HIZENTRA is an Immune Globulin Subcutaneous (Human) (IGSC), 20% Liquid indicated for the treatment of the following conditions:

For subcutaneous infusion only.

HIZENTRA is a 0.2 g/mL (20%) protein solution for subcutaneous infusion available in a single-dose, prefilled syringe (5 mL, 10 mL, 20 mL, and 50 mL) or tamper-evident vial (5 mL, 10 mL, 20 mL and 50 mL).

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)].

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.

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). The IgG subclass distribution is similar to that of normal human plasma.

HIZENTRA has a purity of ≥98% IgG and a pH of 4.6 to 5.2. This product 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, 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 6 shows the virus clearance during the manufacturing process for HIZENTRA, expressed as the mean log10 reduction factor (LRF).

1. Dalakas MC. High-dose intravenous immunoglobulin and serum viscosity: risk of precipitating thromboembolic events. Neurology 1994;44:223-226.
2. Woodruff RK, Grigg AP, Firkin FC, Smith IL. Fatal thrombotic events during treatment of autoimmune thrombocytopenia with intravenous immunoglobulin in elderly patients. Lancet 1986;2:217-218.
3. Wolberg AS, Kon RH, Monroe DM, Hoffman M. Coagulation factor XI is a contaminant in intravenous immunoglobulin preparations. Am J Hematol 2000;65:30-34.
4. Gabor EP, Meningitis and skin reaction after intravenous immune globulin therapy. Ann Intern Med 1997:127:1130.
5. Pierce LR, Jain N. Risks associated with the use of intravenous immunoglobulin. Trans Med Rev 2003;17:241-251.
6. Cayco AV, Perazella MA, Hayslett JP. Renal insufficiency after intravenous immune globulin therapy: a report of two cases and an analysis of the literature. J Am Soc Nephrol 1997;8:1788-1793.
7. Copelan EA, Strohm PL, Kennedy MS, Tutschka PJ. Hemolysis following intravenous immune globulin therapy. Transfusion 1986;26:410-412.
8. Thomas MJ, Misbah SA, Chapel HM, Jones M, Elrington G, Newsom-Davis J. Hemolysis after high-dose intravenous Ig. Blood 1993;15:3789.
9. Wilson JR, Bhoopalam N, Fisher M. Hemolytic anemia associated with intravenous immunoglobulin. Muscle Nerve 1997;20:1142-1145.
10. Kessary-Shoham H, Levy Y, Shoenfeld Y, Lorber M, Gershon H. In vivo administration of intravenous immunoglobulin (IVIg) can lead to enhanced erythrocyte sequestration. J Autoimmun 1999;13:129-135.
11. Rizk A, Gorson KC, Kenney L, Weinstein R. Transfusion-related acute lung injury after the infusion of IVIG. Transfusion 2001;41:264-268.
12. 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.
13. Smith GN, Griffiths B, Mollison D, Mollison PL. Uptake of IgG after intramuscular and subcutaneous injection. Lancet 1972;1:1208-1212.
14. 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.
15. 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.

Advise the patient to read the FDA-approved patient labeling (Information for Patients and Instructions for Use).

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)].

Information for Patients

HIZENTRA®
(hi-ZEN-tra)
Immune Globulin Subcutaneous (Human), 20% Liquid

Information for Patients

This patient package insert summarizes important information about HIZENTRA. Please read it carefully before using this medicine. This information does not take the place of talking with your healthcare professional, and it does not include all of the important information about HIZENTRA. If you have any questions after reading this, ask your healthcare professional.

What is the most important information I should know about HIZENTRA?

HIZENTRA is supposed to be infused under your skin only. DO NOT inject HIZENTRA into a blood vessel (vein or artery).

What is HIZENTRA?

HIZENTRA is a prescription medicine used to treat primary immune deficiency (PI) and chronic inflammatory demyelinating polyneuropathy (CIDP). HIZENTRA is made from human blood. HIZENTRA contains antibodies called immunoglobulin G (IgG). People with PI get a lot of infections, and IgG fights germs (bacteria and viruses). People with CIDP have a form of autoimmune disease where it is believed the body's defenses attack the nerves and cause muscle weakness and numbness mainly in the legs and arms. IgG is believed to help protect the nerve from being attacked.

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. You will place up to 8 needles into different areas of your body each time you use HIZENTRA. The needles are attached to a pump with an infusion tube. For PI, you can have infusions as often as every day up to every two (2) weeks. For CIDP, infusions are given once weekly (in 1 or 2 sessions conducted on 1 day or 2 consecutive days). For weekly infusions, it can take about 1 to 2 hours to complete an infusion; however, this time may be shorter or longer depending on the dose and frequency 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 infusion site
• Headache/migraine
• Nausea and/or vomiting
• Pain (including pain in the chest, back, joints, arms, legs)
• Fatigue
• Diarrhea
• Stomach ache/bloating
• Cough, cold or flu symptoms
• Rash (including hives)
• Itching
• Fever and/or chills
• Shortness of breath
• Dizziness
• Fall
• Runny or stuffy nose

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® (hi-ZEN-tra)
(Immune Globulin Subcutaneous (Human), 20% Liquid)
for subcutaneous use only

HIZENTRA is provided in a carton containing:

• Single-dose prefilled syringes (5 mL, 10 mL, 20 mL, and 50 mL) or
• Single-dose vials (5 mL, 10 mL, 20 mL, and 50 mL).

Store HIZENTRA in its original carton at room temperature until ready to use. Do not use the prefilled syringe or vial if the packaging is damaged.

Step 1: Assemble supplies

Gather the HIZENTRA prefilled syringe(s) or vial(s), all supplies, and infusion log book:

 

Infusion administration tubing

 

Subcutaneous needle or catheter sets

 

Syringes

 

Transfer device or needle(s)

 

Syringe-to-syringe transfer device (tip-to-tip connector)

 

Gauze and tape, or transparent dressing

 

Infusion pump and any adapters (if required)

 

Sharps container

 

Alcohol wipes

 

Antiseptic skin preps

Step 2: Clean surface

Clean a table or other flat surface.

Step 3: Wash hands

Thoroughly wash and dry your hands (Figure 1).

Figure 1

Step 4: Check prefilled syringe(s) or vial(s)

• If using prefilled syringes, carefully peel back the transparent covering from the tray and inspect the protective cap. Peel back the outer layer of the wrap-around label to allow for viewing of HIZENTRA through the fully transparent inner layer, but don't remove the label completely (Figure 2).
  
  

  Figure 2

• If using vials, inspect the protective cap of the vials (Figure 3).
  
  

  Figure 3

Carefully inspect each prefilled syringe(s) or vial(s) of HIZENTRA. HIZENTRA is a clear and pale yellow to light brown solution. Do not use the prefilled syringe or vial if:

Step 5: Prepare HIZENTRA for infusion

• If using HIZENTRA prefilled syringes, go to Step 5.1
• If using HIZENTRA vials, go to Step 5.2

Step 5.1: HIZENTRA prefilled syringe(s)

• The 5 mL, 10 mL, 20 mL, and 50 mL prefilled syringes are supplied and ready to use. The 5 mL and 10 mL prefilled syringes are fully assembled (Figure 4). For the 20 mL and 50 mL prefilled syringes, screw the plunger rod onto the prefilled syringe stopper prior to use Figure 5).
  
  

  Figure 4

  
  
  

  Figure 5

• HIZENTRA prefilled syringes can be placed directly in the infusion pump if the prefilled syringe size matches the pump requirements. If the prefilled syringe can be placed directly in the infusion pump, then go to Step 6.

NOTE:
An additional adapter may be required for the HIZENTRA prefilled syringes to fit properly in the infusion pump. Check with the provider of your supplies for the appropriate adapter and installation instructions.

• If the HIZENTRA prefilled syringe size does not match the infusion pump requirements, transfer the contents of the prefilled syringe to another syringe of a size specific for the infusion pump by following the directions below:
  • Use a syringe-to-syringe transfer device (tip-to-tip connector) (Figure 6) to transfer the contents of the prefilled syringe to the empty syringe specific for the infusion pump.
    
    

    Figure 6

  • Remove the protective cap from the prefilled syringe. Attach the transfer device (tip-to-tip connector) by twisting it onto the prefilled syringe. Attach the empty syringe by screwing it onto the other side of the transfer device (Figure 7).

Figure 7

Go to Step 6.

Step 5.2: Transfer HIZENTRA from vial to syringe

• Take the protective cap off the vial (Figure 8).
  
  

  Figure 8

• Clean the vial stopper with an alcohol wipe (Figure 9). Let the stopper dry.
  
  

  Figure 9

• 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:
  • Attach a sterile transfer needle to a sterile syringe (Figure 10).
    
    

    Figure 10

  • 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. 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 11).
    
    

    Figure 11

  • 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.

When using multiple vials to achieve the prescribed dose, repeat this step.

Step 6: Prepare infusion pump and tubing

• Prior to preparing the pump(s), make sure you have the prescribed dose in the syringe(s) and the infusion tubing is attached.
• Prepare the infusion pump (following the manufacturer's instructions), including attaching any necessary adapters.
• Do not remove the needle caps until you are ready to infuse.
• 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 (e.g., using your fingers, thumb or the palm of your hand) to fill the tubing with HIZENTRA (Figure 12).
• Stop priming before HIZENTRA fluid reaches the capped needle.
• Insert the syringe filled with HIZENTRA into the infusion pump

Figure 12

Step 7: Prepare infusion site(s)

• Select an area on your abdomen, thigh, upper arm, or side of upper leg/hip for the infusion (Figure 13).
  
  

  Figure 13

• Use a different site with every HIZENTRA infusion. New sites should be at least 1 inch from a previous infusion site.
• Never infuse into areas where the skin is tender, bruised, red, or hard. Avoid infusing into scars or stretch marks.
• You can use up to 8 infusion sites at the same time. If you are using more than one infusion site, at the same time, be sure the infusion sites are at least 2 inches apart. More than one infusion device can be used simultaneously.
• Clean the skin at each infusion site with an antiseptic skin prep (Figure 14). Let the skin dry.
  
  

  Figure 14

Step 8: Insert needle(s)

• Use one needle per site. If injecting in more than one site, the following steps should be completed for each needle, one at a time.
• Remove the needle cap.
• Using two fingers, pinch together the skin around the infusion site. With a quick dart-like motion, insert the needle straight into the skin (Figure 15).
  
  

  Figure 15

• Put sterile gauze and tape or a transparent dressing over the infusion site (Figure 16). This will keep the needle from coming out.
  
  

  Figure 16

Step 9: Start infusion

• Follow the manufacturer's instructions to turn on the infusion pump and start the infusion (Figure 17).
  
  

  Figure 17

Step 10: Complete infusion and record treatment (Figure 18)

• When all the HIZENTRA has been infused turn off the infusion pump (if used).
• Remove the needle(s) from the skin.
• Once you have removed the needle(s), remove the empty syringe from the infusion pump. Disconnect the infusion set from the empty syringe.
• Cover the infusion site with a protective dressing.
• Peel off the removable part of the label for each prefilled syringe or vial. Put this label in your log book with the date and time of the infusion and include the exact amount of HIZENTRA that you infused. Scan the prefilled syringe or vial if recording the infusion electronically.
  
  

  Figure 18

Step 11: Clean up

• If applicable, remove adapter from the infusion pump following the manufacturer's instructions.
• Throw away the empty HIZENTRA prefilled syringe(s) or vial(s), along with the used disposable supplies, in the sharps container (Figure 19) in accordance with local requirements.
  
  

  Figure 19

• 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
U.S. License No. 1766

Distributed by:
CSL Behring LLC
Kankakee, IL 60901 USA

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Revised: 04/2023

NDC 44206-451-01

1 g
5 mL

Immune Globulin
Subcutaneous (Human),
20% Liquid

Hizentra®

Single-dose vial

For Subcutaneous Administration
Only

Rx only

CSL Behring

NDC 44206-452-02

2 g
10 mL

Immune Globulin
Subcutaneous (Human),
20% Liquid

Hizentra®

Single-dose vial

For Subcutaneous Administration
Only

Rx only

CSL Behring

NDC 44206-454-04

4 g
20 mL

Immune Globulin
Subcutaneous (Human),
20% Liquid

Hizentra®

Single-dose vial

For Subcutaneous Administration
Only

Rx only

CSL Behring

NDC 44206-455-10

10 g
50 mL

Immune Globulin
Subcutaneous (Human),
20% Liquid

Hizentra®

Single-dose vial

For Subcutaneous Administration
Only

Rx only

CSL Behring

NDC 44206-456-21

1 g
5 mL

Immune Globulin Subcutaneous (Human), 20% Liquid

Hizentra®

Single-dose prefilled syringe

For Subcutaneous Administration Only

Rx only

CSL Behring

NDC 44206-457-22

2 g
10 mL

Immune Globulin Subcutaneous (Human), 20% Liquid

Hizentra®

Single-dose prefilled syringe

For Subcutaneous Administration Only

Rx only

CSL Behring

NDC 44206-458-24

4 g
20 mL

Immune Globulin Subcutaneous (Human),
20% Liquid

Hizentra®

Single-dose prefilled syringe

For Subcutaneous Administration Only

Rx only

CSL Behring

NDC 44206-455-25

10 g
50 mL

Immune Globulin Subcutaneous (Human),
20% Liquid

Hizentra®

Single-dose prefilled syringe

For Subcutaneous Administration Only

Rx only

CSL Behring