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HIZENTRA- human immunoglobulin g liquid CSL Behring AG
Hizentra is an Immune Globulin Subcutaneous (Human) (IGSC), 20% Liquid indicated for the treatment of primary immunodeficiency (PI) in adults and pediatric patients 2 years of age and older (1).
For subcutaneous infusion only.
Administer at regular intervals from daily up to every two weeks (biweekly).
Before switching to Hizentra, obtain the patient's serum IgG trough level to guide subsequent dose adjustments.
0.2 g per mL (20%) protein solution for subcutaneous injection (3)
The most common adverse reactions observed in ≥5% of study subjects were local reactions (i.e., swelling, redness, heat, pain, and itching at the injection site), headache, diarrhea, fatigue, back pain, nausea, pain in extremity, cough, rash, pruritus, vomiting, abdominal pain (upper), migraine, and pain (6).
To report SUSPECTED ADVERSE REACTIONS, contact CSL Behring Pharmacovigilance at 1-866-915-6958 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
The passive transfer of antibodies may interfere with the response to live virus vaccines (7.1), and lead to misinterpretation of the results of serological testing (5.8, 7.2).
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Hizentra is an Immune Globulin Subcutaneous (Human) (IGSC), 20% Liquid indicated as replacement therapy for primary humoral immunodeficiency (PI) in adults and pediatric patients 2 years of age and older. This includes, but is not limited to, the humoral immune defect in congenital agammaglobulinemia, common variable immunodeficiency, X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.
For subcutaneous infusion only.
Hizentra is a clear and pale yellow to light brown solution. Do not use if the solution is cloudy or contains particulates.
Dosage for patients switching to Hizentra from Immune Globulin Intravenous (Human) (IGIV)
Dosage for patients switching to Hizentra from IGSC
Start Hizentra treatment:
Over time, the dose may need to be adjusted to achieve the desired clinical response and serum IgG trough level, irrespective of the frequency of administration. To determine if a dose adjustment should be considered, measure the patient's serum IgG trough level 2 to 3 months after switching to Hizentra.
Weekly dosing: When switching from IGIV to weekly Hizentra dosing, the target serum IgG trough level is projected to be approximately 16% higher than the last trough level during prior IGIV therapy [see Pharmacokinetics (12.3)].
Biweekly dosing: When switching from IGIV to biweekly Hizentra dosing, the target serum IgG trough level is projected to be approximately 10% higher than the last IGIV trough level. When switching from weekly to biweekly Hizentra dosing, the target trough is projected to be approximately 5% lower than the last trough level on weekly therapy [see Pharmacokinetics (12.3)].
Frequent dosing: When switching from weekly dosing to more frequent Hizentra dosing, the target serum IgG trough level is projected to be approximately 3 to 4% higher than the last trough level on weekly therapy [see Pharmacokinetics (12.3)].
To adjust the dose based on trough levels, calculate the difference (in mg/dL) between the patient's serum IgG trough level and the target IgG trough level for weekly or biweekly dosing. Then find this difference in Table 1 (Column 1) and, based on the Hizentra dosing frequency (for weekly or biweekly) and the patient's body weight, locate the corresponding adjustment amount (in mL) by which to increase (or decrease) the dose. For frequent dosing, add the weekly increment from Table 1 to the weekly-equivalent dose and then divide by the number of days of dosing.
Use the patient's clinical response as the primary consideration in dose adjustment. Additional dosage increments may be indicated based on the patient's clinical response (infection frequency and severity).
For example, if a patient with a body weight of 70 kg has an actual IgG trough level of 900 mg/dL and the target trough level is 1000 mg/dL, this results in a difference of 100 mg/dL. Therefore, increase the weekly dose of Hizentra by 10 mL. For biweekly dosing, increase the biweekly dose by 20 mL. For 2 times per week dosing, increase the dose by 5 mL.
Monitor the patient's clinical response, and repeat the dose adjustment as needed.
Dosage requirements for patients switching to Hizentra from another IGSC product: If a patient on Hizentra does not maintain an adequate clinical response or a serum IgG trough level equivalent to that of the previous IGSC treatment, the physician may want to adjust the dose. For such patients, Table 1 also provides guidance for dose adjustment if their desired IGSC trough level is known.
Administer a minimum total weekly Hizentra dose of 200 mg/kg body weight for two consecutive weeks if a patient is at risk of measles exposure (i.e., due to an outbreak in the US or travel to endemic areas outside of the US. For biweekly dosing, one infusion of a minimum of 400 mg/kg is recommended. If a patient has been exposed to measles, ensure this minimum dose is administered as soon as possible after exposure.
Hizentra is for subcutaneous infusion only.
Hizentra is intended for subcutaneous administration using an infusion pump. Infuse Hizentra in the abdomen, thigh, upper arm, and/or lateral hip.
Follow the steps below and use aseptic technique to administer Hizentra.
For self-administration, provide the patient with instructions and training for subcutaneous infusion in the home or other appropriate setting.
Hizentra is a 0.2 g/mL (20%) protein solution for subcutaneous injection.
Hizentra is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin or to components of Hizentra, such as polysorbate 80.
Hizentra is contraindicated in patients with hyperprolinemia (type I or II) because it contains the stabilizer L-proline [see Description (11)].
Hizentra is contraindicated in IgA-deficient patients with antibodies against IgA and a history of hypersensitivity [see Description (11)].
Severe hypersensitivity reactions may occur to human immune globulin or components of Hizentra, such as polysorbate 80. If a hypersensitivity reaction occurs, discontinue the Hizentra infusion immediately and institute appropriate treatment.
Individuals with IgA deficiency can develop anti-IgA antibodies and anaphylactic reactions (including anaphylaxis and shock) after administration of blood components containing IgA. Patients with known antibodies to IgA may have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions with administration of Hizentra. Hizentra contains ≤50 mcg/mL IgA [see Description (11)].
Thrombosis may occur following treatment with immune globulin products1-3, including Hizentra. 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, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. For patients at risk of thrombosis, administer Hizentra 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, and Patient Counseling Information (17)].
AMS has been reported with use of IGIV4 or IGSC. The syndrome usually begins within several hours to 2 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. Cerebrospinal fluid (CSF) studies frequently show pleocytosis up to several thousand cells per cubic millimeter, predominantly from the granulocytic series, and elevated protein levels up to several hundred mg/dL. AMS may occur more frequently in association with high doses (≥2 g/kg) and/or rapid infusion of immune globulin product.
Patients exhibiting such signs and symptoms should receive a thorough neurological examination, including CSF studies, to rule out other causes of meningitis. Discontinuation of immune globulin treatment has resulted in remission of AMS within several days without sequelae.
Acute renal dysfunction/failure, acute tubular necrosis, proximal tubular nephropathy, osmotic nephrosis and death may occur with use of human immune globulin products, especially those containing sucrose.5 Hizentra does not contain sucrose. Ensure that patients are not volume depleted before administering Hizentra.
For patients judged to be at risk for developing renal dysfunction, including patients with any degree of pre-existing renal insufficiency, 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 [see Dosing and Administration (2.3)].
Periodic monitoring of renal function and urine output is particularly important in patients judged to have a potential increased risk of developing acute renal failure.6 Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of Hizentra and at appropriate intervals thereafter. If renal function deteriorates, consider discontinuing Hizentra.
Hizentra can contain blood group antibodies that may act as hemolysins and induce in vivo coating of red blood cells (RBCs) with immunoglobulin, causing a positive direct antiglobulin (Coombs') test result and hemolysis.7-9 Delayed hemolytic anemia can develop subsequent to immune globulin therapy due to enhanced RBC sequestration, and acute hemolysis, consistent with intravascular hemolysis, has been reported.10
Monitor recipients of Hizentra for clinical signs and symptoms of hemolysis. If signs and/or symptoms of hemolysis are present after Hizentra infusion, perform appropriate confirmatory laboratory testing.
Noncardiogenic pulmonary edema may occur in patients administered human immune globulin products.11 TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Typically, it occurs within 1 to 6 hours following transfusion. Patients with TRALI may be managed using oxygen therapy with adequate ventilatory support.
Monitor Hizentra recipients for pulmonary adverse reactions. If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies in both the product and patient's serum.
Because Hizentra is made from human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. This also applies to unknown or emerging viruses and other pathogens. No cases of transmission of viral diseases or CJD have been associated with the use of Hizentra. All infections suspected by a physician possibly to have been transmitted by Hizentra should be reported to CSL Behring Pharmacovigilance at 1-866-915-6958.
Various passively transferred antibodies in immunoglobulin preparations may lead to misinterpretation of the results of serological testing.
The most common adverse reactions (ARs), observed in ≥5% of study subjects receiving Hizentra, were local reactions (e.g., swelling, redness, heat, pain, and itching at the injection site), headache, diarrhea, fatigue, back pain, nausea, pain in extremity, cough, rash, pruritus, vomiting, abdominal pain (upper), migraine, and pain.
Because clinical studies are conducted under widely varying conditions, AR 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.
The safety of Hizentra was evaluated in a clinical study in the U.S. for 15 months (3-month wash-in/wash-out period followed by a 12-month efficacy period) in subjects with PI who had been treated previously with IGIV every 3 or 4 weeks. The safety analyses included 49 subjects in the intention-to-treat (ITT) population. The ITT population consisted of all subjects who received at least one dose of Hizentra [see Clinical Studies (14)].
Subjects were treated with Hizentra at weekly median doses ranging from 66 to 331 mg/kg body weight (mean: 181.4 mg/kg) during the wash-in/wash-out period and from 72 to 379 mg/kg (mean: 213.2 mg/kg) during the efficacy period. The 49 subjects received a total of 2264 weekly infusions of Hizentra.
Table 2 summarizes the most frequent adverse reactions (ARs) (experienced by at least 2 subjects) occurring during or within 72 hours after the end of an infusion. Local reactions were assessed by the investigators 15 to 45 minutes post-infusion and by the subjects 24 hours post-infusion. The investigators then evaluated the ARs arising from the subject assessments. Local reactions were the most frequent ARs observed, with injection-site reactions (e.g., swelling, redness, heat, pain, and itching at the site of injection) comprising 98% of local reactions.
The ratio of infusions with ARs, including local reactions, to all infusions was 1303 to 2264 (57.6%). Excluding local reactions, the corresponding ratio was 56 to 2264 (2.5%).
Table 3 summarizes injection-site reactions based on investigator assessments 15 to 45 minutes after the end of the 683 infusions administered during regularly scheduled visits (every 4 weeks).
Most local reactions were either mild (93.4%) or moderate (6.3%) in intensity.
No deaths or serious ARs occurred during the study. Two subjects withdrew from the study due to ARs. One subject experienced a severe injection-site reaction one day after the third weekly infusion, and the other subject experienced moderate myositis. Both reactions were judged to be "at least possibly related" to the administration of Hizentra.
In a clinical study conducted in Europe, the safety of Hizentra was evaluated for 10 months (3-month wash-in/wash-out period followed by a 7-month efficacy period) in 51 subjects with PI who had been treated previously with IGIV every 3 or 4 weeks or with IGSC weekly.
Subjects were treated with Hizentra at weekly median doses ranging from 59 to 267 mg/kg body weight (mean: 118.8 mg/kg) during the wash-in/wash-out period and from 59 to 243 mg/kg (mean: 120.1 mg/kg) during the efficacy period. The 51 subjects received a total of 1831 weekly infusions of Hizentra.
Table 4 summarizes the most frequent ARs (experienced by at least 2 subjects) occurring during or within 72 hours after the end of an infusion. Local reactions were assessed by the subjects between 24 and 72 hours post-infusion. The investigators then evaluated the ARs arising from the subject assessments.
The proportion of subjects reporting local reactions decreased over time from approximately 20% following the first infusion to <5% by the end of the study.
Three subjects withdrew from the study due to ARs of mild to moderate intensity. One subject experienced injection-site pain and injection-site pruritus; the second subject experienced injection-site reaction, fatigue, and feeling cold; and the third subject experienced injection-site reaction and hypersensitivity. All reactions were judged by the investigator to be "at least possibly related" to the administration of Hizentra.
Biweekly (Every Two Weeks) or Frequent (2 To 7 Times per Week) Dosing
No data regarding ARs are available for these alternative Hizentra dosing regimens because no clinical trials using these regimens were conducted; however, it is unlikely that the safety profile is qualitatively different from that of weekly dosing.
Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure.
The following adverse reactions have been identified during postmarketing use of Hizentra. This list does not include reactions already reported in clinical studies with Hizentra [see Adverse Reactions (6.1)].
The following adverse reactions have been reported during postmarketing use of immune globulin products5:
To report SUSPECTED ADVERSE REACTIONS, contact CSL Behring Pharmacovigilance at 1-866-915-6958 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
The passive transfer of antibodies with immunoglobulin administration may interfere with the response to live virus vaccines such as measles, mumps, rubella, and varicella [see Patient Counseling Information (17)].
No human data are available to indicate the presence or absence of drug associated risk. Animal reproduction studies have not been conducted with Hizentra. It is not known whether Hizentra can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Immune globulins cross the placenta from maternal circulation increasingly after 30 weeks of gestation. Hizentra should be given to pregnant women only if clearly needed. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
No human data are available to indicate the presence or absence of drug-associated risk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Hizentra and any potential adverse effects on the breastfed infant from Hizentra or from the underlying maternal condition.
Clinical Studies (Weekly Dosing)
The safety and effectiveness of weekly Hizentra have been established in the pediatric age groups 2 to 16. Hizentra was evaluated in 10 pediatric subjects with PI (3 children and 7 adolescents) in a study conducted in the U.S. [see Clinical Studies (14)] and in 23 pediatric subjects with PI (18 children and 5 adolescents) in Europe. There were no differences in the pharmacokinetics, safety and efficacy profiles as compared with adult subjects. No pediatric-specific dose requirements were necessary to achieve the desired serum IgG levels.
Pharmacokinetic Modeling and Simulation (Biweekly or more Frequent Dosing)
The biweekly (every two weeks) or more frequent dosing (2 to 7 times per week) regimens, developed from population PK-based modeling and simulation, included 57 pediatric subjects (32 from Hizentra clinical studies) [see Pharmacokinetics (12.3)]. Hizentra dosing is adjusted to body weight. No pediatric-specific dose requirements are necessary for these regimens.
Safety and effectiveness of Hizentra in pediatric patients below the age of 2 have not been established.
Of the 49 subjects evaluated in the U.S. clinical study of Hizentra, 6 subjects were 65 years of age or older. No overall differences in safety or efficacy were observed between these subjects and younger subjects. The clinical study of Hizentra in Europe did not include subjects over the age of 65.
Hizentra, Immune Globulin Subcutaneous (Human), 20% Liquid, is a ready-to-use, sterile 20% (0.2 g/mL) protein liquid preparation of polyvalent human immunoglobulin G (IgG) for subcutaneous administration. Hizentra is manufactured from large pools of human plasma by a combination of cold alcohol fractionation, octanoic acid fractionation, and anion exchange chromatography. The IgG proteins are not subjected to heating or to chemical or enzymatic modification. The Fc and Fab functions of the IgG molecule are retained. Fab functions tested include antigen binding capacities, and Fc functions tested include complement activation and Fc-receptor-mediated leukocyte activation (determined with complexed IgG).
Hizentra has a purity of ≥98% IgG and a pH of 4.6 to 5.2. Hizentra contains approximately 250 mmol/L (range: 210 to 290 mmol/L) L-proline (a nonessential amino acid) as a stabilizer, 8 to 30 mg/L polysorbate 80, and trace amounts of sodium. Hizentra contains ≤50 mcg/mL IgA. Hizentra contains no carbohydrate stabilizers (e.g., sucrose, maltose) and no preservative.
Plasma units used in the manufacture of Hizentra are tested using FDA-licensed serological assays for hepatitis B surface antigen and antibodies to human immunodeficiency virus (HIV)-1/2 and hepatitis C virus (HCV) as well as FDA-licensed Nucleic Acid Testing (NAT) for HBV, HCV and HIV-1. All plasma units have been found to be nonreactive (negative) in these tests. In addition, the plasma has been tested for B19 virus (B19V) DNA by NAT. Only plasma that passes virus screening is used for production, and the limit for B19V in the fractionation pool is set not to exceed 104 IU of B19V DNA per mL.
The manufacturing process for Hizentra includes three steps to reduce the risk of virus transmission. Two of these are dedicated virus clearance steps: pH 4 incubation to inactivate enveloped viruses; and virus filtration to remove, by size exclusion, both enveloped and non-enveloped viruses as small as approximately 20 nanometers. In addition, a depth filtration step contributes to the virus reduction capacity.12
These steps have been independently validated in a series of in vitro experiments for their capacity to inactivate and/or remove both enveloped and non-enveloped viruses. Table 5 shows the virus clearance during the manufacturing process for Hizentra, expressed as the mean log10 reduction factor (LRF).
The manufacturing process was also investigated for its capacity to decrease the infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered a model for CJD and its variant (vCJD).12 Several of the production steps have been shown to decrease infectivity of an experimental TSE model agent. TSE reduction steps include octanoic acid fractionation (≥6.4 log10), depth filtration (2.6 log10), and virus filtration (≥5.8 log10). These studies provide reasonable assurance that low levels of vCJD/CJD agent infectivity, if present in the starting material, would be removed.
Hizentra supplies a broad spectrum of opsonizing and neutralizing IgG antibodies against a wide variety of bacterial and viral agents. The mechanism of action in PI has not been fully elucidated.
The pharmacokinetics (PK) of Hizentra was evaluated in a PK substudy of subjects (14 adults, 1 pediatric subject 6 to <12 years, and 3 adolescent subjects 12 to <16 years) with PI participating in the 15-month efficacy and safety study [see Clinical Studies (14)]. All PK subjects were treated previously with Privigen®, Immune Globulin Intravenous (Human), 10% Liquid and were switched to weekly subcutaneous treatment with Hizentra. After a 3-month wash-in/wash-out period, doses were adjusted individually with the goal of providing a systemic serum IgG exposure (area under the IgG serum concentration vs time curve; AUC) not inferior to that of the previous weekly-equivalent IGIV dose. Table 6 summarizes PK parameters for subjects in the substudy following treatment with Hizentra and IGIV.
For the 19 subjects completing the wash-in/wash-out period, the average dose adjustment for Hizentra was 153% (range: 126% to 187%) of the previous weekly-equivalent IGIV dose. After 12 weeks of treatment with Hizentra at this individually adjusted dose, the final steady-state AUC determinations were made in 18 of the 19 subjects. The geometric mean ratio of the steady-state AUCs, standardized to a weekly treatment period, for Hizentra vs IGIV treatment was 1.002 (range: 0.77 to 1.20) with a 90% confidence limit of 0.951 to 1.055 for the 18 subjects.
With Hizentra, peak serum levels are lower (1616 vs 2564 mg/dL) than those achieved with IGIV while trough levels are generally higher (1448 vs 1127 mg/dL). In contrast to IGIV administered every 3 to 4 weeks, weekly subcutaneous administration results in relatively stable steady-state serum IgG levels.13,14 After the subjects had reached steady-state with weekly administration of Hizentra, peak serum IgG levels were observed after a mean of 2.9 days (range: 0 to 7 days) in 18 subjects.
Table 7 summarizes PK parameters at steady state for pediatric subjects (age groups: 6 to <12 years and 12 to <16 years) and adults subjects (>16 years) in the European Hizentra study following weekly treatment [see Clinical Studies (14.2)]. Pediatric PK parameters are similar to those of adult subjects; thus no pediatric specific dose requirements are needed for Hizentra dosing.
Pharmacokinetic Modeling and Simulation
Biweekly (Every Two Weeks) or more Frequent Dosing
Pharmacokinetic characterization of biweekly or more frequent dosing of Hizentra was undertaken using population PK-based modeling and simulation. Serum IgG concentration data consisted of 3837 samples from 151 unique pediatric and adult subjects with PI from four clinical studies of IGIV (Privigen®) and/or Hizentra. Of the 151 subjects, 94 were adult subjects (63 from Hizentra clinical studies) and 57 were pediatric subjects (32 from Hizentra clinical studies). Compared with weekly administration, PK modeling and simulation predicted that administration of Hizentra on a biweekly basis at double the weekly dose results in comparable IgG exposure [equivalent AUCs, with a slightly higher IgG peak (Cmax) and slightly lower trough (Cmin)]. In addition, PK modeling and simulation predicted that for the same total weekly dose, Hizentra infusions given 2, 3, 5, or 7 times per week (frequent dosing) produce IgG exposures comparable to weekly dosing [equivalent AUCs, with a slightly lower IgG peak (Cmax) and slightly higher trough (Cmin)]. Frequent dosing reduces the peak-to-trough variation in Hizentra exposure, thus resulting in more sustained IgG exposures. See Table 8 (columns for AUC, Cmax and Cmin).
Dose Adjustment Factor
Using data from four clinical studies, results of model-based simulations demonstrated that weekly or biweekly Hizentra dosing regimens with an IGIV:IGSC dose adjustment factor of 1:1.37 adequately maintain median AUC0-28days and Cmin ratios at ≥90% of values observed with 4-weekly IGIV dosing. See Table 8 (top two rows).
Prediction of Trough Levels Following Regimen Changes
PK modeling and simulation also predicted changes in trough levels after switching from (a) monthly IGIV to weekly or biweekly Hizentra dosing, (b) weekly to biweekly Hizentra dosing, or (c) weekly to more frequent dosing. Table 8 (last column) shows the predicted changes in steady-state IgG trough levels after switching between the various dosing regimens.
PK-based modeling and simulation results indicate that, similar to observations from the clinical study with weekly Hizentra dosing (Table 7), body weight-adjusted biweekly dosing accounted for age-related (>3 years) differences in clearance of Hizentra, thereby maintaining systemic IgG exposure (AUC values) in the therapeutic range.
Long- and short-term memory loss was seen in juvenile rats in a study modeling hyperprolinemia. In this study, rats received daily subcutaneous injections with L-proline from day 6 to day 28 of life.15 The daily amounts of L-proline used in this study were more than 60 times higher than the L-proline dose that would result from the administration of 400 mg/kg body weight of Hizentra once weekly. In unpublished studies using the same animal model (i.e., rats) dosed with the same amount of L-proline with a dosing interval relevant to IGSC treatment (i.e., on 5 consecutive days on days 9 to 13, or once weekly on days 9, 16, and 23), no effects on learning and memory were observed. The clinical relevance of these studies is not known.
A prospective, open-label, multicenter, single-arm, clinical study conducted in the U.S. evaluated the efficacy, tolerability, and safety of Hizentra in 49 adult and pediatric subjects with PI. Subjects previously receiving monthly treatment with IGIV were switched to weekly subcutaneous administration of Hizentra for 15 months. Following a 3-month wash-in/wash-out period, subjects received a dose adjustment to achieve an equivalent AUC to their previous IGIV dose [see Pharmacokinetics (12.3)] and continued treatment for a 12-month efficacy period. The efficacy analyses included 38 subjects in the modified intention-to-treat (MITT) population. The MITT population consisted of subjects who completed the wash-in/wash-out period and received at least one infusion of Hizentra during the efficacy period.
Although 5% of the administered doses could not be verified, the weekly median doses of Hizentra ranged from 72 to 379 mg/kg body weight during the efficacy period. The mean dose was 213.2 mg/kg, which was 149% of the previous IGIV dose.
In the study, the number of injection sites per infusion ranged from 1 to 12. In 73% of infusions, the number of injection sites was 4 or fewer. Up to 4 simultaneous injection sites were permitted using 2 pumps; however, more than 4 sites could be used consecutively during one infusion. The infusion flow rate did not exceed 50 mL per hour for all injection sites combined. During the efficacy period, the median duration of a weekly infusion ranged from 1.6 to 2.0 hours.
The study evaluated the annual rate of serious bacterial infections (SBIs), defined as bacterial pneumonia, bacteremia/septicemia, osteomyelitis/septic arthritis, bacterial meningitis, and visceral abscess. The study also evaluated the annual rate of any infections, the use of antibiotics for infection (prophylaxis or treatment), the days out of work/school/kindergarten/day care or unable to perform normal activities due to infections, hospitalizations due to infections, and serum IgG trough levels.
Table 9 summarizes the efficacy results for subjects in the efficacy period (MITT population) of the study. No subjects experienced an SBI in this study.
The mean IgG trough levels increased by 24.2%, from 1009 mg/dL prior to the study to 1253 mg/dL during the efficacy period.
In a prospective, open-label, multicenter, single-arm, clinical study conducted in Europe, 51 adult and pediatric subjects with PI switched from monthly IGIV (31 subjects) or weekly IGSC (20 subjects) to weekly treatment with Hizentra. For the 46 subjects in the efficacy analysis, the weekly mean dose in the efficacy period was 120.1 mg/kg (range 59 to 243 mg/kg), which was 104% of the previous weekly equivalent IGIV or weekly IGSC dose.
None of the subjects had an SBI during the efficacy period, resulting in an annualized rate of 0 (upper one-sided 99% confidence limit of 0.192) SBIs per subject. The annualized rate of any infections was 5.18 infections per subject for the efficacy period.
Each product presentation includes a package insert and the following components:
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Inform patients to immediately report the following signs and symptoms to their healthcare provider:
Inform patients that because Hizentra is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent (see Warnings and Precautions [5.7] and Description ).
Inform patients that Hizentra may interfere with the response to live virus vaccines (e.g., measles, mumps, rubella, and varicella) and to notify their immunizing physician of recent therapy with Hizentra (see Drug Interactions ).
Home Treatment for Primary Humoral Immunodeficiency with Subcutaneous Administration
Information for Patients
This patient package insert summarizes important information about Hizentra. Please read it carefully before using this medicine. This information does not take the place of talking with your healthcare professional, and it does not include all of the important information about Hizentra. If you have any questions after reading this, ask your healthcare professional.
What is the most important information I should know about Hizentra?
Hizentra is supposed to be infused under your skin only. DO NOT inject Hizentra into a blood vessel (vein or artery).
What is Hizentra?
Hizentra (Hi – ZEN – tra) is a prescription medicine used to treat primary immune deficiency (PI). Hizentra is made from human plasma. It contains antibodies, called immunoglobulin G (IgG), that healthy people have to fight germs (bacteria and viruses).
People with PI get a lot of infections. Hizentra helps lower the number of infections you will get.
Who should NOT take Hizentra?
Do not take Hizentra if you have too much proline in your blood (called "hyperprolinemia") or if you have had reactions to polysorbate 80.
Tell your doctor if you have had a serious reaction to other immune globulin medicines or if you have been told that you also have a deficiency of the immunoglobulin called IgA.
Tell your doctor if you have a history of heart or blood vessel disease or blood clots, have thick blood, or have been immobile for some time. These things may increase your risk of having a blood clot after using Hizentra. Also tell your doctor what drugs you are using, as some drugs, such as those that contain the hormone estrogen (for example, birth control pills), may increase your risk of developing a blood clot.
How should I take Hizentra?
You will take Hizentra through an infusion, only under your skin. You will place up to 4 needles into different areas of your body each time you use Hizentra. The needles are attached to a pump with an infusion tube. You can have infusions as often as every day up to every two weeks. For weekly infusions, it can take about 1 to 2 hours to complete an infusion; however, this time may be shorter or longer depending on the dose and frequency your doctor has prescribed for you.
Instructions for using Hizentra are at the end of this patient package insert (see "How do I use Hizentra?"). Do not use Hizentra by yourself until you have been taught how by your doctor or healthcare professional.
What should I avoid while taking Hizentra?
Vaccines may not work well for you while you are taking Hizentra. Tell your doctor or healthcare professional that you are taking Hizentra before you get a vaccine.
Tell your doctor or healthcare professional if you are pregnant or plan to become pregnant, or if you are nursing.
What are possible side effects of Hizentra?
The most common side effects with Hizentra are:
Tell your doctor right away or go to the emergency room if you have hives, trouble breathing, wheezing, dizziness, or fainting. These could be signs of a bad allergic reaction.
Tell your doctor right away if you have any of the following symptoms. They could be signs of a serious problem.
Tell your doctor about any side effects that concern you. You can ask your doctor to give you more information that is available to healthcare professionals.
How do I use Hizentra?
Infuse Hizentra only after you have been trained by your doctor or healthcare professional. Below are step-by-step instructions to help you remember how to use Hizentra. Ask your doctor or healthcare professional about any instructions you do not understand.
Instructions for use
Hizentra comes in single-use vials.
Keep Hizentra in the storage box at room temperature.
Step 1: Assemble suppliesGather the Hizentra vial(s), the following disposable supplies (not provided with Hizentra), and other items (infusion pump, sharps or other container, treatment diary or log book):
Step 2: Clean surfaceThoroughly clean a table or other flat surface using one of the alcohol wipes.
Manufactured by:CSL Behring AGBern, SwitzerlandU.S. License No. 1766
Distributed by:CSL Behring LLCKankakee, IL 60901 USA
NOTE: These photos can be used only for identification by shape, color, and imprint. They do not depict actual or relative size.
The product samples shown here have been supplied by the manufacturer and reproduced in full color by PDR as a quick-reference identification aid. While every effort has been made to assure accurate reproduction, please remember that any visual identification should be considered preliminary. In cases of poisoning or suspected over dosage, the drug's identity should be verified by chemical analysis.