Limitation of Use:

Safety and efficacy of chronic use of Recombinant Human Hyaluronidase in HYQVIA have not been established in conditions other than PI.

2.1 Dosage

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 Recombinant Human Hyaluronidase.
• 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 Recombinant Human Hyaluronidase infusion. For each full or partial vial of Immune Globulin Infusion 10% (Human) used, administer the entire contents of the Recombinant Human Hyaluronidase 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 Recombinant Human Hyaluronidase 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 Recombinant Human Hyaluronidase 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 Recombinant Human Hyaluronidase are pooled into separate containers, skip to Step 5.

3. Prepare the Recombinant Human Hyaluronidase 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 Recombinant Human Hyaluronidase 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.
• Check placement: 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.
• Secure the needle in place with a sterile protective dressing.

7. Administer the Recombinant Human Hyaluronidase of HYQVIA:

Infuse the Recombinant Human Hyaluronidase manually at an initial rate of approximately 1 to 2 mL per minute per infusion site and increase as tolerated. 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 Recombinant Human Hyaluronidase 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 may 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 Recombinant Human Hyaluronidase (PH20)

Eighteen percent (15 of 83) of subjects receiving HYQVIA in clinical studies developed non-neutralizing antibodies to the Recombinant Human Hyaluronidase component. The potential exists for such antibodies to cross-react with endogenous 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.

5.4 Aseptic Meningitis Syndrome (AMS)

AMS has been reported to occur with IgG products, including Immune Globulin Infusion 10% (Human) administered intravenously and subcutaneously. 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 intravenously administered IgG.

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 Baxalta US Inc., a Takeda company at 1-800-999-1785 (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 β-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.

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, 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 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 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 Recombinant Human Hyaluronidase. 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 the 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.

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.

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

Safety has not been established in children.

8.5 Geriatric Use

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

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.

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 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.

12.3 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 (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 absolute bioavailability of HYQVIA was 93.3% relative to IGIV.

The pharmacokinetic parameters of HYQVIA compared with 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 with 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.

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 Recombinant Human Hyaluronidase 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), 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 ×106 Unit/kg), which is 14,400 times higher than the typical monthly human dose.

How Supplied

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.

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.