Subsequent Infusions
`≤50
`≤50
`
`1st Infusion
`≤15
`≤15
`
`1st Infusion
`≤20
`≤20
`
`Subsequent Infusions
`≤25
`≤25
`
`Administration (2.3)
`• PI: Administer at regular intervals from daily up to every 2 weeks.
`• CIDP: Administer weekly.
`• Infusion sites – Up to 8 infusion sites are allowed simultaneously, with at least
`2 inches between sites.
`Administration in PI
`Infusion
`Parameters*
`Volume (mL/site)
`Rate (mL/hr/site)
`*As tolerated
`Administration in CIDP
`Infusion
`Parameters*
`Volume (mL/site)
`Rate (mL/hr/site)
`* As tolerated
`----------------------------DOSAGE FORMS AND STRENGTHS------------------------------
`0.2 g per mL (20%) protein solution for subcutaneous infusion. (3)
`-------------------------------------CONTRAINDICATIONS--------------------------------------
`• Anaphylactic or severe systemic reaction to human immune globulin or inactive
`ingredients of HIZENTRA, such as polysorbate 80. (4)
`• Hyperprolinemia Type I or II (HIZENTRA contains stabilizer L-proline). (4)
`• IgA-deficient patients with antibodies against IgA and a history of hypersensitivity. (4)
`---------------------------------WARNINGS AND PRECAUTIONS----------------------------
`• IgA-deficient patients with anti-IgA antibodies are at greater risk of severe hypersensitivity
`and anaphylactic reactions. (5.1)
`• Thrombosis may occur following treatment with immune globulin products, including
`HIZENTRA. (5.2)
`• Aseptic meningitis syndrome has been reported with IGIV or IGSC, including HIZENTRA
`treatment. (5.3)
`• Monitor renal function, including blood urea nitrogen, serum creatinine, and urine output
`in patients at risk of acute renal failure. (5.4)
`• Monitor for clinical signs and symptoms of hemolysis. (5.5)
`• Monitor for pulmonary adverse reactions (transfusion-related acute lung injury [TRALI]). (5.6)
`• HIZENTRA is made from human blood and may contain infectious agents, e.g., viruses,
`the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-
`Jakob disease (CJD) agent. (5.7)
`-----------------------------------ADVERSE REACTIONS----------------------------------------
`The most common adverse reactions observed in ≥5% of study subjects were local
`infusion site reactions, headache, diarrhea, fatigue, back pain, nausea, pain in extremity,
`cough, upper respiratory tract infection, rash, pruritus, vomiting, abdominal pain (upper),
`migraine, arthralgia, pain, fall and nasopharyngitis. (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 INTERACTIONS---------------------------------------
`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.
`Revised: March 2018
`
`7 DRUG INTERACTIONS
`
`7.1
`Live Virus Vaccines
`
`7.2 Serological Testing
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`8.2
`Lactation
`
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`
`13.2 Animal Toxicology and/or Pharmacology
`14 CLINICAL STUDIES
`
`14.1 Primary Immunodeficiency (PI)
`
`14.2 Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
`15 REFERENCES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
` *
`
` Sections or subsections omitted from the full prescribing information are not listed.
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These 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
`
`WARNING: THROMBOSIS
`See full prescribing information for complete boxed warning.
`• Thrombosis may occur with immune globulin products, including
`HIZENTRA. Risk factors may
`include: advanced age, prolonged
`immobilization, hypercoagulable conditions, history of venous or
`arterial thrombosis, use of estrogens, indwelling vascular catheters,
`hyperviscosity, and cardiovascular risk factors.
`• 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.
`---------------------------------------RECENT MAJOR CHANGES------------------------------
`Indications (1.2)
`
`
`
`
` 3/2018
`Dosage and Administration (2.2, 2.3)
`
`
` 3/2018
`------------------------------------INDICATIONS AND USAGE---------------------------------
`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.
`(1.1)
`• Maintenance therapy in adults with chronic inflammatory demyelinating polyneuropathy
`(CIDP). (1.2)
`------------------------------DOSAGE AND ADMINISTRATION-------------------------------
`For subcutaneous infusion only.
`Dose (2.2)
`PI
`Before switching to HIZENTRA, obtain the patient’s serum IgG trough level to guide sub-
`sequent dose adjustments.
`• Weekly: Start HIZENTRA 1 week after last Immune Globulin Intravenous (Human)
`(IGIV) infusion.
` Initial weekly dose = Previous IGIV dose (in grams) x 1.37
` No. of weeks between IGIV doses
`• Biweekly (every 2 weeks): Start HIZENTRA 1 or 2 weeks after the last IGIV infusion or
`1 week after the last weekly IGSC infusion. Administer twice the calculated weekly dose.
`• Frequent dosing (2 to 7 times per week): Start HIZENTRA 1 week after the last IGIV
`or IGSC infusion. Divide the calculated weekly dose by the desired number of times
`per week.
`• Adjust the dose based on clinical response and serum IgG trough levels.
`CIDP
`• Initiate therapy with HIZENTRA 1 week after the last IGIV infusion.
`• Recommended subcutaneous dose is 0.2 g/kg (1 mL/kg) body weight (bw) per week.
`- In the clinical study after transitioning from IGIV to HIZENTRA, a dose of 0.4 g/kg
` (2 mL/kg) bw per week was also safe and effective to prevent CIDP relapse.
`• If CIDP symptoms worsen, consider re-initiating treatment with an IGIV approved for
`the treatment of CIDP, while discontinuing HIZENTRA.
`- If improvement and stabilization are observed during IGIV treatment, consider re-
`initiating HIZENTRA at 0.4 g/kg bw per week, while discontinuing IGIV.
`- If CIDP symptoms worsen on 0.4 g/kg bw per week, consider re-initiating therapy
`with IGIV, while discontinuing HIZENTRA.
`• Monitor patient’s clinical response and adjust duration of therapy based on patient need.
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: THROMBOSIS
`1
`INDICATIONS AND USAGE
`
`1.1 Primary Immunodeficiency (PI)
`
`1.2 Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Preparation and Handling
`
`2.2 Dose
`
`2.3 Administration
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Hypersensitivity
`
`5.2 Thrombosis
`
`5.3 Aseptic Meningitis Syndrome (AMS)
`
`5.4 Renal Dysfunction/Failure
`
`5.5 Hemolysis
`
`5.6 Transfusion Related Acute Lung Injury (TRALI)
`
`5.7 Transmissible Infectious Agents
`
`5.8
`Laboratory Tests
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`6.2 Postmarketing Experience
`
`Page 1 of 11
`
`CSL EXHIBIT 1096
`
`

`

`Hizentra®
`Immune Globulin Subcutaneous
`(Human) (IGSC), 20% Liquid
`FULL PRESCRIBING INFORMATION
`
`WARNING: THROMBOSIS
` • Thrombosis may occur with immune globulin products13, 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 [see Warnings and
`Precautions (5.2), and Patient Counseling Information (17).
` • 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 Warnings and Precautions (5.2)].
`
`INDICATIONS AND USAGE
`1
`HIZENTRA is an Immune Globulin Subcutaneous (Human) (IGSC), 20% Liquid indicated for
`the treatment of the following conditions:
`1.1 Primary Immunodeficiency (PI)
`HIZENTRA is 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.
`1.2 Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
`HIZENTRA is indicated for the treatment of adult patients with chronic inflammatory
`demyelinating polyneuropathy (CIDP) as maintenance therapy to prevent relapse of
`neuromuscular disability and impairment.
`Limitations of Use:
`HIZENTRA maintenance therapy in CIDP has been systematically studied for 6 months and
`for a further 12 months in a follow-up study. Maintenance therapy beyond these periods
`should be individualized based upon the patient’s response and need for continued therapy
`[see Dosage and Administration (2)].
`2 DOSAGE AND ADMINISTRATION
`For subcutaneous infusion only.
`2.1 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 vial.
` • Use aseptic technique when preparing and administering this product.
` • 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.
`2.2 Dose
`Primary Immunodeficiency (PI)
` • HIZENTRA can be administered at regular intervals from daily up to every 2 weeks
`(biweekly).
` • Individualize the dose based on the patient’s clinical response to HIZENTRA therapy
`and serum immunoglobulin G (IgG) trough levels.
` • Before receiving treatment with HIZENTRA:
`o Ensure that patients have received Immune Globulin Intravenous (Human) (IGIV)
`treatment at regular intervals for at least 3 months.
`o Obtain the patient’s serum IgG trough level to guide subsequent dose adjustments
`(see below, under Dose Adjustment).
`Dosage for patients switching to HIZENTRA from IGIV
` • Establish the initial weekly dose of HIZENTRA by converting the monthly IGIV dose
`into a weekly equivalent and increasing it using the 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.
`
`o 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 1.37
`[see Clinical Pharmacology (12.3, Table 7)].
` Initial HIZENTRA dose = Previous IGIV dose (in grams) x 1.37
` Number of weeks between IGIV doses
`o To convert the HIZENTRA dose (in grams) to milliliters (mL), multiply the calculated
`dose (in grams) by 5.
` • Provided the total weekly dose is maintained, any dosing interval from daily
`up to biweekly can be used and will result in systemic serum IgG exposure that
`is comparable to the previous IGIV or weekly HIZENTRA treatment [see Clinical
`Pharmacology (12.3)].
` • For biweekly dosing, multiply the calculated HIZENTRA weekly dose by 2.
` • For frequent dosing (2 to 7 times per week), divide the calculated weekly dose by the
`desired number of times per week (e.g., for 3 times per week dosing, divide weekly
`dose by 3).
`Dosage for patients switching to HIZENTRA from IGSC
` • The previous weekly IGSC dose should be maintained.
` • For biweekly dosing, multiply the previous weekly dose by 2.
` • For frequent dosing (2 to 7 times per week), divide the previous weekly dose by the
`desired number of times per week (e.g., for 3 times per week dosing, divide weekly
`dose by 3).
`Start HIZENTRA treatment
` • For weekly or frequent dosing, start treatment with HIZENTRA 1 week after the
`patient’s last IGIV infusion or IGSC infusion.
` • For biweekly dosing, start treatment 1 or 2 weeks after the last IGIV infusion or
`1 week after the last weekly IGSC infusion.
`Dose Adjustment
`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 Clinical Pharmacology (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 dosing, the target trough is projected
`to be approximately 5% lower than the last trough level on weekly therapy [see Clinical
`Pharmacology (12.3)].
`Frequent dosing: When switching from weekly dosing to more frequent 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 Clinical Pharmacology (12.3)].
`To adjust the dose based on serum trough levels, calculate the difference (in mg/dL)
`between the patient’s IgG trough level obtained 2 to 3 months following the switch
`from IGIV or the last IGSC dose adjustment 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).
`Table 1. Incremental Adjustment (mL)* of the HIZENTRA Dose† Based on the
`Difference (±mg/dL) from the Target Serum IgG Trough Level
`
`Difference
`From Target
`Serum IgG
`Trough Level
`(mg/dL)
`
`Dosing
`Frequency
`
`50
`
`100
`
`200
`
`Weekly‡
`Biweekly
`Weekly‡
`Biweekly
`Weekly‡
`Biweekly
`
`Weight Adjusted Dose Increment (mL)*
`
`Weight Group
`>30 to
`>50 to
`≤50 kg
`≤70 kg
`2.5
`5
`5
`10
`5
`10
`10
`20
`10
`15
`20
`30
`
`>70 to ≤90
`kg
`5
`10
`10
`20
`20
`40
`
`>90
`kg
`10
`20
`15
`30
`30
`60
`
`>10 to
`≤30 kg
`n/a
`5
`2.5
`5
`5
`10
`
`n/a, not applicable.
`* Incremental adjustments based on slopes of the pharmacometric model predicted relationship between serum IgG
`trough level and HIZENTRA dose increments of 1 mg/kg per week.
`† Includes biweekly, weekly or frequent dosing.
`‡ To determine the dose increment for frequent dosing, add the weekly increment to the weekly-equivalent dose and then
`divide by the number of days of dosing.
`
`Page 2 of 11
`
`

`

`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.
`Measles Exposure
`Administer a minimum total weekly HIZENTRA dose of 0.2 g/kg body weight for 2
`consecutive weeks if a patient is at risk of measles exposure (i.e., due to an outbreak in the
`U.S. or travel to endemic areas outside of the U.S.). For biweekly dosing, one infusion of a
`minimum at 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.
`Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
` • Initiate therapy with HIZENTRA 1 week after the last IGIV infusion.
` • The recommended subcutaneous dose is 0.2 g/kg (1 mL/kg) body weight per week,
`administered in 1 or 2 sessions over 1 or 2 consecutive days.
`-
`In the clinical study after transitioning from IGIV to HIZENTRA treatment, a dose
`of 0.4 g/kg (2 mL/kg) body weight per week was also safe and effective to prevent
`CIDP relapse.
` • If CIDP symptoms worsen, consider re-initiating treatment with an IGIV approved for
`the treatment of CIDP, while discontinuing HIZENTRA.
`If improvement and stabilization are observed during IGIV treatment, consider re-
`-
`initiating HIZENTRA at the dose of 0.4 g/kg body weight per week, administered
`in 2 sessions per week over 1 or 2 consecutive days, while discontinuing IGIV.
`If CIDP symptoms worsen on the 0.4 g/kg body weight per week dose, consider
`re-initiating therapy with an IGIV product approved for treatment of CIDP, while
`discontinuing HIZENTRA.
` • Monitor the patient’s clinical response and adjust the duration of therapy based on
`patient need.
`2.3 Administration
`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.
` • Infusion sites – A HIZENTRA dose may be infused into multiple infusion sites.
`Use up to 8 infusion sites in parallel. More than one infusion device can be used
`simultaneously. Infusion sites should be at least 2 inches apart. Change the actual
`site of infusion with each administration.
` • Volume (as tolerated) – For the first infusion of HIZENTRA, do not exceed a volume of
`15 mL per infusion site in patients with PI or up to 20 mL per infusion site in patients
`with CIDP. For subsequent infusions, the volume may be increased to 25 mL per
`infusion site for patients with PI or to 50 mL per site for patients with CIDP.
` • Rate (as tolerated) – For the first infusion of HIZENTRA, the recommended flow
`rate is up to 15 mL per hour per infusion site in patients with PI or up to 20 mL per
`hour per site in patients with CIDP. For subsequent infusions, the flow rate may be
`increased to 25 mL per hour per site in patients with PI or up to 50 mL per hour per
`site in patients with CIDP.
`Follow the steps below and use aseptic technique to administer HIZENTRA.
`Assemble supplies – Gather the HIZENTRA vial(s),
`disposable supplies (not provided with HIZENTRA),
`and other items (infusion pump, sharps or other
`container, patient’s treatment diary/log book) needed
`for the infusion.
`Clean surface – Thoroughly clean a flat surface
`using an alcohol wipe.
`Wash hands – Thoroughly wash and dry hands. The
`use of gloves when preparing and administering HIZ-
`ENTRA is optional.
`Check vials – Carefully
`inspect each vial of
`HIZENTRA. Do not use the vial if the liquid looks
`cloudy, contains particles, has changed color, the
`protective cap is missing, or the expiration date on the
`label has passed.
`
`-
`
`1.
`
`2.
`
`3.
`
`4.
`
`Transfer HIZENTRA from vial(s) to syringe
` • Remove the protective cap from the vial to expose
`the central portion of the rubber stopper of the
`HIZENTRA vial.
` • Clean the stopper with an alcohol wipe and allow
`it to dry.
`• If using a transfer device, follow the instructions
`provided by the device manufacturer.
`• If using a needle and a syringe to transfer
`HIZENTRA, follow the instructions below.
`• Attach a sterile transfer needle to a
`sterile syringe. Pull back on the plunger
`of the syringe to draw air into the
`syringe that is equal to the amount of
`HIZENTRA to be withdrawn.
`• Insert the transfer needle into the
`center of the vial stopper and, to avoid
`foaming, inject the air into headspace of
`the vial (not into the liquid).
`• Withdraw the desired volume of
`HIZENTRA.
`
`5.
`
`When using multiple vials to achieve the desired dose,
`repeat this step.
`
`Prepare infusion pump and tubing – Follow the
`manufacturer’s instructions for preparing the pump,
`using subcutaneous administration sets and tubing, as
`needed. Be sure to prime the tubing with HIZENTRA to
`ensure that no air is left in the tubing.
`Prepare infusion site(s)
` • The number and location of infusion sites depends
`on the volume of the total dose. Infuse HIZENTRA
`into a maximum of 8 sites simultaneously. Infusion
`sites should be at least 2 inches apart.
`
`6.
`
`7.
`
` • Using an antiseptic skin preparation, clean each
`site beginning at the center and working outward
`in a circular motion. Allow each site to dry before
`proceeding.
`
`Insert needle(s)
` • Grasp the skin between 2 fingers and insert the
`needle into the subcutaneous tissue.
` • If necessary, use sterile gauze and tape or transparent
`dressing to hold the needle in place.
`
`8.
`
`9.
`
`infusion – Follow
`Start
`the manufacturer’s
`instructions to turn on the infusion pump.
`
`10.
`
`Record treatment – Remove the peel-off portion
`of the label from each vial used, and affix it to the
`patient’s treatment diary/log book or scan the vial if
`recording the infusion electronically.
`
`11.
`
`Clean up – After administration is complete, turn
`off the infusion pump. Take off the tape or dressing
`and remove the needle set from the infusion site(s).
`Disconnect the tubing from the pump. Immediately
`discard any unused product and all used disposable
`supplies in accordance with local requirements. Clean
`and store the pump according to the manufacturer’s
`instructions.
`
`For self-administration, provide the patient with instructions and training for subcutaneous
`infusion in the home or other appropriate setting.
`3 DOSAGE FORMS AND STRENGTHS
`HIZENTRA is a 0.2 g/mL (20%) protein solution for subcutaneous infusion.
`
`Page 3 of 11
`
`

`

`4 CONTRAINDICATIONS
`HIZENTRA is contraindicated in patients with:
` • History of anaphylactic or severe systemic reaction to human immune globulin or
`inactive ingredients of HIZENTRA, such as polysorbate 80.
` • Hyperprolinemia Type I or II because it contains L-proline as a stabilizer [see
`Description (11)].
` • IgA-deficiency with antibodies against IgA and a history of hypersensitivity [see
`Description (11)].
`5 WARNINGS AND PRECAUTIONS
`5.1 Hypersensitivity
`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)].
`5.2 Thrombosis
`Thrombosis may occur following treatment with immune globulin products13, 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 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, Dosage and Administration
`(2) and Patient Counseling Information (17)].
`5.3 Aseptic Meningitis Syndrome (AMS)
`AMS has been reported with use of IGIV4 or IGSC, including HIZENTRA. 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.
`5.4 Renal Dysfunction/Failure
`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)].
`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.
`5.5 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.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.
`5.6 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.
`5.7 Transmissible Infectious Agents
`Because HIZENTRA is made from human blood12, 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.
`5.8 Laboratory Tests
`Various passively transferred antibodies in immunoglobulin preparations may lead to
`misinterpretation of the results of serological testing.
`6 ADVERSE REACTIONS
`The most common adverse reactions (ARs) observed in ≥5% of study subjects receiving
`HIZENTRA were local reactions (e.g., swelling, redness, heat, pain, hematoma and itching
`at the infusion site), headache, diarrhea, fatigue, back pain, nausea, pain in extremity,
`cough, upper respiratory tract infection, rash, pruritus, vomiting, abdominal pain (upper),
`migraine, arthralgia, pain, fall and nasopharyngitis.
`6.1 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.
`Treatment of Primary Immunodeficiency (PI)
`PI U.S. Study
`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 infusion-site
`reactions (e.g., swelling, redness, heat, pain, and itching at the site of infusion) comprising
`98% of local reactions.
`Table 2. Incidence of Subjects with Adverse Reactions (ARs)* (Experienced by 2
`or More Subjects) and Rate per Infusion (ITT Population), PI U.S. Study
`ARs* Occurring During or Within 72 Hours of Infusion
`Number (%)
`Number (Rate†)
`of Subjects
`of ARs
`(n=49)
`(n=2264 Infusions)
`49 (100)
`1322 (0.584)
`
`AR (≥2 Subjects)
`Local reactions‡
`Other ARs:
`Headache
`Diarrhea
`Fatigue
`Back pain
`Nausea
`Pain in extremity
`Cough
`Vomiting
`Abdominal pain, upper
`Migraine
`Pain
`Arthralgia
`Contusion
`Rash
`Urticaria
`* Excluding infections.
`† Rate of ARs per infusion.
`‡ Includes infusion-site reactions as well as bruising, scabbing, pain, irritation, cysts, eczema, and nodules at the infusion site.
`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 infusion-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).
`
`12 (24.5)
`5 (10.2)
`4 (8.2)
`4 (8.2)
`4 (8.2)
`4 (8.2)
`4 (8.2)
`3 (6.1)
`3 (6.1)
`3 (6.1)
`3 (6.1)
`2 (4.1)
`2 (4.1)
`2 (4.1)
`2 (4.1)
`
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