Hizentra

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: 2010BOXED WARNING 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 Boxed Warning 09/2013 Dosage and Administration (2.2, 2.3) 09/2013 Warnings and Precautions (5.2) 09/2013 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 ADMINISTRATION For subcutaneous infusion only. Do not inject into a blood vessel. Administer weekly or biweekly (every two weeks). Dosage (2.2)Before switching to Hizentra, obtain the patient's serum IgG trough level to guide subsequent dose adjustments. Weekly: Start Hizentra 1 week after last IGIV infusion Initial weekly dose = Previous IGIV dose (in grams) × 1.53 No. of weeks between IGIV doses Biweekly: Start Hizentra 1 or 2 weeks after the last IGIV infusion or 1 week after the last weekly Hizentra infusion. Administer twice the calculated weekly dose. Adjust the dose based on clinical response and serum IgG trough levels (see Dose Adjustment ). Administration (2.3) Infusion sites – 1 to 4 injection sites simultaneously, with at least 2 inches between sites. Infusion volume – First infusion, up to 15 mL per site. Fifth infusion, up to 20 mL per site, then to 25 mL per site as tolerated. Infusion rate – Up to 15 mL per hr per site. Increase to 25 mL per hr per site as tolerated. DOSAGE FORMS AND STRENGTHS0.2 g per mL (20%) protein solution for subcutaneous injection (3)CONTRAINDICATIONS Anaphylactic or severe systemic reaction to human immune globulin or components of Hizentra, such as polysorbate 80 (4) Hyperprolinemia (type I or II) (Hizentra contains the 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 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). 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 (5.7). Side EffectsThe 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 INTERACTIONSThe 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).USE IN SPECIFIC POPULATIONS Pregnancy: No human or animal data. Use only if clearly needed (8.1). Pediatric: No specific dose requirements are necessary to achieve the desired serum IgG levels (8.4).

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1 HIZENTRA INDICATIONS AND USAGE
• 2 HIZENTRA DOSAGE AND ADMINISTRATION
  • 2.1 Preparation and Handling
  • 2.2 Dosage
  • 2.3 Administration
• 3 DOSAGE FORMS AND STRENGTHS
• 4 HIZENTRA 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 HIZENTRA ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience
  • 6.2 Postmarketing Experience
• 7 DRUG INTERACTIONS
  • 7.1 Live Virus Vaccines
  • 7.2 Serological Testing
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
• 11 HIZENTRA 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 US Study
  • 14.2 European Study
• 15 REFERENCES
• 16 HOW SUPPLIED/STORAGE AND HANDLING
  • 16.1 How Supplied
  • 16.2 Storage and Handling
• 17 PATIENT COUNSELING INFORMATION
• HizentraImmune Globulin Subcutaneous (Human), 20% Liquid
• PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton
• PRINCIPAL DISPLAY PANEL - 20 mL Vial Carton
• PRINCIPAL DISPLAY PANEL - 50 mL Vial Carton

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

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.

2 DOSAGE AND ADMINISTRATION

For subcutaneous infusion only. Do not inject into a blood vessel.

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 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.

2.2 Dosage

• Hizentra can be administered as a weekly or biweekly (every two weeks) infusion.
• 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:
  • Ensure that patients have received Immune Globulin Intravenous (Human) (IGIV) treatment at regular intervals for at least 3 months.
  • Obtain the patient's serum IgG trough level to guide subsequent dose adjustments (see below under Dose Adjustment ).

For weekly dosing, start treatment with Hizentra 1 week after the patient's last IGIV infusion.

For biweekly dosing, start treatment 1 or 2 weeks after the last IGIV infusion or 1 week after that last weekly Hizentra infusion.

Weekly Dosing

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)].

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.

Biweekly (Every Two Weeks) Dosing

Biweekly dosing with Hizentra will result in systemic serum IgG exposure that is comparable to the previous IGIV or weekly Hizentra treatment [see Pharmacokinetics (12.3)].

When switching to biweekly dosing, multiply the calculated Hizentra weekly dose by 2.

Dose Adjustment

Over time, the dose may need to be adjusted to achieve the desired clinical response and serum IgG trough level, irrespective of the frequency of administration. To determine if a dose adjustment should be considered, measure the patient's serum IgG trough level 2 to 3 months after switching to Hizentra.

Weekly dosing: When switching from IGIV to weekly Hizentra dosing, the target serum IgG trough level is projected to be approximately 25% higher than the last trough level during prior IGIV therapy [see Pharmacokinetics (12.3)].

Biweekly dosing: When switching from IGIV to biweekly Hizentra dosing, the target serum trough level is projected to be approximately 15% higher than the last IGIV trough level. When switching from weekly to biweekly Hizentra dosing, the target trough is projected to be approximately 5% lower than the last weekly trough level [see Pharmacokinetics (12.3)].

To adjust the dose based on trough levels, calculate the difference (in mg/dL) between the patient's serum IgG trough level and the target IgG trough level for weekly or biweekly dosing. Then find this difference in Table 1 (Column 1) and, based on the Hizentra dosing frequency (weekly or biweekly) and the patient's body weight, locate the corresponding adjustment amount (in mL) by which to increase (or decrease) the dose.

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)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. of the Weekly or Biweekly 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	Weight Adjusted Dose Increment (mL)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.
		Weight Group
		>10 to 30 kg	>30 to 50 kg	>50 to 70 kg	>70 to 90 kg	>90 kg
n/a, not applicable.
50	Weekly	n/a	2.5	5	5	10
	Biweekly	5	5	10	10	20
100	Weekly	2.5	5	10	10	15
	Biweekly	5	10	20	20	30
200	Weekly	5	10	15	20	30
	Biweekly	10	20	30	40	60

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.

Monitor the patient's clinical response, and repeat the dose adjustment as needed.

Dosage requirements for patients switching to Hizentra (weekly or biweekly) 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 weekly Hizentra dose of 200 mg/kg body weight for two consecutive weeks if a patient is at risk of measles exposure (i.e., due to an outbreak in the US or travel to endemic areas outside of the US. For biweekly dosing, one infusion of a minimum of 400 mg/kg is recommended. If a patient has been exposed to measles, ensure this minimum dose is administered as soon as possible after exposure.

2.3 Administration

Hizentra is for subcutaneous infusion only. Do not inject into a blood vessel.

Hizentra is intended for weekly or biweekly (every two weeks) 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. For weekly dosing, use up to 4 sites simultaneously or up to 12 sites consecutively per infusion. For biweekly dosing, increase the number of injection sites as needed. 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 then to 25 mL per site as tolerated.
• Rate – For the first infusion of Hizentra, the recommended flow rate is 15 mL per hour per site. For subsequent infusions, the flow rate may be increased to 25 mL per hour per site as tolerated.

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 Hizentra is optional.Check vials – Carefully inspect each vial of Hizentra. Do not use the vial if the liquid looks cloudy, contains particles, or has changed color, if the protective cap is missing, or if the expiration date on the label has passed.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.

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 injection site(s)

• The number and location of injection sites depends on the volume of the total dose. Infuse Hizentra into a maximum of 4 sites simultaneously; or up to 12 consecutively per infusion. Injection sites should be at least 2 inches apart.
• 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.
• Before starting the infusion, attach a sterile syringe to the end of the primed administration tubing and gently pull back on the plunger to make sure no blood is flowing back into the tubing. If blood is present, remove and discard the needle and tubing. Repeat the process beginning with step 6 (priming) using a new needle, new infusion tubing, and a different injection site.

Start infusion – Follow the manufacturer's instructions to turn on the infusion pump.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.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.

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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 injection.

4 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 (type I or II) because it contains the stabilizer L-proline [see Description (11)].

Hizentra is contraindicated in IgA-deficient patients with antibodies against IgA and a history of hypersensitivity [see Description (11)].

5 WARNINGS AND PRECAUTIONS

5.1 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)].

5.2 Thrombosis

Thrombosis may occur following treatment with immune globulin products^1-3, 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 Counseling Information (17)].

5.3 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.

5.4 Renal Dysfunction/Failure

Renal dysfunction/failure, osmotic nephropathy, 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 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.⁶ 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.

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 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.

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 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. 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.

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, 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.

6.1 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.

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.

Table 2: Incidence of Subjects With Adverse Reactions (ARs)Excluding infections. (Experienced by 2 or More Subjects) and Rate per Infusion (ITT Population), US Study

	ARsExcluding infections. Occurring During or Within 72 Hours of Infusion
AR (≥2 Subjects)	Number (%) of Subjects (n=49)	Number (RateRate of ARs per infusion.) of ARs (n=2264 Infusions)
Local reactionsIncludes injection-site reactions as well as bruising, scabbing, pain, irritation, cysts, eczema, and nodules at the injection site.	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).

Table 3: Investigator Assessments15 to 45 minutes after the end of infusions administered at regularly scheduled visits (every 4 weeks). of Injection-Site Reactions by Infusion, US Study

Injection-Site Reaction	NumberFor multiple injection sites, every site was judged, but only the site with the strongest reaction was recorded. (RateRate of injection-site reactions per infusion.) of Reactions (n=683 InfusionsNumber of infusions administered during regularly scheduled visits.)
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 weekly infusions of Hizentra.

Table 4 summarizes the most frequent ARs (experienced by at least 2 subjects) occurring during or within 72 hours after the end of an infusion. Local reactions were assessed by the subjects between 24 and 72 hours post-infusion. The investigators then evaluated the ARs arising from the subject assessments.

Table 4: Incidence of Subjects With Adverse Reactions (ARs) Excluding infections. (Experienced by 2 or More Subjects) and Rate per Infusion, European Study

	ARs Excluding infections. Occurring During or Within 72 Hours of Infusion
AR (≥2 Subjects)	Number (%) of Subjects (n=51)	Number (RateRate of ARs per infusion.) of ARs (n=1831 Infusions)
Local reactionsIncludes infusion-related reaction; infusion-site mass; infusion/injection-site erythema, hematoma, induration, inflammation, edema, pain, pruritus, rash, reaction, swelling; injection-site extravasation, nodule; puncture-site reaction.	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.

Biweekly (Every Two Weeks) Dosing

No data regarding ARs are available for the biweekly dosing regimen for Hizentra because no clinical trials using this dosage regimen were conducted. However, it is unlikely that the safety profile of Hizentra biweekly dosing is qualitatively different from that of weekly dosing.

6.2 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.

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)].

• Infusion reactions: Allergic-anaphylactic reactions such as swollen face or tongue and pharyngeal edema, pyrexia, chills, dizziness, hypertension/changes in blood pressure, malaise.
• Cardiovascular: Chest discomfort (including chest pain)
• Respiratory: Dyspnea
• Neurological: Tremor, burning sensation

The following adverse reactions have been reported during postmarketing use of immune globulin products⁵:

• Infusion reactions: Tachycardia, flushing, wheezing, rigors, myalgia
• Renal: Osmotic nephropathy
• Respiratory: Apnea, Acute Respiratory Distress Syndrome (ARDS), cyanosis, hypoxemia, pulmonary edema, bronchospasm
• Cardiovascular: Cardiac arrest, vascular collapse, hypotension
• Neurological: Coma, loss of consciousness, seizures, 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

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.

7 DRUG INTERACTIONS

7.1 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)].

7.2 Serological Testing

Various passively transferred antibodies in immunoglobulin preparations may lead to misinterpretation of the results of serological testing.

8 USE IN SPECIFIC POPULATIONS

8.1 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.

8.3 Nursing Mothers

Hizentra has not been evaluated in nursing mothers.

8.4 Pediatric Use

Clinical Studies (Weekly Dosing)

The safety and effectiveness of weekly 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 pharmacokinetics, safety and efficacy profiles as compared with adult subjects. No pediatric-specific dose requirements were necessary to achieve the desired serum IgG levels.

Pharmacokinetic Modeling and Simulation (Biweekly Dosing)

The biweekly (every two weeks) dosing regimen, developed from population PK-based modeling and simulation, included 57 pediatric subjects (32 from Hizentra clinical studies) [see Pharmacokinetics (12.3)]. No pediatric-specific dose requirements are necessary for biweekly dosing.

Safety and effectiveness of Hizentra in pediatric patients below the age of 2 have not been established.

8.5 Geriatric Use

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.

11 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 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).

Table 5: Virus Inactivation/Removal in HizentraThe virus clearance of human parvovirus B19 was investigated experimentally at the pH 4 incubation step. The estimated LRF obtained was ≥5.3.

	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.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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.

12.3 Pharmacokinetics

Clinical Studies

The pharmacokinetics (PK) of Hizentra was evaluated in a PK substudy of subjects (14 adults, 1 pediatric subject 6 to <12 years, and 3 adolescent subjects 12 to <16 years) with PI participating in the 15-month efficacy and safety study [see Clinical Studies (14)]. All PK subjects were treated previously with Privigen^®, Immune Globulin Intravenous (Human), 10% Liquid and were switched to weekly subcutaneous treatment with Hizentra. After a 3-month wash-in/wash-out period, doses were adjusted individually with the goal of providing a systemic serum IgG exposure (area under the IgG serum concentration vs time curve; AUC) not inferior to that of the previous weekly-equivalent IGIV dose. Table 6 summarizes PK parameters for subjects in the substudy following treatment with Hizentra and IGIV.

Table 6: Pharmacokinetics Parameters of Hizentra and IGIV, US Study

	Hizentra	IGIVFor IGIV: weekly-equivalent dose. (Privigen®)
AUC, area under the curve; CL, clearance.
Number of subjects	18	18
DoseFor IGIV: weekly-equivalent dose. (mg/kg)
Mean	228	152
Range	141-381	86-254
IgG peak levels (mg/dL)
Mean	1616	2564
Range	1090-2825	2046-3456
IgG trough levels (mg/dL)
Mean	1448	1127
Range	952-2623	702-1810
AUCStandardized to a 7-day period. (day × mg/dL)
Mean	10560	10320
Range	7210-18670	8051-15530
CLApparent clearance (CL/F) for Hizentra (F = bioavailability) (mL/day/kg)
Mean	2.2	1.3Based on n=25 from the US Privigen PI study.
Range	1.2-3.7	0.9-2.1

For the 19 subjects completing the wash-in/wash-out period, the average dose adjustment for Hizentra was 153% (range: 126% to 187%) of the previous weekly-equivalent IGIV dose. After 12 weeks of treatment with Hizentra at this individually adjusted dose, the final steady-state AUC determinations were made in 18 of the 19 subjects. The geometric mean ratio of the steady-state AUCs, standardized to a weekly treatment period, for Hizentra vs IGIV treatment was 1.002 (range: 0.77 to 1.20) with a 90% confidence limit of 0.951 to 1.055 for the 18 subjects.

With Hizentra, peak serum levels are lower (1616 vs 2564 mg/dL) than those achieved with IGIV while trough levels are generally higher (1448 vs 1127 mg/dL). In contrast to IGIV administered every 3 to 4 weeks, weekly subcutaneous administration results in relatively stable steady-state serum IgG levels.^13,14 After the subjects had reached steady-state with weekly administration of Hizentra, peak serum IgG levels were observed after a mean of 2.9 days (range: 0 to 7 days) in 18 subjects.

Table 7 summarizes PK parameters at steady state for pediatric subjects (age groups: 6 to <12 and 12 to <16 years) and adults subjects (>16 years) in the European Hizentra study following weekly treatment [see Clinical Studies (14.2)]. Pediatric PK parameters are similar to those of adult subjects; thus no pediatric specific dose requirements are needed for Hizentra dosing.

Table 7: Pediatric Pharmacokinetics Parameters of Hizentra, European Study

	Age Group
	6 to <12 years (n=9)	12 to <16 years (n=3)	16 to <65 years (n=11)	Total (n=23)
AUC0-7d, area under the curve for the 7-day dosing interval; CL, apparent clearance (CL/F) (F = bioavailability).
Dose (mg/kg)
Mean	120	115	117	118
Range	71-170	72-150	87-156	71-170
IgG trough levels (mg/dL)
Mean	731	764	754	746
Range	531-915	615-957	505-898	505-957
AUC0-7d (day × mg/dL)
Mean	5230	5491	5452	5370
Range	3890-6950	4480-6750	3860-6810	3860-6950
CL (mL/day/kg)
Mean	2.19	2.17	2.30	2.23
Range	1.57-3.05	1.38-3.34	1.82-3.01	1.38-3.34

Pharmacokinetic Modeling and Simulation

Biweekly (Every Two Weeks) Dosing

Pharmacokinetic characterization of biweekly administration of Hizentra was undertaken using population PK-based modeling and simulation. Serum IgG concentration data consisted of 3837 samples from 151 unique pediatric and adult subjects with PI from four clinical studies of IGIV (Privigen^®) and/or Hizentra. Of the 151 subjects, 94 were adult subjects (63 from Hizentra clinical studies) and 57 were pediatric subjects (32 from Hizentra clinical studies). Compared with weekly administration, PK modeling and simulation predicted that administration of Hizentra on a biweekly basis at double the weekly dose results in comparable IgG exposure [equivalent AUCs, with a slightly higher IgG peak (C_max) and slightly lower trough (C_min)]. See Table 8 (bottom row).

Prediction of Trough Levels Following Regimen Changes

Pharmacokinetic modeling and simulation also predicted changes in trough levels after switching from (a) monthly IGIV to weekly or biweekly Hizentra dosing, and (b) weekly to biweekly Hizentra dosing (Table 8). Steady-state trough levels three to four months after switching from IGIV to weekly Hizentra will be approximately 25% higher than trough levels with the previous IGIV treatment. When switching from IGIV to biweekly Hizentra, trough levels will be approximately 15% higher than previous IGIV trough levels. When switching from weekly to biweekly Hizentra, trough levels will be approximately 5% lower than previous weekly trough levels.

Table 8: Predicted RatiosRatios are based on comparison of second regimen vs. first regimen. [Median (5^th, 95^th percentiles)] of AUC, C_max and C_min and Changes in IgG Trough Levels Upon Switching Between IgG Dosing Regimens

IgG Dosing Regimen Switch		AUC	Cmax	Cmin	Predicted Change in TroughApproximate change in trough based on predicted median Cmin ratio.
From:	To:
AUC, area under the curve, calculated as AUC0-28days for the IGIV to Hizentra switches and as AUC0-14days for the weekly to biweekly Hizentra switch; Cmax, maximum IgG concentration; Cmin, minimum IgG concentration during a 28-day period (for the IGIV to Hizentra switches) or a 14-day period (for the weekly to biweekly Hizentra switch).
IGIV	Weekly HizentraWeekly dose based on dose adjustment coefficient of 1.53 when switching from IGIV.	1.04 (0.96-1.12)	0.73 (0.65-0.81)	1.23 (1.13-1.33)	25% increase
IGIV	Biweekly HizentraBiweekly dose = 2× weekly dose.	1.03 (0.96-1.11)	0.76 (0.69-0.85)	1.16 (1.07-1.25)	15% increase
Weekly Hizentra	Biweekly HizentraBiweekly dose = 2× weekly dose.	1.00 (0.98-1.03)	1.06 (1.02-1.09)	0.95 (0.92-0.98)	5% decrease

Pediatric Pharmacokinetics

The population PK-based modeling and simulation results indicate that, similar to observations from the clinical study with weekly Hizentra dosing (Table 7), body weight-adjusted biweekly dosing accounted for age-related (>3 years) differences in clearance of Hizentra, thereby maintaining systemic IgG exposure (AUC values) in the therapeutic range.

13 NONCLINICAL TOXICOLOGY

13.2 Animal Toxicology and/or Pharmacology

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.

14 CLINICAL STUDIES

14.1 US Study

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 9 summarizes the efficacy results for subjects in the efficacy period (MITT population) of the study. No subjects experienced an SBI in this study.

Table 9: Summary of Efficacy Results (MITT Population)

Number of subjects (efficacy period)	38
Total number of subject days	12,697
Infections
Annual rate of SBIsDefined as bacterial pneumonia, bacteremia/septicemia, osteomyelitis/septic arthritis, bacterial meningitis, and visceral abscess.	0 SBIs per subject yearUpper 99% confidence limit: 0.132.
Annual rate of any infections	2.76 infections/subject year95% confidence limits: 2.235; 3.370.
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)Based on 1 subject.
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.

14.2 European Study

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.

15 REFERENCES

• Dalakas MC. High-dose intravenous immunoglobulin and serum viscosity: risk of precipitating thromboembolic events. Neurology 1994;44:223-226.
• 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.
• Wolberg AS, Kon RH, Monroe DM, Hoffman M. Coagulation factor XI is a contaminant in intravenous immunoglobulin preparations. Am J Hematol 2000;65:30-34.
• Gabor EP, Meningitis and skin reaction after intravenous immune globulin therapy. Ann Intern Med 1997:127:1130.
• Pierce LR, Jain N. Risks associated with the use of intravenous immunoglobulin. Trans Med Rev 2003;17:241-251.
• 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.
• Copelan EA, Strohm PL, Kennedy MS, Tutschka PJ. Hemolysis following intravenous immune globulin therapy. Transfusion 1986;26:410-412.
• Thomas MJ, Misbah SA, Chapel HM, Jones M, Elrington G, Newsom-Davis J. Hemolysis after high-dose intravenous Ig. Blood 1993;15:3789.
• Wilson JR, Bhoopalam N, Fisher M. Hemolytic anemia associated with intravenous immunoglobulin. Muscle Nerve 1997;20:1142-1145.
• 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.
• Rizk A, Gorson KC, Kenney L, Weinstein R. Transfusion-related acute lung injury after the infusion of IVIG. Transfusion 2001;41:264-268.
• Stucki M, Boschetti N, Schäfer W, et al. Investigations of prion and virus safety of a new liquid IVIG product. Biologicals 2008;36:239-247.
• Smith GN, Griffiths B, Mollison D, Mollison PL. Uptake of IgG after intramuscular and subcutaneous injection. Lancet 1972;1:1208-1212.
• Waniewski I, Gardulf A, Hammarström L. Bioavailability of γ-globulin after subcutaneous infusions in patients with common variable immunodeficiency. J Clin Immunol 1994;14:90-97.
• Bavaresco CS, Streck EL, Netto CA, et al. Chronic hyperprolinemia provokes a memory deficit in the Morris Water Maze Task. Metabolic Brain Disease 2005;20:73-80.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

• Hizentra is supplied in a single-use, tamper-evident vial containing 0.2 grams of protein per mL of preservative-free liquid.

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 (NDC 44206-452-91)
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)

16.2 Storage and Handling

• Keep Hizentra in its original carton to protect it from light.
• Each vial label contains a peel-off strip with the vial size and product lot number for use in recording doses in a patient treatment record.
• When stored at room temperature (up to 25°C [77°F]), Hizentra is stable for up to 30 months, as indicated by the expiration date printed on the outer carton and vial label.
• Do not shake.
• Do not freeze. Do not use product that has been frozen.
• The components used in the packaging for Hizentra contain no latex.

17 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 [5.1]).
• 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 and Precautions [5.2]).
• Severe headache, neck stiffness, drowsiness, fever, sensitivity to light, painful eye movements, nausea, and vomiting (see Warnings and Precautions [5.3]).
• Decreased urine output, sudden weight gain, fluid retention/edema, and/or shortness of breath (see Warnings and Precautions [5.4]).
• Fatigue, increased heart rate, yellowing of the skin or eyes, and dark-colored urine (see Warnings and Precautions [5.5]).
• Severe breathing problems, lightheadedness, drops in blood pressure, and fever (see Warnings and Precautions [5.6]).

Inform patients that because Hizentra is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent (see Warnings and Precautions [5.7] and Description [11]).

Inform patients that Hizentra may interfere with the response to live virus vaccines (e.g., measles, mumps, rubella, and varicella) and to notify their immunizing physician of recent therapy with Hizentra (see Drug Interactions [7]).

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 (weekly or every two weeks) to maintain appropriate steady IgG levels.
• Instruct patients to keep a diary/log book that includes information about each infusion such as, the time, date, dose, lot number(s) and any reactions.
• 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 vessel.
• Inform patients to consider adjusting the injection-site location, volume per site, and rate of infusion based on how infusions are tolerated.
• 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.

HizentraImmune 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. You will need to have infusions once a week or every two weeks. It usually takes about 1 to 2 hours to complete one infusion; however, the infusion may take longer depending on what your doctor has prescribed for you.

Instructions for using Hizentra are at the end of this patient package insert (see "How do I use Hizentra?"). Do not use Hizentra by yourself until you have been taught how by your doctor or healthcare professional.

What should I avoid while taking Hizentra?

Vaccines may not work well for you while you are taking Hizentra. Tell your doctor or healthcare professional that you are taking Hizentra before you get a vaccine.

Tell your doctor or healthcare professional if you are pregnant or plan to become pregnant, or if you are nursing.

What are possible side effects of Hizentra?

The most common side effects with Hizentra are:

• Redness, swelling, itching, and/or bruising at the injection site
• Headache/migraine
• Nausea and/or vomiting
• Pain (including pain in the chest, back, joints, arms, legs)
• Fatigue
• Diarrhea
• Stomach ache/bloating
• Cough
• Rash (including hives)
• Itching
• Fever and/or chills
• Shortness of breath
• Dizziness

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.

• Reduced urination, sudden weight gain, or swelling in your legs. These could be signs of a kidney problem.
• 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. These could be signs of a blood clot.
• Bad headache with nausea, vomiting, stiff neck, fever, and sensitivity to light. These could be signs of a brain swelling called meningitis.
• Brown or red urine, fast heart rate, yellow skin or eyes. These could be signs of a blood problem.
• Chest pains or trouble breathing.
• Fever over 100ºF. This could be a sign of an infection.

Tell your doctor about any side effects that concern you. You can ask your doctor to give you more information that is available to healthcare professionals.

How do I use Hizentra?

Infuse Hizentra only after you have been trained by your doctor or healthcare professional. Below are step-by-step instructions to help you remember how to use Hizentra. Ask your doctor or healthcare professional about any instructions you do not understand.

Instructions for use

Hizentra comes in single-use vials.

Keep Hizentra in the storage box at room temperature.

Step 1: Assemble 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):

•  Infusion administration tubing
•  Needle or catheter sets (for subcutaneous infusion)
•  Y-site connectors (if needed)
•  Alcohol wipes
•  Antiseptic skin preps
•  Syringes
•  Transfer device or needle(s)
•  Gauze and tape, or transparent dressing
•  Gloves (if recommended by your doctor)

Step 2: Clean surface
Thoroughly clean a table or other flat surface using one of the alcohol wipes.

• Attach a sterile transfer needle to a sterile syringe (Figure 5).
• Pull out the plunger of the syringe to fill the syringe with air. Make sure the amount of air is the same as the amount of Hizentra you will transfer from the vial.
• Put the Hizentra vial on a flat surface. Keeping the vial upright, insert the transfer needle into the center of the rubber stopper.
• Check that the tip of the needle is not in the liquid. Then, push the plunger of the syringe down. This will inject the air from the syringe into the airspace of the vial.
• Leaving the needle in the stopper, carefully turn the vial upside down (Figure 6).
• Slowly pull back on the plunger of the syringe to fill the syringe with Hizentra.
• Take the filled syringe and needle out of the stopper. Take off the needle and throw it away in the sharps container.

Step 3: Wash hands
Thoroughly wash and dry your hands (Figure 1). If you have been told to wear gloves when preparing your infusion, put the gloves on.
Step 4: Check vials Carefully look at the liquid in each vial of Hizentra (Figure 2). Hizentra is a pale yellow to light brown solution. Check for particles or color changes. Do not use the vial if:
The liquid looks cloudy, contains particles, or has changed color. The protective cap is missing. The expiration date on the label has passed.
Step 5: Transfer Hizentra from vial(s) to syringe Take the protective cap off the vial (Figure 3).
Clean the vial stopper with an alcohol wipe (Figure 4). Let the stopper dry.
Attach a needle or transfer device to a syringe tip, using aseptic technique. 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.
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) Select an area on your abdomen, thigh, upper arm, or side of upper leg/hip for the infusion (Figure 8). Use a different site from the last time you infused Hizentra. New sites should be at least 1 inch from a previous site. Never infuse into areas where the skin is tender, bruised, red, or hard. Avoid infusing into scars or stretch marks. If you are using more than one injection site, be sure the injection sites are at least 2 inches apart. During an infusion, do not use more than 4 injection sites at the same time. Clean the skin at each site with an antiseptic skin prep (Figure 9). Let the skin dry. Step 8: Insert needle(s) With two fingers, pinch together the skin around the injection site. Insert the needle under the skin (Figure 10).
Put sterile gauze and tape or a transparent dressing over the injection site (Figure 11). This will keep the needle from coming out.
Make sure you are not injecting Hizentra into a blood vessel. To test for this, attach a sterile syringe to the end of the infusion tubing. Pull the plunger back gently (Figure 12). If you see any blood flowing back into the tubing, take the needle out of the injection site. Throw away the tubing and needle. Start the infusion over at a different site with new infusion tubing and a new needle.
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 When all the Hizentra has been infused, turn off the pump. Take off the dressing and take the needle out of the injection site. Disconnect the tubing from the pump. Throw away any Hizentra that is leftover in the single-use vial, along with the used disposable supplies, in the sharps container (Figure 15). Clean and store the infusion pump, following the manufacturer's instructions.
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 - 10 mL Vial Carton

NDC 44206-452-02

2 g
10 mL

Immune Globulin
Subcutaneous (Human),
20% Liquid
Hizentra ^®

Single-use vial

For Subcutaneous Administration
Only

Rx only

CSL Behring

PRINCIPAL DISPLAY PANEL - 20 mL Vial Carton

NDC 44206-454-04

4 g
20 mL

Immune Globulin
Subcutaneous (Human),
20% Liquid
Hizentra ^®

Single-use vial

For Subcutaneous Administration
Only

Rx only

CSL Behring

PRINCIPAL DISPLAY PANEL - 50 mL Vial Carton

NDC 44206-455-10

10 g
50 mL

Immune Globulin
Subcutaneous (Human),
20% Liquid
Hizentra ^®

Single-use vial

For Subcutaneous Administration
Only

Rx only

CSL Behring

Hizentra HUMAN IMMUNOGLOBULIN G LIQUID Product Information Product Type Plasma derivative Item Code (Source) NDC:44206-451 Route of Administration SUBCUTANEOUS DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength HUMAN IMMUNOGLOBULIN G Human Immunoglobulin G 0.2 g Inactive Ingredients Ingredient Name Strength PROLINE polysorbate 80 HUMAN IMMUNOGLOBULIN A Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:44206-451-90 5 in 1 VIAL, SINGLE-DOSE 2 NDC:44206-451-01 1 in 1 CARTON Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA125350 2011-10-03

Hizentra HUMAN IMMUNOGLOBULIN G LIQUID Product Information Product Type Plasma derivative Item Code (Source) NDC:44206-452 Route of Administration SUBCUTANEOUS DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength HUMAN IMMUNOGLOBULIN G Human Immunoglobulin G 0.2 g Inactive Ingredients Ingredient Name Strength PROLINE polysorbate 80 HUMAN IMMUNOGLOBULIN A Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:44206-452-91 10 in 1 VIAL, SINGLE-DOSE 2 NDC:44206-452-02 1 in 1 CARTON Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA125350 2011-10-03

Hizentra HUMAN IMMUNOGLOBULIN G LIQUID Product Information Product Type Plasma derivative Item Code (Source) NDC:44206-454 Route of Administration SUBCUTANEOUS DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength HUMAN IMMUNOGLOBULIN G Human Immunoglobulin G 0.2 g Inactive Ingredients Ingredient Name Strength PROLINE polysorbate 80 HUMAN IMMUNOGLOBULIN A Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:44206-454-92 20 in 1 VIAL, SINGLE-DOSE 2 NDC:44206-454-04 1 in 1 CARTON Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA125350 2011-10-03

Hizentra HUMAN IMMUNOGLOBULIN G LIQUID Product Information Product Type Plasma derivative Item Code (Source) NDC:44206-455 Route of Administration SUBCUTANEOUS DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength HUMAN IMMUNOGLOBULIN G Human Immunoglobulin G 0.2 g Inactive Ingredients Ingredient Name Strength PROLINE polysorbate 80 HUMAN IMMUNOGLOBULIN A Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:44206-455-93 50 in 1 VIAL, SINGLE-DOSE 2 NDC:44206-455-10 1 in 1 CARTON Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA125350 2011-10-03