Sterile Water for Injection,
`USP. (2.1)
`• Use a silicone-free syringe for reconstitution and administration. (2.1)
`• Administer at room temperature within 8 hours after reconstitution. (2.1)
`
`------------------------- DOSAGE FORMS AND STRENGTHS ----------------------
`HAEGARDA is available as a white lyophilized powder supplied in single-use
`vials containing 2000 or 3000 International Units (IU) of C1-INH. (3)
`
`---------------------------------- CONTRAINDICATIONS -------------------------------
`Do not use in patients with a history of life-threatening immediate hypersensitivity
`reactions, including anaphylaxis to C1-INH preparations or its excipients. (4)
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
` 1
`
`
`2
`
`INDICATIONS AND USAGE
`DOSAGE AND ADMINISTRATION
`2.1 Preparation and Handling
`2.2 Reconstitution and Administration
`DOSAGE FORMS AND STRENGTHS
`3
`CONTRAINDICATIONS
`4
`5 WARNINGS AND PRECAUTIONS
`5.1 Hypersensitivity
`5.2 Thromboembolic Events
`5.3 Transmissible Infectious Agents
`ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`DRUG INTERACTIONS
`
`6
`
`7
`
`Page 1 of 23
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`CSL EXHIBIT 1024
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`

`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`26
`27
`28
`29
`30
`31
`32
`33
`34
`35
`36
`37
`38
`39
`
`HAEGARDA®,
`C1 Esterase Inhibitor Subcutaneous(Human)
`
`INDICATIONS AND USAGE
`
`DOSAGE AND ADMINISTRATION
`
`CSL Behring
`1.14.1.3 Draft Labeling Text
`
`
`FULL PRESCRIBING INFORMATION
`
`1
`
`HAEGARDA is a plasma-derived concentrate of C1 Esterase Inhibitor (Human) (C1-INH)
`indicated for routine prophylaxis to prevent Hereditary Angioedema (HAE) attacks in adolescent
`and adult patients.
`
`
`2
`
`After reconstitution, for subcutaneous use only.
`
`HAEGARDA is intended for self-administration after reconstitution at a dose of 60 International
`Units (IU) per kg body weight by subcutaneous (S.C.) injection twice weekly (every 3 or 4
`days). The patient or caregiver should be trained on how to administer HAEGARDA.
`
`HAEGARDA is provided as a freeze-dried powder for reconstitution with Sterile Water for
`Injection, USP.
`
`2.1 Preparation and Handling
`• Check the expiration date on the product vial label. Do not use beyond the expiration date.
`• Work on a clean surface and wash hands before performing the following procedures.
`• Prepare and administer using aseptic techniques [see Dosage and Administration (2.2)].
`• Use a silicone-free syringe for reconstitution and administration.
`• Each vial of HAEGARDA is for single-use only. Promptly use the reconstituted solution. The
`solution must be used within 8 hours. Discard partially used vials. HAEGARDA contains no
`preservative.
`• Do not freeze the reconstituted solution.
`
`2.2 Reconstitution and Administration
`Use either the Mix2Vial® transfer set provided with HAEGARDA or a commercially available
`double-ended needle and vented filter spike [see How Supplied/Storage and Handling (16)].
`
`Reconstitution
`The procedures below are provided as general guidelines for the reconstitution and
`administration of HAEGARDA.
`
`Table 1. HAEGARDA Reconstitution Instructions
`1. Ensure that the HAEGARDA vial and Sterile Water for Injection (diluent) vial
`are at room temperature.
`2. Place the HAEGARDA vial, diluent vial and Mix2Vial transfer set on a flat
`surface.
`3. Remove flip caps from the HAEGARDA and diluent vials.
`
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`

`

`CSL Behring
`1.14.1.3 Draft Labeling Text
`
`
`4. Wipe the stoppers with an alcohol swab and allow to dry prior to opening the
`Mix2Vial transfer set package.
`5. Open the Mix2Vial transfer set package by peeling away the lid (Figure 1). Do
`not remove the device from the package.
`
`HAEGARDA®,
`C1 Esterase Inhibitor Subcutaneous(Human)
`
`6. Place the diluent vial on a flat surface and hold the vial tightly. Grip the
`Mix2Vial transfer set together with the clear package and push the plastic spike
`at the blue end of the Mix2Vial transfer set firmly through the center of the
`stopper of the diluent vial (Figure 2).
`
`7. Carefully remove the clear package from the Mix2Vial transfer set. Do not
`remove the Mix2Vial transfer set or touch the exposed end of the device (Figure
`3).
`
`8. With the HAEGARDA vial placed firmly on a flat surface, invert the diluent vial
`with the Mix2Vial transfer set attached and push the plastic spike of the
`transparent adapter firmly through the center of the stopper of the HAEGARDA
`vial (Figure 4). The diluent will automatically transfer into the HAEGARDA vial.
`
`9. With the diluent and HAEGARDA vial still attached to the Mix2Vial transfer set,
`gently swirl the HAEGARDA vial to ensure that the powder is fully dissolved
`(Figure 5). Do not shake the vial.
`
`10. With one hand, grasp the HAEGARDA side of the Mix2Vial transfer set and with
`the other hand grasp the blue diluent side of the Mix2Vial transfer set, and
`unscrew the set into two pieces (Figure 6).
`
`11. Draw air into an empty, sterile syringe. Use a silicone-free syringe. While the
`HAEGARDA vial is upright, screw the syringe to the Mix2Vial transfer set.
`Inject air into the HAEGARDA vial.
`
`
`
`
`Figure 1
`
`
`Figure 2
`
`
`Figure 3
`
`
`Figure 4
`
`
`Figure 5
`
`
`Figure 6
`
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`

`CSL Behring
`1.14.1.3 Draft Labeling Text
`
`
`12. 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).
`
`HAEGARDA®,
`C1 Esterase Inhibitor Subcutaneous(Human)
`
`13. Disconnect the filled syringe by unscrewing it from the Mix2Vial transfer set
`(Figure 8). The reconstituted solution should be colorless, clear, and free from
`visible particles. Do not use if particles or discoloration are observed.
`
`14. Use immediately or within 8 hours of reconstitution. Store reconstituted solution
`at room temperature. Do not refrigerate.
`15. If the dose requires more than one vial, use a separate, unused Mix2Vial transfer
`set and diluent vial for each product vial. Repeat steps 10-12 to pool the contents
`of the vials into one syringe.
`
`
`Figure 7
`
`
`Figure 8
`
`
`
`
`
`Administration
`
`For subcutaneous injection only.
`
`• Train the patient or caregiver on how to self-administer HAEGARDA .
`• Do not mix HAEGARDA with other medicinal products.
`• Visually inspect the final solution for particles and discoloration prior to administration, and
`whenever solution and container permit. Do not use if particles or discoloration is observed.
`• Attach the syringe containing the reconstituted HAEGARDA solution to a hypodermic
`needle or subcutaneous infusion set and administer by subcutaneous injection. Adapt the rate
`of administration to the comfort level of the patient.
`Inject in the abdominal area or other subcutaneous injection sites. Rotate injection sites so
`that the same site is not used repeatedly.
`• Administer HAEGARDA at room temperature and within 8 hours after reconstitution.
`Following administration, discard any unused solution and all administration equipment in an
`appropriate manner as per local requirements.
`
`•
`
`
`
`
`40
`41
`42
`43
`44
`45
`46
`47
`48
`49
`50
`51
`52
`53
`54
`55
`56
`57
`58
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`

`59
`60
`61
`62
`63
`64
`65
`66
`67
`68
`69
`70
`71
`72
`73
`74
`75
`76
`77
`78
`79
`80
`81
`82
`83
`84
`85
`86
`87
`88
`89
`90
`91
`92
`93
`94
`95
`96
`97
`98
`99
`100
`101
`102
`103
`
`HAEGARDA®,
`C1 Esterase Inhibitor Subcutaneous(Human)
`
`DOSAGE FORMS AND STRENGTHS
`
`CSL Behring
`1.14.1.3 Draft Labeling Text
`
`
`3
`
`HAEGARDA is available as a white lyophilized powder supplied in single-use vials containing
`2000 or 3000 IU of C1-INH.
`• The 2000 IU vial must be reconstituted with 4 mL of Sterile Water for Injection, USP.
`• The 3000 IU vial must be reconstituted with 6 mL of Sterile Water for Injection, USP.
`
`
`4
`
`HAEGARDA is contraindicated in individuals who have experienced life-threatening
`hypersensitivity reactions, including anaphylaxis, to C1-INH preparations or its excipients [see
`Description (11)].
`
`
`5 WARNINGS AND PRECAUTIONS
`
`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)].
`
`Initiate individualized treatment in case of an acute HAE attack.
`
`5.1 Hypersensitivity
`Severe hypersensitivity reactions may occur. The signs and symptoms of hypersensitivity
`reactions may include hives (local and generalized), tightness of the chest, difficulty breathing,
`wheezing, hypotension, and/or anaphylaxis during or after injection of HAEGARDA. In case of
`severe hypersensitivity, discontinue HAEGARDA administration and institute appropriate
`treatment. Epinephrine should be immediately available for treatment of severe hypersensitivity
`reaction [see Patient Counseling Information (17)].
`
`5.2 Thromboembolic Events
`At the recommended subcutaneous dose, a causal relationship between thromboembolic events
`(TEEs) and the use of HAEGARDA has not been established [see Patient Counseling
`Information (17)]. Thrombosis has occurred in treatment attempts with high doses of C1-INH
`intravenous (I.V.) for prevention or therapy of capillary leak syndrome before, during or after
`cardiac surgery (unapproved indication and dose).
`
`5.3 Transmissible Infectious Agents
`Because HAEGARDA is made from human blood, it may carry a risk of transmitting infectious
`agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the
`Creutzfeldt-Jakob disease (CJD) agent. 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 (11) and Patient
`Counseling Information (17)]. Despite these measures, such products may still contain human
`
`CONTRAINDICATIONS
`
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`

`ADVERSE REACTIONS
`
`HAEGARDA®,
`C1 Esterase Inhibitor Subcutaneous(Human)
`
`CSL Behring
`1.14.1.3 Draft Labeling Text
`
`
`pathogenic agents, including those not yet known or identified. Thus, the risk of transmission of
`infectious agents cannot be totally eliminated.
`
`All infections thought by a physician possibly to have been transmitted by HAEGARDA should
`be reported by lot number, by the physician or other healthcare provider, to the CSL Behring
`Pharmacovigilance Department at 1-866-915-6958.
`
`
`6
`
`Adverse reactions occurring in more than 4% of subjects treated with HAEGARDA were
`injection site reaction, hypersensitivity, nasopharyngitis and dizziness.
`
`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.
`
`Of the 90 subjects randomized in the double-blind, placebo-controlled, cross-over study [see
`Clinical Studies (14)], 86 subjects received at least one dose of HAEGARDA and 86 subjects
`received at least one dose of placebo (Table 2). A total of 5081 injections of HAEGARDA and
`placebo were administered over a range of 3 to 19 weeks (median of 16.6 weeks for
`HAEGARDA; median of 16.3 weeks for placebo).
`
`
`104
`105
`106
`107
`108
`109
`110
`111
`112
`113
`114
`115
`116
`117
`118
`119
`120
`121
`122
`123
`124
`125
`126
`127
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`CSL Behring
`1.14.1.3 Draft Labeling Text
`
`
`Table 2. Adverse Reactions in >4% of Subjects Treated with HAEGARDA
`HAEGARDA
`
`HAEGARDA®,
`C1 Esterase Inhibitor Subcutaneous(Human)
`
`128
`
`MedDRA System
`Organ Class
`General Disorders
`and Administration
`Site Conditions
`
`Immune System
`Disorders
`
`Infections and
`Infestations
`
`Nervous System
`Disorders
`
`Adverse Reaction
`
`Injection Site
`Reaction†
`
`Hypersensitivity‡
`
`Nasopharyngitis
`
`Dizziness
`
`60 IU/kg
`(N=43)
`n (%)
`
`40 IU/kg
`(N=43)
`n (%)
`
`
`Overall*
`(N=86)
`n (%)
`
`Placebo
`(N=86)
`n (%)
`
`15
`(35)
`
`3
`(7)
`
`8
`(19)
`
`0
`(0)
`
`12
`(28)
`
`2
`(5)
`
`1
`(2)
`
`4
`(9)
`
`27
`(31)
`
`5
`(6)
`
`9
`(11)
`
`4
`(5)
`
`21
`(24)
`
`1
`(1)
`
`6
`(7)
`
`1
`(1)
`
`129
`130
`131
`132
`133
`134
`135
`136
`137
`138
`139
`140
`141
`142
`143
`144
`145
`146
`147
`148
`149
`150
`151
`152
`153
`154
`
`DRUG INTERACTIONS
`
`N = number of subjects receiving the treatment; n = number of subjects experiencing ≥1 event.
`* Includes subjects who were treated with 40 IU/kg or 60 IU/kg HAEGARDA.
`† Includes: Injection site bruising, coldness, discharge, erythema, hematoma, hemorrhage, induration, edema, pain, pruritus, rash,
`reaction, scar, swelling, urticaria, warmth.
`‡ Includes: hypersensitivity, pruritus, rash, and urticaria.
`
`Of the injection site reactions occurring after treatment with HAEGARDA, 95% were of mild
`intensity and 83% resolved within 1 day after onset.
`
`
`7
`
`No interaction studies have been conducted.
`
`
`8
`
`8.1 Pregnancy
`
`Risk Summary
`There are no prospective clinical data from HAEGARDA use in pregnant women. C1-INH is a
`normal component of human plasma. Animal developmental or reproduction toxicity studies
`have not been conducted with HAEGARDA. In the U.S. general population, the estimated
`background risk of major birth defects occurs in 2-4% of the general population and miscarriage
`occurs in 15-20% of clinically recognized pregnancies.
`
`
`USE IN SPECIFIC POPULATIONS
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`

`HAEGARDA®,
`C1 Esterase Inhibitor Subcutaneous(Human)
`
`CSL Behring
`1.14.1.3 Draft Labeling Text
`
`
`Data
`In a retrospective case collection study, 22 pregnant women with type I HAE and ranging in age
`from 20 to 38 years received C1-INH doses of 500 or 1000 IU per I.V. administration for the
`treatment of acute attacks before, during, and/or after pregnancy (total of 35 pregnancies). No
`adverse events were associated with C1-INH treatment before, during, or after pregnancy.1
`
`In an observational registry (overall 318 subjects) data were collected on 11 pregnancies in
`10 subjects (16 to 40 years old) receiving up to 3000 IU C1-INH (I.V. administration) to treat or
`prevent HAE attacks. No adverse events were associated with C1-INH treatment.2
`
`8.2 Lactation
`
`Risk Summary
`There is no information regarding the excretion of HAEGARDA in human milk, the effect on the
`breastfed infant, or the effects on milk production. The developmental and health benefits of
`breastfeeding should be considered along with the mother’s clinical need for HAEGARDA and
`any potential adverse effects on the breastfed infant from HAEGARDA or from the underlying
`maternal condition.
`
`Data
`In a retrospective case collection study, breastfeeding was documented for neonates from 21 of
`35 births with a median duration of 4.8 months (ranging from 1 to 34 months). Mothers were
`treated postpartum with C1-INH doses up to 1000 IU per I.V. administration for the treatment of
`acute HAE attacks. No adverse events to the mothers were associated with C1-INH treatment
`after pregnancy. No information regarding the effect on the breastfed infant was reported.1
`
`8.4 Pediatric Use
`The safety and effectiveness of HAEGARDA were evaluated in a subgroup of six patients 12 to
`<17 years of age in the randomized, double-blind, placebo-controlled, crossover, routine
`prophylaxis trial. Results of subgroup analysis by age were consistent with overall study results.
`
`8.5 Geriatric Use
`The safety and effectiveness of HAEGARDA were evaluated in a subgroup of eight patients 65
`to 72 years of age in the randomized, double-blind, placebo-controlled, crossover, routine
`prophylaxis trial. Results of subgroup analysis by age were consistent with overall study results.
`
`
`10 OVERDOSAGE
`
`No case of overdose has been reported. Doses corresponding to up to 117 IU/kg S.C. have been
`administered twice weekly in a fixed-dose clinical study.
`
`
`
`155
`156
`157
`158
`159
`160
`161
`162
`163
`164
`165
`166
`167
`168
`169
`170
`171
`172
`173
`174
`175
`176
`177
`178
`179
`180
`181
`182
`183
`184
`185
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`189
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`

`HAEGARDA®,
`C1 Esterase Inhibitor Subcutaneous(Human)
`
`CSL Behring
`1.14.1.3 Draft Labeling Text
`
`
`11 DESCRIPTION
`
`HAEGARDA is a human plasma-derived, purified, pasteurized, lyophilized concentrate of
`C1-INH to be reconstituted for S.C. administration. HAEGARDA is prepared from large pools
`of human plasma from U.S. donors. The potency of C1-INH is expressed in International Units
`(IU), which is related to the current WHO Standard for C1-INH products.
`
`Reconstituted HAEGARDA has a concentration of 500 IU/mL C1-INH, 65 mg/mL total protein,
`10 mg/mL glycine, 8.5 mg/mL sodium chloride and 2.7 mg/mL sodium citrate.
`
`C1 Esterase Inhibitor
`C1-INH is a soluble, single-chain highly glycosylated protein containing 478 amino acid
`residues which belongs to the serine protease inhibitor (serpin) family.
`
`All plasma used in the manufacturing of C1-INH is obtained from U.S. donors and is tested
`using serological assays for hepatitis B surface antigen and antibodies to HIV-1/2 and HCV.
`Additionally, the plasma is tested with Nucleic Acid Testing (NAT) for HBV, HCV, HIV-1 and
`HAV and found to be non-reactive (negative). The plasma is also tested by NAT for Human
`Parvovirus B19. Only plasma that has passed virus screening is used for production, and the limit
`for Parvovirus B19 in the fractionation pool is set not to exceed 104 IU of Parvovirus B19 DNA
`per mL.
`
`The manufacturing process for HAEGARDA includes multiple steps that reduce the risk of virus
`transmission. The virus inactivation/reduction capacity consists of three steps:
`• Pasteurization in aqueous solution at 60°C for 10 hours
`• Hydrophobic interaction chromatography
`• Virus filtration (also called nanofiltration) by two filters, 20 nm and 15 nm, in series.
`
`Viral inactivation and reduction were evaluated in a series of in vitro spiking experiments. The
`total mean cumulative virus inactivation/reduction is shown in Table 3.
`
`
`198
`199
`200
`201
`202
`203
`204
`205
`206
`207
`208
`209
`210
`211
`212
`213
`214
`215
`216
`217
`218
`219
`220
`221
`222
`223
`224
`225
`226
`227
`228
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`229
`
`230
`231
`232
`233
`234
`235
`236
`237
`238
`239
`240
`241
`242
`243
`244
`245
`246
`247
`248
`249
`250
`251
`252
`253
`254
`255
`256
`257
`
`HAEGARDA®,
`C1 Esterase Inhibitor Subcutaneous(Human)
`
`CSL Behring
`1.14.1.3 Draft Labeling Text
`
`
`Table 3. Mean Virus Inactivation/Reductions in HAEGARDA
`Hydrophobic
`Interaction
`Chromatography
`[log10]
`
`Virus
`Studied
`
`Pasteurization
`[log10]
`
`Virus Filtration
`[log10]
`
`Total
`Cumulative
`[log10]
`
`≥4.5
`≥4.7
`≥6.5
`ND
`
`≥5.1
`≥5.3
`≥7.1
`≥8.0
`
`≥5.3
`≥7.2
`ND
`
`≥16.2
`≥19.2
`≥19.9
`≥15.0
`
`≥14.5
`≥15.0
`NA
`
`Enveloped Viruses
`HIV-1
`≥6.6
`BVDV
`≥9.2
`6.3
`PRV
`WNV
`≥7.0
`Non-Enveloped Viruses
`2.8
`HAV
`≥6.4
`6.4
`CPV
`1.4
`ND
`B19V
`3.9
`HIV-1, Human immunodeficiency virus type 1, a model for HIV-1 and HIV-2
`BVDV, Bovine viral 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
`B19V, Human Parvovirus B19
`ND, Not determined
`NA, Not applicable
`
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`C1-INH is a normal constituent of human plasma and belongs to the group of serine protease
`inhibitors (serpins) that includes antithrombin III, alpha1-protease inhibitor, alpha2-antiplasmin,
`and heparin cofactor II. As with the other inhibitors in this group, C1-INH has an important
`inhibiting potential on several of the major human cascade systems, including the complement,
`fibrinolytic and coagulation systems. Regulation of these systems is performed through the
`formation of complexes between the protease and the inhibitor, resulting in inactivation of both
`and consumption of the C1-INH.
`
`C1-INH, which is usually activated during the inflammatory process, inactivates its substrate by
`covalently binding to the reactive site. C1-INH is the only known inhibitor for the C1r and C1s
`subcomponents of complement component 1 (C1), coagulation factor XIIa, and plasma
`kallikrein. Additionally, C1-INH is the main inhibitor for coagulation factor XIa of the intrinsic
`coagulation cascade.
`
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`HAEGARDA®,
`C1 Esterase Inhibitor Subcutaneous(Human)
`
`CSL Behring
`1.14.1.3 Draft Labeling Text
`
`
`HAE patients have absence or low levels of endogenous or functional C1-INH. Although the
`events that cause 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-INH through the inactivation of plasma kallikrein and factor XIIa is thought to
`modulate this vascular permeability by preventing the generation of bradykinin. Administration
`of HAEGARDA replaces the missing or malfunctioning C1-INH protein in patients with HAE.
`
`12.2 Pharmacodynamics
`In untreated patients, insufficient levels of functional C1-INH lead to increased activation of C1,
`which results in decreased levels of complement component 4 (C4). The administration of
`HAEGARDA increases plasma levels of C1-INH in a dose-dependent manner and subsequently
`increases plasma concentrations of C4. The C4 plasma concentrations after S.C. administration
`of 60 IU/kg HAEGARDA were in the normal range (16 to 38 mg/dL).
`
`12.3 Pharmacokinetics
`The pharmacokinetics (PK) of C1-INH were described using population PK analysis.
`
`The PK parameters of C1-INH following twice weekly subcutaneous 60 IU/kg dosing are
`shown in Table 4.
`
`Table 4. Pharmacokinetic Parameter for HAEGARDA (60 IU/kg) from Population
`Pharmacokinetic Analysis
`95% CI
`Mean
`Parameter
`CL (mL/hr/kg)*
`0.90-1.17
`1.03
`Vd (L/kg)*
`0.04-0.06
`0.05
`35.2-50.2
`42.7
`Bioavailability %
`31.8-128‡
`60.7†
`Cmax %
`25.1-102‡
`48.0†
`Ctrough %
`23-134‡
`59§
`Tmax (hr)
`24-251‡
`69§
`Half-life (hr)||
`*Calculated based on median weight of 80.7 kg of the population, †Geometric mean, ‡2.5-97.5 percentile of the
`population, §Median, ||Apparent half-life.
`
`The steady state PK of S.C. C1-INH is independent of dose between 20-80 IU/kg in HAE
`subjects.
`
`Studies have not been conducted to evaluate the PK of C1-INH in specific patient populations
`stratified by gender, race, age, or the presence of renal or hepatic impairment. The PK of C1-INH
`was not influenced at the age range of 12-72 years.
`
`13 NONCLINICAL TOXICOLOGY
`
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`HAEGARDA®,
`C1 Esterase Inhibitor Subcutaneous(Human)
`
`CSL Behring
`1.14.1.3 Draft Labeling Text
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`No animal studies have been conducted to evaluate the effects of C1-INH on carcinogenesis,
`mutagenesis, and impairment of fertility.
`
`13.2 Animal Toxicology and/or Pharmacology
`Single subcutaneous administration of HAEGARDA in rabbits at dose levels up to
`approximately 670 IU/kg did not result in adverse findings.
`
`
`14 CLINICAL STUDIES
`
`The efficacy and safety of HAEGARDA for routine prophylaxis to prevent HAE attacks were
`demonstrated in a multicenter, randomized, double-blind, placebo-controlled, crossover study.
`The study assessed 90 adult and adolescent subjects with symptomatic HAE type I or II. The
`median (range) age of subjects was 40 (12 to 72) years ; 60 subjects were female and 30 subjects
`were male. Subjects were randomized to receive either 60 IU/kg or 40 IU/kg HAEGARDA in
`one 16-week treatment period and placebo in the other 16-week treatment period. Patients
`self-administered HAEGARDA or placebo subcutaneously 2 times per week. Efficacy was
`evaluated for the last 14 weeks of each treatment period.
`
`Twice per week S.C. doses of 60 IU/kg or 40 IU/kg HAEGARDA resulted in a significant
`difference in the time-normalized number of HAE attacks (the rate of attacks) relative to placebo
`(Table 5). The time normalized number of HAE attacks in subjects dosed with 60 IU/kg was
`0.52 attacks per month compared to 4.03 attacks per month while receiving placebo (p <0.001).
`The time normalized number of HAE attacks in subjects dosed with 40 IU/kg was 1.19 attacks
`per month compared to 3.61 attacks per month while receiving placebo (p <0.001).
`
`
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`HAEGARDA®,
`C1 Esterase Inhibitor Subcutaneous(Human)
`
`Placebo
`44
`3.6 (2.1)
`0.0, 8.9
`3.8
`3.6 (0.3)
`(3, 4.3)
`
`CSL Behring
`1.14.1.3 Draft Labeling Text
`
`
`Table 5. Time-normalized Number of HAE Attacks (Number/Month)
`40 IU/kg HAEGARDA
`60 IU/kg HAEGARDA
`Treatment Sequences
`Treatment Sequences
`(N = 45)
`(N = 45)
`HAEGARDA
`HAEGARDA
`43
`43
`0.5 (0.8)
`1.2 (2.3)
`0.0, 3.1
`0.0, 12.5
`0.3
`0.3
`0.5 (0.3)
`1.2 (0.3)
`(0.0, 1.0)
`(0.5, 1.9)
`
`Placebo
`42
`4.0 (2.3)
`0.6, 11.3
`3.8
`4.0 (0.3)
`(3.5, 4.6)
`
`
`n
`Mean (SD)
`Min, Max
`Median
`LS Mean (SE)*
`95% CI for LS Mean*
`Treatment difference
`60 IU/kg HAEGARDA – Placebo 40 IU/kg HAEGARDA – Placebo
`(within-subjects)
`LS Mean* (95% CI)
`-3.5 (-4.2, -2.8)
`-2.4 (-3.4, -1.5)
`p-value*
`< 0.001
`< 0.001
`CI = confidence interval; HAE = hereditary angioedema; N = number of randomized subjects; n = number of subjects with data;
`LS = Least squares.
`* From a mixed model.
`
`The median (25th, 75th percentile) percentage reduction in the time-normalized number of HAE
`attacks relative to placebo was 95% (79, 100) on 60 IU/kg HAEGARDA and 89% (70, 100) on
`40 IU/kg HAEGARDA among subjects with evaluable data in both treatment periods.
`
`The percentage of responders (95% CI) with a ≥50% reduction in the time‑normalized number
`of HAE attacks on HAEGARDA relative to placebo was 83% (73%, 90%). Ninety percent
`(90%) of subjects on 60 IU/kg responded to treatment and 76% of subjects on 40 IU/kg
`responded to treatment.
`
`The percentages of subjects (95% CI) with ≥70% and ≥90% reductions in the time‑normalized
`number of HAE attacks on HAEGARDA relative to placebo were 74% (64%, 83%) and 50%
`(39%, 61%), respectively. The percentages of subjects with ≥70% and ≥90% reductions in
`comparison to placebo in the time-normalized number of HAE attacks were 83% and 58% on
`60 IU/kg and 67% and 43% on 40 IU/kg. Seventy-one percent (71%) of subjects on 60 IU/kg and
`53% of subjects on 40 IU/kg had ≥1 HAE attack per 4 week period on placebo and <1 HAE
`attack per 4 week period on HAEGARDA.
`
`A total of 40% of subjects on 60 IU/kg and 38% of subjects on 40 IU/kg were attack-free, and
`the median rate of HAE attacks per month was 0.3 on both doses.
`
`HAEGARDA resulted in a significant difference in the time-normalized number of uses of
`rescue medication (the rate of rescue medication use) relative to placebo. A dose of 60 IU/kg
`resulted in a mean rate of rescue medication of 0.3 uses per month, compared to 3.9 uses per
`
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`386
`387
`
`HAEGARDA®,
`C1 Esterase Inhibitor Subcutaneous(Human)
`
`CSL Behring
`1.14.1.3 Draft Labeling Text
`
`
`month with placebo. A dose of 40 IU/kg resulted in a mean rate of rescue medication use of 1.1
`uses per month, compared to 5.6 uses per month with placebo.
`
`
`15 REFERENCES
`1. Martinez-Saguer I, Rusicke E, Aygören-Pürsün E, et al. Characterization of acute hereditary
`angioedema attacks during pregnancy and breast-feeding and their treatment with C1
`inhibitor concentrate. Am J Obstet Gynecol. 2010;203:131.e1-7.
`2. Fox J, Vegh AB, Martinez-Saguer I, et al. Safety of a C1-inhibitor concentrate in pregnant
`women with hereditary angioedema. Allergy Asthma Proc. 2017;38(3):216-221.
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`How Supplied
`HAEGARDA is supplied in a kit containing a lyophilized powder in a single-use vial.
`
`HAEGARDA is packaged with Sterile Water for Injection, USP (4 mL for reconstitution of
`2000 IU or 6 mL for reconstitution of 3000 IU) and one Mix2Vial filter transfer set. Not made
`with natural rubber latex.
`
`
`Nominal Strength
`2000 IU
`3000 IU
`
`Fill Size Color Indicator
`Fuschia
`Yellow
`
`Kit NDC
`63833-828-02
`63833-829-02