Included as part of the PRECAUTIONS section.
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].
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, PATIENT INFORMATION].
Aseptic Meningitis Syndrome (AMS)
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
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.
Transfusion-Related Acute Lung Injury (TRALI)
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.
Transmissible Infectious Agents
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
Patient Counseling Information
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:
- Hypersensitivity reactions to Hizentra (including hives,
generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis)
(see WARNINGS AND PRECAUTIONS).
- Pain and/or swelling of an arm or leg with warmth over
the affected area, discoloration of an arm or leg, unexplained shortness of
breath, chest pain or discomfort that worsens on deep breathing, unexplained
rapid pulse, or numbness or weakness on one side of the body (see WARNINGS
- Severe headache, neck stiffness, drowsiness, fever,
sensitivity to light, painful eye movements, nausea, and vomiting (see
WARNINGS AND PRECAUTIONS).
- Decreased urine output, sudden weight gain, fluid
retention/edema, and/or shortness of breath (see WARNINGS AND PRECAUTIONS).
- Fatigue, increased heart rate, yellowing of the skin or
eyes, and dark-colored urine (see WARNINGS AND PRECAUTIONS).
- Severe breathing problems, lightheadedness, drops in
blood pressure, and fever (see WARNINGS AND PRECAUTIONS).
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 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
Home Treatment for Primary Humoral Immunodeficiency
with Subcutaneous Administration
- If self-administration is deemed to be appropriate,
ensure that the patient receives clear instructions and training on
subcutaneous administration in the home or other appropriate setting and has
demonstrated the ability to independently administer subcutaneous infusions.
- Ensure the patient understands the importance of adhering
to their prescribed administration schedule to maintain appropriate steady IgG
- Instruct patients to scan the vial if recording the
infusion electronically and keep a diary/log book that includes information
about each infusion such as, the time, date, dose, lot number(s) and any
- Inform the patient that mild to moderate local
injection-site reactions (e.g., swelling and redness) are a common side effect
of subcutaneous therapy, but to contact their healthcare professional if a
local reaction increases in severity or persists for more than a few days.
- Inform patients of the importance of having an infusion
needle long enough to reach the subcutaneous tissue and of changing the actual
site of injection with each infusion. Explain that Hizentra is for subcutaneous
infusion only, and must not be injected into a blood vessel. Make sure patients
know how to avoid blood vessels and check if the needle has entered a blood
- Inform patients to consider adjusting the injection-site
location, volume per site, and rate of infusion based on how infusions are
- Inform patient to interrupt or terminate the Hizentra
infusion if a hypersensitivity reaction occurs.
- Inform patients that they should be tested regularly to
make sure they have the correct levels of Hizentra (IgG) in their blood. These
tests may result in adjustments to the Hizentra dose.
Use In Specific Populations
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
Hizentra has not been evaluated in nursing mothers.
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 US [see Clinical Studies] 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
Pharmacokinetic Modeling And Simulation (Biweekly or more
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]. 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 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
1. Dalakas MC. High-dose intravenous immunoglobulin and
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2. Woodruff RK, Grigg AP, Firkin FC, Smith IL. Fatal
thrombotic events during treatment of autoimmune thrombocytopenia with
intravenous immunoglobulin in elderly patients. Lancet 1986;2:217-218.
3. Wolberg AS, Kon RH, Monroe DM, Hoffman M. Coagulation
factor XI is a contaminant in intravenous immunoglobulin preparations. Am J
4. Gabor EP, Meningitis and skin reaction after
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5. Pierce LR, Jain N. Risks associated with the use of
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6. Cayco AV, Perazella MA, Hayslett JP. Renal
insufficiency after intravenous immune globulin therapy: a report of two cases
and an analysis of the literature. J Am Soc Nephrol 1997;8:1788-1793.
7. Copelan EA, Strohm PL, Kennedy MS, Tutschka PJ.
Hemolysis following intravenous immune globulin therapy. Transfusion 1986;26:410-412.
8. Thomas MJ, Misbah SA, Chapel HM, Jones M, Elrington G,
Newsom-Davis J. Hemolysis after high-dose intravenous Ig. Blood 1993;15:3789.
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10. Kessary-Shoham H, Levy Y, Shoenfeld Y, Lorber M,
Gershon H. In vivo administration of intravenous immunoglobulin (IVIg) can lead
to enhanced erythrocyte sequestration. J Autoimmun 1999;13:129-135.
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