Consumer medicine information

Hyqvia

Vorhyaluronidase alfa; Immunoglobulin, normal (human)

BRAND INFORMATION

Brand name

Hyqvia

Active ingredient

Vorhyaluronidase alfa; Immunoglobulin, normal (human)

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Hyqvia.

SUMMARY CMI

HYQVIA®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using HYQVIA?

HYQVIA contains the active ingredient normal immunoglobulin (human) with vorhyaluronidase alfa. HYQVIA is used in patients who do not have enough antibodies in their blood. HYQVIA can be used as antibody replacement therapy to raise antibody levels in your blood to normal levels. The vorhyaluronidase alfa component of HYQVIA helps more immunoglobulin gets absorbed into the body.

For more information, see Section 1. Why am I using HYQVIA? in the full CMI.

2. What should I know before I use HYQVIA?

Do not use HYQVIA if you have severe immunoglobulin A (IgA) deficiency and history of hypersensitivity to human immunoglobulin treatment. Do not use if you have ever had an allergic reaction to HYQVIA or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use HYQVIA? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with HYQVIA and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use HYQVIA?

  • HYQVIA should be used exactly as your doctor has told you.
  • HYQVIA must be infused under the skin.

More instructions can be found in Section 4. How do I use HYQVIA? in the full CMI.

5. What should I know while using HYQVIA?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using HYQVIA.
  • Talk to your healthcare provider before travelling. It is important to obtain a written statement from your physician, explaining the reasons why you need to have this medicine and injecting devices with you, otherwise you may not be allowed to bring it into the country of travelling.
Things you should not do
  • Do not stop using this medicine or lower the dosage, without checking with your doctor, unless you have an allergic reaction.
Driving or using machines
  • HYQVIA has no, or negligible, influence on the ability to drive or use machines.
  • If you experience adverse reactions, such as dizziness and nausea, you should wait for these to resolve before driving or operating machines.
Looking after your medicine
  • Store at 2°C - 8°C in a refrigerator for the duration of its shelf life. Do not freeze.
  • Store in the original package to protect from light.

For more information, see Section 5. What should I know while using HYQVIA? in the full CMI.

6. Are there any side effects?

Common side effects include decreased appetite, migraine, headache, dizziness, burning sensation, hypertension, blood pressure decreased, nasal congestion, nausea, abdominal pain, vomiting, diarrhoea, chest pain, oral pain, infusion site swelling, redness, or itching, fever or chills, back and muscle pain or joint pain, fatigue, swelling of hands, ankles or feet unusual weakness, feeling abnormal.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

HYQVIA®

Active ingredient(s): normal immunoglobulin 10% (Human) with vorhyaluronidase alfa

Consumer Medicine Information (CMI)

This leaflet provides important information about using HYQVIA. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using HYQVIA.

Where to find information in this leaflet:

1. Why am I using HYQVIA?
2. What should I know before I use HYQVIA?
3. What if I am taking other medicines?
4. How do I use HYQVIA?
5. What should I know while using HYQVIA?
6. Are there any side effects?
7. Product details

1. Why am I using HYQVIA?

HYQVIA contains the active normal immunoglobulin 10% (Human) with vorhyaluronidase alfa. HYQVIA belongs to a class of medicines called "human immunoglobulins". Immunoglobulins are also known as antibodies and are found in healthy people's blood. Antibodies are part of the immune system (the body's natural defences) and help your body to fight infections. If you do not have enough antibodies you may not be able to fight off infections.

HYQVIA is used in patients who do not have enough antibodies in their blood. HYQVIA can be used as antibody replacement therapy to raise antibody levels in your blood to normal levels.

HYQVIA should only be used in adults.

2. What should I know before I use HYQVIA?

Warnings

About blood products

When medicines are made from human blood or plasma, processes are used to prevent infections being passed from the blood/plasma donor to the person receiving the medicine.

These processes include careful selection of the people who donate blood and plasma to make sure that those who might be carrying infections are excluded. In addition, each donation and pools of donations are tested for indicators of virus or virus infection(s).

Manufacturers of these medicines also include steps in the processing of blood or plasma that inactivate or remove viruses. A three-step viral inactivation/reduction has been applied during the manufacturing of the Normal Immunoglobulin Infusion. Despite the stringent measures, which have been put in place during the manufacturing processes, the risk of contamination by viral and other unknown agents cannot be totally excluded.

The measures taken during manufacturing are considered effective for enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus and hepatitis C virus, and for the non-enveloped viruses hepatitis A (HAV) and B19 virus (B19V).

Immunoglobulins have not been associated with hepatitis A or parvovirus B19 infections possibly because the antibodies against these infections, which are contained in the product, are protective.

HYQVIA must not be used if

You are allergic to immunoglobulins, hyaluronidase, vorhyaluronidase alfa or are allergic to any ingredients in HYQVIA (see "Product Description").

Do not use HYQVIA if:

  • you have had a history of anaphylactic or severe systemic reactions to the administration of IgG
  • you have antibodies against immunoglobulin A (IgA) in your blood. This may occur if you have IgA deficiency
  • you have systemic hypersensitivity to hyaluronidase or vorhyaluronidase alfa, or any of the other excipients
  • have allergies to any other medicines, or if you have ever had an allergic reaction to an injection
  • Always check the ingredients to make sure you can use this medicine.

Check with your doctor if you:

  • have any other medical problems
  • have had a vaccination recently.

Your doctor may request regular monitoring of your kidney function after you started receiving HYQVIA.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect HYQVIA.

4. How do I use HYQVIA?

  • Always use HYQVIA exactly as your doctor has told you. Check with your doctor if you are not sure
  • HYQVIA has to be infused under the skin
  • Treatment with HYQVIA will be started by your doctor or nurse, but you may be allowed to use the medicine at home once you have received the first few infusions under medical supervision and you (and/or your guardian) have been adequately trained. You and your doctor will decide if you can use HYQVIA at home. Do not begin treatment with HYQVIA at home until you have received complete instructions
  • Always wash your hands before doing the following procedures. Use germ-free methods during the making up procedure and during injection
  • HYQVIA must not be mixed with other injectable medicines
  • Do not inject HYQVIA near an infected or inflamed area of the body
  • Follow the instructions provided and HYQVIA until your doctor tells you to stop.

How to use HYQVIA

If you do not understand the instructions, ask your doctor or health professional.

Always follow the specific instructions given by your healthcare provider. The steps listed below are general guidelines for using your medicine.

For the ease of identification the vorhyaluronidase alfa (Hyaluronidase) vial is labelled HY and the Normal Immunoglobulin Infusion 10% (human) vial is labelled IG.

  1. Check each vial of HYQVIA before using:
  • Expiration date:
Do not use beyond expiration date.
  • Colour:
    - The vorhyaluronidase alfa should be clear and colourless
    - The Normal Immunoglobulin Infusion should be clear and colourless or pale yellow
    - If either liquid is cloudy or has particles, do not use.
  • Cap:
Protective cap is on the dual vial unit. Do not use the product if it does not have the cap.
  1. Prepare for infusion:
  • Gather supplies: HYQVIA dual vial unit(s), ancillary supplies, sharps container and infusion pump (program pump per physician recommendation following manufacturer's instructions)
  • Prepare a clean work area
  • Wash hands.
If the Normal Immunoglobulin Infusion 10% (Human) and vorhyaluronidase alfa are pooled into separate containers, skip to Step 5.
  1. Prepare the vorhyaluronidase alfa of HYQVIA (Labelled as "HY"):
  • Remove the protective cap
  • Wipe each stopper with a sterile alcohol wipe and allow to dry
  • Attach a syringe to a needle/needle-less transfer device
  • Pull back on plunger of the syringe to fill the syringe with air equal to the amount in the HY vial
  • Insert needle into the centre of the vial stopper
  • Inject air into the vial and withdraw the full contents of the HY vial(s) into a syringe
  • Attach the syringe containing the vorhyaluronidase alfa to the subcutaneous needle set
  • Point the syringe tip up and push the plunger of the syringe to remove the air and fill the needle set up to the needle hub with the HY.
  1. Prepare Normal Immunoglobulin Infusion 10% (Human) of HYQVIA (Labelled as "IG"):
  • Wipe each stopper with a sterile alcohol wipe and allow to dry
  • Transfer the vial(s) labelled IG into either syringe(s), infusion bag or directly from the vial as shown by your healthcare professional:
a. If using syringe(s):
1. Attach a sterile syringe to a vented spike
2. Insert the vented spike into the centre of the IG vials
3. Turn the vial upside down and pull back on the plunger to pull the IG into the syringe(s)
4. Repeat these steps, if using multiple vials to achieve the desired dose.
b. If using an infusion bag:
1. Insert the vented spike into the centre of each IG vial Open the vent
2. Turn the vial upside down and fill the bag with the IG Repeat this step, if using multiple vials to achieve the desired dose
3. Remove the filling tube(s) of the bag and place a sterile cap over the open end of the bag and close the clamp on bag
4. Insert the spike of the administration pump tubing into the bag and fill as directed by your healthcare professional.
c. If directly from the IG vial:
1. Insert the spike of the vented pump tubing into centre of the stopper of the IG vial(s). Fill the administration pump tubing and set aside until the vorhyaluronidase alfa has been administered
Repeat the steps above for each remaining vial of the IG.
  1. Prepare the infusion site(s):
  • Potential sites for infusion include the middle to upper abdomen and thighs
  • Avoid: bony prominences, blood vessels, scars, or areas that are inflamed or infected
  • If two sites are desired, a bifurcated needle set may be used on opposite sides of the body, for doses above 600mL
  • Rotate sites by choosing opposite sides of the body between successive infusions.
Cleanse the infusion site(s) with a sterile alcohol wipe beginning at the centre of each infusion site and moving outward in a circular motion. Allow the infusion site(s) to dry (at least 30 seconds).
  1. Insert and secure the 24 gauge subcutaneous needle:
  • Pinch at least one inch (2 to 2.5 cm) of skin between two fingers. Insert the needle at a 90-degree angle into the subcutaneous tissue and secure the needle with sterile tape
  • Check placement: gently pull back on the plunger of attached syringe and monitor for any blood return in the tubing
    - If blood is seen in the tubing, remove and discard the needle and repeat steps 3, 5 and 6 with a new subcutaneous needle and infusion site
  • Secure the needle in place with a sterile protective dressing.
  1. Administer the vorhyaluronidase alfa of HYQVIA:
Administer the entire vorhyaluronidase alfa dose first. Start at a rate of 1 to 2 mL per minute per site or as tolerated. If more than one site is used, divide the contents equally between sites. At the end of infusion, disconnect the empty syringe and attach pump tubing/syringe containing the Normal Immunoglobulin of HYQVIA to the same subcutaneous needle set.
  1. Administer the Normal Immunoglobulin of HYQVIA:
Within approximately 10 minutes of completing the infusion of the vorhyaluronidase alfa of HYQVIA, start the variable rate program of the infusion pump to initiate the infusion of the full therapeutic dose of Normal Immunoglobulin Infusion of HYQVIA. At the end of infusion, flush infusion tubing up to the needle with normal saline or 5% Glucose in water, if directed by your healthcare professional.
  1. Remove subcutaneous needle(s) from the infusion site(s):
After the infusion is complete, remove the needle set and cover with a protective dressing.
  1. Document the infusion:
Remove the peel-off label from each Normal Immunoglobulin Infusion vial of HYQVIA used and affix to the patient's treatment record or infusion log. In addition, record the time, date, dose, infusion site location and any reactions after each infusion.
For self-administration, provide the patient with instructions and training for infusion in the home or other appropriate setting.

If you forget to use HYQVIA

Do not infuse a double dose of HYQVIA to make up for a missed dose. If you think that you have missed a dose speak to your doctor as soon as possible.

If you use too much HYQVIA

The effects of an overdose of HYQVIA are not known. Please tell your doctor if you accidently use more than instructed.

5. What should I know while using HYQVIA?

Things you must do

  • Stop the infusion immediately and contact your doctor, if you experience allergic reactions such as skin rash, itching, chest tightness, wheezing, dizziness, hives, faintness, chills, flushing, rapid heartbeat, shortness of breath and/or a swollen face
  • Always follow your doctor's instructions carefully
  • Tell all the doctors, dentists and pharmacists who are treating you that you are using HYQVIA
  • If you are about to be started on any new medicine, tell your doctor and pharmacist that you are using HYQVIA
  • If you become pregnant while you are using your medicine, tell your doctor
  • Talk to your healthcare provider before travelling. Plan to bring enough medicine for your treatment during this time. It is important to obtain a written statement from your physician, explaining the reasons why you need to have this medicine and injecting devices with you, otherwise you may not be allowed to bring it into the country of travelling.

Things you must not do

  • Do not give your medicine to anyone else, even if they have the same condition as you
  • Do not use your medicine to treat any other complaints unless your doctor tells you to
  • Do not stop using your medicine or lower the dosage, without checking with your doctor, unless you have an allergic reaction.

Driving or using machines

HYQVIA has no, or negligible, influence on the ability to drive or use machines.

If you experience adverse reactions, such as dizziness and nausea, you should wait for these to resolve before driving or operating machines.

Looking after your medicine

HYQVIA should be stored at 2°C - 8°C in a refrigerator for the duration of its shelf life. Store in the original package in order to protect from light.

Do not freeze.

Keep out of the reach and sight of children.

Do not use HYQVIA after the expiry date which is printed on the label after the word 'EXP'.

The expiry date refers to the last day of that month.

Getting rid of any unwanted medicine

HYQVIA contains no preservatives.

Discard any medicine left in the vials at the end of your infusion.

Dispose of all materials, including any leftover reconstituted medicine, in an appropriate container.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

6. Are there any side effects?

Like all medicines, this medicine can have side effects, although not everybody gets them. Certain side effects, such as headache, chills, or body aches, may be reduced by slowing the infusion rate.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
  • Pain, itching, redness or swelling where the injection was given
  • Nausea or vomiting
  • Back and muscle pain
  • Diarrhoea
  • Headache
  • Fever or chills
  • Feeling faint (fall in blood pressure)
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • Chest pain or tightness
  • Difficulty breathing
  • Lightheadedness
  • Dizziness, nausea, or fainting
  • Fast heart rate
  • Swelling in the mouth or throat, wheezing
  • Abnormal heart rate, blueness of lips or fingers and toes
  • Blurred vision
Call your doctor straight away or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people. You can ask your doctor or pharmacist for information that is written for healthcare professionals.

Reporting side effects

After you have received medical advice for any side affects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

HYQVIA is a dual vial unit consisting of one vial of Normal Immunoglobulin Infusion 10% (Human) and one vial of vorhyaluronidase alfa.

HYQVIA is a dual vial unit containing:

  1. a solution of vorhyaluronidase alfa (Step 1 of HYQVIA/Infuse first) and
  2. a solution of Normal Immunoglobulin Infusion 10% (Human) (Step 2 of HYQVIA/Infuse second).

What HYQVIA contains

Active ingredients
(main ingredients)		Normal Immunoglobulin 10% (Human) Infusion
Vorhyaluronidase alfa
Other ingredients
(inactive ingredients)		Glycine, water for injection
Dibasic sodium phosphate dihydrate, sodium hydroxide, human albumin 25%, calcium chloride, sodium chloride, disodium edetate, water for injection

Do not take this medicine if you are allergic to any of these ingredients.

What HYQVIA looks like

The Normal Immunoglobulin Infusion is a clear or slightly opalescent and colourless or pale yellow solution. Vorhyaluronidase alfa is a clear, colourless solution.

The following pack sizes are available:

  • Vorhyaluronidase alfa - 1.25mL (volume); Normal immunoglobulin 10% (Human) - 2.5g (protein) 25mL (volume)
  • Vorhyaluronidase alfa - 2.5mL (volume); Normal immunoglobulin 10% (Human) - 5g (protein) 50mL (volume)
  • Vorhyaluronidase alfa - 5mL (volume); Normal immunoglobulin 10% (Human) - 10g (protein) 100mL (volume)
  • Vorhyaluronidase alfa - 10mL (volume); Normal immunoglobulin 10% (Human) - 20g (protein) 200mL (volume)
  • Vorhyaluronidase alfa - 15mL (volume); Normal immunoglobulin 10% (Human) - 30g (protein) 300mL (volume)

Not all pack sizes may be marketed.

AUST R 235178

Who distributes HYQVIA

Takeda Pharmaceuticals Australia Pty Ltd
Level 39, 225 George Street
Sydney NSW 2000
Australia
Telephone: 1800 012 612

This leaflet was prepared in December 2022.

HYQVIA® is a registered trademark of Baxalta Incorporated.

TAKEDA® and the TAKEDA Logo® are registered trademarks of Takeda Pharmaceutical Company Limited.

Published by MIMS March 2023

BRAND INFORMATION

Brand name

Hyqvia

Active ingredient

Vorhyaluronidase alfa; Immunoglobulin, normal (human)

Schedule

S4

 

1 Name of Medicine

Normal immunoglobulin infusion 10% (human) with vorhyaluronidase alfa.

2 Qualitative and Quantitative Composition

Hyqvia is a dual vial unit consisting of one vial of normal immunoglobulin 10% (human) and one vial of vorhyaluronidase alfa. Vorhyaluronidase alfa enables the facilitated subcutaneous administration of normal immunoglobulin (human).

Normal immunoglobulin.

Hyqvia vials contain 2.5 g in 25 mL, 5.0 g in 50 mL, 10.0 g in 100 mL, 20.0 g in 200 mL or 30.0 g in 300 mL of the active normal immunoglobulin (human) [immunoglobulin G (IgG) 100 mg/mL].
The active ingredient in Hyqvia is a human plasma derived immunoglobulin, concentration of 100 mg/mL (10% w/v), produced from large pools of human plasma by a modified Cohn-Oncley cold ethanol fractionation, yielding an intermediate immunoglobulin G, referred to as precipitate G. During the cold ethanol plasma fractionation manufacturing process, the level of viral burden in a plasma pool has been largely reduced, as demonstrated by viral spiking experiments. Precipitate G is further purified by means of a weak cation exchange and anion exchange chromatography.
To reduce further a possible viral transmission to a minimal level, a triple step of viral inactivation (TVR inactivation), [solvent detergent (S/D), nanofiltration (35 nanometer), and incubation at a low pH and elevated temperature (30°C to 32°C, pasteurisation for 21 to 23 days)] was incorporated into the downstream purification. Thus, the active ingredient normal immunoglobulin has been subjected to a rigorous elimination for both lipid and nonlipid enveloped viruses.
The manufacturing processes do not affect the composition of the immunoglobulin from the normal human plasma origin. The distribution of the immunoglobulin G (IgG) subclasses formulated in this product comprises IgG ≥ 56.9%, IgG2 ≥ 26.6%, IgG3 ≥ 3.4%, and IgG4 ≥ 1.7%.
It contains immunoglobulin A (IgA) at a trace level, which is not more than 0.14 mg/mL. The preparation is a sterile, nonpyrogenic, isotonic solution with osmolality of 240 to 300 mOsmol/kg and a pH of 4.6 to 5.1. At this low pH the formation of the IgG aggregates is much reduced, leading to reduction in the incidence of infusion related adverse reactions. It contains glycine which acts as a stabilising agent for the proteins. The product does not contain preservative. The composition of normal immunoglobulin is shown in Section 6.1 List of Excipients.

Vorhyaluronidase alfa.

Hyqvia vials contain 200 units in 1.25 mL, 400 units in 2.5 mL, 800 units in 5 mL, 1600 units in 10 mL or 2400 units in 15 mL of the active vorhyaluronidase alfa [160 U/mL].
The vorhyaluronidase alfa of Hyqvia is used as a permeation enhancer. It is produced from genetically engineered Chinese hamster ovary (CHO) cells containing a DNA plasmid encoding for a soluble fragment of human hyaluronidase rHuPH20. The purified hyaluronidase glycoprotein contains 447 amino acids with an approximate molecular weight of 61,000 Daltons. This component is supplied as a sterile, clear, colourless, ready for use solution and has an approximate pH of 7.4 and an osmolality of 290 to 350 mOsm. Each vial contains 160 U/mL of vorhyaluronidase alfa with 8.5 mg/mL sodium chloride, 1.78 mg/mL sodium phosphate dibasic dihydrate, 1.0 mg/mL human albumin, 1.0 mg/mL edetate disodium dihydrate, 0.40 mg/mL calcium chloride dihydrate, and 0.17 mg/mL sodium hydroxide added for pH adjustment. It does not contain preservatives.
Due to comprehensive virus testing at the master cell bank, working cell bank and bulk harvest stage, effective virus reduction during the purification process and the use of pharmaceutical grade human albumin as an excipient with no other materials of human or animal origin involved in the manufacturing process, vorhyaluronidase alfa provides for high margins of safety with respect to viruses. The composition of vorhyaluronidase alfa is shown in Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for infusion for subcutaneous use.

Appearance.

Hyqvia is a dual vial unit consisting of one vial of normal immunoglobulin 10% (human) and one vial of vorhyaluronidase alfa. Normal immunoglobulin is a clear or slightly opalescent and colourless or pale yellow solution. Vorhyaluronidase alfa is a clear, colourless solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Hyqvia is indicated for replacement therapy in adults in:
primary immunodeficiency disease (PID); and
symptomatic hypogammaglobulinaemia secondary to underlying disease or treatment.

4.2 Dose and Method of Administration

Hyqvia must only be administered subcutaneously.
Treatment should be commenced and initially monitored under the supervision of a physician experienced in the treatment of immunodeficiency.
Hyqvia is for single use in one patient only.

Dosage.

Hyqvia must be administered sequentially beginning with the vorhyaluronidase alfa followed by normal immunoglobulin.
The dose level may need to be individualised for each patient dependent on the pharmacokinetic and clinical response. The following dosage regimen is given as a guideline.
The recommended dose of normal immunoglobulin of Hyqvia for patients is 300 to 600 mg/kg bodyweight infused at 3 to 4 week intervals. For each full or partial vial of normal immunoglobulin used, the full contents of vorhyaluronidase alfa should be administered.
The first infusion of Hyqvia should be given one week after the last treatment with the previous immunoglobulin. At the initiation of treatment, it is recommended that the treatment intervals for the first infusions be gradually prolonged from a 1 week dose to a 3 or 4 week dose. For example, adjusting a subcutaneous dose of 10 g every week, to 20 g every 2 weeks, 30 g every 3 weeks, and 40 g every 4 weeks. See Table 1.

Patients previously treated with immunoglobulin administered intravenously.

For patients switching directly from intravenous administration of immunoglobulin (IVIG), or who have a previous intravenous dose of immunoglobulin that can be referenced, the medicinal product should be administered at the same dose and at the same frequency as their previous intravenous immunoglobulin treatment. If patients were previously on a 3 week dosing regimen, increasing the interval to 4 weeks can be accomplished by administering the same weekly equivalents.

Patients naive to immunoglobulin treatment and patients previously treated with immunoglobulin administered subcutaneously.

For patients naive to immunoglobulin treatment, or those currently being administered immunoglobulin subcutaneously, the initial dose of Hyqvia is 300 to 600 mg/kg.
For patients directly switching from an immunoglobulin treatment administered subcutaneously, the first infusion of Hyqvia should be given one week after the last treatment with the previous immunoglobulin.
The dosage regimen should achieve the desired clinical response and a sustained level of IgG. Trough levels should be measured in order to adjust the dose and dosage interval.

Method of administration.

Hyqvia must only be administered subcutaneously. Do not infuse intravenously.
Hyqvia is comprised of two vials. Each vial of normal immunoglobulin 10% (human) is supplied with the appropriate corresponding quantity of vorhyaluronidase alfa as stated in Table 2. The full contents of the vorhyaluronidase alfa vial should be administered regardless of whether the full content of the normal immunoglobulin 10% (human) vial is administered.
For the ease of identification the vorhyaluronidase alfa vial is labelled HY and the normal immunoglobulin 10% (human) vial is labelled IG.
The two components of Hyqvia must be administered sequentially through the same needle beginning with the vorhyaluronidase alfa followed by normal immunoglobulin 10% (human), as described below.
Infusion site leakage can occur during or after subcutaneous administration of immunoglobulin, including Hyqvia. Consider using longer needles and/or more than one infusion site.
The Hyqvia components may be infused using a variable rate, electromechanical pump. The pump must have the ability to titrate the flow rate up or down if required to improve tolerability. To ensure maximum flow rates, use a subcutaneous needle set that is 24 gauge and labelled for high flow rates.
The suggested site(s) for the infusion are the middle to upper abdomen and thighs. If two sites are used, the two infusion sites should be on contralateral sides of the body. Avoid bony prominences.
First, the full dose of vorhyaluronidase alfa solution is infused at a rate of 1 to 2 mL/minute per infusion site or as tolerated. Within 10 minutes of completing the infusion of vorhyaluronidase alfa, the infusion of the required dose of normal immunoglobulin has to be initiated at the same needle site.
The rate of administration of the normal immunoglobulin of Hyqvia should be ramped up, at least for the first several infusions. If the patient tolerates these infusions at the full dose and maximum rate, adjust both the time intervals and number of rate changes of the ramp up used for successive infusions at the discretion of the physician and patient.
If two infusion sites are used, the total dosages of the vorhyaluronidase alfa and normal immunoglobulin each have to be divided before start of the infusion.
The following infusion rates of the normal immunoglobulin are recommended:
Patients with a bodyweight of 40 kg or above: normal immunoglobulin should be infused at an initial rate of 10 mL/hour/infusion site. If well tolerated, the rate of the administration may be increased at intervals of at least 10 minutes to a maximum of 240 mL/hour/site for the initial one or two infusions. For subsequent infusions, the rate can be adjusted to a maximum of 300 mL/hour/site.
Patients with a bodyweight under 40 kg: normal immunoglobulin should be infused at an initial rate of 5 mL/hour/infusion site. If well tolerated, the rate of the administration may be increased at intervals of at least 10 minutes to a maximum of 80 mL/hour/site for the initial one or two infusions. For subsequent infusions, the rate can be adjusted to a maximum of 160 mL/hour/site.

Home treatment.

If self administration at home or other appropriate setting is planned, the healthcare professional should provide the patient or the carer with adequate training in terms of the correct technique of subcutaneous administration and the correct recognition and management in cases of acute adverse reactions.
For detailed instructions, please see Method of administration.

Instructions for administration.

Do not use Hyqvia at home until you get instructions and training from your healthcare professional.
Your healthcare professional will decide which administration system is right for you. You will take vorhyaluronidase alfa first. Then, within 10 minutes, you will take the normal immunoglobulin through an infusion pump.
For the ease of identification the vorhyaluronidase alfa vial is labelled HY and the normal immunoglobulin 10% (human) vial is labelled IG.
Prepare Hyqvia vial(s). Remove Hyqvia from the box. Allow vials to reach room temperature. This may take up to 60 minutes.
Do not apply heat or place in microwave.
Do not shake the vials. Use aseptic technique when preparing and administering Hyqvia for infusion.

1. Check each vial of Hyqvia before using.

Expiration date: do not use beyond expiration date.
Colour: the contents of vorhyaluronidase alfa (HY) should be clear and colourless;
the contents of normal immunoglobulin (IG) should be clear and colourless or pale yellow;
if either liquid is cloudy or has particles, do not use.
Cap: protective cap is on the dual vial unit. Do not use the product if it does not have the cap.

2. Prepare for infusion.

Gather supplies: Hyqvia dual vial unit(s), ancillary supplies, sharps container and infusion pump (program pump per physician recommendation following manufacturer's instructions).
Prepare a clean work area.
Wash hands.
If the normal immunoglobulin and vorhyaluronidase alfa are pooled into separate containers, skip to step 5.

3. Prepare the vorhyaluronidase alfa of Hyqvia (labelled as "HY").

Remove the protective cap.
Wipe each stopper with a sterile alcohol wipe and allow to dry.
Attach a syringe to a needle/ needleless transfer device.
Pull back on plunger of the syringe to fill the syringe with air equal to the amount in the HY vial.
Insert needle into the center of the vial stopper.
Inject air into the vial and withdraw the full contents of the HY vial(s) into a syringe.
Attach the syringe containing the vorhyaluronidase alfa to the subcutaneous needle set.
Point the syringe tip up and push the plunger of the syringe to remove the air and fill the needle set up to the needle hub with the vorhyaluronidase alfa.

4. Prepare the normal immunoglobulin of Hyqvia (labelled as "IG").

Wipe each stopper with a sterile alcohol wipe and allow to dry.
Transfer the vial(s) labelled IG into either syringe(s), infusion bag or directly from the vial as shown by your healthcare professional.
a. If using syringe(s):
a.1. Attach a sterile syringe to a vented spike.
a.2. Insert the vented spike into the center of the IG vial.
a.3. Turn the vial upside down and pull back on the plunger to pull the IG into the syringe(s).
a.4. Repeat these steps, if using multiple vials to achieve the desired dose.
b. If using an infusion bag:
b.1. Insert the vented spike into the center of each IG vial. Open the vent.
b.2. Turn the vial upside down and fill the bag with the IG. Repeat this step, if using multiple vials to achieve the desired dose.
b.3. Remove the filling tube(s) of the bag and place a sterile cap over the open end of the bag and close the clamp on bag.
b.4. Insert the spike of the administration pump tubing into the bag and fill as directed by your healthcare professional.
c. If directly from the IG vial:
c.1. Insert the spike of the vented pump tubing into center of the stopper of the IG vial(s). Fill the administration pump tubing and set aside until the vorhyaluronidase alfa has been administered.
c.2. Repeat the steps above for each remaining vial of the IG.

5. Prepare the infusion site(s).

Potential sites for infusion include the middle to upper abdomen and thighs.
Avoid: bony prominences, blood vessels, scars, or areas that are inflamed or infected.
If two sites are desired, a bifurcated needle set may be used on opposite sides of the body, for doses above 600 mL.
Rotate sites by choosing opposite sides of the body between successive infusions.
Cleanse the infusion site(s) with a sterile alcohol wipe beginning at the centre of each infusion site and moving outward in a circular motion. Allow the infusion site(s) to dry (at least 30 seconds).

6. Insert and secure the 24 gauge subcutaneous needle.

Pinch at least one inch (2 to 2.5 cm) of skin between two fingers. Insert the needle at a 90 degree angle into the subcutaneous tissue and secure the needle with sterile tape.
Check placement: gently pull back on the plunger of attached syringe and monitor for any blood return in the tubing.
If blood is seen in the tubing, remove and discard the needle and repeat steps 3, 5 and 6 with a new subcutaneous needle and infusion site.
Secure the needle in place with a sterile protective dressing.

7. Administer the vorhyaluronidase alfa of Hyqvia.

Administer the entire vorhyaluronidase alfa dose first. Start at a rate of 1 to 2 mL per minute per site or as tolerated. If more than one site is used, divide the contents equally between sites. At the end of infusion, disconnect the empty syringe and attach pump tubing/ syringe containing the normal immunoglobulin of Hyqvia to the same subcutaneous needle set.

8. Administer the normal immunoglobulin of Hyqvia.

Within approximately 10 minutes of completing the infusion of the vorhyaluronidase alfa of Hyqvia, start the variable rate program of the infusion pump to initiate the infusion of the full therapeutic dose of normal immunoglobulin of Hyqvia. At the end of infusion, flush infusion tubing up to the needle with normal saline or 5% glucose in water, if directed by your healthcare professional.

9. Remove subcutaneous needle(s) from the infusion site(s).

After the infusion is complete, remove the needle set and cover with a protective dressing.

10. Document the infusion.

Remove the peel off label from each IG vial of Hyqvia used and affix to the patient's treatment record or infusion log. In addition, record the time, date, dose, infusion site location and any reactions after each infusion.
For self administration, provide the patient with instructions and training for infusion in the home or other appropriate setting.

4.3 Contraindications

Hyqvia is contraindicated in:
patients who have had a history of anaphylactic or severe systemic reactions to the administration of IgG;
IgA deficient patients with antibodies to IgA and a history of hypersensitivity;
patients with known systemic hypersensitivity to hyaluronidase or vorhyaluronidase alfa, or known systemic hypersensitivity to any of the excipients.

4.4 Special Warnings and Precautions for Use

Hyqvia must not be administered intravenously.
If Hyqvia is inadvertently administered into a blood vessel, patients could develop shock. In the case of shock, current medical standards for shock treatment should be observed.
It is strongly recommended that every time Hyqvia is administered to a patient, the name and batch number of the product is recorded in order to maintain a link between the patient and the batch number of the product.

Hypersensitivity.

Severe hypersensitivity reactions may occur, even in patients who have tolerated previous treatment with human normal immunoglobulin. In case of hypersensitivity, discontinue the Hyqvia infusion immediately and institute appropriate treatment.
The normal immunoglobulin contains trace amounts of IgA (average concentration of 37 microgram/mL). Patients with antibodies to IgA potentially are at greater risk of developing potentially severe hypersensitivity and anaphylactic reactions.
Rarely, human normal immunoglobulin can induce an anaphylactic reaction with a fall in blood pressure, even in patients who had tolerated previous treatment with human normal immunoglobulin. If a patient is at high risk for any hypersensitivity/ anaphylaxis reactions, the product should be administered only where supportive care is available for life threatening reactions.
Potential complications can often be avoided by ensuring that patients:
are not sensitive to human normal immunoglobulin, by initially injecting the product slowly;
are carefully monitored for any symptoms throughout the infusion period. Certain adverse reactions may occur more frequently in patients naive to human normal immunoglobulin, patients switched from an alternate product or when there has been a long interval since the previous infusion. Such patients should be monitored during the first infusion and for the first hour after the first infusion, in order to detect potential adverse signs. All other patients should be observed for at least 20 minutes after the administration.
Patients on self home treatment and/or their guardian should also be trained to detect early signs of hypersensitivity reactions.

Spread of localised infections.

Hyqvia should not be injected at or around an infected or acutely inflamed area because of the danger of spreading a localised infection.
No chronic changes in the skin were observed in the clinical studies. Patients should be reminded to report any chronic inflammation, nodules or inflammation that occurs at the infusion site and lasts more than a few days.

Thromboembolism.

Thromboembolic events may occur following treatment with immunoglobulin products, including Hyqvia. These include myocardial infarction, cerebral vascular accident, deep vein thrombosis and pulmonary embolism.
Patients at risk may include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, and/or known or suspected hyperviscosity, hypercoagulable disorders and prolonged periods of immobilisation, obesity, diabetes mellitus, acquired or inherited thrombophilic disorder, a history of vascular disease and a history of a previous thrombotic or thromboembolic event.
For patients at risk of thrombosis, Hyqvia should be administered at the minimum dose and infusion rate practicable. Patients should be adequately hydrated before administration and these individuals should be monitored for signs and symptoms of thrombosis.

Reactions reported to occur with intravenously administered immunoglobulins.

The following reactions have been reported to occur with IVIG treatment and may occur with SCIG treatment. Thromboembolic events (myocardial infarction, cerebral vascular accident, deep vein thrombosis, and pulmonary embolism), renal dysfunction/ failure, aseptic meningitis syndrome, haemolysis, transfusion related acute lung injury (TRALI) have been observed with immunoglobulin infusion (human), 10% administered intravenously and cannot be excluded with use of Hyqvia.

Aseptic meningitis syndrome.

Aseptic meningitis syndrome (AMS) has been reported to occur in association with human immunoglobulin treatment. Discontinuation of human immunoglobulin treatment has resulted in remission of AMS within several days without sequelae. The syndrome usually begins within several hours to 2 days following human immunoglobulin treatment. Cerebrospinal fluid studies are frequently positive with pleocytosis up to several thousand cells per mm, predominantly from the granulocytic series, and elevated protein levels up to several hundred mg/dL. AMS may occur more frequently in association with high dose (2 g/kg) intravenous immunoglobulin treatment.
AMS may occur more frequently in female patients.

Haemolysis.

Immunoglobulin products can contain blood group antibodies which may act as haemolysins and induce in vivo coating of red blood cells with immunoglobulin, causing a positive direct antiglobulin reaction (Coombs' test) and, rarely, haemolysis. Haemolytic anaemia can develop subsequent to immunoglobulin therapy due to enhanced red blood cells (RBC) sequestration. Immunoglobulin product recipients should be monitored for clinical signs and symptoms of haemolysis.

Use in renal impairment.

Acute renal dysfunction/failure, acute tubular necrosis, proximal tubular nephropathy, osmotic nephrosis, and death may occur in patients receiving IVIG therapy, especially those containing sucrose. In most cases, risk factors have been identified, such as pre-existing renal insufficiency, diabetes mellitus, hypovolemia, overweight, sepsis, hyperviscosity, paraproteinemia, concomitant nephrotoxic medicinal products or age over 65.
Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk for developing acute renal failure. Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine before the initial infusion of Hyqvia and again at appropriate intervals thereafter. In case of renal impairment or if renal function deteriorates, Hyqvia discontinuation should be considered.
While these reports of renal dysfunction and acute renal failure have been associated with the use of many of the registered IVIG products containing various excipients such as sucrose, glucose and maltose, those containing sucrose as a stabiliser accounted for a disproportionate share of the total number. In patients at risk, the use of immunoglobulin products that do not contain these excipients may be considered. Hyqvia does not contain sucrose, maltose or glucose.
In patients over age 65 or in any patient at risk of developing renal insufficiency, do not exceed the recommended dose, and consider infusing Hyqvia at lower, more frequent doses.

Pathogen safety.

Hyqvia is manufactured using components of human blood, which may contain the causative agents of hepatitis and other viral diseases, and theoretically Creutzfeldt-Jacob disease (CJD) agents. Prescribed manufacturing procedures utilised at the plasma collection centres and plasma testing laboratories are designed to reduce the risk of transmitting viral infection.
Important elements of the rigorous screening include: careful selection of donors for plasma pools, viral testing at multiple stages, and the application of a rigorously validated method of testing. Prior to the manufacturing of the bulk drug substance, the plasma pool is tested for viral markers using HIQ-PCR method (Hyland Immuno Quality Assured Polymerase Chain Reaction is nucleic acid amplification test, NAT), which allows for the detection of viruses at a level of 500 genome equivalents (ge) per mL of the plasma.
The inclusion of solvent detergent (S/D) into the manufacturing process, which is effective for removal of enveloped lipid viruses (HIV-1, HBV and HCV) and nanofiltration and incubation at elevated temperatures and low pH, which are effective for both enveloped and nonenveloped lipid viruses (HAV and parvovirus B19), would theoretically provide an assurance that the viral infectious agents have been removed. In addition, normal immunoglobulin of Hyqvia contains specific antibodies directed against parvovirus B19. Despite the use of those rigorous tests and triple viral inactivation (TVR), as discussed, see Section 2 Qualitative and Quantitative Composition, a possibility of transmitting infectious agent cannot be totally excluded. This also applies to unknown or emerging viruses or other pathogens.
Appropriate vaccinations (hepatitis A and B) should be considered for immune competent patients who receive regular/ repeated treatment with Hyqvia.

Immunogenicity of vorhyaluronidase alfa.

Eighteen percent (15 of 83) of subjects receiving Hyqvia in clinical studies developed non-neutralising antibodies to the vorhyaluronidase alfa component. The potential exists for such antibodies to cross react with endogenous hyaluronidase, which is known to be expressed in the adult male testes, epididymis, and sperm. It is unknown whether these antibodies may interfere with fertilisation in humans. The clinical significance of these antibodies is not known.

Hypersensitivity to vorhyaluronidase alfa.

Any suspicion of allergic or anaphylactic like reactions following vorhyaluronidase alfa administration requires immediate discontinuation of the infusion and standard medical treatment should be administered, if necessary.

Paediatric use.

Hyqvia was evaluated in 24 paediatric patients between 4 and 17 years old (13 were 4 to < 12 years and 11 were 12 to < 18 years old). Results of the studies indicated similar safety profiles in adults and paediatric patients, such as nature, frequency or seriousness or reversibility of adverse reactions.
However, these data are not sufficient to establish the safety and efficacy of Hyqvia in this age group.

Use in the elderly.

Hyqvia was evaluated in 7 subjects over age 65 in the clinical trial, and sufficient data is not available to determine whether safety of this product is different in this population.

Effect on laboratory tests.

Interference with serological testing.

After infusion of immunoglobulin the transitory rise of the various passively transferred antibodies in the patient's blood may result in misleading positive results in serological testing, for example, hepatitis A, hepatitis B, measles and varicella.
Passive transmission of antibodies to erythrocyte antigens, e.g. A, B, D may interfere with some serological tests for red cell antibodies for example the direct antiglobulin test (DAT, direct Coombs' test).
Infusions of immune globulin products may lead to false positive readings in assays that depend on detection of β-D-glucans for diagnosis of fungal infections; this may persist during the weeks following infusion of the product.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Immunoglobulin administration may impair for a period of at least 6 weeks and up to 3 months the efficacy of live attenuated virus vaccines such as measles, rubella, mumps and varicella. After administration of this product, an interval of 3 months should elapse before vaccination with live attenuated virus vaccines. In the case of measles, this impairment may persist for up to 1 year. Therefore, patients receiving measles vaccine should have their antibody status checked.
Admixtures of Hyqvia with other drugs and intravenous solutions have not been evaluated. It is recommended that Hyqvia be administered separately from other drugs or medications that the patient may be receiving. The product should not be mixed with immunoglobulin products from other manufacturers.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Clinical experience with immunoglobulins suggests that no harmful effects of Normal Immunoglobulin on fertility are to be expected. With Hyqvia, currently data is not available for clinical safety on development of the reproductive system.
Reversible infertility has been observed in male and female guinea pigs immunized to produce antibodies to hyaluronidase. However, antibodies to hyaluronidase did not influence reproduction following immunization of mice, rabbits, sheep, or cynomolgus monkeys. The effects of antibodies that bind to vorhyaluronidase alfa on human fertility are unknown.
There are no adequate data from the use of Hyqvia in pregnant women. Maternally administered immunoglobulins have been shown to cross the placenta, increasingly during the third trimester.
The effects of antibodies to the vorhyaluronidase alpha component of Hyqvia on the human embryo or on human foetal development are unknown.
Developmental studies in mice demonstrated that administration of hyaluronidase did not produce teratogenicity or signs of maternal toxicity at doses up to 18 mg/kg (2.2 x 106 U/kg), which is 28,100 times higher than the typical monthly human dose. Maternal doses of 9 and 18 mg/kg were associated with reduced foetal weight and an increased number of foetal resorptions. No adverse effects on foetal development were observed at a maternal dose of 3 mg/kg (360,000 U/kg), which is 4700 times higher than the typical monthly human dose.
Healthcare providers should carefully consider the potential risks and benefits for each specific patient before prescribing Hyqvia. Hyqvia should be given to a pregnant woman only if clearly indicated.
 There are no adequate data from the use of Hyqvia in lactating women. In animal studies, maternal antibodies binding to vorhyaluronidase alfa were transferred to offspring during lactation. In a peri- and post-natal reproduction trial, female mice were dosed daily with recombinant human hyaluronidase from implantation through lactation and weaning. There were no adverse effects on gestation, parturition, lactation and maternal behavior or on the development of the male or female offspring of the treated female mice in terms of sexual maturation, learning and memory of offspring, or their ability to produce another generation of offspring at doses up to 9 mg/kg (1.1 x 106 U/kg) which is 14,200 times higher than the typical monthly human dose.
The effects of antibodies that bind to vorhyaluronidase alfa of Hyqvia transferred during human lactation are unknown. Healthcare providers should carefully consider the potential risks and benefits for each specific patient before prescribing Hyqvia.

4.7 Effects on Ability to Drive and Use Machines

Hyqvia has no or negligible influence on the ability to drive and use machines. Patients who experience adverse reactions (such as dizziness and nausea) during treatment should wait for these to resolve before driving or operating machines.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

The most frequently reported adverse reactions (ARs) of Hyqvia occurring at a rate of 0.203 per infusion were local reactions. Among the 365 intravenous infusions, systemic ARs occurred at a rate of 0.42 per infusion. Of the 1,129 Hyqvia infusions, systemic ARs occurred at a rate of 0.20 per infusion.
The most frequently reported systemic ARs were headache, fatigue and pyrexia. The majority of these ARs were mild to moderate.
Normal immunoglobulin (human). Patients naive to immunoglobulin may experience a higher frequency of adverse effects including those of a minor nature.
Cases of transient aseptic meningitis, transient haemolytic reactions, increase in serum creatinine level and/or acute renal failure have been observed with human normal immunoglobulin (see Section 4.4 Special Warnings and Precautions for Use).
Adverse reactions such as chills, headache, dizziness, fever, vomiting, allergic reactions, nausea, arthralgia, low blood pressure and moderate low back pain may occur occasionally.
Thromboembolic reactions such as myocardial infarction, stroke, pulmonary embolism, and deep vein thrombosis have been rarely observed with intravenous and subcutaneous administration of immunoglobulin products.
The following additional adverse reactions have been reported for subcutaneously administered immunoglobulin products in general, listed by MedDRA system organ class and preferred term in order of severity:

Immune system disorders.

Hypersensitivity reaction.

Nervous system disorders.

Paraesthesia, tremor.

Cardiac disorders.

Tachycardia.

Vascular disorders.

Flushing, pallor, peripheral coldness.

Respiratory, thoracic, and mediastinal disorders.

Dyspnoea.

Gastrointestinal disorders.

Paraesthesia oral.

Skin and subcutaneous tissue disorders.

Swelling face, urticaria, dermatitis allergic, hyperhidrosis, pruritus.

Musculoskeletal and connective tissue disorders.

Back pain, musculoskeletal stiffness.

General disorders and administration site conditions.

Chest discomfort, feeling hot.

Investigations.

Alanine aminotransferase increased.
Vorhyaluronidase alfa. The most frequent adverse reactions reported during postmarketing use of vorhyaluronidase alfa in similar formulations administered subcutaneously for the dispersion and absorption of subcutaneously administered fluids or medicinal products have been mild local injection site reactions such as erythema and pain. Oedema has been reported most frequently in association with large volume subcutaneous fluid administration.

Tabulated list of adverse reactions.

The safety of Hyqvia was evaluated in a 12 month clinical study in patients with PID. The analysis of safety was conducted on 83 subjects in the intent to treat population who received at least one treatment of Hyqvia. A total of 1359 infusions of Hyqvia were administered during the study, 1129 infusions in 81 subjects during the 12 month safety and efficacy period. See Table 3.
Local reactions, reported in 50.6% of subjects and at a rate of 0.203 per infusion, were the most frequently reported ADRs during the efficacy period. The most frequently reported systemic ADRs were headache, fatigue, and pyrexia. The majority of these ADRs were mild to moderate and did not necessitate discontinuing the infusions. See Table 4.

Description of selected adverse reactions.

Local reactions observed during the pivotal clinical study include mild swelling of the site (present in most infusions) due to the large volumes infused, but in general were not considered an adverse reaction unless they caused discomfort. Only two instances of local adverse reactions were severe, infusion site pain and infusion site swelling. There were two instances of transient genital oedema, one considered severe, that resulted from diffusion of Hyqvia from the infusion site in the abdomen. No skin changes were observed that did not resolve during the clinical study.

Post-marketing adverse reactions.

In addition to the adverse reactions noted in clinical trials, the following adverse reactions have been reported in the postmarketing experience.

Immune system disorders.

Hypersensitivity.

General disorders and administration site conditions.

Influenza-like illness, infusion site leaking.
The following adverse reactions have been identified and reported during postmarketing use of vorhyaluronidase alfa administered subcutaneously for the dispersion and absorption of subcutaneously administered fluids or drugs.
The most frequently reported adverse experiences include injection site reactions such as erythema and pain. Oedema has been frequently reported in conjunction with subcutaneous fluid administration.

Class reactions.

The following adverse reactions have been reported in subcutaneously administered immunoglobulin products.

Immune system disorders.

Anaphylactic shock, anaphylactic/ anaphylactoid reactions, hypersensitivity reaction.

Nervous system disorders.

Paraesthesia, tremor.

Cardiac disorders.

Tachycardia.

Vascular disorders.

Hypotension, flushing, pallor, peripheral coldness.

Respiratory, thoracic, and mediastinal disorders.

Dyspnoea.

Gastrointestinal disorders.

Paraesthesia oral.

Skin and subcutaneous tissue disorders.

Swelling face, urticaria, dermatitis allergic, hyperhidrosis, pruritus, exfoliative dermatitis.

Musculoskeletal and connective tissue disorders.

Back pain, musculoskeletal stiffness.

General disorders and administration site conditions.

Chest discomfort, feeling hot, injection site reaction (including urticaria, induration, warmth, haemorrhage, hematoma, and rash), infusion site leaking.

Investigations.

Alanine aminotransferase increased.

Infections and infestations.

Meningitis aseptic.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Consequences of an overdose of Hyqvia are unknown.
For information on the management of overdose, contact the Poisons Information Centre telephone: 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Normal immunoglobulin.

IgG antibodies are protein molecules that are capable of specific interaction with molecules that are part of the membranes of infectious agents, foreign or abnormal cells, or toxic materials (antigens). Antibodies are produced by B lymphocytes, often with the help of T lymphocytes, macrophages, or dendritic cells. Following an initial interaction, some of the B cells differentiate to memory cells, which upon encountering with the same infectious agent later in life, are capable of rapidly reproducing and producing increased quantities of the IgG antibodies specific to the same infectious agent.
The IgG molecules have two distinct and separable functions. One function is to bind specifically to the epitope in the antigen through the Fab end of the molecule, which is formed by the combination of the heavy and light chains. The other end of the IgG molecule, the Fc portion, can activate complement, bind to receptors on phagocytic cells to promote engulfment of the antigen/ antibody complexes, and binding to the neonatal receptor which modulates the catabolism of IgG. In addition, binding of the Fc portion of the IgG molecule to regulatory receptors on B cells, T cells, and macrophages can modulate the activity of those cells, which may be useful in the control of autoimmune disease.
Thus, the mode of action of normal immunoglobulin mimics the action of the normal plasma immunoglobulin in a healthy adult individual having a broad spectrum of antibodies against infectious agents.

Vorhyaluronidase alfa.

Hyaluronan is a polysaccharide found in the extracellular matrix of the connective tissue. It is depolymerised by the naturally occurring enzyme hyaluronidase. Unlike the stable structural components of the extracellular matrix, hyaluronan has a very fast turnover with a half-life of approximately 0.5 days. The vorhyaluronidase alfa of Hyqvia increases permeability of the subcutaneous tissue by temporarily depolymerising hyaluronan. In the doses administered, vorhyaluronidase alfa of Hyqvia acts locally. The effects of the hyaluronidase are reversible and permeability of the subcutaneous tissue is restored within 24 to 48 hours.

Clinical trials.

A prospective, open label, noncontrolled, multicentre trial was conducted to determine the efficacy, tolerability and pharmacokinetics (PK) of Hyqvia in subjects with PID. Two cohorts of subjects were enrolled. Thirty one subjects had been treated intravenously for three months and then subcutaneously each week at 137% of the intravenous dose for approximately one year before transitioning to the Hyqvia trial. The remaining subjects were also treated intravenously for 3 months and then immediately began treatment with Hyqvia in the trial.
One week after the last intravenous or subcutaneous infusion, each subject began subcutaneous treatment with Hyqvia. After placing the subcutaneous needle set, the hyaluronidase of Hyqvia was infused through the needle set followed within 10 minutes by the immunoglobulin of Hyqvia at 108% of the intravenous dose. Dosing began with a 1 week equivalent dose. One week later, a 2 week dose was administered, followed 2 weeks later with a 3 week dose. For those subjects who were on a 4 week dose interval prior to entering the trial, 3 weeks later the 4 week dose was administered. This ramp up period allowed subjects to become familiar with the large volumes required for a full 3 or 4 week treatment. Subsequently, subjects continued the 3 or 4 week dosing for the remainder of the trial. After 3 doses at the full volume, a serum IgG trough level was obtained for all subjects, and used to individually adapt the subcutaneous dose of Hyqvia to compensate for individual variation from the mean value of 108%. All subjects who completed the trial received a minimum of 12 infusions at this individually adapted dose. The period after the ramp up was considered the efficacy period and used for safety and efficacy analyses.
Outcome measures included the rate of infections, adverse reactions, tolerability of the infusions of Hyqvia, number of infusion sites per month, and infusion rate. Eighty nine subjects were enrolled, 87 treated intravenously and 83 treated with Hyqvia. The majority were Caucasian (79/87, 90.8%). Median age was 35.0 years (range 4 to 78 years). Forty four of the subjects were naive to subcutaneous treatment. Median serum IgG trough levels for the 6 months before enrolment were 1,033.5 mg/dL (range: 405 to 3,200 mg/dL) in subcutaneous experienced subjects and 1,000 mg/dL (range: 636 to 3,200) in the subcutaneous naive subjects.
The 83 subjects received a total of 1359 infusions of Hyqvia during the entire trial. Of these, 1,129 were administered after the ramp up when the subjects were on a consistent interval of 3 or 4 weeks, which was predetermined to be the efficacy period for data analysis.
Median duration of treatment in the IVIG period was 91 days (range 84 to 122 days). Median duration of Hyqvia treatment during the dose ramp up period was 42 days (range 20 to 49), and during the efficacy period was 366 days (range 42 to 507 days). None of the subjects withdrew due to a severe or serious local or systemic adverse reaction.
There were two acute serious bacterial infections (ASBI); both episodes of pneumonia treated as outpatients with oral antibiotics, during the 12 month efficacy period and one additional pneumonia that required hospitalisation during the ramp up. Based on this, the annualised rate of ASBI while treated with Hyqvia was 0.025, with an upper 99% confidence limit of 0.046, which is significantly less than (p < 0.0001) the rate of one infection per year. The overall rates of infections throughout both the efficacy and extension trials are shown in Table 5. The secondary endpoints evaluated in the efficacy trial were the annual rate of all infections and other efficacy measures.
An objective of the trial was to achieve the same number or fewer infusions with Hyqvia per month as with intravenous administration and significantly fewer than with conventional subcutaneous administration. Summary of infusions of intravenous administration compared to Hyqvia administration is presented in Table 6.
Sixteen of 83 subjects (19.3%) were infused every 3 weeks and 67 (80.7%) were infused every 4 weeks. Seventy eight of 83 (94%) of subjects attained the same 3 or 4 week dosing as their previous IVIG treatment. One decreased from 4 to 3 weeks, one from 4 to 2 weeks and one from 3 to 2 weeks. The primary reason for decreasing the interval was discomfort due to swelling.
In a separate study evaluating subcutaneous treatment with normal immunoglobulin (human) 10% a median of 21.43 sites were required each month with a median monthly infusion time of 5.35 hours.

5.2 Pharmacokinetic Properties

The pharmacokinetics (PK) of Hyqvia was evaluated during a clinical trial of adults with primary immunodeficiency disease (PID) after they achieved steady state at their 3 or 4 week dosing interval and underwent individual dose adjustment (see Section 5.1 Pharmacodynamic Properties, Clinical trials). For adults, adjustment of dose was based on comparison of the ratios of the area under the IgG concentration versus time curve (AUC) during intravenous treatment versus during Hyqvia treatment.
The AUC of Hyqvia compared to conventional subcutaneous immunoglobulin (SCIG) administration was 20% higher. The absolute bioavailability of Hyqvia was 93.3% relative to intravenous immunoglobulin (IVIG).
The pharmacokinetic parameters of Hyqvia compared to intravenously administered normal immunoglobulin 10% are shown in Table 7. The mean IgG dose in weekly equivalents was 147 mg/kg ± 50 (range 134 to 160 mg/kg). The serum IgG trough levels are comparable: mean serum IgG trough with Hyqvia was 1,077 mg/dL compared to 1,095 mg/dL with intravenously administered normal immunoglobulin 10%. Cmax was lower with Hyqvia (1,607 mg/dL) than with intravenously administered normal immunoglobulin 10% (2,248 mg/dL). Time to reach maximum concentration of IgG following Hyqvia administration was 5 (3.3-5.1) days.
In the extension trial, reducing the dosing interval from 4 to 2 weeks resulted in a mean increase of 13% in serum immunoglobulin trough levels.
Figure 1 shows mean concentration time plot of IgG in subjects 12 years and older. The concentration time profile of Hyqvia is similar to that of intravenous administration but without the high peak. The peak to trough variation is more similar to subcutaneous administration.

5.3 Preclinical Safety Data

Genotoxicity.

Genotoxicity studies were not performed as the hyaluronidase is the recombinant form of a naturally occurring protein; as such it is not expected to interact with DNA or other chromosomal material, nor has it been shown to transform cells and promote the growth of normal or malignant cells.

Carcinogenicity.

Carcinogenicity studies were not performed as the hyaluronidase is the recombinant form of a naturally occurring protein; as such it is not expected to interact with DNA or other chromosomal material, nor has it been shown to transform cells and promote the growth of normal or malignant cells.

6 Pharmaceutical Particulars

6.1 List of Excipients

Composition of normal immunoglobulin (human) [immunoglobulin G (IgG) 100 mg/mL].

Active ingredient: normal immunoglobulin (Human) contains at least 98% IgG.
Stabilising agent: glycine, water for injection.

Composition of vorhyaluronidase alfa strength (160 U/mL).

Active ingredient: vorhyaluronidase alfa.
Excipients: dibasic sodium phosphate dihydrate, sodium hydroxide, human albumin 25%, calcium chloride, sodium chloride, disodium edetate, water for injection.

6.2 Incompatibilities

Admixtures of Hyqvia with other drug solutions have not been evaluated. Do not mix or administer components of Hyqvia with other products.
For interactions, please see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

36 months from date of manufacture.

6.4 Special Precautions for Storage

Store in a refrigerator (2°C-8°C) for 36 months. Do not freeze.
Keep the vials in the outer carton in order to protect from light.
Do not use beyond the expiration date printed on the vial or carton.

Special precautions for handling.

The product should be brought to room temperature before use.
Normal immunoglobulin is a clear or slightly opalescent and colourless or pale yellow solution. Vorhyaluronidase alfa is a clear, colourless solution. Visually inspect both components of Hyqvia for discolouration and particulate matter prior to administration.
Allow refrigerated product to come to room temperature before use. Do not heat or microwave.
Do not shake.
Do not mix the components of Hyqvia prior to administration.
Do not use vented vial access devices to remove vorhyaluronidase alfa from vials.
Use aseptic technique when preparing and administering Hyqvia. In cases where more than one vial of normal immunoglobulin or vorhyaluronidase alfa is required to obtain the required dose of the infusion, the normal immunoglobulin and/or vorhyaluronidase alfa should be prepared separately in appropriate solution containers before administration.

6.5 Nature and Contents of Container

Normal immunoglobulin 10% (human) vial.

25, 50, 100, 200 or 300 mL of solution in a vial (type I glass) with a stopper (bromobutyl rubber).

Vorhyaluronidase alfa vial.

1.25, 2.5, 5, 10 or 15 mL of solution in a vial (type I glass) with a stopper (chlorobutyl rubber).

Pack size.

One vial of normal immunoglobulin 10% (human) and one vial of vorhyaluronidase alfa in a dual vial unit.
Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal

Hyqvia contains no antimicrobial preservative. Partially used vials should be discarded.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

CAS number.

Normal immunoglobulin 10% (human): Not available.
Vorhyaluronidase alfa: 757971-58-7.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine (S4).

Summary Table of Changes