Immune Globulin Infusion 10%

HYQVIA is a dual vial unit with one vial of Immune Globulin Infusion 10% (Human) and one vial of Recombinant Human Hyaluronidase.

The Immune Globulin Infusion 10% (Human) of HYQVIA is a ready-for-use sterile, liquid preparation of highly purified and concentrated IgG antibodies. The distribution of the IgG subclasses is similar to that of normal plasma. The Fc and Fab functions are maintained in the primary component. Pre-kallikrein activator activity is not detectable. The Immune Globulin Infusion 10% (Human) of HYQVIA contains 100 mg/mL protein. At least 98% of the protein is IgG, average immunoglobulin A (IgA) concentration is 37μg/mL, and immunoglobulin M (IgM) is present in trace amounts. The Immune Globulin Infusion 10% (Human) of HYQVIA contains a broad spectrum of IgG antibodies against bacterial and viral agents. Glycine (0.25M) serves as a stabilizing and buffering agent. There is no added sugar, sodium, or preservatives. The pH is 4.6 to 5.1. The osmolality is 240 to 300 mOsmol/kg.

The Immune Globulin Infusion 10% (Human) of HYQVIA is manufactured from large pools of human plasma. IgG preparations are purified from plasma pools using a modified Cohn-Oncley cold ethanol fractionation process, as well as cation and anion exchange chromatography.

Screening against potentially infectious agents begins with the donor selection process and continues throughout plasma collection and plasma preparation. Each individual plasma donation used in the manufacture of the Immune Globulin Infusion 10% (Human) of HYQVIA is collected only at FDA approved blood establishments and is tested by FDA licensed serological tests for Hepatitis B Surface Antigen (HBsAg), and for antibodies to Human Immunodeficiency Virus (HIV-1/HIV-2) and Hepatitis C Virus (HCV) in accordance with U.S. regulatory requirements. As an additional safety measure, mini-pools of the plasma are tested for the presence of HIV-1 and HCV by FDA licensed Nucleic Acid Testing (NAT).

To further improve the margin of safety, three dedicated, independent and effective virus inactivation/removal steps have been integrated into the manufacturing and formulation processes, namely solvent/detergent (S/D) treatment, 35 nm nanofiltration, and a low pH incubation at elevated temperature. The S/D process includes treatment with an organic mixture of tri-n-butyl phosphate, octoxynol 9 and polysorbate 80 at 18°C to 25°C for a minimum of 60 minutes7.

In vitro virus spiking studies have been used to validate the capability of the manufacturing process to inactivate and remove viruses. To establish the minimum applicable virus clearance capacity of the manufacturing process, these virus clearance studies were performed under extreme conditions (e.g., at minimum S/D concentrations, incubation time and temperature for the S/D treatment). Virus clearance studies for the Immune Globulin Infusion 10% (Human) of HYQVIA performed in accordance with good laboratory practices (Table 6) have demonstrated that:

• S/D treatment inactivates the lipid-enveloped viruses investigated to below detection limits within minutes.
• 35 nm nanofiltration removes lipid-enveloped viruses to below detection limits and reduces the non-lipid enveloped viruses HAV and B19V. As determined by a polymerase chain reaction assay, nanofiltration reduced B19V by a mean log10 reduction factor of 4.8 genome equivalents.
• Treatment with low pH at elevated temperature of 30°C to 32°C inactivates lipidenveloped viruses and encephalomyocarditis virus (EMCV, model for HAV) to below detection limits, and reduces mice minute virus (MMV, model for B19V).

Table 6: Three Dedicated Independent Virus Inactivation/Removal Steps Mean Log10 Reduction Factorsa (RFs) For Each Virus and Manufacturing Step

The Recombinant Human Hyaluronidase of HYQVIA is produced from genetically engineered Chinese Hamster Ovary (CHO) cells containing a DNA plasmid encoding for a soluble fragment of human hyaluronidase PH20. The purified hyaluronidase glycoprotein contains 447 amino acids with an approximate molecular weight of 61,000 Daltons [see Mechanism of Action]. This component is supplied as a sterile, clear, colorless, readyfor- use solution and has approximate pH of 7.4 and an osmolality of 290 to 350 mOsm. Each vial contains 160 U/mL of recombinant human hyaluronidase with 8.5 mg/mL sodium chloride, 1.78 mg/mL, sodium phosphate dibasic dihydrate, 1.0 mg/mL human albumin, 1.0 mg/mL edentate disodium dihydrate, 0.40 mg/mL calcium chloride dihydrate, and 0.17 mg/mL sodium hydroxide added for pH adjustment. It does not contain preservatives.

Due to comprehensive virus testing at the Master Cell Bank, Working Cell Bank and bulk harvest stage, effective virus reduction during the purification process and the use of pharmaceutical grade human albumin as an excipient with no other materials of human or animal origin involved in the manufacturing process, recombinant human hyaluronidase provides for high margins of safety with respect to viruses.

HYQVIA is an immune globulin with a recombinant human hyaluronidase indicated for the treatment of Primary Immunodeficiency (PI) in adults. This includes, but is not limited to, common variable immunodeficiency (CVID), X-linked agammaglobulinemia, congenital agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies1,2.

Limitation Of Use

Safety and efficacy of chronic use of recombinant human hyaluronidase in HYQVIA have not been established in conditions other than PI.

Dosage Forms And Strengths

HYQVIA is a dual vial unit consisting of one vial of a liquid solution containing Immune Globulin Infusion 10% (Human) and one vial of a liquid solution containing 160 U/mL Recombinant Human Hyaluronidase.

HYQVIA is supplied in a dual vial unit of two single use vials containing the labeled amount of functionally active Immune Globulin Infusion 10% (Human) and Recombinant Human Hyaluronidase. The packaging of this product is not made with natural rubber latex.

The following presentations of HYQVIA are available:

Storage And Handling

Do not freeze.

Keep the vials in the carton in order to protect from light.

Refrigeration: 2°to 8°C [36°to 46°F] for up to 36 months.

Room Temperature: up to 25°C [77°F] for up to 3 months during the first 24 months from the date of manufacturing (Mfg date) printed on the carton.

• HYQVIA must be used within 3 months after removal to room temperature but within the expiration date on the carton and vial label.
• Do not return HYQVIA to the refrigerator after it has been stored at room temperature.

REFERENCES

1. Orange JS, Hossny EM, Weiler CR, Ballow M, Berger M, Bonilla FA, Buckley R, Chinen J, El-Gamal Y, Mazer BD, Nelson Jr. RP, Patel DD, Secord E, Sorenson RU, Wasserman RL, Cunningham-Rundles C, Use of Intravenous Immunoglobulin in Human Disease: A Review of Evidence by Members of the Primary Immunodeficiency   Committee of the American Academy of Allergy, Asthma, and Immunology. J Allergy Clin Immunol 2006; 117:S525-53.

2. Bonilla FA, Bernstein IL, Khan DA, Ballas ZK, Chinen J, Frank MM, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. Ann Allergy Asthma Immunol. 2005; 94(suppl 1):S1-63.

Baxalta US Inc., Westlake Village, CA 91362 USA. Revised: Feb 2016

Common adverse reactions observed in clinical trials in > 5% of subjects were: local reactions, headache, antibody formation against recombinant human hyaluronidase (rHuPH20), fatigue, nausea, pyrexia, and vomiting.

Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in clinical studies of a product cannot be directly compared to rates in the clinical studies of another product and may not reflect the rates observed in clinical practice.

Immune Globulin Infusion 10% (Human) administered intravenously: Prior to initiation of treatment with HYQVIA, 87 patients received 365 infusions of immune globulin infusion 10% (Human) encompassing 22.2 patient-years. Among the 87 patients treated, 56 (64.4%) experienced 1 or more adverse reactions. Among the 365 intravenous infusions, 158 adverse reactions occurred for a rate per infusion of 0.43.

A total of 1359 infusions of HYQVIA were administered during the trial; 230 of these infusions occurred during the ramp-up period and the other 1129 occurred during the observation period. During the observation period, 81 patients received 1129 infusions of HYQVIA, of those, 67 (82.7%) experienced one or more adverse reactions. Among the 1129 HYQVIA infusions, 456 adverse reactions occurred for a rate per infusion of 0.40. Seven of these adverse reactions were severe defined as marked impairment of function or can lead to temporary inability to resume normal life pattern; requires prolonged intervention or results in sequelae.

Adverse reactions occurring in greater than 5% of subjects associated with infusions of HYQVIA vs. Immune Globulin Infusion 10% (Human) given intravenously are shown in Table 4. The majority of these adverse reactions was mild to moderate in severity and did not necessitate discontinuing the infusions. Mild is defined as transient discomfort that resolves spontaneously or with minimal intervention; moderate is defined as limited impairment of function and resolves spontaneously or with minimal intervention with no sequelae. No serious adverse reactions occurred during the HYQVIA clinical trials.

Table 4 : Adverse Reactionsa in greater than 5% of Subjects Associated with Infusions of HYQVIA vs. Immune Globulin Infusion 10% (Human) (IGIV) Given Intravenously

Six subjects, 2 children and 4 adults, withdrew from the trial during the efficacy treatment period with HYQVIA due to mild to moderate adverse reactions. One child withdrew due to local pain and one due to fever, vomiting, and headaches. Of the four adults, two withdrew due to local pain and swelling, one had moderate swelling that transiently extended from the abdominal infusion site to the genitalia, and one had back injury.

Antibodies binding to rHuPH20: A total of 15 out of 83 subjects who were treated with HYQVIA developed an antibody capable of binding to recombinant human hyaluronidase in the clinical trials. These antibodies were not capable of neutralizing recombinant human hyaluronidase.

In the clinical trial, no temporal association between adverse reactions and the presence of antibodies capable of binding to the Recombinant Human Hyaluronidase of HYQVIA could be demonstrated. There was no increase in incidence or severity of adverse reactions in subjects who developed antibodies to Recombinant Human Hyaluronidase of HYQVIA. In all subjects, antibody titers decreased despite continued treatment.

The effect of exposure to antibodies capable of binding to Recombinant Human Hyaluronidase of HYQVIA for periods longer than this clinical trial has not been evaluated.

The local adverse reactions are listed by frequency in Table 5. Mild swelling around the infusion site was present in most infusions due to the large volumes infused, but in general was not considered to be an adverse reaction unless it caused discomfort. Among the 234 local adverse reactions, three were severe (infusion site pain, infusion site swelling and infusion site edema that extended from the abdominal infusion site to the genitalia); all were transient and resolved without sequelae. More than 98% of local reactions were either mild (70.5%) or moderate (28.2%) in severity.

Table 5: Most Frequent Local Adverse Reactions Reported in greater than 1% of Infusion During Treatment With HYQVIA

During the combined efficacy and extension trials encompassing more than 3 years, the local adverse reaction rate was 2.6 per patient-year. During the first 12 month period (months 1- 12), the rate was 3.68 local adverse reactions per patient-year. During the subsequent 12 month period (months 13-24), the rate declined to 2.12 local adverse reactions per-patient year. Finally, during the third 12 month period (months 25-36), the rate further declined to 0.37 local adverse reactions per patient-year.

Sixty-six of the 68 subjects who completed the efficacy clinical trial enrolled in a prospective, open-label, multicenter extension trial to assess the long-term safety and tolerability of HYQVIA. Sixty-three of 66 subjects enrolled received HYQVIA and 3 received IGIV. Of the 63 subjects who received HYQVIA, 48 completed the extension trial. The cumulative exposure of HYQVIA across the two trials was 188 subject-years and 2959 infusions, and a maximum exposure of 188 weeks or up to approximately 3.5 years. There were no clinically observable changes in the skin or subcutaneous tissue in either the efficacy or extension clinical trials.

Postmarketing Experience

Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure.

The following adverse reactions have been identified and reported during the postmarketing use of Immune Globulin products administered intravenously:

Hematologic Leukopenia, Pancytopenia

Neurological Transient ischemic attack, Tremor, Burning sensation, Cerebral vascular accident, Coma, Seizures, Loss of consciousness

Cardiovascular Hypotension, Hypertension, Myocardial infarction, Chest pain, Cardiac arrest, Vascular collapse

Respiratory Pulmonary edema, Dyspnea, Oxygen saturation decreased, Cyanosis, Hypoxemia, Bronchospasm, Apnea, Acute Respiratory Distress Syndrome (ARDS)

Gastrointestinal Integumentary Abdominal pain, Hepatic dysfunction Hyperhidrosis, Allergic dermatitis, Bullous dermatitis, Epidermolysis, Erythema multiforme, Stevens-Johnson Syndrome

Psychiatric Anxiety, Insomnia

Musculoskeletal Back Pain

General/Body as a Whole Edema, Rigors

Mechanism Of Action

The Immune Globulin Infusion 10% (Human) provides the therapeutic effect of HYQVIA. The Recombinant Human Hyaluronidase of HYQVIA increases dispersion and absorption of the Immune Globulin Infusion 10% (Human). The Immune Globulin Infusion 10% (Human) of HYQVIA supplies a broad spectrum of opsonizing and neutralizing IgG antibodies against a wide variety of bacterial and viral agents. The Immune Globulin Infusion 10% (Human) also contains a spectrum of antibodies capable of interacting with and altering the activity of cells of the immune system as well as antibodies capable of reacting with cells such as erythrocytes. The role of these antibodies and the mechanisms of action of IgG in the Immune Globulin Infusion 10% (Human) of HYQVIA have not been fully elucidated.

Hyaluronan is a polysaccharide found in the extracellular matrix of the connective tissue8. It is depolymerized by the naturally occurring enzyme hyaluronidase. Unlike the stable structural components of the interstitial matrix, hyaluronan has a very fast turnover with a half-life of approximately 0.5 days. The Recombinant Human Hyaluronidase of HYQVIA increases permeability of the subcutaneous tissue by temporarily depolymerizing hyaluronan. In the doses administered, Recombinant Human Hyaluronidase of HYQVIA acts locally. The effects of the hyaluronidase are reversible and permeability of the subcutaneous tissue is restored within 24 to 48 hours.

Pharmacokinetics

The pharmacokinetics (PK) of HYQVIA was evaluated during a clinical trial of adults with PI after they achieved steady state at their 3 or 4 week dosing interval and underwent individual dose adjustment [see Clinical Studies]. For adults, adjustment of dose was based on comparison of the ratios of the area under the IgG concentration versus time curve (AUC) during intravenous treatment versus during HYQVIA treatment.

The AUC of HYQVIA compared to conventional IGSC administration was 20% higher. The absolute bioavailability of HYQVIA was 93.3% relative to IGIV.

The pharmacokinetic parameters of HYQVIA compared to intravenously administered Immune Globulin Infusion 10% (Human) are shown in Table 7. The mean IgG dose in weekly equivalents was 147 mg/kg ± 50 (range 134 to 160 mg/kg). The serum IgG trough levels are comparable: mean serum IgG trough with HYQVIA was 1077 mg/dL compared to 1095 mg/dL with intravenously administered Immune Globulin Infusion 10% (Human). C max was lower with HYQVIA (1607 mg/dL) than with intravenously administered Immune Globulin Infusion 10% (Human) (2248 mg/dL). Time to reach maximum concentration of IgG following HYQVIA administration was 5 (3.3-5.1) days.

In the extension trial, reducing the dosing interval from 4 to 2 weeks resulted in a mean increase of 13% in serum IG trough levels.

Table 7: Pharmacokinetic Parameters of HYQVIA Compared to Intravenously Administered Immune Globulin Infusion 10% (Human) (IGIV)

Figure 1 shows mean concentration-time plot of IgG in subjects 12 years and older. The concentration-time profile of HYQVIA is similar to that of intravenous administration but without the high peak. The peak to trough variation is more similar to subcutaneous administration.

Figure 1 : Pharmacokinetic Comparison of Mean IgG Values for HYQVIA vs. Intravenously and Subcutaneously Administered Immune Globulin Infusion 10% (Human)*

* IGIV and HYQVIA data at 28 day dosing interval; IGSC data at 7 day dosing interval; IGSC dotted line shows weekly dose extrapolated over 21 additional days.

Animal Toxicology And/Or Pharmacology

Developmental studies in mice demonstrated that administration of recombinant human hyaluronidase did not produce teratogenicity or signs of maternal toxicity at doses up to 18 mg/kg (2.2 x 106 U/kg), which is 28,800 times higher than the typical monthly human dose. Maternal doses of 9 and 18 mg/kg were associated with reduced fetal weight and an increased number of fetal resorptions. No adverse effects on fetal development were observed at a maternal dose of 3 mg/kg (360,000 U/kg), which is 4800 times higher than the typical monthly human dose.

In a peri-and post-natal reproduction study, female mice were dosed daily with recombinant human hyaluronidase from implantation through lactation and weaning. There were no adverse effects on gestation, parturition, lactation and maternal behavior or on the development of the male or female offspring of the treated female mice in terms of sexual maturation, learning and memory of offspring, or their ability to produce another generation of offspring at doses up to 9 mg/kg (1.1 x106 Unit/kg) which is 14,400 times higher than the typical monthly human dose.

Clinical Studies

A prospective, open-label, non-controlled, multi-center trial was conducted in the US to determine the efficacy, tolerability and pharmacokinetics (PK) of HYQVIA in subjects with PI. Two cohorts of subjects were enrolled. Thirty-one subjects had been treated intravenously for three months and then subcutaneously each week at 137% of the intravenous dose for approximately one year before transitioning to the HYQVIA trial. The remaining subjects also were treated intravenously for 3 months and then immediately began treatment with HYQVIA in the trial.

One week after the last intravenous or subcutaneous infusion, each subject began subcutaneous treatment with HYQVIA. After placing the subcutaneous needle set, the hyaluronidase of HYQVIA was infused through the needle set followed within 10 minutes by the immune globulin of HYQVIA at 108% of the intravenous dose. Dosing began with a 1- week equivalent dose. One week later, a 2-week dose was administered, followed 2 weeks later with a 3-week dose. For those subjects who were on a 4-week dose interval prior to entering the trial, 3 weeks later the 4-week dose was administered. This ramp-up period allowed subjects to become familiar with the large volumes required for a full 3- or 4-week treatment. Subsequently, subjects continued the 3- or 4-week dosing for the remainder of the trial. After 3 doses at the full volume, a serum IgG trough level was obtained for all subjects, and used to individually adapt the subcutaneous dose of HYQVIA to compensate for individual variation from the mean value of 108% [see Pharmacokinetics and DOSAGE AND ADMINISTRATION]. All subjects who completed the trial received a minimum of 12 infusions at this individually adapted dose. The period after the ramp-up was considered the efficacy period and used for safety and efficacy analyses.

Outcome measures included the rate of infections, adverse reactions, tolerability of the infusions of HYQVIA, number of infusion sites per month, and infusion rate. Eighty-nine subjects were enrolled, 87 treated intravenously and 83 treated with HYQVIA. The majority were Caucasian (79/87, 90.8%). Median age was 35.0 years (range 4 to 78 years). Fortyfour of the subjects were naïve to subcutaneous treatment. Median serum IgG trough levels for the 6 months before enrollment were 1033.5 mg/dL (range: 405 to 3200 mg/dL) in subcutaneous-experienced subjects and 1000 mg/dL (range: 636 to 3200) in the subcutaneous-naïve subjects.

The 83 subjects received a total of 1359 infusions of HYQVIA during the entire trial. Of these, 1129 were administered after the ramp-up when the subjects were on a consistent interval of 3 or 4 weeks, which was predetermined to be the efficacy period for data analysis.

Median duration of treatment in the IGIV period was 91 days (range 84 to 122 days). Median duration of HYQVIA treatment during the dose ramp up period was 42 days (range 20 to 49), and during the efficacy period was 366 days (range 42 to 507 days). None of the subjects withdrew due to a severe or serious local or systemic adverse reaction [see Clinical Trial Experience].

There were two acute serious bacterial infections (ASBI); both episodes of pneumonia treated as outpatients with oral antibiotics, during the 12-month efficacy period and one additional pneumonia that required hospitalization during the ramp-up. Based on this, the annualized rate of ASBI while treated with HYQVIA was 0.025, with an upper 99% confidence limit of 0.046, which is significantly less than (p < 0.0001) the rate of one infection per year10.

The overall rates of infections throughout both the efficacy and extension trials are shown in Table 8. The secondary endpoints evaluated in the efficacy trial were the annual rate of all infections and other efficacy measures.

Table 8: Summary of Infections and Other Secondary Efficacy Endpoints

An objective of the trial was to achieve the same number or fewer infusions with HyQvia per month as with intravenous administration and significantly fewer than with conventional subcutaneous administration. Summary of infusions of intravenous administration compared to HYQVIA administration is presented in Table 9.

Table 9: Summary of Infusions

Sixteen of 83 subjects (19.3%) were infused every 3 weeks and 67 (80.7%) were infused every 4 weeks. Seventy-eight of 83 (94%) of subjects attained the same 3- or 4-week dosing as their previous IV treatment. One decreased from 4 to 3 weeks, one from 4 to 2 weeks and one from 3 to 2 weeks. The primary reason for decreasing the interval was discomfort due to swelling.

In a separate study evaluating subcutaneous treatment with Immune Globulin Infusion 10% (Human), a median of 21.43 sites were required each month with a median monthly infusion time of 5.35 hours.

REFERENCES

3. Eijkhout HW, Der Meer JW, Kallenberg CG, et al. The effect of two different dosages of intravenous immunoglobulin on the incidence of recurrent infections in patients with primary hypogammaglobulinemia. A randomized, double-blind, multicenter crossover trial. Ann Intern Med. 2001;135:165-174.

4. Pierce LR, Jain N. Risks associated with the use of intravenous immunoglobulin. Transfusion Med Rev. 2003;17:241-251.

5. Katz U, Sheonfeld Y. Review: intravenous immunoglobulin therapy and thromboembolic complications. Lupus 2005;14:802-8

6. Daw Z, Padmore R, Neurath D, Cober N, Tokessy M, Desjardins D, et al. Hemolytic transfusion reactions after administration of intravenous intravenous immune (gamma) globulin: a case series analysis. Transfusion 2008; 48:1598-601

7. Kreil TR, Berting A, Kistner O, Kindermann J. West Nile virus and the safety of plasma derivatives: verification of high safety margins, and the validity of predictions based on model virus data. Transfusion 2003;43:1023-1028.

8. Bookbinder LH, Hofer A, Haller MF, Zepeda ML, Keller G-A, Lim JE, Edginton TS, Shepard HM, Patton JS, Frost GI. A recombinant human enzyme for enhanced interstitial transport of therapeutics. J of Controlled Release 2006; 114:230-241.

9. Wasserman RL, Melamed I, Kobrynski L, Strausbaugh SD, Stein MR, Sharkhawy M, Engl W, Leibl H, Sobolevsky L, Gelmont D, Schiff RI, Grossman WJ. Efficacy, Safety, and Pharmacokinetics of a 10% Liquid Immune Globulin Preparation (GAMMAGARD LIQUID, 10%) Administered Subcutaneously in Subjects with Primary Immunodeficiency Disease. J Clin Immunol. 2011 Mar 22. [Epub ahead of print]

10. Golding B. IGIV Clinical Endpoints. Presented at: Blood Products Advisory Committee, 65th Meeting. 17 March 2000. Silver Spring, MD.