Consumer medicine information

Cuvitru

Immunoglobulin, normal (human)

BRAND INFORMATION

Brand name

Cuvitru

Active ingredient

Immunoglobulin, normal (human)

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Cuvitru.

What is in this leaflet

This leaflet answers some common questions about CUVITRU.

It does not contain all of the available information. All medicines have risks and benefits. Your doctor has weighed the risks of using your medicine against the benefit that it will have for you. It does not take the place of talking to your doctor or pharmacist.

If you have any concerns about having this medicine, ask your doctor or pharmacist.

Please read this leaflet carefully and keep it for future reference.

Please also note that this leaflet is subjected to change, therefore, ask your doctor whether this is the latest information regarding this medicine.

What CUVITRU is

Your medicine is CUVITRU, an immunoglobulin solution for subcutaneous infusion.

CUVITRU contains 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.

What CUVITRU is used for

CUVITRU is used in patients who do not have enough antibodies in their blood.

CUVITRU can be used as antibody replacement therapy to raise antibody levels in your blood to normal levels.

Your doctor may have prescribed CUVITRU for another reason.

CUVITRU has not been evaluated in patients aged < 2 years.

Ask your doctor if you have any questions about why it has been prescribed for you.

Before you use CUVITRU

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.

When you must not use it

CUVITRU must not be used if you are allergic to immunoglobulins or are allergic to any ingredients in CUVITRU (see “Product Description”).

Tell your doctor if you:

  • if you have antibodies against immunoglobulin A (IgA) in your blood. This may occur if you have IgA deficiency.
  • have allergies to any other medicines, or if you have ever had an allergic reaction to an injection.

Patients with pre-existing factors for thrombotic events or that increase risk of renal complications.

Please discuss the risks and benefits of this product with your doctor.

What should I tell my doctor before using CUVITRU

You should tell your doctor if you:

  • have or have had any medical problems.
  • take any medicines, including prescription and non-prescription medicines, such as over-the-counter medicines, supplements or herbal remedies including medicines that you buy without a prescription from your pharmacy, supermarket or health food shop.
  • have had a vaccination recently
  • are planning to become pregnant, pregnant or breastfeeding

If you have not told your doctor about any of the above, tell him/her before you start using CUVITRU.

How to use CUVITRU

Always use CUVITRU exactly as your doctor has told you. Check with your doctor if you are not sure.

Ensure you are adequately hydrated before administration of CUVITRU.

CUVITRU has to be infused under the skin.

Treatment with CUVITRU 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 CUVITRU at home. Do not begin treatment with CUVITRU 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.

CUVITRU is for single use in one patient only.

Instructions for use

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.

Do not use CUVITRU at home until you get instructions and training from your healthcare professional.

Prepare CUVITRU vial(s):

  • Remove CUVITRU from the box. Allow vials to reach room temperature. This may take up to 90 minutes.
  • Do not apply heat or place in microwave.
  • Do not shake the vial(s).
  1. Check the vial(s):
  • Do not use beyond expiration date.
  • Do not use if the protective cap is missing or broken.
  • Look at the colour: it should be clear and colourless to pale yellow or light brown.
  • Do not use if the solution is cloudy or has particles.
  1. Gather all supplies
  • Gather all supplies:
Items include: vial(s) of CUVITRU, infusion supplies: subcutaneous needle set, transfer device(s), syringe(s), sterile tip caps, sterile clear bandage, tape, gauze, sharps container, infusion pump, infusion log.

  • Clean work area.
  • Program the infusion pump according to prescribed infusion rates and manufacturer’s instructions.
  • Wash hands thoroughly and allow to dry.

  • Open supplies as shown by your healthcare professional.
  1. Prepare the syringe(s):
  • Remove the cap from the vial.

  • Wipe each stopper with a sterile alcohol wipe and allow to dry.

  • Attach a sterile syringe to a vented spike.
  • Insert the vented spike into the centre of the IG vial.
  • Turn the vial upside down and pull back on the plunger to pull the IG into the syringe(s).

  • Repeat these steps, if using multiple vials to achieve the desired dose.
  • Start the infusion promptly after drawing CUVITRU into the syringe(s). It is suggested to complete the administration within 2 hours.
If using a sterile needle: Attach a sterile syringe to the sterile needle and pull back the plunger of syringe to fill with air which should equal the amount of the solution you will be taking from the vial. Insert the needle into the centre of the stopper, and inject air in. Pull back on the plunger to withdraw the desired volume.
  1. Prepare the infusion pump and tubing:
  • Use manufacturer directions for filling the tubing and using the pump.
  • Attach the syringe filled with CUVITRU to the needle set.
  • Point the syringe tip up and gently push the plunger of the syringe to remove the air and fill the needle set up to the needle hub.

  1. Prepare the infusion site(s):
  • Select the number of infusion sites based on the volume of the total dose.
  • Choose infusion site(s): upper arms, abdomen, thighs, or lower back.
  • Avoid: bony areas, visible blood vessels, scars and any areas of inflammation (irritation) or infection.

  • Infuse CUVITRU from 1 to 4 infusion sites at the same time. Select sites at least 4 inches apart.
  • Rotate sites between future infusions.
  • Wipe the infusion site(s) with a sterile alcohol wipe beginning at the centre of each infusion site and moving outward in circular motion. Allow the infusion site(s) to dry (at least 30 seconds).

  1. Insert and secure the subcutaneous needle set:
  • Remove the needle cover. Firmly grasp and pinch at least 1 inch of skin between two fingers.
  • Insert needle with a rapid motion straight into the skin at a 90 degree angle. Tape needle in place with sterile tape (included on transparent dressing).

  • If more than one site is used, repeat the steps.
  • Check for proper needle placement by pulling back on the syringe plunger to check for blood return in the tubing of the needle set.

  • If blood is seen in the tubing, remove and discard the subcutaneous needle and repeat steps 4, 5 and 6 with a new subcutaneous needle and infusion site.
  • Secure the needle set in place by applying a sterile protective dressing over the site(s).

  1. Start the infusion:
  • Follow the manufacturer’s instructions to turn pump on and start the infusion.
  • Check infusion site(s) occasionally throughout the infusion.
  1. Remove subcutaneous needle(s) from the infusion site(s):
  • Remove the needle set by loosening the tape on all edges.
  • Pull the needle wings straight up and out.
  • Gently press a small piece of gauze over the needle site and cover with a dressing.
  • Throw away the needle(s) into the sharps container.

  1. Record the infusion:
  • Remove the peel-off label from the vial(s), which has the product lot number and expiration date, and place the label in your treatment record/infusion log.
  • Write down the date, time, dose, site(s) of infusion (to assist in rotating sites) and any reactions after each infusion.
  • Throw away the disposable supplies, vials, and unused product as recommended by your healthcare professional.

If you miss/forget your injection

Do not infuse a double dose of CUVITRU 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 take too much(overdose)

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

While you are using CUVITRU

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 CUVITRU
  • If you are about to be started on any new medicine, tell your doctor and pharmacist that you are taking CUVITRU
  • If you become pregnant while you are using your medicine, tell your doctor.
  • Talk to your healthcare provider before traveling. 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.

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.

Do not be alarmed by the following lists of possible side effects. You may not experience any of them. If you have any questions, ask your doctor.

Tell your doctor immediately or go to Accident and Emergency Department at your nearest hospital if you notice any of the following symptoms:

  • reduced urination
  • severe headache
  • neck stiffness
  • inability to stand bright light
  • painful eye movements
  • pain/tenderness, swelling/discolouration of an arm or leg
  • tingling, numbness or weakness on one side of the body
  • shortness of breath
  • chest pain
  • fever
  • allergic or anaphylactic reaction, symptoms of which may include:
    - swelling of the lips, tongue or eyes
    - loss of consciousness
    - hives
    - difficulty in breathing.

Tell your doctor if you notice any of the following and they worry you.

This list includes the more common side effects of CUVITRU. They are usually mild and often reduce over time.

  • swelling, pain, redness or itching where the injection was given
  • headache/migraine
  • nausea or vomiting
  • pain (including pain in the chest, back, joints, arms, legs)
  • muscle pain
  • fatigue
  • diarrhoea
  • stomach ache or bloating
  • cough
  • fever or chills
  • feeling faint, dizzy or light headed (fall in blood pressure)
  • infusion site ulcer.

Other side effects not listed above may also occur in some patients.

Tell your doctor if you notice any other effects.

After using CUVITRU

CUVITRU 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.

Storage

CUVITRU should be stored below 25C. 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 CUVITRU 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.

Product description

What CUVITRU looks like

CUVITRU is a clear and colourless to pale yellow or light brown solution.

CUVITRU is available in the following pack sizes:

8 g in 40 mL

4 g in 20 mL

1 g in 5 mL

2 g in 10 mL

Ingredients

Active ingredient: 20% plasma proteins of which at least 98% are immunoglobulins.

Inactive ingredients: Glycine and water for injection

Manufacturer/Distributor/Supplier

CUVITRU is distributed in Australia by:

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

Australian Register Number: 282579

Not all pack sizes may be marketed.

CUVITRU® is a trademark of Baxalta Incorporated. TAKEDA® and the TAKEDA Logo® are registered trademarks of Takeda Pharmaceutical Company Limited.

This leaflet was prepared in December 2020.

Published by MIMS January 2021

BRAND INFORMATION

Brand name

Cuvitru

Active ingredient

Immunoglobulin, normal (human)

Schedule

S4

 

1 Name of Medicine

Normal immunoglobulin subcutaneous (human).

2 Qualitative and Quantitative Composition

Composition.

See Table 1.
For the full list of excipients, see Section 6.1 List of Excipients.

Description.

The manufacturing processes do not affect the composition of the immunoglobulin in the normal human plasma origin. The distribution of the IgG sub-classes formulated in this product comprises IgG1 ≥ 56.9%, IgG2 ≥ 26.6%, IgG3 ≥ 3.4%, and IgG4 ≥ 1.7%.

3 Pharmaceutical Form

Solution for subcutaneous injection.

Appearance.

Cuvitru is a clear and colourless to a pale yellow or light brown solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Cuvitru is indicated as replacement therapy in adult and paediatric patients for:
primary immunodeficiency diseases (PID); and
symptomatic hypogammaglobulinaemia secondary to underlying disease or treatment.

4.2 Dose and Method of Administration

For subcutaneous administration only.
Cuvitru should be inspected visually for particulate matter and discoloration prior to administration. Do not use if particulate matter and/or discoloration is observed.
Start the infusion promptly after drawing Cuvitru into the syringe. It is suggested to complete the administration within 2 hours due to the potential formation of particles caused by siliconised syringes.
Cuvitru must not be diluted.
Replacement therapy should be initiated and monitored under the supervision of a physician experienced in the treatment of immunodeficiency. Patients should be closely monitored and carefully observed for any adverse reactions throughout the infusion period, particularly patients starting with therapy.

Dosage.

The dose and dose regimen is dependent on the indication.

Replacement therapy.

In replacement therapy the dose may need to be individualised for each patient dependent on the pharmacokinetic and clinical response. The following dose regimens are given as a guideline.
The dose regimen should achieve a trough level of IgG (measured before the next infusion) of at least 5 to 6 g/L and aim to be within the reference interval of serum IgG for age. A loading dose of at least 0.2 to 0.5 g/kg (1 to 2.5 mL/kg) body weight may be required. This may need to be divided over several days, with a maximal daily dose of 0.1 to 0.15 g/kg. After steady state IgG levels have been attained, maintenance doses are administered at repeated intervals to reach a cumulative monthly dose of the order of 0.3 to 1.0 g/kg. Each single dose may need to be injected at different anatomic sites.
Trough levels should be measured and assessed in conjunction with the incidence of infection. To reduce the rate of infection, it may be necessary to increase the dose and aim for higher trough levels. (See Table 2.)

Dose guidance.

A dose guidance table has been added below, which shows the suggested dose change (in mL) to achieve a desired IgG trough level change (increase or decrease), once Cuvitru treatment has been initiated. Calculate the difference between the patient's target serum IgG trough level and the IgG trough level during subcutaneous treatment. Find this difference in Table 3, and the corresponding amount (in mL) by which to increase (or decrease) the weekly/biweekly dose based on the patient's body weight. If the difference between measured and target trough levels is less than 100 milligram/dL, then no adjustment is necessary.
However, the patient's clinical response should be the primary consideration which guides dosing.

Example 1.

A patient with a body weight of 70 kg who is on a weekly treatment has a measured IgG trough level of 600 milligrams/dL, and the target trough level is 800 milligrams/dL. The desired target trough level difference is 200 milligrams/dL (800 milligrams/dL minus 600 milligrams/dL). The weekly dose of Cuvitru should be increased by 17 mL.

Example 2.

A patient with a body weight of 50 kg who is on a biweekly treatment has a measured IgG trough of 900 milligrams/dL, and the target trough level is 700 milligrams/dL. The desired target trough level difference is 200 milligrams/dL (900 milligrams/dL minus 700 milligrams/dL). The biweekly dose of Cuvitru should be decreased by 24 mL.

Paediatric population.

The posology in children and adolescents (0-18 years) is not different to that of adults as the posology for each indication is given by body weight and adjusted to the clinical outcome of the above mentioned indications.
No clinical trials have been conducted with Cuvitru in children at age 0 to < 2 years, but experience with immunoglobulins suggests that no harmful effects on treatment of children at age 0 to < 2 years with Cuvitru are to be expected.

Method of administration.

Subcutaneous infusion should be commenced and initially monitored by a healthcare professional experienced in the guidance of patients for home treatment with regular follow-ups. Infusion pumps appropriate for subcutaneous administration of immunoglobulins can be used. The patient or caregiver must be instructed in the use of a syringe driver, the infusion techniques, the keeping of treatment diary, recognition of and measures to be taken in case of severe adverse reactions.
Cuvitru may be injected into sites such as abdomen, thigh, upper arm, and lateral hip.
Adjustment of the infusion rate and infusion volume per site is based on subject tolerability.
It is recommended to use an initial administration speed of 10 mL/h/infusion site. If well tolerated, the rate of administration may be increased at intervals of at least 10 minutes to a maximum of 20 mL/h/infusion site for the initial two infusions. More than one pump can be used simultaneously. The amount of product infused into a particular site varies. In infants and children, infusion site may be changed every 5-15 mL. In adults doses over 30 mL may be divided according to patient preference. There is no limit to the number of infusion sites.
Cuvitru does not contain antimicrobial preservative. It is for single use in one patient only. Discard any residue.

Detailed instructions for administration for patients.

Do not use Cuvitru at home until you get instructions and training from your healthcare professional.
Prepare Cuvitru vial(s):
Remove Cuvitru from the box. Allow vials to reach room temperature. This may take up to 90 minutes.
Do not apply heat or place in microwave.
Do not shake the vial(s).

1. Check the vial(s).

Do not use beyond expiration date.
Do not use if the protective cap is missing or broken.
Look at the colour: it should be clear and colourless to pale yellow or light brown.
Do not use if the solution is cloudy or has particles.

2. Gather all supplies.

Gather all supplies:
Items include: vial(s) of Cuvitru, infusion supplies: subcutaneous needle set, transfer device(s), syringe(s), sterile tip caps, sterile clear bandage, tape, gauze, sharps container, infusion pump, infusion log.
Clean work area.
Program the infusion pump according to prescribed infusion rates and manufacturer's instructions.
Wash hands thoroughly and allow to dry.
Open supplies as shown by your healthcare professional.

3. Prepare the syringe(s).

Remove the cap from the vial.
Wipe each stopper with a sterile alcohol wipe and allow to dry.
Attach a sterile syringe to a vented spike.
Insert the vented spike into the centre of the IG vial.
Turn the vial upside down and pull back on the plunger to pull the IG into the syringe(s).
Repeat these steps, if using multiple vials to achieve the desired dose.
Start the infusion promptly after drawing Cuvitru into the syringe(s). It is suggested to complete the administration within 2 hours.
If using a sterile needle: attach a sterile syringe to the sterile needle and pull back the plunger of syringe to fill with air which should equal the amount of the solution you will be taking from the vial. Insert the needle into the centre of the stopper, and inject air in. Pull back on the plunger to withdraw the desired volume.

4. Prepare the infusion pump and tubing.

Use manufacturer directions for filling the tubing and using the pump.
Attach the syringe filled with Cuvitru to the needle set.
Point the syringe tip up and gently push the plunger of the syringe to remove the air and fill the needle set up to the needle hub.

5. Prepare the infusion site(s).

Select the number of infusion sites based on the volume of the total dose.
Choose infusion site(s): upper arms, abdomen, thighs, or lower back.
Avoid: bony areas, visible blood vessels, scars and any areas of inflammation (irritation) or infection.
Infuse Cuvitru from 1 to 4 infusion sites at the same time. Select sites at least 4 inches apart.
Rotate sites between future infusions.
Wipe the infusion site(s) with a sterile alcohol wipe beginning at the centre of each infusion site and moving outward in circular motion. Allow the infusion site(s) to dry (at least 30 seconds).

6. Insert and secure the subcutaneous needle set.

Remove the needle cover. Firmly grasp and pinch at least 1 inch of skin between two fingers.
Insert needle with a rapid motion straight into the skin at a 90 degree angle. Tape needle in place with sterile tape (included on transparent dressing).
If more than one site is used, repeat the steps.
Check for proper needle placement by pulling back on the syringe plunger to check for blood return in the tubing of the needle set.
If blood is seen in the tubing, remove and discard the subcutaneous needle and repeat steps 4, 5 and 6 with a new subcutaneous needle and infusion site.
Secure the needle set in place by applying a sterile protective dressing over the site(s).

7. Start the infusion.

Follow the manufacturer's instructions to turn pump on and start the infusion.
Check infusion site(s) occasionally throughout the infusion.

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

Remove the needle set by loosening the tape on all edges.
Pull the needle wings straight up and out.
Gently press a small piece of gauze over the needle site and cover with a dressing.
Throw away the needle(s) into the sharps container.

9. Record the infusion.

Remove the peel-off label from the vial(s), which has the product lot number and expiration date, and place the label in your treatment record/infusion log.
Write down the date, time, dose, site(s) of infusion (to assist in rotating sites) and any reactions after each infusion.
Throw away the disposable supplies, vials, and unused product as recommended by your healthcare professional.

4.3 Contraindications

Cuvitru is contraindicated in:
patients with known anaphylactic or severe hypersensitivity reactions to the subcutaneous administration of the active substance or any of the excipients;
patients with severe IgA deficiency and a history of hypersensitivity to human immunoglobulin treatment.

4.4 Special Warnings and Precautions for Use

Cuvitru must not be given intravascularly or intramuscularly.
If Cuvitru is accidentally administered into a blood vessel patients could develop shock.
The recommended infusion rate given, see Section 4.2 Dose and Method of Administration, must be closely followed. Patients must be closely monitored and carefully observed for any symptoms throughout the infusion period.
Certain adverse reactions may occur more frequently in patients who receive human normal immunoglobulin for the first time or, in rare cases, when the human normal immunoglobulin product is switched or when there has been a long interval since the previous infusion.
Potential complications can often be avoided by:
initially injecting the product slowly (see Section 4.2 Dose and Method of Administration);
ensuring that patients are carefully monitored for any symptoms throughout the infusion period. In particular, patients naive to human normal immunoglobulin, patients switched from an alternative immunoglobulin product or when there has been a long interval since the previous infusion 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 administration.
In case of adverse reaction, either the rate of administration must be reduced or the infusion stopped. Suspicion of severe hypersensitivity or anaphylactic-type reactions requires immediate discontinuation of the injection. The treatment required depends on the nature and severity of the adverse reaction.
In case of shock, standard medical treatment for shock should be implemented.
It is strongly recommended that every time that Cuvitru is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.

Hypersensitivity.

True hypersensitivity reactions may occur. They can particularly occur in cases of IgA deficiency with anti-IgA antibodies and these patients should be treated with caution.
Patients with anti-IgA antibodies, in whom treatment with subcutaneous IgG products remains the only option, should be switched to IGSC, 20% only under close medical supervision. IGSC, 20% contains trace amounts of IgA (contains ≤ 280 microgram/mL IgA).
Human normal immunoglobulin can induce an anaphylactic reaction, even in patients who had tolerated previous treatment with human normal immunoglobulin.
Rarely, human normal immunoglobulin can induce a fall in blood pressure with anaphylactic reaction, even in patients who had tolerated previous treatment with human normal immunoglobulin.

Thromboembolism.

Arterial and venous thromboembolic events including myocardial infarction, cerebral vascular accident (stroke), deep vein thrombosis and pulmonary embolism have been associated with the use of immunoglobulins. Caution should be exercised in patients with pre-existing risk factors for thrombotic events (such as advanced age, hypertension, diabetes mellitus and a history of vascular disease or thrombotic episodes, patients with acquired or inherited thrombophilic disorders, patients with prolonged periods of immobilisation, severely hypovolemic patients, patients with diseases which increase blood viscosity). Patients should be informed about first symptoms of thromboembolic events including shortness of breath, pain and swelling of a limb, focal neurological deficits and chest pain and should be advised to contact their physician immediately upon onset of symptoms.
Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity.

Renal complications.

Severe renal adverse reactions have been reported in patients receiving immune globulin treatment, particularly those products containing sucrose (Cuvitru does not contain sucrose). These include acute renal failure, acute tubular necrosis, proximal tubular nephropathy and osmotic nephrosis.
Factors that increase the risk of renal complications include, but are not limited to pre-existing renal insufficiency, diabetes mellitus, hypovolemia, concomitant nephrotoxic medicinal products, age over 65, sepsis, hyperviscosity and paraproteinaemia.

Aseptic meningitis syndrome (AMS).

Aseptic meningitis syndrome (AMS) has been reported to occur in association with immunoglobulin treatment, including Cuvitru (see Section 4.8 Adverse Effects (Undesirable Effects)). AMS may occur more frequently in female patients. Discontinuation of Ig treatment may result in remission of AMS within several days without sequelae. The syndrome usually begins within several hours to 2 days following IG treatment. Cerebrospinal fluid studies are frequently positive with pleocytosis up to several thousand cells per mm3, predominantly from the granulocytic series, and elevated protein levels up to several hundred mg/dL.
Patients should be informed about first symptoms which encompass severe headache, neck stiffness, drowsiness, fever, photophobia, nausea, and vomiting.

Haemolysis.

Cuvitru contains blood group antibodies that may act as haemolysins and induce in vivo coating of red blood cells (RBC) with immunoglobulin. This may cause a positive direct antiglobulin reaction [DAT, (Coombs' test)] and, rarely, haemolysis. Delayed haemolytic anaemia can develop subsequent to IG therapy due to enhanced RBC sequestration. Acute haemolytic anaemia, consistent with intravascular haemolysis, has been reported.

Transmissible agents.

Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infectious agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.
The measures taken are considered effective for enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV), and for the non-enveloped viruses hepatitis A virus (HAV) and parvovirus B19.
There is reassuring clinical experience regarding the lack of hepatitis A or parvovirus B19 transmission with immunoglobulins and it is also assumed that the antibody content makes an important contribution to the viral safety.

Paediatric use.

The listed precautions apply both to adults and children.
Cuvitru was evaluated in pivotal clinical studies which included a total of 53 paediatric subjects with PID: 25 paediatric subjects in study 170903 (5 aged 2 to < 6 years, 8 aged 6 to < 12 years and 12 aged 12 to < 18 years old) and 28 paediatric subjects in study 170904 (1 aged < 6 years, 14 aged 6 to < 12 years and 13 aged 12 to < 18 years old). Cuvitru has not been evaluated in patients aged < 2 years.

Use in the elderly.

Cuvitru was evaluated in pivotal studies which included a total of 12 subjects of the age 65 years and older. No differences in safety or efficacy were observed for this group.
Monitor patients who are at an increased risk for developing renal failure or thrombotic events. Do not exceed the recommended dose, and infuse at the minimum infusion rate practicable.

Effects on laboratory tests.

After infusion of IgG, 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, and D) may interfere with some serological tests for red cell antibodies, for example the DAT (Coombs' test).
Administration of Cuvitru can lead to false positive readings in assays that depend on detection of beta-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 Cuvitru 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.

Paediatric population.

The listed interactions apply both to adults and children.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Cuvitru contains a human plasma derived native protein, which is not anticipated to have an adverse effect on fertility.
The safety of Cuvitru product for use in human pregnancy has not been established in controlled clinical trials and therefore it should only be given with caution to pregnant women. Immunoglobulin products have been shown to cross the placenta, increasingly during the third trimester.
Clinical experience with immunoglobulins suggests that no harmful effects on the course of pregnancy, or on the foetus and the neonate are to be expected.
Physicians should balance the potential risks and only prescribe Cuvitru, if clearly needed.
During breast-feeding immunoglobulins are excreted into the milk and may contribute to the transfer of protective antibodies to the neonate.
Physicians should balance the potential risks and only prescribe Cuvitru, if clearly needed.

4.7 Effects on Ability to Drive and Use Machines

The ability to drive and operate machines may be impaired by some adverse reactions associated with Cuvitru. Patients who experience adverse reactions during treatment should wait for these to resolve before driving or operating machines.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

Adverse reactions such as chills, headache, dizziness, fever, vomiting, allergic reactions, nausea, arthralgia, low blood pressure and moderate low back pain may occur occasionally.
Rarely human normal immunoglobulins may cause a sudden fall in blood pressure and, in isolated cases, anaphylactic shock, even when the patient has shown no hypersensitivity to previous administration.
Local reactions at infusion site: swelling, soreness, redness, induration, local heat, local pain, itching, bruising and rash, may frequently occur.
For safety information with respect to transmissible agents, see Section 4.4 Special Warnings and Precautions for Use.

Tabulated list of adverse reactions.

The safety of Cuvitru administered subcutaneously was evaluated in two prospective, open-label, non-controlled, multi-centre studies in 122 subjects with PID.
Cuvitru treatment was well tolerated with local adverse reactions (ARs) mostly mild in intensity. One subject discontinued treatment due to a local AR. 112 out of 122 subjects treated with Cuvitru completed a study. (See Table 5).
There were no deaths or serious adverse events related to treatment with Cuvitru in the clinical studies.
Table 4 is presented according to the MedDRA system organ classification (SOC and Preferred Term Level).

Paediatric population.

The safety profile in the paediatric population was similar to that in adult subjects.

Post-marketing adverse reactions.

Nervous system disorders.

Meningitis aseptic.

Class reactions.

The following additional adverse reactions have been identified and reported during the post-marketing use of another subcutaneous immune globulin product: anaphylactic reaction, paraesthesia, tremor, tachycardia, dyspnoea, laryngospasm, chest discomfort, injection site reactions (such as induration, warmth).

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 are not known.
For more information on the management of overdose, contact the Poisons Information Centre on telephone: 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

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 subcutaneous immunoglobulin (IGSC) mimics the action of the normal plasma immunoglobulin in a healthy adult individual having a broad spectrum of antibodies against infectious agents. As the active ingredient in Cuvitru, IgG 20% w/v, is a plasma-derived immunoglobulin isolated from pooled plasma of healthy donors, this product can be classified as a replacement therapy in patients who are unable to produce sufficient amount of IgG antibodies. Adequate doses of this medicinal product may restore the abnormally low IgG levels of immune deficient patients to a normal range.
The active ingredient in Cuvitru is a human plasma-derived immunoglobulin, concentration of 200 mg/mL (20% w/v), produced from large pools of human plasma by a modified Cohn-Oncley cold ethanol fractionation, yielding an intermediate immunoglobulin G (IgG), 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 to a certain extent, as demonstrated by viral spiking experiment. 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), nano-filtration (35 nanometre), and incubation at a low pH and elevated temperature (30°C to 32°C, pasteurisation for 21 to 23 days) has been incorporated into the downstream purification. Thus, the active ingredient formulated in Cuvitru has been subjected to a rigorous elimination for both lipid and non-lipid enveloped viruses.

Pharmacodynamic properties.

Pharmacotherapeutic group: immune sera and immunoglobulins: immunoglobulins, normal human, for extravascular administration.

Mechanism of action.

Human normal immunoglobulin contains mainly immunoglobulin G (IgG) with a broad spectrum of antibodies against infectious agents.
Human normal immunoglobulin contains the IgG antibodies present in the normal population. It is usually prepared from pooled plasma from not fewer than 1000 donations. It has a distribution of immunoglobulin G subclasses closely proportional to that in native human plasma. Adequate doses of this medicinal product may restore abnormally low immunoglobulin G levels to the normal range.

Paediatric population.

There are no theoretical or observed differences in the action of immunoglobulins in children compared to adults.

Clinical trials.

The efficacy of Cuvitru was investigated in two prospective uncontrolled multi-centre phase 2/3 studies in adult and paediatric subjects with PID. The pivotal study 170903 conducted in Europe was designed to examine Cuvitru efficacy when administered at the same weekly-equivalent dose as with the previously used IG product. In the supportive study conducted in North America, study 170904, subjects received Cuvitru at a dose adjusted to achieve the bioavailability of IGIV, 10%.

Study 170903.

A prospective, open-label, non-controlled, multi-centre study was conducted to evaluate the efficacy, safety, tolerability, and PK parameters of Cuvitru in subjects with PID aged 2 years and older at time of screening. The study consisted of 2 parts. In study part 1, subjects were treated with IGSC 16% for 12 weeks or with IGIV 10% for 13 weeks. Administration, dosage frequency, and dose were dependent on the pre-study treatment. However, the dose range had to be within 0.3-1.0 g/kg BW per 4 weeks.
During study part 2, subjects received weekly Cuvitru infusions for 51 weeks at the dose used during study part 1, adjusted to a weekly equivalent dose if necessary. PK assessments were performed before the end of study part 1 and after approximately 5 months in study part 2 in subjects aged ≥ 12 years. For younger subjects (aged 2 to < 12 years) only IgG trough levels were assessed to avoid multiple blood draws. The geometric mean of Cuvitru trough levels was 827 mg/dL [95% CI: 748-913]. Human and population PK parameters for Cuvitru were calculated from levels of immunoglobulin G (IgG) measured during each part of the study.
Cuvitru was administered at the same weekly-equivalent dose as with the previously used IG product (mean (± SD) dose: 0.125 ± 0.042 g/kg/week). Cuvitru administered at this dose was shown to be effective in PID subjects aged ≥ 2 years.
One acute serious bacterial infection (ASBI) of pneumonia was reported in a 12-year old subject with a more severe form of hypogammaglobulinaemia (XLA) while receiving Cuvitru. The point estimate of the annualised rate of ASBIs was 0.022 (upper limit of 99% CI: 0.049) during Cuvitru treatment. This annual rate of ASBIs was lower than 1.0 ASBIs/year, (p < 0.0001), the threshold specified as providing substantial evidence of efficacy.
The summary of infections and associated events for subjects in study 170903 during subcutaneous treatment with Cuvitru are summarised in Table 6.

Study 170904.

A prospective, open-label, non-controlled, multi-centre clinical study was conducted to determine the efficacy, tolerability and PK of Cuvitru in 77 adult and paediatric subjects with PID. Efficacy was determined in 53 adults aged 16 years or older, 6 adolescents aged 12 to < 16 years, and 15 children aged 2 to < 12 years. Cuvitru was administered to 74 subjects with a mean dose of 222 mg/kg/week ± 71 mg/kg/week for a median treatment duration of 380.5 days (range: 30 - 629 days) and a mean (± SD) of 413.1 ± 116.5 days. The median duration of treatment did not vary significantly between age groups. The total exposure to Cuvitru was 83.70 subject-years and 4327 infusions.
Initially subjects received immune globulin 10% intravenously (IGIV) every 3 or 4 weeks at a monthly dose equivalent to that received prior to the study for 13 weeks. The objective of part 1 of the study was to determine AUCIV of total IgG following IGIV administration. In part 2 of the study, subjects received Cuvitru subcutaneously at an adjusted dose of 145% of the IGIV dose. The objective of part 2 was to determine AUCSC of total IgG following weekly Cuvitru administration and to calculate an adjusted dose to be used in part 3. The dose adjustment factor was assessed to be 145% of the IGIV 10% dose by comparing the AUCSC with the AUCIV, 0-t (standardised to 1 week) of part 1 for the first 15 subjects that completed part 2. Subjects who completed part 1 after this assessment was available, went directly into part 3. In part 3 of the study, subjects were treated weekly for 12 weeks at the adjusted dose. The ratio of serum IgG trough levels for part 1 and 3 were compared to the expected trough level determined in part 2 to establish the individually adapted dose for part 4 for each subject. In part 4 of the study, subjects were infused weekly with Cuvitru at the individually adapted dose for 40 weeks. During part 4, an additional pharmacokinetic assessment was performed. Follow-up with the subject either by diary system or by investigator occurred 3-5 days after every infusion in each study part to document adverse events. Adverse events were assessed using the subject's eDiary - all subjects received eDiary tablet to continuously record home treatments, adverse events, and additional information as they occurred.
One acute serious bacterial infection (ASBI) of pneumonia was reported in a 78-year old subject who had specific antibody deficiency and allergic bronchopulmonary aspergillosis while receiving Cuvitru. The point estimate of the annualised rate of ASBIs was 0.012 (upper limit of 99% CI: 0.024) during Cuvitru treatment. This annual rate of ASBIs was lower than 1.0 ASBIs/year (p < 0.0001), the threshold specified as providing substantial evidence of efficacy.
The summary of infections and associated events for subjects during subcutaneous treatment with Cuvitru is summarised in Table 7.
In the clinical study 170904, across all age groups, the median maximum infusion rate was 60 mL/h/site. This infusion rate was achieved in 57.3% (2480/4327) of completed Cuvitru infusions. Cuvitru infusion rate of 60 mL/h/site was achieved in 28.6% (6/21) of paediatric subjects (2 years to < 16 years of age), in 88.7% (47/53) of adults (16 years of age and older) and in 71.6% (53/74) of all subject. For more than half of Cuvitru infusions (2393/4327), a volume of 30 to 39 mL (1096/4327 infusions) or 40 to 49 mL (1297/4327 infusions) was infused per site. For 320/4327 of Cuvitru infusions, a volume of 60 mL/site or more was infused. Infusion parameters resulted in a median of 2 infusion sites (range: 1 to 4) per Cuvitru administration. During Cuvitru treatment, 84.9% (3662/4314) of infusions were administered using 1 infusion site (18.5%; 798/4314) or 2 infusion sites (66.4%; 2864/4314) across all ages. The median duration of infusions was less than 1 hour (0.95 h; range: 0.2-6.4 hours). During all treatment periods, 99.8% of infusions were completed without a reduction, interruption, or discontinuation for tolerability reasons. Infusion characteristics did not significantly differ between adult and paediatric subjects.
Throughout the study, health-related quality of life was assessed using the Paediatric Quality of Life Inventory (PEDS-QL) questionnaire (paediatric subjects) or the self-administered SF-36 survey (adult subjects). Quality of life was analysed separately for the age groups 2 to 4 and 5 to 7 years (PEDS-QL, observer: parent), 8 to 12 and 13 years (PEDS-QL, observer: subject) and 14 years and older (SF-36, observer: subject). Treatment satisfaction was measured using the Life Quality Index questionnaire (LQI) and the Treatment Satisfaction Questionnaire for Medication (TSQM-9). The LQI was assessed for the age group 2 years to 12 years (observer: parent) and the age group 13 years and older (observer: subject) in three domains: treatment interference, therapy-related problems and therapy settings. The TSQM-9 was assessed in subjects aged 2 to 12 years (observer: parent) and 13 years and older (observer: subject) in 3 domains: effectiveness, convenience and global satisfaction. Differences between scores during the intravenous study part and subcutaneous 20% study part were calculated for selected domains of the instruments, see Table 8.

5.2 Pharmacokinetic Properties

Following subcutaneous administration of Cuvitru, peak serum levels are achieved after approximately 3 days.
In a clinical trial 170903 with Cuvitru (n = 48), the subjects achieved sustained IgG trough levels (median 8.26 g/L) over a period of 52 weeks when receiving median weekly doses of 0.125 g/kg.
Data from the clinical trial 170903 of Cuvitru show that serum IgG trough levels can be maintained by dosing regimens of 0.3 to 1.0 g/kg body weight per 4 weeks.
The pharmacokinetics of Cuvitru were evaluated in the phase 3 efficacy and safety study in 31 patients with primary immunodeficiency (PID) aged 12 years and older. The pharmacokinetic results are presented in Table 9.
IgG and IgG-complexes are broken down in cells of the reticuloendothelial system.

Once weekly, biweekly or more frequent dosing (2-7 times per week).

Pharmacokinetic (PK) characterisation of biweekly or more frequent dosing of Cuvitru was undertaken using population PK-based modelling and simulation. Serum IgG concentration data consisted of 724 samples from 32 unique paediatric and adult subjects with PID. Compared with weekly administration, PK modelling and simulation predicted that administration of Cuvitru on a biweekly basis at double the weekly dose results in overlapping IgG exposure across an entire 2-week interval. In addition, PK modelling and simulation predicted that for the same total weekly dose, Cuvitru infusions given 2-7 times per week (frequent dosing) results also in overlapping IgG exposure across an entire 2-week interval.

Paediatric population.

There are no theoretical or observed differences in the pharmacokinetics of immunoglobulins in children compared to adults.

5.3 Preclinical Safety Data

Genotoxicity.

Cuvitru contains a human plasma derived native protein, which is not anticipated to possess genotoxic potential.

Carcinogenicity.

Cuvitru contains a human plasma derived native protein, which is not anticipated to possess carcinogenic potential.

6 Pharmaceutical Particulars

6.1 List of Excipients

Cuvitru contains the excipients listed in Table 10.

6.2 Incompatibilities

Administration of Cuvitru with other medicinal products is not recommended.

6.3 Shelf Life

24 months from date of manufacture.

6.4 Special Precautions for Storage

Store below 25°C (do not freeze). Keep the vial in the outer carton in order to protect from light.
Do not use after the expiry date printed on the carton and the label.

6.5 Nature and Contents of Container

Cuvitru is presented as a 20% (20 g/100 mL) solution for subcutaneous administration. The solution is dispensed into a glass vial and closed with a rubber stopper and aluminium crimp cap, with a plastic flip off disc providing a tamper evident seal.

Pack size.

The product is supplied in the following pack sizes:
1 g in a 5 mL solution;
2 g in a 10 mL solution;
4 g in a 20 mL solution;
8 g in a 40 mL solution.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Cuvitru has a purity ≥ 98% IgG and a pH of 4.6 to 5.1. The osmolality is 280-292 milliosmoles per kilogram. Cuvitru contains 200 mg/mL protein. The average immunoglobulin A (IgA) concentration is 0.08 mg/mL. Cuvitru contains a broad spectrum of IgG antibodies against bacterial and viral agents, glycine (which acts as a stabilising and buffering agent), and does not contain preservatives.

Chemical name.

Normal immunoglobulin (human).

Chemical structure.

The active ingredient in Cuvitru is a human polyvalent IgG. Immunoglobulins are made up of four polypeptide chains, comprising two identical light chains of a molecular weight of approximately 25 kD and two identical heavy chain of a molecular weight of approximately 50 kD. The four chains form a three-dimensional Y-shaped structure as shown by X-ray crystallography. Carbohydrate groups are attached covalently at a distinct position of the heavy chains. The overall molecular weight of IgG is approximately 150 kD.
Immunoglobulin G antibodies are the most common immunoglobulin class, with a level of 9-12 grams per litre of plasma, accounting for about 75% of the total immunoglobulins in plasma of healthy individuals. Immunoglobulin G is further divided into subclasses with different heavy chain isotypes: IgG1, IgG2, IgG3, and IgG4.

CAS number.

Normal immunoglobulin 20% (human): not available.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine (S4).

Summary Table of Changes