Switching from Immune Globulin Intravenous (Human) [IGIV] treatment: Use same dose and frequency as previous intravenous treatment after the initial ramp-up. (2.1)
DOSAGE FORMS AND STRENGTHS
A dual vial unit containing 10% IgG (100 mg/mL) and 160 U/mL Recombinant Human Hyaluronidase ( 3). HYQVIA is available in the following strengths:
• History of anaphylactic or severe systemic hypersensitivity reactions to Immune Globulin (Human). ( 4)
• IgA deficient patients with antibodies against IgA and a history of hypersensitivity. ( 4)
• Known systemic hypersensitivity to hyaluronidase or Recombinant Human Hyaluronidase of HYQVIA. ( 4)
WARNINGS AND PRECAUTIONS
• IgA-deficient patients with anti-IgA antibodies are at greater risk of severe hypersensitivity and anaphylactic reactions. ( 5.1)
• Thrombosis may occur following treatment with immune globulin products including HYQVIA. ( 5.2)
• Antibodies to PH20 (recombinant human hyaluronidase) can develop. 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 may interfere with fertilization in humans. The clinical significance of these antibodies is not known. ( 5.3)
• Aseptic Meningitis Syndrome (AMS) may occur. Discontinue treatment if AMS symptoms appear. ( 5.4)
• Acute intravascular hemolysis may occur. Monitor for clinical signs and symptoms of hemolysis and hemolytic anemia. ( 5.5)
• Infusion into or around an infected area can spread a localized infection. ( 5.7)
• Monitor for pulmonary adverse reactions (transfusion-related acute lung injury [TRALI]). ( 5.8)
• May carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. ( 5.9)
Passive transfer of antibodies may transiently interfere with the immune responses to live virus vaccines, such as measles, mumps, and rubella. (7)
USE IN SPECIFIC POPULATIONS
• Pregnancy: No human data. Use only if clearly indicated. Pregnancy registry available. ( 8.1)
• Geriatric: In patients over age 65 or in any patient at risk of developing renal insufficiency, do not exceed the recommended dose, and consider infusing HYQVIA at lower, more frequent doses. ( 8.5)
See 17 for PATIENT COUNSELING INFORMATION.
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
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.
2 DOSAGE AND ADMINISTRATION
For subcutaneous use only.
Initiation of Treatment with HYQVIA
• For patients previously on another IgG treatment, administer the first dose approximately one week after the last infusion of their previous treatment.
• Increase the dose and frequency from a 1-week dose to a 3- or 4-week dose (see ramp-up schedule in Table 1).
• Initiating treatment at a full monthly dose was not evaluated in the clinical trial.
Table 1 Initial Treatment Interval/Dosage Ramp-Up Schedule
Administer HYQVIA at the same dose and frequency as the previous intravenous treatment, after the initial dose ramp-up.
For patients naïve to IgG treatment or switching from Immune Globulin Subcutaneous (Human) [IGSC]:
Administer HYQVIA at 300 to 600 mg/kg at 3 to 4 week intervals, after initial ramp-up.
Individualization of Dose
If HYQVIA is administered at the same dose and frequency, the serum IgG levels from HYQVIA should be comparable to serum IgG levels from intravenous treatment.
For dose adjustment:
• Calculate the difference between the patient's serum IgG trough level during HYQVIA treatment and the IgG trough level during the previous intravenous treatment.
• Find this difference (in mg/dL) in the columns of Table 2 and the corresponding amount (in mL) by which to increase or decrease the dose based on the patient's body weight and desired change in IgG trough level.
Table 2 Individualization in Volume Administered per Dosing Interval for Intended Change in IgG Trough Levela
Example 1: A patient with a body weight of 80 kg has a measured IgG trough level of 800 mg/dL and the reference trough level is 1000 mg/dL. The trough level difference is 200 mg/dL (1000 mg/dL minus 800 mg/dL). The dose of HYQVIA would be increased by 48 mL (4.8 grams) per dosing interval.
Example 2: A patient with a body weight of 60 kg has a measured IgG trough level of 1000 mg/dL and the reference trough level is 900 mg/dL. The trough level difference is -100 mg/dL (900 mg/dL minus 1000 mg/dL). The dose of HYQVIA would be decreased by 18 mL (1.8 grams) per dosing interval.
HYQVIA can be used to administer a full therapeutic dose in one site up to every four weeks. Adjust the frequency and number of infusion sites taking into consideration volume, total infusion time, and tolerability. Adjust the frequency as needed so that the patient receives the same weekly equivalent dose.
Example: When adjusting a dose of 30 grams administered every 3 weeks; administer 40 grams of HYQVIA every 4 weeks. If a higher trough level is required, relative to intravenous treatment at 3 or 4 week intervals, increase the dose or decrease the dosing interval. Evaluate the use ofa second site or infusing at shorter intervals when the volume of HYQVIA is greater than 600 mL.
If a patient misses a dose, administer the missed dose as soon as possible and then resume scheduled treatments as applicable.
If HYQVIA is administered at a different interval than the previous treatment, either intravenously or subcutaneously, then Table 2 should not be used and the dose of HYQVIA should be adjusted, if necessary, based on clinical response.
HYQVIA should be administered by a healthcare professional, caregiver or self-administered by the patient after appropriate training.
• Infusion 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.
• Infuse the two components of HYQVIA sequentially, beginning with the Recombinant Human Hyaluronidase.
• Initiate the 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.
Selection of Infusion Site(s)
The suggested site(s) for the infusion of HYQVIA are the abdomen and thighs. If two sites are used, the two infusion sites should be on opposite sides of the body. Avoid bony prominences, or areas that are scarred, inflamed or infected.
Volume per Site
Administer up to 600 mL per site for patients greater than or equal to 40 kg and up to 300 mL per site for patients less than 40 kg.
A second site can be used at the discretion of the physician and patient based on tolerability and total volume. If a second site is used, administer half of total volume of the Recombinant Human Hyaluronidase of HYQVIA in each site.
Rate of Infusion
Administer the Recombinant Human Hyaluronidase of HYQVIA at an initial rate per site of approximately 1 to 2 mL per minute, or as tolerated.
Administer Immune Globulin Infusion 10% (Human) of HYQVIA at rates as shown in Table 3 for the initial infusions. If the patient tolerates these infusions at the full dose and maximum rate, adjust both the time intervals and number of rate changes of the ramp-up used for successive infusions at the discretion of the physician and patient.
Table 3 Immune Globulin Infusion 10% (Human) Infusion Rates
• 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 protective cap.
• Wipe each stopper with a sterile alcohol wipe and allow to dry.
• Attach a syringe to a needle/needle-less transfer device . Due to the small stopper diameter; use an 18 – 22 gauge sterile needle for the 1.25 mL vial. A sterile needle or needle-less transfer device may be used for other 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.
b Excluding infections
c Rate = total number of events divided by total number of infusions.
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.
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.
Postmarketing Experience of Immune Globulin Products
The following adverse reactions have been identified and reported during the postmarketing use of Immune Globulin products administered intravenously:
Passive transfer of antibodies may transiently impair the immune responses to live attenuated virus vaccines, such as mumps, rubella and varicella for up to 6 months and for a year or more to measles. [see Patient Counseling Information (17)].
Admixtures of HYQVIA with other drugs solutions have not been evaluated. Do not mix or administer components of HYQVIA with other products.
8 USE IN SPECIFIC POPULATIONS
Pregnancy Category C. Animal reproduction studies have not been conducted with Immune Globulin Infusion 10% (Human) component of HYQVIA. It is not known whether HYQVIA can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.
Development and reproductive toxicology studies have been conducted with recombinant human hyaluronidase in mice and rabbits [see Animal Toxicology and/or Pharmacology (13.2)]. No adverse effects on pregnancy were associated with anti-rHuPH20 antibodies. In these studies, maternal antibodies to recombinant human hyaluronidase were transferred to offspring in utero. The effects of antibodies to the recombinant human hyaluronidase component of HYQVIA on the human embryo or on human fetal development are unknown. HYQVIA should be given to a pregnant woman only if clearly indicated.
Women who become pregnant during HYQVIA treatment are encouraged to enroll in the HYQVIA Pregnancy Registry by calling 1-866-424-6724.
8.3 Nursing Mothers
In animal studies, maternal antibodies binding to recombinant human hyaluronidase were transferred to offspring during lactation. The effects of antibodies that bind to recombinant human hyaluronidase of HYQVIA transferred during human lactation are unknown. HYQVIA should be given to a nursing woman only if clearly indicated.
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 limited to draw safety conclusions.
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 lipid-enveloped 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
a For the calculation of these RF data from virus clearance study reports, applicable manufacturing conditions were used. Log10 RFs on the order of 4 or more are considered effective for virus clearance in accordance with the Committee for Medicinal Products for Human Use (CHMP, formerly CPMP) guidelines.
b No RF obtained due to immediate neutralization of HAV by the anti-HAV antibodies present in the product.
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 (12.1)]. This component is supplied as a sterile, clear, colorless, ready-for-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.
12 CLINICAL PHARMACOLOGY
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 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.
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, 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)
b Standardized to a 7 day interval
c N=58 for HYQVIA
d Apparent clearance
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.
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
every 4 weeks. Seventy-eight of 83 (94%) of subjects attained the same 3- or 4-week dosingas their previous IV treatment. One decreased from 4 to 3 weeks, one from 4 to 2 weeks andone from 3 to 2 weeks. The primary reason for decreasing the interval was discomfort due toswelling.
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 infusiontime of 5.35 hours.
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.
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]
Golding B. IGIV Clinical Endpoints. Presented at: Blood Products Advisory Committee, 65th Meeting. 17 March 2000. Silver Spring, MD.
16 HOW SUPPLIED/STORAGE AND HANDLING
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:
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.
17 PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling (Information for Patients).
Inform patients to immediately report the following signs and symptoms to their healthcare professional:
• Acute respiratory distress, wheezing, swelling of the airway or severe hives or itching. [see Warnings and Precautions (5.1)]
• Instruct patients to immediately report symptoms of thrombosis. These symptoms may include pain and/or swelling of an arm or leg with warmth over the affected area, discoloration of an arm or leg, unexplained shortness of breath, chest pain or discomfort that worsens on deep breathing, unexplained rapid pulse, numbness or weakness on one side of the body. [see Warnings and Precautions (5.2)]
• Advise patients that PH20 antibodies can develop. The potential exists for such antibodies to cross-react with endogenous PH20, which is known to be expressed in the adult male reproductive tract. The clinical significance of these antibodies is unknown. [see Warning and Precautions (5.3)]
• Severe headache, neck stiffness, drowsiness, fever, sensitivity to light, painful eye movements, nausea, and vomiting. [see Warnings and Precautions (5.3)]
• Increased heart rate, fatigue, yellowing of the skin or eyes, and dark-colored urine. [see Warnings and Precautions (5.5)]
• Decreased urine output, sudden weight gain, fluid retention/edema, and/or shortness of breath. [see Warnings and Precautions (5.6)]
• Trouble breathing, chest pain, blue lips or extremities, or fever that can occur 1 to 6 hours after an infusion of HYQVIA. [see Warnings and Precautions (5.8)]
• Inform patients that HYQVIA is made from human plasma and may contain infectious agents that can cause disease (e.g., viruses and, theoretically, the vCJD agent). Patients should report any symptoms that concern them which might be caused by virus infections. [see Warnings and Precautions (5.9)]
• Inform the female patient of the possibility of participating in the pregnancy registry. [see Use in Specific Populations (8.1)]
• Inform patients that HYQVIA can interfere with their immune response to live viral vaccines such as measles, mumps, rubella, and varicella, and instruct patients to notify their healthcare professional of this potential interaction when they are receiving vaccinations [see Drug Interactions (7)].
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.
Baxalta and Hyqvia are trademarks of Baxalta Incorporated.
简介： 2014年9月15日，皮下注射药物HyQvia获FDA批准，用于原发性免疫缺陷症（PI）的治疗。HyQvia由人正常免疫球蛋白（IG，10%）和重组人透明质酸酶（hyaluronidase）组成，透明质酸酶有利于IGSC的分散和吸收。 ...