HIZENTRA- human immunoglobulin g liquid
CSL Behring AG
----------
HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use Hizentra safely and effectively. See full prescribing information for Hizentra.
Hizentra, Immune Globulin Subcutaneous (Human), 20% Liquid Initial U.S. Approval: 2010 INDICATIONS AND USAGEHizentra 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). DOSAGE AND ADMINISTRATIONFor subcutaneous infusion only. Do not inject into a blood vessel. Start treatment with Hizentra 1week after the patient's last Immune Globulin Intravenous (Human) (IGIV) infusion, when the patient has received IGIV infusions at regular intervals for at least 3 months. Dosage (2.2)
Administration (2.3)
DOSAGE FORMS AND STRENGTHS0.2 g/mL (20%) protein solution for subcutaneous injection (3) CONTRAINDICATIONSWARNINGS AND PRECAUTIONS
ADVERSE REACTIONSThe 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. DRUG INTERACTIONSUSE IN SPECIFIC POPULATIONSSee 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 07/2013 |
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. Do not inject into a blood vessel.
Hizentra is a clear and pale yellow to light brown solution. Do not use if the solution is cloudy or contains particulates.
The dose should be individualized based on the patient's clinical response to Hizentra therapy and serum immunoglobulin G (IgG) trough levels.
Start treatment with Hizentra 1 week after the patient's last Immune Globulin Intravenous (Human) (IGIV) infusion. Before receiving treatment with Hizentra, patients need to have received IGIV treatment at regular intervals for at least 3 months. Before switching to Hizentra, obtain the patient's serum IgG trough level to guide subsequent dose adjustments (see below under Dose Adjustment).
Establish the initial weekly dose of Hizentra by converting the monthly IGIV dose into a weekly equivalent and increasing it using a dose adjustment factor. The goal is to achieve a systemic serum IgG exposure (area under the concentration-time curve [AUC]) not inferior to that of the previous IGIV treatment [see Pharmacokinetics (12.3)].
Initial Weekly Dose
To calculate the initial weekly dose of Hizentra, divide the previous IGIV dose in grams by the number of weeks between doses during the patient's IGIV treatment (e.g., 3 or 4); then multiply this by the dose adjustment factor of 1.53.
Initial Hizentra dose = | Previous IGIV dose (in grams) | × 1.53 |
Number of weeks between IGIV doses |
To convert the Hizentra dose (in grams) to milliliters (mL), multiply the calculated dose (in grams) by 5.
Dose Adjustment
Over time, the dose may need to be adjusted to achieve the desired clinical response and serum IgG trough level. To determine if a dose adjustment should be considered, measure the patient's serum IgG trough level 2 to 3 months after switching from IGIV to Hizentra. The target serum IgG trough level on weekly Hizentra treatment is projected to be approximately 290 mg/dL higher than the last trough level during prior IGIV therapy.
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. Then find this difference in Table 1 (Column 1) and, based on the patient's body weight, the corresponding amount (in mL) by which to increase (or decrease) the weekly dose. The patient's clinical response should be the primary consideration in dose adjustment. Additional dosage increments may be indicated based on the patient's clinical response (infection frequency and severity).
Difference From Target IgG Trough Level (mg/dL) | Body Weight (kg) | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
10 | 15 | 20 | 30 | 40 | 50 | 60 | 70 | 80 | 90 | 100 | 110 | 120 | |
Dose Adjustment (mL per Week)* | |||||||||||||
|
|||||||||||||
100 | 1 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 8 | 9 | 10 | 11 |
150 | 1 | 2 | 3 | 4 | 6 | 7 | 8 | 10 | 11 | 13 | 14 | 15 | 17 |
200 | 2 | 3 | 4 | 6 | 8 | 9 | 11 | 13 | 15 | 17 | 19 | 21 | 23 |
250 | 2 | 4 | 5 | 7 | 9 | 12 | 14 | 16 | 19 | 21 | 23 | 26 | 28 |
300 | 3 | 4 | 6 | 8 | 11 | 14 | 17 | 20 | 23 | 25 | 28 | 31 | 34 |
350 | 3 | 5 | 7 | 10 | 13 | 16 | 20 | 23 | 26 | 30 | 33 | 36 | 39 |
400 | 4 | 6 | 8 | 11 | 15 | 19 | 23 | 26 | 30 | 34 | 38 | 41 | 45 |
450 | 4 | 6 | 8 | 13 | 17 | 21 | 25 | 30 | 34 | 38 | 42 | 46 | 51 |
500 | 5 | 7 | 9 | 14 | 19 | 23 | 28 | 33 | 38 | 42 | 47 | 52 | 56 |
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 7 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.
Measles Exposure
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), the weekly Hizentra dose should be a minimum of 200 mg/kg body weight for two consecutive weeks. 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. Do not inject into a blood vessel.
Hizentra is intended for weekly 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 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. In case of hypersensitivity, 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)].
Thrombotic events have been reported with the use of immune globulin products1-3, including Hizentra. Patients at increased risk may include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, hypercoagulable disorders, prolonged periods of immobilization, Factor V Leiden, known or suspected hyperviscosity, and/or those who use estrogen-containing products. Because of the potentially increased risk of thrombosis, 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 judged to be at risk of developing thrombotic events, administer Hizentra at the minimum rate practicable.
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.
The following reactions have been reported to occur with IGIV treatment and may occur with IGSC treatment.
Renal Dysfunction/Failure
Renal dysfunction/failure, osmotic nephropathy, and death may occur with use of human immune globulin products. Ensure that patients are not volume depleted and assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of Hizentra and at appropriate intervals thereafter.
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.5 If renal function deteriorates, consider discontinuing Hizentra. For patients judged to be at risk of developing renal dysfunction because of pre-existing renal insufficiency or predisposition to acute renal failure (such as those with diabetes mellitus or hypovolemia, those who are overweight or use concomitant nephrotoxic medicinal products, or those who are over 65 years of age), administer Hizentra at the minimum rate practicable.
Hemolysis
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.6-8 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.9
Monitor recipients of Hizentra for clinical signs and symptoms of hemolysis. If these are present after a Hizentra infusion, perform appropriate confirmatory laboratory testing. If transfusion is indicated for patients who develop hemolysis with clinically compromising anemia after receiving Hizentra, perform adequate cross-matching to avoid exacerbating on-going hemolysis.
Transfusion-Related Acute Lung Injury (TRALI)
Noncardiogenic pulmonary edema may occur in patients administered human immune globulin products.10 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, and theoretically, the Creutzfeldt-Jakob disease [CJD] agent). The risk of infectious agent transmission has been reduced by screening plasma donors for prior exposure to certain viruses, testing for the presence of certain current virus infections, and including virus inactivation/removal steps in the manufacturing process for Hizentra.
Report all infections thought to be possibly transmitted by Hizentra to CSL Behring Pharmacovigilance at 1-866-915-6958.
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.
US Study
The safety of Hizentra was evaluated in a clinical study in the US 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.
ARs* Occurring During or Within 72 Hours of Infusion | ||
---|---|---|
AR (≥2 Subjects) | Number (%) of Subjects (n=49) | Number (Rate†) of ARs (n=2264 Infusions) |
Local reactions‡ | 49 (100) | 1322 (0.584) |
Other ARs: | ||
Headache | 12 (24.5) | 32 (0.014) |
Diarrhea | 5 (10.2) | 6 (0.003) |
Fatigue | 4 (8.2) | 4 (0.002) |
Back pain | 4 (8.2) | 5 (0.002) |
Nausea | 4 (8.2) | 4 (0.002) |
Pain in extremity | 4 (8.2) | 6 (0.003) |
Cough | 4 (8.2) | 4 (0.002) |
Vomiting | 3 (6.1) | 3 (0.001) |
Abdominal pain, upper | 3 (6.1) | 3 (0.001) |
Migraine | 3 (6.1) | 4 (0.002) |
Pain | 3 (6.1) | 4 (0.002) |
Arthralgia | 2 (4.1) | 3 (0.001) |
Contusion | 2 (4.1) | 3 (0.001) |
Rash | 2 (4.1) | 3 (0.001) |
Urticaria | 2 (4.1) | 2 (< 0.001) |
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).
Injection-Site Reaction | Number† (Rate‡) of Reactions (n=683 Infusions§) |
---|---|
|
|
Edema/induration | 467 (0.68) |
Erythema | 346 (0.51) |
Local heat | 108 (0.16) |
Local pain | 88 (0.13) |
Itching | 64 (0.09) |
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.
European Study
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 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.
ARs* Occurring During or Within 72 Hours of Infusion | ||
---|---|---|
AR (≥2 Subjects) | Number (%) of Subjects (n=51) | Number (Rate†) of ARs (n=1831 Infusions) |
Local reactions‡ | 24 (47.1) | 105 (0.057) |
Other ARs: | ||
Headache | 9 (17.6) | 20 (0.011) |
Rash | 4 (7.8) | 4 (0.002) |
Pruritus | 4 (7.8) | 13 (0.007) |
Fatigue | 3 (5.9) | 5 (0.003) |
Abdominal pain, upper | 2 (3.9) | 3 (0.002) |
Arthralgia | 2 (3.9) | 2 (0.001) |
Erythema | 2 (3.9) | 4 (0.002) |
Abdominal discomfort | 2 (3.9) | 3 (0.002) |
Back pain | 2 (3.9) | 2 (0.001) |
Hematoma | 2 (3.9) | 3 (0.002) |
Hypersensitivity | 2 (3.9) | 4 (0.002) |
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.
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.
Hizentra
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)].
General
The following adverse reactions have been reported during postmarketing use of immune globulin products11:
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)].
The safety and effectiveness of Hizentra have been established in the pediatric age groups 2 to 16, as supported by evidence from adequate and well-controlled studies. Hizentra was evaluated in 10 pediatric subjects with PI (3 children and 7 adolescents) in a study conducted in the US [see Clinical Studies (14)] and in 23 pediatric subjects with PI (18 children and 5 adolescents) in Europe. There were no differences in the safety and efficacy profiles as compared with adult subjects. No pediatric-specific dose requirements were necessary to achieve the desired serum IgG levels.
Safety and effectiveness of Hizentra in pediatric patients below the age of 2 have not been established.
Of the 49 subjects evaluated in the US 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).
HIV-1 | PRV | BVDV | WNV | EMCV | MVM | |
---|---|---|---|---|---|---|
HIV-1, human immunodeficiency virus type 1, a model for HIV-1 and HIV-2; PRV, pseudorabies virus, a nonspecific model for large enveloped DNA viruses (e.g., herpes virus); BVDV, bovine viral diarrhea virus, a model for hepatitis C virus; WNV, West Nile virus; EMCV, encephalomyocarditis virus, a model for hepatitis A virus; MVM, minute virus of mice, a model for a small highly resistant non-enveloped DNA virus (e.g., parvovirus); LRF, log10 reduction factor; nt, not tested; na, not applicable. | ||||||
|
||||||
Virus Property | ||||||
Genome | RNA | DNA | RNA | RNA | RNA | DNA |
Envelope | Yes | Yes | Yes | Yes | No | No |
Size (nm) | 80-100 | 120-200 | 50-70 | 50-70 | 25-30 | 18-24 |
Manufacturing Step | Mean LRF | |||||
pH 4 incubation | ≥5.4 | ≥5.9 | 4.6 | ≥7.8 | nt | nt |
Depth filtration | ≥5.3 | ≥6.3 | 2.1 | 3.0 | 4.2 | 2.3 |
Virus filtration | ≥5.3 | ≥5.5 | ≥5.1 | ≥5.9 | ≥5.4 | ≥5.5 |
Overall Reduction (Log10 Units) | ≥16.0 | ≥17.7 | ≥11.8 | ≥16.7 | ≥9.6 | ≥7.8 |
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 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.
Hizentra | IGIV* (Privigen®) | |
---|---|---|
bw, body weight. | ||
Number of subjects | 18 | 18 |
Dose* | ||
Mean | 228 mg/kg bw | 152 mg/kg bw |
Range | 141-381 mg/kg bw | 86-254 mg/kg bw |
IgG peak levels | ||
Mean | 1616 mg/dL | 2564 mg/dL |
Range | 1090-2825 mg/dL | 2046-3456 mg/dL |
IgG trough levels | ||
Mean | 1448 mg/dL | 1127 mg/dL |
Range | 952-2623 mg/dL | 702-1810 mg/dL |
AUC† | ||
Mean | 10560 day × mg/dL | 10320 day × mg/dL |
Range | 7210-18670 day × mg/dL | 8051-15530 day × mg/dL |
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.
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 US 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 7 summarizes the efficacy results for subjects in the efficacy period (MITT population) of the study. No subjects experienced an SBI in this study.
Number of subjects (efficacy period) | 38 |
Total number of subject days | 12,697 |
Infections | |
Annual rate of SBIs* | 0 SBIs per subject year† |
Annual rate of any infections | 2.76 infections/subject year‡ |
Antibiotic use for infection (prophylaxis or treatment) | |
Number of subjects (%) | 27 (71.1) |
Annual rate | 48.5 days/subject year |
Total number of subject days | 12,605 |
Days out of work/school/kindergarten/day care or unable to perform normal activities due to infections | |
Number of days (%) | 71 (0.56) |
Annual rate | 2.06 days/subject year |
Hospitalizations due to infections | |
Number of days (%) | 7 (0.06)§ |
Annual rate | 0.2 days/subject year |
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:
Presentation | Carton NDC Number | Components |
---|---|---|
5 mL | 44206-451-01 | Vial containing 1 gram of protein (NDC 44206-451-90) |
10 mL | 44206-452-02 | Vial containing 2 grams of protein (NDC44206-452-91) |
20 mL | 44206-454-04 | Vial containing 4 grams of protein (NDC 44206-454-92) |
50 mL | 44206-455-10 | Vial containing 10 grams of protein (NDC 44206-455-93) |
The attached Hizentra "Information for Patients" contains more detailed instructions for patients who will be self-administering Hizentra.
Hizentra
Immune Globulin Subcutaneous (Human), 20% Liquid
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. Make sure that the infusion is not into a blood vessel. 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. It usually takes about 60 minutes to do one infusion. You will need to have infusions once a week.
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.
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 supplies
Gather 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 surface
Thoroughly clean a table or other flat surface using one of the alcohol wipes.
Step 3: Wash hands
|
Step 4: Check vials
Carefully look at the liquid in each vial of Hizentra (Figure 2). It should look clear and be pale yellow to light brown. Check for particles or color changes. Do not use the vial if:
|
Step 5: Transfer Hizentra from vial(s) to syringe
|
|
|
|
When using multiple vials to achieve the desired dose, repeat this step.
Step 6: Prepare infusion pump and tubing
Prepare the infusion pump (following the manufacturer's instructions) and prime (fill) the infusion tubing. To prime the tubing, connect the syringe filled with Hizentra to the infusion tubing and gently push on the syringe plunger to fill the tubing with Hizentra (Figure 7). |
Step 7: Prepare injection site(s)
|
Step 8: Insert needle(s)
|
|
|
Step 9: Start infusion
Follow the manufacturer's instructions to turn on the infusion pump (Figure 13). |
Step 10: Record treatment (Figure 14) Peel off the removable part of the label of the Hizentra vial. Put this label in your treatment diary or log book with the date and time of the infusion. Also include the exact amount of Hizentra that you infused. |
Step 11: Clean up
|
Be sure to tell your doctor about any problems you have doing your infusions. Your doctor may ask to see your treatment diary or log book, so be sure to take it with you each time you visit the doctor's office.
Call your doctor for medical advice about side effects. You can also report side effects to FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Manufactured by:
CSL Behring AG
Bern, Switzerland
US License No. 1766
Distributed by:
CSL Behring LLC
Kankakee, IL 60901 USA
PRINCIPAL DISPLAY PANEL - 5 mL Carton
NDC 44206-451-01
1 g
5 mL
Immune Globulin
Subcutaneous (Human),
20% Liquid
Hizentra®
Single-use vial
For Subcutaneous Administration
Only
Rx only
CSL Behring
PRINCIPAL DISPLAY PANEL - 5 mL Vial Label
NDC 44206-451-90
A5614/200
1 g
5 mL
Immune Globulin Subcutaneous
(Human), 20% Liquid
Hizentra®
Subcutaneous use only
Rx only
Each Hizentra single-use vial
contains 1g IgG. Store Hizentra
up to 25°C (77°F). Do not freeze.
Manufactured by:
CSL Behring AG
Bern, Switzerland
US License No. 1766
HIZENTRA
human immunoglobulin g liquid |
|||||||||||||
|
|||||||||||||
|
|||||||||||||
|
|||||||||||||
|
|||||||||||||
|
HIZENTRA
human immunoglobulin g liquid |
|||||||||||||
|
|||||||||||||
|
|||||||||||||
|
|||||||||||||
|
|||||||||||||
|
HIZENTRA
human immunoglobulin g liquid |
|||||||||||||
|
|||||||||||||
|
|||||||||||||
|
|||||||||||||
|
|||||||||||||
|
HIZENTRA
human immunoglobulin g liquid |
|||||||||||||
|
|||||||||||||
|
|||||||||||||
|
|||||||||||||
|
|||||||||||||
|
Labeler - CSL Behring AG (481152762) |
Establishment | |||
Name | Address | ID/FEI | Business Operations |
CSL Behring AG | 481152762 | MANUFACTURE |