1.1 Primary Immunodeficiency (PI)

HYQVIA is an Immune Globulin Infusion 10% (Human) with a Recombinant Human Hyaluronidase (rHuPH20) indicated for the treatment of Primary Immunodeficiency (PI) in adults and pediatric patients two years of age and older. This includes, but is not limited to, common variable immunodeficiency (CVID), X-linked agammaglobulinemia, congenital agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.1,2

1.2 Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

HYQVIA is indicated for the treatment of chronic inflammatory demyelinating polyneuropathy (CIDP) as maintenance therapy to prevent relapse of neuromuscular disability and impairment in adults.

2.1 Dose

The recommended rHuPH20 dose is 80 U/g Immune Globulin (IgG), which corresponds to 0.5 mL rHuPH20 solution per 10 mL Immune Globulin Infusion 10% (Human) solution for both indications.

The recommended Immune Globulin Infusion 10% (Human) dose is given below.

Primary Immunodeficiency (PI)

2.2 Administration

HYQVIA should be administered by a healthcare professional, caregiver or self-administered by the patient after appropriate training.

• Infusion of Immune Globulin Infusion 10% (Human) requires an infusion pump capable of infusing a patient's therapeutic dose at infusion rates up to 300 mL/hr/site. The pump must have the ability to titrate the flow rate up or down if required to improve tolerability. To ensure maximum flow rates, use a subcutaneous needle set that is 24 gauge and labeled for high flow rates.
• Infusion site leakage can occur during or after subcutaneous administration of immunoglobulin, including HYQVIA. Consider using longer needles (14 or 12 mm rather than 9 mm) and/or more than one infusion site.
• Infuse the two components of HYQVIA sequentially, beginning with the rHuPH20. If using two or three infusion sites, divide the rHuPH20 evenly between all sites.
• Initiate infusion of the full dose of the Immune Globulin Infusion 10% (Human) through the same subcutaneous needle set within approximately 10 minutes of the rHuPH20 infusion. For each full or partial vial of Immune Globulin Infusion 10% (Human) used, administer the entire contents of the rHuPH20 vial.

2.3 Preparation and Handling

• Visually inspect both vials of HYQVIA for discoloration and particulate matter prior to administration.
  • The appearance of the Immune Globulin Infusion 10% (Human) of HYQVIA can vary from clear or slightly opalescent and colorless or pale yellow.
  • The appearance of the rHuPH20 of HYQVIA should be clear and colorless.
  • Do not use either component of HYQVIA if either solution is cloudy or has particulates.
• Allow refrigerated product to come to room temperature before use. Do not apply heat or place in microwave.
• Do not shake HYQVIA.
• Do not mix the rHuPH20 and the Immune Globulin Infusion 10% (Human) of HYQVIA into the same container prior to administration.
• Do not mix or administer components of HYQVIA with other products. Administer components of HYQVIA sequentially. Do not use either component alone.
• Flush the infusion line with normal saline or Dextrose 5% in water (D5W) if required.
• HYQVIA contains no preservative. Discard any unused product according to local standards for biohazard products.

2.4 Instructions for Administration

Use aseptic technique when preparing and administering HYQVIA for infusion.

For more detail on steps, see accompanying Information for Patients.

1. Inspect the vials: Inspect for clarity, color, and expiration date(s).

2. Prepare for infusion:

• Gather supplies: HYQVIA dual vial unit(s), ancillary supplies, sharps container and infusion pump (program pump per physician recommendation following manufacturer's instructions).
• Prepare a clean work area.
• Wash hands.
• If the Immune Globulin Infusion 10% (Human) and rHuPH20 are pooled into separate containers, skip to Step 5.

3. Prepare the rHuPH20 of HYQVIA (Labeled as “HY”):

• Remove the purple protective cap and ensure the blue vial caps are removed.
• Wipe each stopper with a sterile alcohol wipe and allow to dry.
• Attach a syringe to a needle/needle-less transfer device. A sterile needle or needle-less transfer device [(18-22) gauge sterile needle] may be used for all vial sizes. Position the sharp tip of the needle/needle-less transfer device over the center of the vial stopper and insert it at a 90-degree angle. Inject air and then draw the full contents of each vial labeled "HY" into a single syringe, if possible.
• Attach the syringe containing the rHuPH20 to the subcutaneous needle set and prime up to the needle hub.

4. Prepare Immune Globulin Infusion 10% (Human) of HYQVIA (Labeled as “IG”):

• Wipe each stopper with a sterile alcohol wipe and allow to dry.
• Transfer the vial(s) labeled "IG" using one of the following methods:
  • Pool into an infusion bag, using a transfer device per manufacturer's directions. Attach and prime the pump administrating tubing; or
  • Directly spike the vial using a vented pump administration tubing and prime as directed.

If using a syringe driver, transfer into the syringe(s), preferably using a vented spike.

5. Prepare the infusion site(s):

• Potential sites for infusion include the middle to upper abdomen and thigh.
• Avoid: bony prominences, blood vessels, scars, or areas that are inflamed or infected.
• If two sites are desired, a bifurcated needle set may be used on opposite sides of the body.
• Rotate sites by choosing opposite sides of the body between successive infusions.
• Cleanse the infusion site(s) with a sterile alcohol wipe beginning at the center of each infusion site and moving outward in a circular motion. Allow the infusion site(s) to dry.

6. Insert and secure the 24-gauge subcutaneous needle:

• Pinch at least one inch of skin between two fingers. Insert the needle at a 90-degree angle into the subcutaneous tissue and secure the needle with sterile tape and check the placement.
• If using the push method:
  • Gently pull back on the plunger of the attached syringe and monitor for any blood return in the tubing.
  • If blood is seen in the tubing, remove and discard the needle and repeat steps 3, 5, and 6 with a new subcutaneous needle and infusion site.
• If using the pump method:
  • Close the clamp above the lower port of the pump tubing.
  • Clean the lower port with an alcohol swab and allow to dry, for at least 30 seconds.
  • Attach a 5 mL syringe to the lower port of the pump tubing.
  • Pull back gently on the syringe plunger. If no blood, remove the syringe and open the lower port clamp.
• Secure the needle in place with a sterile protective dressing.

7. Administer the rHuPH20 of HYQVIA:

• If using push method:
  • Infuse the rHuPH20manually at an initial rate of approximately 1 to 2 mL per minute per infusion site and increase as tolerated.
• If using a pump method:
  • start at an initial rate at 60 mL to 120 mL/hr per infusion site and may increase as tolerated up to 300 mL/hr.
• If more than one site is used, divide the contents equally between sites. At the end of infusion, disconnect the empty syringe and attach the pump tubing/syringe containing the Immune Globulin Infusion 10% (Human) of HYQVIA to the same subcutaneous needle set.

8. Administer the Immune Globulin Infusion 10% (Human) of HYQVIA:

Within approximately 10 minutes of completing the infusion of the rHuPH20 of HYQVIA, start the variable rate program of the infusion pump to initiate the infusion of the full therapeutic dose of Immune Globulin Infusion 10% (Human) of HYQVIA. At the end of infusion, flush the infusion tubing up to the needle with normal saline or Dextrose 5% in water (D5W), if required.

9. Remove subcutaneous needle(s) from the infusion site(s):

After the infusion is complete, remove the needle set and cover with a protective dressing. Discard any partially used vial(s) and disposable supplies in accordance with local requirements.

10. Document the infusion:

Remove the peel-off label from each Immune Globulin Infusion 10% (Human) vial of HYQVIA used and affix to the patient’s treatment record or infusion log. In addition, record the time, date, dose, infusion site location and any reactions after each infusion.

For self-administration, provide the patient with instructions and training for infusion in the home or other appropriate setting.

5.1 Hypersensitivity

Severe hypersensitivity reactions may occur, even in patients who have tolerated previous treatment with IgG. In case of hypersensitivity, discontinue the HYQVIA infusion immediately and institute appropriate treatment.
Immune Globulin Infusion 10% (Human) of HYQVIA contains trace amount of IgA (average concentration of 37µg/mL). Patients with antibodies to IgA potentially are at greater risk of developing potentially severe hypersensitivity and anaphylactic reactions.

5.2 Thrombosis

Thrombosis has been reported to occur following treatment with immune globulin products, including HYQVIA. Risk factors may include advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, and cardiovascular risk factors. Thrombosis may occur in the absence of known risk factors.

Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, such as those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. For patients at risk of thrombosis, administer HYQVIA at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity [see Boxed Warning, Dosage and Administration (2), Patient Counseling Information (17)].

5.3 Immunogenicity of rHuPH20

Eighteen percent (15 of 83) of subjects receiving HYQVIA in PID clinical studies developed non-neutralizing antibodies to the rHuPH20 component. The potential exists for such antibodies to cross-react with endogenous Hyaluronidase (PH20), which is known to be expressed in the adult male testes, epididymis, and sperm. It is unknown whether these antibodies can interfere with fertilization in humans. The clinical significance of these antibodies is not known.

Clinical studies in CIDP based on 3,188 rHuPH20 infusions in 132 patients revealed one incidence of anti-rHuPH20 neutralizing antibody positivity. Elevation in neutralizing antibody titers was transient and occurred at a single measurement over a 3-year follow-up period. No efficacy or safety issues were identified with the occurrence of neutralizing antibody positivity.

5.4 Aseptic Meningitis Syndrome (AMS)

AMS has been reported to occur with IGIV or IGSC, including HYQVIA. AMS may occur more frequently in female patients. Discontinuation of IgG treatment has resulted in remission of AMS within several days without sequelae. The syndrome usually begins within several hours to two days following immune globulin treatment.

AMS is characterized by the following signs and symptoms: severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea, and vomiting [see Patient Counseling Information (17)]. Cerebrospinal fluid (CSF) studies frequently reveal pleocytosis up to several thousand cells per mm3, predominantly from the granulocytic series, and elevated protein levels up to several hundred mg/dL, but negative culture results. Conduct a thorough neurological examination on patients exhibiting such symptoms and signs, including CSF studies, to rule out other causes of meningitis.

5.5 Hemolysis

IgG products, including HYQVIA, contain blood group antibodies which may act as hemolysins and induce in vivo coating of red blood cells (RBC) with IgG. These antibodies may cause a positive direct antiglobulin reaction and hemolysis.6 Acute intravascular hemolysis has been reported following intravenously administered IgG, including Immune Globulin Infusion 10% (Human) administered intravenously, and delayed hemolytic anemia can develop due to enhanced RBC sequestration [see Adverse Reactions (6)].

Monitor patients for clinical signs and symptoms of hemolysis. If signs and/or symptoms of hemolysis are present after HYQVIA infusion, perform appropriate confirmatory laboratory testing [see Patient Counseling Information (17)].

5.6 Renal Dysfunction/Failure

Acute renal dysfunction/failure, acute tubular necrosis, proximal tubular nephropathy, osmotic nephrosis, and death may occur upon use of IgG products administered intravenously, especially those containing sucrose4. HYQVIA does not contain sucrose. Acute renal dysfunction/failure has been reported in association with Immune Globulin Infusion 10% (Human) administered intravenously. Ensure that patients are not volume depleted prior to the initiation of infusion of HYQVIA. In patients who are at risk of developing renal dysfunction because of pre-existing renal insufficiency or predisposition to acute renal failure (such as diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs), monitor renal function and consider lower, more frequent dosing.

Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk for developing acute renal failure. Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of HYQVIA and again at appropriate intervals thereafter. If renal function deteriorates, consider discontinuation of HYQVIA.

5.7 Spread of Localized Infection

Infusion into or around an infected area can spread a localized infection. Do not infuse HYQVIA into these areas due to potential risk of spreading a localized infection.

5.8 Transfusion-Related Acute Lung Injury (TRALI)

Non-cardiogenic pulmonary edema (TRALI) may occur with intravenously administered IgG and has been reported to occur with Immune Globulin Infusion 10% (Human) administered intravenously. TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Symptoms typically occur within 1 to 6 hours after treatment.

Monitor patients for pulmonary adverse reactions [see Patient Counseling Information (17)]. If TRALI is suspected, conduct an evaluation, including appropriate tests for the presence of anti-neutrophil and anti-HLA antibodies in both the product and patient serum. TRALI may be managed using oxygen therapy with adequate ventilatory support.

5.9 Transmissible Infectious Agents

Because Immune Globulin Infusion 10% (Human) of HYQVIA is made from human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant CJD (vCJD) agent, and theoretically, the classic Creutzfeldt-Jakob disease agent. This also applies to unknown or emerging viruses and other pathogens. No cases of transmission of viral diseases or vCJD have been associated with HYQVIA.

Report all infections thought to be possibly transmitted by HYQVIA to Takeda Pharmaceuticals U.S.A, Inc. at 1-877-TAKEDA-7 (1-877-825-3327) (In the U.S.).

5.10 Interference with Laboratory Tests

• After infusion of IgG, the transitory rise of the various passively transferred antibodies in the patient's blood may yield false positive serological testing results, with the potential for misleading interpretation. Passive transmission of antibodies to erythrocyte antigens (e.g., A, B, and D) may cause a positive direct or indirect antiglobulin (Coombs') test.
• Infusions of immune globulin products can lead to false positive readings in assays that depend on detection of ß-D-glucans for diagnosis of fungal infections; this may persist during the weeks following infusion of the product.

6.1 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.

Primary Immunodeficiency (PI)

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 1,359 infusions of HYQVIA were administered during the trial; 230 of these infusions occurred during the ramp-up period and the other 1,129 occurred during the observation period. During the observation period, 81 patients received 1,129 infusions of HYQVIA; of those, 67 (82.7%) experienced one or more adverse reactions. Among the 1,129 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, can lead to temporary inability to resume normal life pattern, requires prolonged intervention and/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 6. 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 that resolves spontaneously or with minimal intervention with no sequelae. No serious adverse reactions occurred during the HYQVIA clinical trials.

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 in the clinical trial who were treated with HYQVIA developed an antibody capable of binding to rHuPH20. These antibodies were not capable of neutralizing rHuPH20.

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 the incidence or severity of adverse reactions in subjects who developed antibodies to rHuPH20 of HYQVIA. In all subjects, antibody titers decreased despite continued treatment.

The effect of exposure to antibodies capable of binding to rHuPH20 of HYQVIA for periods longer than this clinical trial has not been evaluated.

The local adverse reactions are listed by frequency in Table 7. 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.

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 2,959 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.

6.2 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.

In addition to the adverse reactions listed above in clinical trials, the following adverse reactions have been reported in the postmarketing experience:

Immune System Disorder: Hypersensitivity

General Disorder and Administration Site Conditions: Influenza-like illness, Infusion site leaking

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

Primary Immunodeficiency (PI)

The safety and effectiveness of HYQVIA for the treatment of Primary Immunodeficiency have been established in pediatric patients 2 years and older.

Use of HYQVIA for this indication is supported by evidence from the pivotal efficacy and safety study in 44 pediatric subjects (aged 2 to 16 years of age). Results from pre-specified interim data analysis, where all subjects completed 12 months of participation (one year of observation period) in the study, indicated similar safety profiles to adults. No pediatric-specific dose requirements were necessary to achieve the desired serum IgG levels. [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)].

Safety and effectiveness of HYQVIA has not been evaluated in patients <2 years of age.

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

The safety and effectiveness of HYQVIA for the treatment of CIDP have not been established in pediatric patients under the age of 18 years.

8.5 Geriatric Use

Primary Immunodeficiency (PI)

HYQVIA was evaluated in 7 subjects over age 65 in the PI clinical trial. The available data are too limited to draw safety conclusions.

Chronic Inflammatory Demyelinating Polyneuropathy

HyQvia was evaluated in 13 subjects over age 65 in the pivotal clinical trial. No clinically significant differences in safety were observed between those 13 elderly subjects and the subjects 18 to 65 years of age.

Use caution when administering HYQVIA to patients age 65 and over who are judged to be at increased risk of developing thrombosis and acute renal insufficiency [see Boxed Warning, Warnings and Precautions (5.2, 5.6)]. Do not exceed recommended doses and administer HYQVIA at the minimum dose and infusion rate practicable.

12.1 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.

The mechanism of action of immunoglobulins in the treatment of CIDP in adults has not been fully elucidated but may include immunomodulatory effects.

Hyaluronan is a polysaccharide found in the extracellular matrix of 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 rHuPH20 of HYQVIA increases permeability of the subcutaneous tissue by temporarily depolymerizing hyaluronan. In the doses administered, rHuPH20 of HYQVIA acts locally. The effects of the hyaluronidase are reversible, and permeability of the subcutaneous tissue is restored within 24 to 48 hours.

12.3 Pharmacokinetics

Primary Immunodeficiency (PI)

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 (14)]. For adults, dose adjustment was based on a 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 bioavailability of HYQVIA based on weekly AUC was 93.3% relative to IGIV.

The pharmacokinetic parameters of HYQVIA compared with intravenously administered Immune Globulin Infusion 10% (Human) are shown in Table 13. 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 with 1095 mg/dL with intravenously administered Immune Globulin Infusion 10% (Human). Cmax 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.

Figure 1* shows a 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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

Developmental studies in mice demonstrated that administration of rHuPH20 did not produce teratogenicity or signs of maternal toxicity at doses up to 18 mg/kg (2.2 × 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) in mice and 0.76 mg/kg (91,000 U/kg) in rabbits, which is 4,800 and 1,200 times higher than the typical monthly human dose.

In a peri-and post-natal reproduction study, female mice were dosed daily with rHuPH20 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 ×106 Unit/kg), which is 14,400 times higher than the typical monthly human dose.

14.1 Primary Immunodeficiency (PI)

A prospective, open-label, non-controlled, multicenter 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 rHuPH20 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 Clinical Pharmacology (12.3) and Administration (2.2)]. 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). Forty-four 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 mg/dL) in the subcutaneous-naïve subjects.

The 83 subjects received a total of 1,359 infusions of HYQVIA during the entire trial. Of these, 1,129 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 Adverse Reactions (6.1)].

There were two acute serious bacterial infections (aSBI), both of which were episodes of pneumonia treated as outpatients with oral antibiotics during the 12-month efficacy period; an additional pneumonia requiring hospitalization occurred 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 0.089, which is significantly less than (p<0.0001) the rate of one infection per year.10

The overall rates of infections throughout both the efficacy and extension trials are shown in Table 15. The secondary endpoints evaluated in the efficacy trial were the annual rate of all infections and other efficacy measures.

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. A summary of intravenous administration compared with HYQVIA administration is presented in Table 16.

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%) 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.

Pediatric Study

A prospective, open-label, non-controlled, multicenter trial was conducted in the US to determine the efficacy, safety, immunogenicity and pharmacokinetics (PK) of HYQVIA in pediatric subjects with PI who had received IVIG or SCIG treatment before enrollment into the trial. A total of 44 subjects were enrolled, and the median age of pediatric subjects was 9.5 years (range: 3 to 15 years). Of the enrolled subjects, 26 subjects (59.1%) were male, 18 subjects (40.9%) were female, and 40 subjects (90.9%) were White. Most subjects were not Hispanic or Latino (39 subjects [88.6%]).

Pediatric subjects switched to HYQVIA SC immunoglobulin treatment schedule administered at doses (volumes and treatment intervals) typical for IVIG administration. Treatment intervals and doses gradually increased in a ramp-up phase to an interval of 3 or 4 weeks. Data were analyzed when all subjects completed 12 months of participation (one year of observation) in the trial. Overall, the median number of infusions per month was 1.1 (range: 1.0 to 1.5) and was comparable across the age groups. The median number of infusion sites per month was 2.2 (range: 1.1 to 2.9), with a similar median number for all age categories. There were no clinically meaningful differences in trough IgG levels across age groups.

The primary analysis for efficacy was based on the rate of aSBIs, defined as bacteremia/sepsis, bacterial meningitis, osteomyelitis/septic arthritis, bacterial pneumonia, and visceral abscess, per subject per year. Secondary analyses included the annual rate of other infections and health resource utilization outcome measures (e.g., days out of work/school/daycare).

During the 12-month trial period, the mean aSBI rate per year was 0.04 (with an upper 1-sided 99% confidence interval of 0.21, p<0.001), which met the predefined success rate of less than one aSBI per subject per year. One subject experienced two aSBIs of bacterial pneumonia, and there were no other episodes of serious bacterial infections reported in this trial. The mean rate of all infections per subject-year was 3.20, with an upper limit of the 95% CI of 4.05. The overall rate of infections per subject is consistent with results obtained in the pivotal clinical study. Pediatric subjects missed a mean (95% CI) of 5.0 (2.2 to 7.9) days of work/school/daycare.

14.2 Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

Safety and efficacy of HYQVIA in adult subjects with CIDP was evaluated in a randomized, placebo-controlled study (Study 1) and a single-arm, open-label, extension study (Study 2).

Study 1:

In a multicenter, randomized, placebo-controlled, phase 3 study, 132 adult subjects with CIDP underwent evaluation of safety and tolerability, 122 subjects underwent efficacy evaluation of HYQVIA as a maintenance therapy to prevent relapse that allowed self-infusion of a total therapeutic dose every 2 to 4 weeks. The study enrolled subjects ≥18 years of age (male or female) at the time of screening who had a documented diagnosis of definite or probable CIDP as per the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) 2010 criteria. All eligible subjects had responded to IgG treatment in the past (partial or complete resolution of neurological symptoms and deficits) and were on a stable dose of IGIV treatment within the dose range equivalent to a cumulative monthly dose of 0.4 to 2.4 g/kg body weight administered intravenously for at least 12 weeks before screening. The primary endpoint was the proportion of subjects who experienced a relapse, defined as an increase of ≥1 point relative to the pre-SC treatment baseline score in 2 consecutive adjusted inflammatory neuropathy cause and treatment (INCAT) disability scores obtained less than seven days apart.

Overall, a total of 184 subjects were screened, of which 46 (25%) were screen failures, 138 (75%) were randomized, and 132 (71.7%) received either HYQVIA (N=62) or placebo (N=70), 17 discontinued in Epoch 1, and 94 completed the study without developing a relapse in Epoch 1 and 21 rolled over to Epoch 2. All 132 treated subjects were analyzed for safety and 122 subjects (N= 57 for HYQVIA, N=65 for placebo) were analyzed for efficacy included in the modified intent-to-treat (mITT). The mean duration of exposure was 5.3 months in the HYQVIA group and 4.7 months in the placebo group. The mean monthly equivalent dose was 1.1g/kg. The average time to deliver the monthly HYQVIA dose was approximately 2 hrs. HYQVIA infusions were administered through 1 to 3 injection sites, and the majority of infusions (85.8%) were administered through 2 infusion sites using 12mm to 14mm needles.

The analysis of the primary endpoint demonstrated a statistically significant difference between the relapse rates in the HYQVIA group (N=57, 14.0%) compared to the placebo group (N=65, 32.3%) (p=0.0314). The treatment difference of –18.3% (two-sided 95% CI: -32.1%, -3.1%) indicated that HYQVIA demonstrated superiority over placebo in preventing relapse of CIDP.

Kaplan-Meier curves (Figure 2) demonstrated early separation between HYQVIA and placebo at approximately Week 4.

Figure 2: Kaplan-Meier Curves for Time to Relapse by Treatment Group

The effect of HYQVIA on activities of daily living was measured by the Rasch-built Overall Disability Scale (R ODS) centile score. The least squares (LS) mean changes were -1.2 in the HYQVIA group and -6.3 in the placebo group. The LS mean treatment difference between HYQVIA and placebo was 5.1.

Study 2:

A Phase 3b, single-arm, open-label, multicenter, extension study to assess the long-term safety, tolerability, and immunogenicity of HYQVIA for maintenance therapy for CIDP. The study was open to subjects who completed Study 1 without CIDP worsening or relapse. The dosing range was 0.4 g/kg to 2.4 g/kg, given in a frequency of 2-, 3-, or 4-week intervals. An interim analysis was performed, and the data included 79 subjects with a range of follow-ups from 0 to 5.1 years and a total follow-up of 169 patient-years. A total of 2,590 HYQVIA infusions were administered.

The proportion of subjects who developed CIDP relapse was 8.8% (5/57) during the interim study period. The 6-month relapse rate was 1.6%.

How Supplied

HYQVIA is supplied in a dual vial unit of two single dose vials containing the labeled amount of functionally active Immune Globulin Infusion 10% (Human) and rHuPH20. 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.

Self-administration – If self-administration is deemed appropriate by the physician, give clear instructions and training on how to administer HYQVIA. Document their ability to independently administer HYQVIA.

• Ensure the patient understands the importance of following regularly scheduled infusions to maintain appropriate steady IgG levels.
• Instruct the patient to keep a treatment infusion log. This infusion log should include information about each infusion such as, the lot number(s), infusion site location, the time, date, dose, and any reactions.
• Inform the patient that due to the volume that can be infused, swelling is common with HYQVIA. Mild to moderate local infusion-site reactions (e.g., swelling and redness) are common side effects of facilitated subcutaneous treatment with HYQVIA. Instruct the patient to contact their healthcare professional if a local reaction increases in severity or persists for more than a few days.
• Instruct the patient on the importance of following the directions for the pump for infusion of the Immune Globulin Infusion 10% (Human) of HYQVIA.