Hizentra is an Immune Globulin Subcutaneous (Human) (IGSC), 20% Liquid indicated as replacement therapy for primary humoral immunodeficiency (PI). 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.
Hizentra Dosage and Administration
For subcutaneous infusion only. Do not inject into a blood vessel.
Preparation and Handling
Hizentra is a clear and pale yellow to light brown solution. Do not use if the solution is cloudy or contains particulates.
- Prior to administration, visually inspect each vial of Hizentra for particulate matter or discoloration, whenever the solution and container permit.
- Do not freeze. Do not use any solution that has been frozen.
- Check the product expiration date on the vial label. Do not use beyond the expiration date.
- Do not mix Hizentra with other products.
- Do not shake the Hizentra vial.
- Use aseptic technique when preparing and administering Hizentra.
- The Hizentra vial is for single-use only. Discard all used administration supplies and any unused product immediately after each infusion in accordance with local requirements.
Dosage
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) Number of weeks between IGIV doses | × 1.53 |
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 have not been studied. 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.
Administration
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.
- Injection sites – A Hizentra dose may be infused into multiple injection sites. Do not use more than 4 sites simultaneously. However, if more injection sites are needed for the full weekly dose, they can be used consecutively. Injection sites should be at least 2 inches apart. Change the actual site of injection with each weekly administration.
- Volume – For the first infusion of Hizentra, do not exceed a volume of 15 mL per injection site. The volume may be increased to 20 mL per site after the fourth infusion and to a maximum of 25 mL per site as tolerated.
- Rate – For the first infusion of Hizentra, the maximum recommended flow rate is 15 mL per hour per site. For subsequent infusions, the flow rate may be increased to a maximum of 25 mL per hour per site as tolerated. However, the maximum flow rate is not to exceed a total of 50 mL per hour for all sites combined at any time.
Follow the steps below and use aseptic technique to administer Hizentra.
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For self-administration, provide the patient with instructions and training for subcutaneous infusion in the home or other appropriate setting.
Dosage Forms and Strengths
Hizentra is a 0.2 g/mL (20%) protein solution for subcutaneous injection.
Contraindications
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]).
Warnings and Precautions
Hypersensitivity
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]).
Aseptic Meningitis Syndrome (AMS)
AMS has been reported with use of IGIV1 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.
Reactions Reported to Occur With IGIV Treatment
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.2 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.
Thrombotic Events
Thrombotic events may occur with use of human immune globulin products3-5. 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, and/or known or suspected hyperviscosity. 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.
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.
Transmissible Infectious Agents
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.
Laboratory Tests
Various passively transferred antibodies in immunoglobulin preparations may lead to misinterpretation of the results of serological testing.
Adverse Reactions
The most common adverse reactions (ARs), observed in ≥5% of study subjects receiving Hizentra, were local reactions (i.e., swelling, redness, heat, pain, and itching at the injection site), headache, vomiting, pain, and fatigue.
Clinical Trials Experience
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 for 15 months 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 doses ranging from 66 to 331 mg/kg body weight during the wash-in/wash-out period and from 72 to 379 mg/kg during the efficacy period. The 49 subjects received a total of 2264 weekly infusions of Hizentra.
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.
Table 2 summarizes the most frequent adverse events (AEs) (experienced by at least 4 subjects), irrespective of causality. Included are all AEs and those considered temporally associated with the Hizentra infusion, i.e., occurring during or within 72 hours after the end of an infusion. Local reactions were the most frequent AEs observed, with injection-site reactions (i.e., swelling, redness, heat, pain, and itching at the site of injection) comprising 98% of local reactions.
| Table 2: Incidence of Subjects With Adverse Events (AEs)* (Experienced by 4 or More Subjects) and Rate per Infusion, Irrespective of Causality (ITT Population) | ||||
|---|---|---|---|---|
| All AEs* | AEs* Occurring During or Within 72 Hours of Infusion | |||
| AE (≥4 Subjects) | Number (%) of Subjects (n=49) | Number (Rate†) of AEs (n=2264 Infusions) | Number (%) of Subjects (n=49) | Number (Rate†) of AEs (n=2264 Infusions) |
| ||||
| Local reactions‡ | 49 (100) | 1340 (0.592) | 49 (100) | 1322 (0.584) |
| Other AEs: | ||||
| Headache | 13 (26.5) | 40 (0.018) | 12 (24.5) | 32 (0.014) |
| Cough | 8 (16.3) | 9 (0.004) | 5 (10.2) | 6 (0.003) |
| Diarrhea | 7 (14.3) | 8 (0.004) | 5 (10.2) | 6 (0.003) |
| Fatigue | 6 (12.2) | 6 (0.003) | 4 (8.2) | 4 (0.002) |
| Back pain | 5 (10.2) | 11 (0.005) | 4 (8.2) | 5 (0.002) |
| Nausea | 5 (10.2) | 5 (0.002) | 4 (8.2) | 4 (0.002) |
| Abdominal pain, upper | 5 (10.2) | 5 (0.002) | 3 (6.1) | 3 (0.001) |
| Rash | 5 (10.2) | 7 (0.003) | 2 (4.1) | 3 (0.001) |
| Pain in extremity | 4 (8.2) | 7 (0.003) | 4 (8.2) | 6 (0.003) |
| Migraine | 4 (8.2) | 5 (0.002) | 3 (6.1) | 4 (0.002) |
| Pain | 4 (8.2) | 5 (0.002) | 3 (6.1) | 4 (0.002) |
| Epistaxis | 4 (8.2) | 6 (0.003) | 2 (4.1) | 3 (0.001) |
| Pharyngolaryngeal pain | 4 (8.2) | 6 (0.003) | 2 (4.1) | 2 (<0.001) |
| Arthralgia | 4 (8.2) | 5 (0.002) | 2 (4.1) | 3 (0.001) |
The ratio of infusions with temporally associated AEs, including local reactions, to all infusions was 1338 to 2264 (59.1%; upper 95% confidence limit of 62.4%). Excluding local reactions, the corresponding ratio was 173 to 2264 (7.6%; upper 95% confidence limit of 8.9%).
Table 3 summarizes the most frequent ARs (i.e., those AEs considered by the investigators to be "at least possibly related" to Hizentra administration) experienced by at least 2 subjects.
| Adverse Reaction (≥2 Subjects) | Number (%) of Subjects (n=49) | Number (Rate*) of Adverse Reactions (n=2264 Infusions) |
|---|---|---|
| ||
| Local reactions† | 49 (100) | 1338 (0.591) |
| Other ARs: | ||
| Headache | 12 (24.5) | 36 (0.016) |
| Vomiting | 3 (6.1) | 3 (0.001) |
| Pain | 3 (6.1) | 4 (0.002) |
| Fatigue | 3 (6.1) | 3 (0.001) |
| Contusion | 2 (4.1) | 3 (0.001) |
| Back pain | 2 (4.1) | 3 (0.001) |
| Migraine | 2 (4.1) | 3 (0.001) |
| Diarrhea | 2 (4.1) | 2 (<0.001) |
| Abdominal pain, upper | 2 (4.1) | 2 (<0.001) |
| Nausea | 2 (4.1) | 2 (<0.001) |
| Rash | 2 (4.1) | 2 (<0.001) |
| Arthralgia | 2 (4.1) | 2 (<0.001) |
Table 4 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 (0.50) |
| 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.
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.
The following adverse reactions have been identified and reported during the postmarketing use of IGIV products11:
- Infusion reactions: Hypersensitivity (e.g., anaphylaxis), headache, diarrhea, tachycardia, fever, fatigue, dizziness, malaise, chills, flushing, urticaria or other skin reactions, wheezing or other chest discomfort, nausea, vomiting, rigors, back pain, myalgia, arthralgia, and changes in blood pressure
- Renal: Acute renal dysfunction/failure, osmotic nephropathy
- Respiratory: Apnea, Acute Respiratory Distress Syndrome (ARDS), TRALI, cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm
- Cardiovascular: Cardiac arrest, thromboembolism, vascular collapse, hypotension
- Neurological: Coma, loss of consciousness, seizures, tremor, aseptic meningitis syndrome
- Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema multiforme, dermatitis (e.g., bullous dermatitis)
- Hematologic: Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs') test
- Gastrointestinal: Hepatic dysfunction, abdominal pain
- General/Body as a Whole: Pyrexia, rigors
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 Interactions
Live Virus Vaccines
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]).
Serological Testing
Various passively transferred antibodies in immunoglobulin preparations may lead to misinterpretation of the results of serological testing.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C. 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. Hizentra should be given to pregnant women only if clearly needed.
Nursing Mothers
Hizentra has not been evaluated in nursing mothers.
Pediatric Use
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.
Geriatric Use
Of the 49 subjects evaluated in the 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.
Hizentra Description
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 (range: 210 to 290 mmol/L) L-proline (a nonessential amino acid) as a stabilizer, 10 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 HIV-1 and HCV. All plasma units have been found to be nonreactive (negative) in these tests. For hepatitis B virus (HBV), an investigational NAT procedure is used and the plasma units found to be negative; however, the significance of a negative result has not been established. 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, pse | ||||||
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