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-dose 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)].

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 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.

6.1 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 (Study 1) [see Clinical Studies (14)], 86 subjects received at least one dose of HAEGARDA and 86 subjects received at least one dose of placebo (Table 1). 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). Eligible patients were also able to participate in a randomized, open-label, active treatment-controlled study (Study 2) for up to 140 weeks (n=120).

Of the injection site reactions occurring after treatment with HAEGARDA, 95% were of mild intensity and 83% resolved within 1 day after onset.

Overall, safety data from the open-label study (Study 2), consisting of 59 patients who participated in Study 1 and 61 patients who did not participate in Study 1 (n=120), were consistent with the safety data from the randomized, double-blind, placebo-controlled, crossover, routine prophylaxis trial (Study 1).

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of HAEGARDA were evaluated in a subgroup of nine patients 8 to <17 years of age, in the randomized, double-blind, placebo-controlled, crossover, routine prophylaxis trial (Study 1) and the randomized, open-label, active treatment-controlled study (Study 2). 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 nine subjects 65 to 72 years of age, eight subjects who received the high 60 IU/kg dose and one subject who received the 40 IU/kg dose, in the randomized, double-blind, placebo-controlled, crossover, routine prophylaxis trial (Study 1) and in the randomized, open-label, active treatment-controlled study (Study 2). Clinical studies of HAEGARDA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

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 2.

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.

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 3.

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, or the presence of renal or hepatic impairment. Body weight was included as covariate in the population PK analysis of C1-INH in the age range of 8-72 years while age was not a statistically significant covariate. The body weight adjusted clearance is 11% and 10 % higher in children (8 to < 12 years old) and adolescents (12 to < 18 years old) as compared to adult subjects (18 to 72 years), respectively.

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.

Study 1:

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.

Eligible patients were also able to participate in Study 2 for up to 140 weeks. Approximately half of the subjects enrolled in Study 2 also participated in Study 1 (59/120, 49.2%).

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 4). 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).

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 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.

Study 2:

The study assessed 120 adult and pediatric subjects with symptomatic HAE type I or II. The median (range) age of subjects was 41.0 (8-72) years. Patients with a monthly attack rate of 4.3 in 3 months before entry in the study were enrolled and treated for a mean of 1.4 years; 41 patients (34.2%) had more than 2 years of exposure. Mean steady-state C1-INH functional activity increased to 52.0% with 40 IU/kg and 66.6% with 60 IU/kg. Incidence of adverse events was similar in both dose groups (12.0 and 8.6 events per patient-year for 40 IU/kg and 60 IU/kg, respectively). The percentages of subjects with ≥50% reductions in the time-normalized number of HAE attacks on HAEGARDA relative to the time-normalized number of HAE attacks at baseline were 93.1% and 93.1% in 40 IU/kg and 60 IU/kg treatment arms, respectively. The percentages of subjects with time normalized HAE attack frequency of < 1 HAE attack per 4-week period were 79.7% on 40 IU/kg and 86.9% on 60 IU/kg. For 40 IU/kg and 60 IU/kg, median annualized attack rates were 1.0 and 1.0, respectively, and median rescue medication use was 0.0 and 0.0 times per year, respectively. The proportion of HAE attack-free subjects throughout the study duration with a maximum exposure of >2.5 years was 35.6% and 44.3% in the 40 IU/kg and 60 IU/kg treatment arms, respectively.

Storage and Handling

• When stored at temperatures up to 30°C (86°F), HAEGARDA is stable for the period indicated by the expiration date on the carton and vial label.
• Keep HAEGARDA in its original carton until ready to use.
• Do not freeze.
• Protect from light.
• Discard any unused product and all used disposable supplies.

Inform patients/caregivers to immediately report the following to their physician:

• Signs and symptoms of allergic hypersensitivity reactions, such as hives, tightness of the chest, difficulty breathing, wheezing, hypotension and/or anaphylaxis experienced during or after injection of HAEGARDA [see Warnings and Precautions (5.1)].
• Signs and symptoms of a thromboembolic event, including pain and/or swelling of an arm or leg with warmth over the affected area, discoloration of an arm or leg, unexplained shortness of breath, chest pain or discomfort that worsens on deep breathing, unexplained rapid pulse, numbness or weakness on one side of the body [see Warnings and Precautions (5.2)].

Inform all patients/caregivers:

• HAEGARDA is indicated for HAE prophylaxis and should not be used for the treatment of acute HAE attacks. Patients/caregivers should be counselled regarding the appropriate course of action if breakthrough HAE attacks occur while on HAEGARDA, including:
  • Individualized rescue treatment for acute HAE attacks.
  • Situations in which to seek immediate medical attention, such as acute laryngeal HAE attacks.
• Patients/caregivers must ensure an adequate supply of HAEGARDA when traveling.
• 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 [see Warnings and Precautions (5.3) and Description (11)].
• Patients with known risk factors for thromboembolic events are at an increased risk for these events [see Warnings and Precautions (5.2)].
• Ensure that the patient/caregiver has access to and has received training in the administration of subcutaneous epinephrine and/or other appropriate supportive therapy for the treatment of any acute anaphylactic or severe hypersensitivity reaction [see Warnings and Precautions (5.1)].

Advise female patients:

• Patients should notify their physician if they become pregnant or intend to become pregnant while taking HAEGARDA [see Use in Specific Populations (8.1)].
• Patients should notify their physician if they are breastfeeding or plan to breastfeed while taking HAEGARDA [see Use in Specific Populations (8.2)].

Self-administration - Ensure that the patient/caregiver receives clear instructions and training on S.C. administration in the home or other appropriate setting and has demonstrated the ability to perform S.C. injection.

• Ensure the patient (or caregiver) has the necessary dexterity and comprehension to be trained to self-administer.
• Instruct patients/caregivers to record the lot number from the HAEGARDA vial label every time they use HAEGARDA.

The attached HAEGARDA "Patient Product Information (PPI)" contains more detailed instructions for patients/caregivers who will be self-administering HAEGARDA.