Consumer medicine information

Kiovig

Immunoglobulin, normal (human)

BRAND INFORMATION

Brand name

Kiovig

Active ingredient

Immunoglobulin, normal (human)

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Kiovig.

SUMMARY CMI

KIOVIG®

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 treated with KIOVIG?

KIOVIG contains the active ingredient normal immunoglobulin (human). KIOVIG is used for the treatment of patients who do not have sufficient antibodies (replacement therapy). KIOVIG is also used for the treatment of patients with certain inflammatory disorders (immunomodulation).

For more information, see Section 1. Why am I treated with KIOVIG? in the full CMI.

2. What should I know before treatment with KIOVIG?

Do not use if you have ever had an allergic reaction to immunoglobulins 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 treatment with KIOVIG? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with KIOVIG 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 is KIOVIG given?

  • KIOVIG is a 10% solution (100 mg/mL) for intravenous or a subcutaneous infusion.

More instructions can be found in Section 4. How is KIOVIG given? in the full CMI.

5. What should I know during treatment with KIOVIG?

Things you should do
  • Remind any doctor, dentist, or pharmacist you visit that you are being treated with KIOVIG
  • Tell your doctor, if you are suffering from an immunoglobulin A deficiency or planning to receive an immunization
  • Discuss with your doctor, the progress you have experienced following the treatment.
Things you should not do
  • Do not attempt to self-administer unless you have been trained by your healthcare professional
  • Use of KIOVIG during pregnancy or breast-feeding is not recommended.
Looking after your medicine
  • Store at 2°C to 8°C for up to 36 months. Refrigerate. Do not freeze.
  • Keep the container in the outer carton to protect from light.

For more information, see Section 5. What should I know during treatment with KIOVIG? in the full CMI.

6. Are there any side effects?

Infusion site side reactions include, redness, warmth, itching, swelling, mild or moderate pain and bruising. Side effects that may occur during infusion include, headache, migraine, chills, mild fever, fatigue, weakness, nausea, rash/hives, increased heart rate, abdominal pain, dizziness /increased blood pressure. Serious side effects: fever or other signs of an infection, chest pain or breathing problems, night sweats, reduced urination, sudden weight gain, or swelling in your legs, brown or red urine, fast heart rate, yellow skin, or eyes. Very serious side effects: hives, swelling in the mouth or throat, itching, trouble breathing, wheezing, fainting or dizziness; bad headache with nausea, vomiting, stiff neck, fever, and sensitivity to light; pain, swelling, warmth, redness, or a lump in your legs or arms; chest pain or trouble breathing, blue lips or extremities.

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

KIOVIG®

Active ingredient(s): normal immunoglobulin (human)

Consumer Medicine Information (CMI)

This leaflet provides important information about treatment with KIOVIG. 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 KIOVIG.

Where to find information in this leaflet:

1. Why am I treated with KIOVIG?
2. What should I know before treatment with KIOVIG?
3. What if I am taking other medicines?
4. How is KIOVIG given?
5. What should I know during treatment with KIOVIG?
6. Are there any side effects?
7. Product details

1. Why am I treated with KIOVIG?

KIOVIG contains the active ingredient human plasma derived immunoglobulin (IgG) protein.

KIOVIG belongs to a class of medicines called immunoglobulins. These medicines contain human antibodies, which are also present in your blood. Antibodies help your body to fight infections. Immunoglobulins are used in patients who do not have enough antibodies in their blood and tend to get frequent infections. They can also be used in patients who need additional antibodies for the treatment of certain inflammatory disorders.

The active component in KIOVIG, immunoglobulin, is isolated from the plasma of human donors. As required by the Regulatory Authority, the viral DNA testing procedures for finding out whether the collected bloods contain infectious viruses have been incorporated in the process. Possible viruses which may be present in the donated blood include hepatitis (A, B and C), human immunodeficiency virus (HIV), and parvovirus B19.

Further viral inactivation procedure has also been included during the manufacturing steps to reduce a potential viral transmission via KIOVIG administration. A three-step viral inactivation/reduction has been applied during the manufacturing of KIOVIG. 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 completely eliminated.

KIOVIG is used for:

Treatment of patients who do not have sufficient antibodies (replacement therapy):

  • Primary immunodeficiency disorders
  • Disease or medical treatment that leads to a lack of antibody production and frequent infection (secondary hypogammaglobulinemia).

Treatment of patients with certain inflammatory disorders (immunomodulation):

  • Idiopathic thrombocytopenic purpura (ITP, a disease where patients do not have enough blood platelets), who are at high risk of bleeding or prior to surgery to correct the platelet count.
  • Guillain Barré syndrome (a disease with multiple inflammations of the nervous system of the whole body)
  • Kawasaki disease (a disease which results in multiple inflammations of several organs)
  • Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in adults
  • Multifocal motor neuropathy (a rare condition characterised by slow progressive asymmetrical weakness of limbs without sensory loss).

2. What should I know before treatment with KIOVIG?

Warnings

Do not use KIOVIG if:

  • you are hypersensitive (allergic) to immunoglobulin, or any of the ingredients listed at the end of this leaflet
  • always check the ingredients to make sure you can use this medicine
  • you are suffering from an immunoglobulin A deficiency (lack of IgA antibodies), you may have antibodies against immunoglobulin A in your blood. Since KIOVIG contains small amounts of immunoglobulin A, you might develop an allergic reaction.

Check with your doctor if you:

  • are suffering from an immunoglobulin A deficiency
  • have or have had any kidney problem
  • have or have ever had cerebrovascular disease (such as a stroke) or cardiovascular disease (such as a heart attack or angina), including high blood pressure and narrowing or hardening of the arteries
  • have any heart condition or problem
  • are a smoker
  • have previously had a blood clot in your legs (deep vein thrombosis), lungs (pulmonary embolism) or other parts of your body
  • have immediate family members who have had blood clots in the legs, a heart attack, a stroke, or high cholesterol
  • diabetes
  • have any other medical conditions
  • are taking the contraceptive pill or hormone replacement treatment
  • are having difficulty in breathing or fatigue (anaemic).

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.

The use of KIOVIG during pregnancy or breast-feeding is not recommended, due to insufficient information in supporting of such usages. If there is a need to consider the use of this product during pregnancy, it should only be given in such condition if clearly needed. Ask your doctor about the risks and benefits involved.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any prescription medicine or any other medicines purchased from a pharmacy, health food store or supermarket. Some medicines and KIOVIG may interfere with each other.

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

4. How is KIOVIG given?

How much is given

  • KIOVIG is a 10% solution (100 mg/mL) of human immunoglobulin (IgG) for intravenous or subcutaneous infusion
  • Your doctor will decide how much KIOVIG will be given to you. Dosage will vary depending on your condition and your bodyweight. Each individual will receive a different dosage, which in itself may vary between doctor visits
  • Ask your doctor if you want to know more about the dose of KIOVIG you receive
  • Follow the instructions provided and use KIOVIG until your doctor tells you to stop.

How is KIOVIG given

  • KIOVIG is given as an intravenous (into a vein) or a subcutaneous (under the skin) infusion. Your doctor will decide which way is best for you.
  • At the beginning of your infusion, you will receive KIOVIG at a slow rate. Depending on how comfortable you are, your doctor may then gradually increase the infusion rate.
  • When given subcutaneously, the dose may be infused through several needles simultaneously. Do not exceed the recommended maximum amount given through each needle.
  • If your doctor decides that you may administer KIOVIG yourself, your doctor or nurse will teach you how to prepare and give the infusion subcutaneously (under the skin).
  • Do not attempt to administer KIOVIG yourself until you have been trained and understand the procedure and requirement of self-administration.
  • There is an Instruction Leaflet for subcutaneous administration inside the box which describes the procedures involved.
  • Ask your doctor any questions you may have about KIOVIG.

If you use too much KIOVIG

If you think that you have used too much KIOVIG, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know during treatment with KIOVIG?

Things you should do

Discuss with your doctor the progress you have experienced after the treatment, especially during the first few days. As KIOVIG is generally given in a hospital, your healthcare professional will take records of the progress and unexpected reactions.

You must tell your doctor if you are planning to receive an immunization.

Immunoglobulins may impair the effects of some virus vaccines such as mumps, rubella, and varicella for up to 6 months and for a year or more to measles (rubeola). Inform the immunising physician of recent therapy with KIOVIG so that appropriate precautions can be taken.

Remind any doctor, dentist, or pharmacist or any other health professionals you visit that you are using KIOVIG.

Driving or using machines

No information available. Be careful before you drive or use any machines or tools until you know how KIOVIG affects you.

Drinking alcohol

No information available.

Looking after your medicine

  • Store at 2°C to 8°C
  • Refrigerate. Do not freeze.
  • Do not use this medicine after the expiry date.

Keep the container in the outer carton to protect from light.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. Certain side effects, e.g., headache or flushing, may be reduced by slowing the infusion rate. However, some side effects may need medical attention.

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are under KIOVIG treatment.

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
At the site of infusion:
  • redness
  • warmth
  • itching
  • swelling
  • mild or moderate pain
  • bruising
During infusion:
  • headache
  • migraine
  • chills
  • mild fever
  • fatigue
  • weakness
  • nausea
  • rash/hives
  • increased heart rate
  • abdominal pain
  • dizziness /increased blood pressure
Speak to your doctor if you have any of these less serious side effects and they worry you.
These generally go away within a few hours and are less likely after the first few infusions.

Serious side effects

Serious side effectsWhat to do
  • Fever or other signs of an infection
  • Chest pain or breathing problems
  • Night sweats
  • Reduced urination, sudden weight gain, or swelling in your legs. These could be signs of a kidney problem.
  • Brown or red urine, fast heart rate, yellow skin, or eyes. These could be signs of a liver problem or a blood problem.
Tell your doctor as soon as possible if you notice any of these side effects
This list includes serious side effects that may require medical attention.
  • Hives, swelling in the mouth or throat, itching, trouble breathing, wheezing, fainting or dizziness. These could be signs of a serious allergic reaction.
  • Bad headache with nausea, vomiting, stiff neck, fever, and sensitivity to light. These could be signs of irritation of the lining around your brain.
  • Pain, swelling, warmth, redness, or a lump in your legs or arms. These could be signs of a blood clot.
  • Chest pain or trouble breathing, blue lips or extremities. These could be signs of a serious heart or lung problem.
Tell your doctor immediately or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.
This list includes very serious side effects. You may need urgent medical attention or hospitalisation.

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.

Reporting side effects

After you have received medical advice for any side effects 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

This medicine is only available with a doctor's prescription.

What KIOVIG contains

Active ingredientHuman plasma derived immunoglobulin (IgG) protein.
Other ingredientsGlycine, water for injections
Potential allergensKIOVIG contains a small amount of immunoglobulin A.

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

What KIOVIG looks like

KIOVIG is a clear or slightly opalescent and colourless or pale-yellow solution.

Do not use this medicine, if you notice particulate matter or discolouration of the solution.

KIOVIG is available in single use glass vials of:

1 g in 10 mL - AUST R 131953

2.5 g in 25 mL - AUST R 131966

5 g in 50 mL - AUST R 131968

10 g in 100 mL - AUST R 131969

20 g in 200 mL - AUST R 131973

30 g in 300 mL - AUST R 198488

Not all pack sizes may be distributed.

Who distributes KIOVIG?

KIOVIG is distributed in Australia by:

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

This leaflet was prepared in May 2022.

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

Published by MIMS February 2023

BRAND INFORMATION

Brand name

Kiovig

Active ingredient

Immunoglobulin, normal (human)

Schedule

S4

 

1 Name of Medicine

Normal immunoglobulin (human).

2 Qualitative and Quantitative Composition

Kiovig vials contain 1.0 g in 10 mL, 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].
For the full list of excipients, see Section 6.1 List of Excipients.

Description.

The active ingredient in Kiovig 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 (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), nanofiltration (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 Kiovig 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 in the normal human plasma origin. The distribution of the IgG subclasses formulated in this product comprises IgG1 ≥ 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 a 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 preservatives.

3 Pharmaceutical Form

Solution for intravenous and subcutaneous injection.

Appearance.

The solution is clear or slightly opalescent and colourless.

4 Clinical Particulars

4.1 Therapeutic Indications

Kiovig administered intravenously is indicated for:
1. Replacement therapy indications: primary immunodeficiency disorders (PID); symptomatic hypogammaglobulinaemia secondary to underlying disease or treatment.
2. Immunomodulation indications: idiopathic thrombocytopenia purpura (ITP), in patients at high risk of bleeding or prior to surgery to correct the platelet count; Guillain-Barré syndrome; Kawasaki disease; chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in adults; multifocal motor neuropathy (MMN).
Kiovig administered subcutaneously is indicated for:
1. Replacement therapy indications: primary immunodeficiency disorders (PID).

4.2 Dose and Method of Administration

Kiovig should be at room temperature during administration. Kiovig should be inspected visually for particulate matter and discoloration prior to administration. Do not use if particulate matter and/or discoloration is observed. Only clear or slightly opalescent and colourless or pale yellow solutions are to be administered. Kiovig should only be administered intravenously or subcutaneously. Other routes of administration have not been evaluated. The use of an in-line filter is optional.
Kiovig is recommended for administration by intravenous infusion for all indications. Kiovig may also be administered subcutaneously for replacement therapy in PID only (see Section 4.1 Therapeutic Indications).
See Section 4.4 Special Warnings and Precautions for Use about interchangeability of IVIGs.

For intravenous (IV) administration.

The dose and dosage regimen are dependent on the indication. In replacement therapy the dosage may need to be individualised for each patient depending on the pharmacokinetic and clinical response. The dosage regimens are given as a guideline below.

Recommended dose and dosage adjustment.

Dosage will vary depending on condition and bodyweight. The following doses are in agreement with currently suggested dosing schedules (see Table 1).
If the treatment is effective, long-term treatment should be subject to the physician's discretion based upon the patient response and maintenance response. The dosing and intervals may have to be adapted according to the individual course of the disease.
As there are significant differences in the half-life of IgG among patients with PID, the frequency and amount of immunoglobulin therapy may vary from patient to patient. The proper amount can be determined by monitoring clinical response. The minimum serum concentration of IgG necessary for protection varies among patients and has not been established by controlled clinical studies.

Dose adjustments for IV administration in MMN.

Intravenous immunoglobulin (IVIG) should be used for three to six months (three to six courses) before determining whether the patient has responded. Most individuals will respond within three months unless there is significant axonal degeneration whereby a six month course will be necessary. If there is no benefit after three to six courses, IVIg therapy should be abandoned.
Regular review by neurologist is required: frequency as determined by clinical status of patient. For stable patients on maintenance treatment, review by a neurologist is required at least annually. The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.

Rate of administration.

It is recommended that Kiovig be infused at an initial rate of 0.5 mL/kg/h. If the infusion at this rate and concentration does not cause the patient to have distress, the administration rate may be gradually increased.
During the first infusion of the phase 3 clinical study, Kiovig was infused at an initial rate of 0.5 mL/kg/h (0.8 mg/kg/min). The rate was gradually increased every 30 minutes to a rate of 5.0 mL/kg/h (8.9 mg/kg/min) if it was well tolerated. However, some patients completed the infusion before the maximum rate could be obtained.
During subsequent infusions, the initial rate and the rate of escalation were based on their previous infusion history; however, the maximum rate attained during the first infusion was used throughout the remainder of the study. A maximum tolerable infusion rate of up to 4 mL/kg/h was attained in majority (78.7%) of the patients, with a small proportion (19.7%) of patients achieving > 4 but < 6 mL/kg/h.
In general, it is recommended that patients beginning treatment with IVIG or switching from one IVIG brand to Kiovig be started at the lowest rate and then increased to the maximal rate if they have tolerated several infusions at intermediate rates of infusion. It is important to individualise rates for each patient.
In patients at risk for acute renal failure or thromboembolic adverse reactions, Kiovig should not be infused rapidly.
Although there are no prospective studies demonstrating that any concentration or rate of infusion is completely safe, it is believed that risk is decreased at lower rates of infusion. Therefore, as a guideline, it is recommended that these patients who are judged to be at risk of renal dysfunction or thrombotic complications be gradually titrated up to a more conservative maximal rate of less than 3.3 mg IgG/kg/min (< 2 mL/kg/h).
Certain adverse reactions such as headaches and flushing may be related to the rate of infusion. Slowing or stopping the infusion usually allows the symptoms to disappear promptly. The infusion may then be resumed at a rate that does not result in recurrence of the symptoms (see Section 4.8 Adverse Effects (Undesirable Effects)).
Adverse reactions may occur more frequently in patients who receive human normal immunoglobulin for the first time, when they switch from another IVIG brand, or when there has been a long interval since the previous infusion (see Section 4.8 Adverse Effects (Undesirable Effects)).
Trough levels should be measured in order to adjust the dose and dose intervals in particular patients with primary immunodeficiency syndrome.
Kiovig is recommended for infusion at a concentration of 10%. If Kiovig must be diluted, 5% glucose in water should be used as a diluent. Normal saline should not be used as a diluent though it may be used to flush intravenous lines.
Dilution with 5% glucose solution may result in increased blood glucose levels. This should be taken into account in case of diabetic patients or patients on low sugar diet.

For subcutaneous (SC) administration.

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 refer to the instruction leaflet for subcutaneous administration in the package insert.
Subcutaneous dosage. Prior to switching from intravenous to subcutaneous treatment, obtain the patient's serum IgG trough level to guide subsequent dose adjustments. Start the initial subcutaneous dose approximately one week after the last intravenous infusion in a patient who has been on stable intravenous therapy. Convert the intravenous dose into weekly equivalents and recheck the serum IgG trough level after several months. The level should be the same or higher than when treated intravenously. Because there is a wide variation in metabolism of IgG between patients with immune deficiency diseases, it is important to individualise dosing. The most important factor when determining dosage of IgG is the clinical response of the patient.
Subcutaneous administration. Use of an infusion pump and multineedle administration set is recommended.
Selection of infusion site.

Volume per site.

The recommended maximum volume is 30 mL/site for patients above 40 kg and 20 mL/site for patients under 40 kg. The weekly dose (mL) should be divided by 30 or 20, based on patient weight above, to determine the number of sites required. Simultaneous subcutaneous infusion at multiple sites can be facilitated by use of a multineedle administration set.
Rate of infusion.

Patients over 40 kg.

For the first infusion, the recommended maximum rate of infusion of Kiovig is 20 mL/h/site. For subsequent infusions, the flow rate should be adjusted as tolerated to a maximum of 30 mL/h/site. If multiple sites are used, the rate set on the pump should be the rate per site multiplied by the number of sites (e.g. 30 mL x 4 sites = 120 mL/h). The number of simultaneous sites should be limited to 8, or maximum infusion rate of 240 mL/h.

Patients under 40 kg (88 lbs).

for the first infusion, the recommended maximum rate of infusion of Kiovig is 15 mL/h/site. For subsequent infusions, the flow rate should be adjusted as tolerated to a maximum of 20 mL/h/site. If multiple sites are used, the rate set on the pump should be the rate per site multiplied by the number of sites (e.g. 20 mL x 3 sites = 60 mL/h). The number of simultaneous sites should be limited to 8, or maximum infusion rate of 160 mL/h.

4.3 Contraindications

Kiovig, IgG 10% solution is contraindicated in patients with known anaphylactic or severe hypersensitivity responses to normal immunoglobulin (human). Patients with severe selective immunoglobulin A (IgA) deficiency (IgA < 0.05 g/L) may develop anti-IgA antibodies that can result in a severe anaphylactic reaction.
Anaphylaxis can occur using Kiovig, IgG 10% solution even though it contains low amounts of IgA (average concentration of 37 microgram/mL). These patients should be treated only if their IgA deficiency is associated with an immune deficiency for which therapy with IVIG is clearly indicated. Such patients should only receive IVIG with utmost caution and in a setting where supportive care is available for treating life threatening reactions.

4.4 Special Warnings and Precautions for Use

Infusions of immunoglobulin have been associated with thromboembolic events and impaired renal function, including acute renal failure. Risk is increased in patients with pre-existing impaired renal function, and cardiovascular risk factors such as hypertension, history of cardiac disease, hyperviscosity, poor ambulation. Risk of these events may be increased with rapid rates of infusion and high (1-2 g/kg) doses of IgG. Risk can be reduced by ensuring adequate hydration before administration and using slower rates of infusion in patients considered to be at high risk of renal dysfunction or cardiovascular disease. In subjects with impaired renal function consider monitoring urine output and serum creatinine, and avoiding loop diuretics and sucrose containing IVIG products.
Intravenous infusions of IVIG have been associated with an aseptic meningitis syndrome (AMS) with severe headache, nuchal rigidity, cerebrospinal fluid (CSF) pleocytosis and elevated CSF protein. Symptoms can begin during and up to 48 hours after an infusion. It is thought that the risk is increased with higher (1-2 g/kg) doses of IVIG and in subjects with frequent headaches, especially migraine headaches. Consider slower rates of infusion for such patients.
In case of these events, either the rate of administration must be reduced or the infusion stopped. 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 recommended that subcutaneous infusions not be given to patients with ITP due to the increased risk of bleeding and hematoma.
While IVIGs are interchangeable, they are not therapeutically equivalent in terms of efficacy and safety profiles.

Infusion related precautions.

Certain adverse reactions such as headache, flushing and changes in pulse rate and blood pressure may be related to the rate of infusion (see Section 4.2 Dose and Method of Administration). The recommended infusion rate given (see Section 4.2 Dose and Method of Administration) must be closely followed.
Potential complications can often be avoided by ensuring that patients are carefully monitored for any symptoms throughout the infusion period. Patients naive to human normal immunoglobulin, patients switched from an alternative product to Kiovig, 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.
Slower rates of infusion should be considered for the following:
patients with hypo- or agammaglobulinemia with or without IgA deficiency;
patients who receive human normal immunoglobulin for the first time or, when the human normal immunoglobulin product is switched or when there has been a long interval since the previous infusion;
patients at risk for acute renal failure or thromboembolic adverse reactions; and
patients who have underlying renal disease or who are judged to be at risk of developing thrombotic events.

Hyperproteinemia, increased serum viscosity and hyponatremia.

Hyperproteinemia, increased serum viscosity and hyponatremia may occur in patients receiving IVIG products, including Kiovig. It is clinically critical to distinguish true hyponatremia from a pseudohyponatremia that is associated with concomitant decreased calculated serum osmolality or elevated osmolar gap; because treatment aimed at decreasing serum free water in patients with pseudohyponatremia may lead to volume depletion, a further increase in serum viscosity and a possible predisposition to thromboembolic events.

Viral transmission.

This product 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. Despite the use of those rigorous tests and triple viral inactivation (TVR), as discussed in the Description, a possibility of transmitting infectious agent cannot be totally excluded. This also applies to unknown or emerging viruses or other pathogens.
Some viruses, such as parvovirus B19 (B19V) or hepatitis A (HAV), are particularly difficult to remove or inactivate. B19V most seriously affects pregnant women, or immunocompromised individuals or those with increased erythropoiesis (e.g. haemolytic anaemia). Symptoms of B19V infection include fever, drowsiness, chills and runny nose followed about two weeks later by rash and joint pain. Evidence of HAV may include several days to weeks of poor appetite, tiredness, and low grade fever followed by nausea, vomiting and abdominal pain. Dark urine and yellowed complexion are also common symptoms. Patients should be encouraged to consult their physician if such symptoms appear.
Appropriate vaccinations (hepatitis A and B) should be considered for immune competent patients who receive regular/ repeated treatment with Kiovig.
It is strongly recommended that every time Kiovig is administered to a patient, the name and batch number of products are recorded in order to maintain a link between the patient and the batch of the product.

Hypersensitivity reactions including anaphylaxis.

As with any intravenous product, in particular with a protein substance, allergic type hypersensitivity reactions are possible. Anaphylaxis has been reported with the intravenous use of Kiovig and is theoretically possible following subcutaneous administration. Prior to commencing subcutaneous therapy, it is recommended that patients should be on stable Kiovig intravenous therapy that is administered where there are adequate life support facilities and health care professionals prepared to manage anaphylaxis. Patients should be informed of the signs of hypersensitivity reactions including hives, generalised urticaria, and tightness of the chest, wheezing, hypotension and anaphylaxis and trained in the proper recognition and management of these serious reactions. If these symptoms occur, they should be advised to discontinue use of the product immediately, initiate appropriate treatment, and seek urgent medical attention. In the case of anaphylactic shock, the current medical standards for shock treatment should be implemented. 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. Patients with antibodies to IgA may be at increased risk of anaphylactic reaction.

Serious warning.

Intravenously administered normal immunoglobulin (human) products have been reported to be associated with renal adverse reactions including renal dysfunction, acute renal failure, acute tubular necrosis, proximal tubular nephropathy, osmotic nephrosis, and death. Patients predisposed to acute renal failure include patients with any degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65 years, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. Especially in such patients, adequate hydration is essential and IVIG products should be administered at the minimum concentration available and the minimum rate of infusion practicable. While these reports of renal dysfunction and acute renal failure have been associated with the use of many of the licensed IVIG products, those containing sucrose as a stabiliser accounted for a disproportionate share of the total number.
Formulation of Kiovig, IgG 10% solution uses glycine, an amino acid as a stabiliser and it does not contain sucrose. The physician should discuss the risks and benefits of this product with the patient.

Renal function.

Periodic monitoring of renal function tests and urine output is particularly important in patients judged to have a potential increased risk for developing acute renal failure. Assure that patients are not volume depleted prior to the initiation of infusion of Kiovig. Renal function, including measurement of blood urea nitrogen (BUN)/ serum creatinine, should be assessed prior to the initial infusion of IVIG products and again at appropriate intervals thereafter. If renal function deteriorates, discontinuation of the product should be considered.
Severe renal adverse reactions have been reported in patients receiving IVIG treatment and are theoretically possible following subcutaneous administration, particularly when using those products containing sucrose (Kiovig does not contain sucrose). These include acute renal failure (including Kiovig administered intravenously), acute tubular necrosis, proximal tubular nephropathy and osmotic nephrosis.

Haemolysis.

Kiovig contains blood group antibodies that may act as haemolysins and induce in vivo coating of red blood cells (RBC) with immune globulin. This may cause a positive direct antiglobulin test (DAT) (Coombs' test). Delayed haemolytic anaemia can develop subsequent to Kiovig therapy due to enhanced RBC sequestration; acute haemolysis, consistent with intravascular haemolysis, has been reported.
The following risk factors may be related to the development of haemolysis: high doses (single administration or divided over several days) and non-O blood group. Underlying inflammatory state in an individual patient may increase the risk of haemolysis but its role is uncertain.
If signs and/or symptoms of haemolysis are present after Kiovig infusion, appropriate confirmatory laboratory testing should be done.

Thrombotic and thromboembolic events.

Thrombotic and thromboembolic events have been reported in association with IVIG treatment (including Kiovig administered intravenously), and are possible following subcutaneous administration. These include myocardial infarction, cerebral vascular accident, deep vein thrombosis and pulmonary embolism (see Section 4.8 Adverse Effects (Undesirable Effects)). Thrombotic events have also been reported with subcutaneous administration of immunoglobulin. 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. The potential risks and benefits of IVIG should be weighed against those of alternative therapies for all patients for whom IVIG administration is being considered. Baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/ markedly high triacylglycerols (triglycerides).

Aseptic meningitis syndrome.

An aseptic meningitis syndrome (AMS) has been reported to occur in association with immunoglobulin treatment (including Kiovig administered intravenously). Discontinuation of IVIG treatment has resulted in remission of AMS within several days without sequelae. The syndrome usually begins within several hours to two days following IVIG treatment. It is characterised by symptoms and signs including severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, and nausea and vomiting. Cerebrospinal fluid (CSF) studies are frequently positive with pleocytosis up to several thousand cells per cubic mm, predominantly from the granulocytic series, and elevated protein levels up to several hundred mg/dL. Patients exhibiting such symptoms and signs should receive a thorough neurological examination, including CSF studies, to rule out other causes of meningitis. AMS may occur more frequently in association with high dose (2 g/kg) IVIG treatment.
AMS may occur more frequently in female patients.

IgA deficiency.

Kiovig is not indicated in patients with IgA deficiency where the IgA deficiency is the only abnormality of concern. These patients should be treated only if their IgA deficiency is associated with an immune deficiency for which therapy with intravenous immunoglobulin is clearly indicated.

Noncardiogenic pulmonary oedema.

There have been reports of noncardiogenic pulmonary oedema or transfusion related acute lung injury (TRALI), in patients administered IVIG (including Kiovig administered intravenously).

Paediatric use.

The safety and effectiveness of Kiovig have been established in the age groups 2 to 16. Use of Kiovig in these age groups is supported by evidence from adequate and well controlled studies of Kiovig including paediatric subjects. Kiovig administered intravenously was evaluated in 15 paediatric subjects with PID (7 were 2 to < 12 years old and 8 were 12 to < 16) in a multicentre clinical study. Kiovig administered subcutaneously was evaluated in 18 paediatric subjects with PID (14 were 2 to < 12 years old and 4 were 12 to < 16) in another multicentre clinical study (see Section 5.1 Pharmacodynamic Properties, Clinical trials). There were no differences in the safety and efficacy profiles as compared with adult subjects. No paediatric specific dose requirements were necessary to achieve the desired serum IgG levels.
Safety and efficacy of Kiovig in paediatric patients below the age of 2 have not been established.
The use of Kiovig in the treatment of CIDP in the paediatric population has not been established.

Use in the elderly.

Limited information is available for the geriatric use of Kiovig. Intravenous administration of Kiovig was evaluated in 4 subjects over the age of 65 years, ranging from 67 to 71 years. No overall differences in safety or efficacy were observed for this group. However, caution should be exercised in administering Kiovig to patients who are at an increased risk for developing renal failure or thromboembolic events. For intravenous administration, infuse Kiovig at a rate less than 3.3 mg IgG/kg/min (< 2 mL/kg/hr) for patients over 65 years of age. Do not exceed the recommended dose, and infuse Kiovig at the minimum infusion rate practicable. (See Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration).
Subcutaneous administration of Kiovig was evaluated in 4 PID subjects over the age of 65 years. No overall differences in safety or efficacy were observed for this group.

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 Kiovig 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

Antibodies in IVIG products may interfere with patient responses to live vaccines, such as those for measles, mumps, rubella and varicella. The immunising physician should be informed of recent therapy with IVIG products so that appropriate precautions can be taken.
Admixtures of Kiovig with other drugs and intravenous solutions have not been evaluated. It is recommended that Kiovig be administered separately from other drugs or medications that the patient may be receiving. The product should not be mixed with IVIG products from other manufacturers.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Kiovig contains a human plasma derived native protein, which is not anticipated to have an adverse effect on fertility.
(Category B2)
There are no adequate data from the use of Kiovig in pregnant women.
Maternally administered IVIG products have been shown to cross the placenta, increasingly during the third trimester. Physicians should balance the potential risks and only prescribe Kiovig if clearly needed.
 Safety of Kiovig for use during lactation has not been established. Use this product in a nursing woman only when clearly needed and the potential benefits outweigh the potential risks to the baby.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Intravenous (IV) administration.

Adverse reactions may occur more frequently in patients who receive human normal immunoglobulin for the first time, when they switch from another IVIG brand, or when there has been a long interval since the previous infusion.
Adverse reactions such as chills, headache, 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.
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug related adverse events and for approximating rates.
Adverse reactions from Kiovig clinical trials (studies 160001, 160002, 160101, 160601 Epoch 1, 160602, 160603 Epoch 1, 160604, 160902, 160701, 161003, 161202) are shown in Table 2:

Primary immune deficiency.

Two serious adverse events were reported in the PID clinical trials, 2 episodes of aseptic meningitis in one patient. It is not possible to come to any conclusions regarding risk factors by indication, dose, or individual patient characteristics. See Table 3.

Idiopathic thrombocytopenic purpura (ITP).

Headache was reported more frequently in ITP patients than in PID or MMN, however, no patients in the ITP study reported migraine, which occurred commonly in the other patient populations. Muscle spasms and pain in extremity were common for patients with ITP but uncommon for other indications. See Table 4.

Multifocal motor neuropathy (MMN).

One serious adverse event, pulmonary embolism, was reported in the MMN clinical trial. Due to the low incidence of pulmonary embolism, it is not possible to come to any conclusions regarding risk factors by indication, dose, or individual patient characteristics.
Muscle twitching and weakness were reported only in patients with MMN and may also be related to their underlying neuromuscular condition. See Table 5.

Infusion related adverse events.

Certain adverse reactions such as headache, flushing and changes in pulse rate and blood pressure may occur.
Subcutaneous (SC) administration. The safety of Kiovig subcutaneous infusion was evaluated in a prospective, open label, noncontrolled, multicentre clinical study in the 47 subjects who received at least one dose of subcutaneous treatment.
One subject withdrew from the study after 10 treatments with Kiovig subcutaneous infusion (2.5 months), due to increased fatigue and malaise. No serious adverse events (SAEs) occurred during subcutaneous treatment.
The most common adverse drug reactions (ADRs) with subcutaneous infusion of Kiovig observed in ≥ 5% of study subjects in the clinical trial were local infusion site reactions (e.g. swelling, redness, pain), as well as systemic reactions of headache, fever, fatigue, increased heart rate, increased systolic blood pressure, and upper abdominal pain.
Of the 632 nonserious adverse events (AEs), the most frequent AEs, regardless of causality, and the most frequent temporally associated AEs, which occurred in ≥ 10% subjects.
There were 150 AEs considered to be related to Kiovig use. Of the nonserious AEs related to Kiovig use, 124 (83%) were mild (transient discomfort that resolves spontaneously or with minimal intervention), 24 (16%) were moderate (limited impairment of function and resolves spontaneously or with minimal intervention with no sequelae), and 2 were severe (marked impairment of function or can lead to temporary inability to resume normal life pattern); requires prolonged intervention or results in sequelae. Neither of the severe AEs required hospitalisation or resulted in sequelae. See Table 6.

Local adverse events.

The incidence of local AEs by MedDRA term during all Kiovig subcutaneous treatment is shown in Table 7.
The overall rate of local AEs (excluding infections) during the subcutaneous treatment periods was 2.8% per infusion. In subcutaneous naïve patients, the incidence of local AEs (N = 1757 infusions) was 3.3% (2.6% mild and 0.7% moderate with no severe AEs). In the subjects who were subcutaneous experienced (N = 537 infusions), the incidence of local AEs was 1.1% (1.1% mild, and no moderate or severe AEs).
In the clinical study after all subcutaneous doses were adjusted, all subjects but one reached the maximum rate allowed in the protocol, 20 mL/site/hour if weight was below 40 kg and 30 mL/hour for weight above 40 kg, for one or more of the infusions. 70% (31 of 44) of these subjects opted for the highest rate for all infusions. No subject restricted the rate due to an ADR. In the clinical study, median duration of each weekly infusion was 1.2 hours (range: 0.8-2.3 hours) after all subcutaneous doses were adjusted. The rate set on the pump was that rate per site multiplied by the number of sites, with no maximum.
During all subcutaneous treatment periods, 99.8% of infusions were completed without a reduction, interruption, or discontinuation for tolerability reasons. The proportion of subjects who experienced local AEs (excluding infections) was highest immediately following the switch from intravenous to subcutaneous treatment in all age groups. Over subsequent subcutaneous infusions, there was a decrease of local AEs. The rate of all local AEs per infusion immediately after switching from intravenous to subcutaneous therapy was 4.9% (29/595), decreasing to 1.5% (8/538) by the end of the study and to 1.1% (10/893) in the study extension.
Eight (17%) subjects experienced a local adverse reaction during the first infusion, but that decreased to 1 (2.1%) for the subsequent infusions, ranging from 0 to 4 (8.7%) during the first year of subcutaneous therapy. No subject reported a local adverse reaction from week 53 to end of study at week 68.

Postmarketing adverse reactions.

In addition to the adverse reactions noted in clinical trials, the following adverse reactions have been reported in the postmarketing experience. These adverse reactions are listed by system order class (SOC), then by preferred MedDRA term in order of severity.
Intravenous administration.

Blood and lymphatic system disorders.

Haemolysis.

Immune system disorders.

Anaphylactic shock, anaphylactic reaction, hypersensitivity.

Nervous system disorders.

Cerebral vascular accident, transient ischemic attack, tremor.

Cardiac disorders.

Myocardial infarction.

Vascular disorders.

Myocardial infarction, deep vein thrombosis, hypotension.

Respiratory, thoracic and mediastinal disorders.

Pulmonary embolism, pulmonary oedema, dyspnoea.

Skin and subcutaneous tissue disorders.

Hyperhidrosis, exfoliative dermatitis.

Injury, poisoning and procedural complications.

Transfusion related acute lung injury.

General disorders and administration site conditions.

Chest pain, chills.

Investigations.

Coombs' direct test positive, oxygen saturation decreased.
Subcutaneous administration.

Immune system disorders.

Hypersensitivity.

Musculoskeletal and connective tissue disorders.

Myalgia.

General disorders and administration site conditions.

Chills.

Class reactions.

Subcutaneous administration.

Postmarketing ADRs have not been reported with Kiovig administered subcutaneously. However, the following additional ADRs have been identified and reported during the postmarketing use of another subcutaneous immune globulin product: anaphylactic reaction, paresthesia, tremor, tachycardia, hypotension, dyspnoea, laryngospasm, chest discomfort, injections site reaction (including 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 reaction at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

With intravenous administration, overdose may lead to fluid overload and hyperviscosity. Patients at particular risk of complications of fluid overload and hyperviscosity include elderly patients and patients with cardiac or renal impairment.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Immunological mode 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 intravenous immunoglobulin (IVIG) 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 Kiovig, IgG 10% w/v, is a plasma derived immunoglobulin isolated from a 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.

Clinical trials.

Clinical studies of intravenous (IV) administration.

Efficacy and safety of Kiovig, 10% IVIG solution, was assessed in three clinical studies, a European study in 22 patients with hypo- or agammaglobulinemia, a US study in 61 patients with PID, and a European study in 23 patients with idiopathic thrombocytopenia purpura (ITP). None of these studies were designed to compare Kiovig with another IVIG product.
The use of Kiovig, 10% IVIG solution in patients with PID is supported by phase 3 clinical study 160101 in subjects who were treated with 300 to 600 mg/kg every 21 to 28 days for 12 months. The 61 subjects in this study were between 6 to 72 years of age, 54% female and 46% male, and 93% Caucasian, 5% African-American, and 2% Asian. The description of this study is shown in Table 8.
Three subjects were excluded from the protocol analysis due to nonstudy product related reasons. The primary efficacy endpoint was the annualised rate of specified acute serious bacterial infections, i.e. the mean number of specified acute serious bacterial infections per subject per year (see Table 9).
The secondary efficacy endpoints in this study were the annualised rate of other specified validated bacterial infections and the number of hospitalisations secondary to infectious complications (see Table 10). In this study, there were no validated acute serious bacterial infections in any of the treated subjects. The annualised rate of acute serious bacterial infections was significantly less than (p < 0.0001) the rate of one infection per year, in accordance with recommendations by the FDA Blood Products Advisory Committee. Four of the 61 subjects reported a total of 4 other specified validated bacterial infections. None were serious or severe, none resulted in hospitalisation, and all resolved completely.
The rate of all clinically defined but nonvalidated infections was 3.4 infections per patient per year. These consisted primarily of recurrent episodes of common infections in this patient population (sinusitis, bronchitis, nasopharyngitis, urinary tract infections, and upper respiratory infections).

Multifocal motor neuropathy (MMN).

A randomised withdrawal, double blind, placebo controlled, crossover study 160604 was conducted to evaluate the efficacy and safety/ tolerability of Kiovig in 44 adult subjects with MMN. The study examined grip strength in the more affected hand (measured with dynamometer), and Guy's Neurological Disability Scale (GNDS) [upper limb part 6 subsection].
The median monthly dose of IVIG, 10% administered was 1.2 g/kg BW (range: 0.5 to 2.4). Subjects were treated at infusion cycles of 2, 3 or 4 weeks, the dose for each infusion cycle being administered either in a single infusion or divided over a maximum of 5 consecutive days.
Study subjects were on a regimen of licensed immunoglobulin (existing maintenance dose ranging from 0.5 to 2.0 g/kg/month) prior to enrolment. The clinical trial was an enrichment design; therefore, the results cannot be generalised to naïve patients. Each subject completed a five part, 12 week study (3 stabilisation phases, one randomised withdrawal and one crossover period). If, during the double blinded treatment period, the subject's upper limb function involving the affected muscles deteriorated, such that the subject had difficulty completing daily activities or the subject experienced a decline in grip strength of ≥ 50% in the more affected hand, the subject was switched directly to the next stabilisation phase of open label Kiovig (accelerated switch) without breaking the blind.
All subjects were treated for 12 weeks with Kiovig during the initial stabilisation (stabilisation 1) phase. In the crossover 1 period, each subject was then randomised to either withdrawal from Kiovig to placebo or continue Kiovig for a period of 12 weeks and then transferred to stabilisation phase 2. Subjects that did not tolerate the treatment during the double blind crossover period were immediately transferred to open label Kiovig stabilisation phase 2.
Following stabilisation phase 2, the subjects were assigned to a second double blind treatment for 12 weeks to either placebo or Kiovig depending on randomisation received in crossover period 1. No subject was allowed to experience placebo more than one time during the clinical study. Following this period, the subjects were further stabilised for 12 weeks on open label Kiovig, stabilisation phase 3.
Sixty nine percent (n = 29) required an accelerated switch to open label treatment with Kiovig during the placebo period due to functional deterioration, but did not switch when receiving Kiovig. The median treatment days for treatment with Kiovig was 84 days and the median treatment days for the placebo was 28 days. Only one subject (2.4%) switched to open label treatment during blinded Kiovig crossover period 1 but did not switch during placebo administration (p < 0.001).
Forty four subjects were evaluated to demonstrate effectiveness of Kiovig to improve or maintain muscle strength and functional ability in patients with MMN.
Statistical significance in favour of Kiovig over placebo was demonstrated by a substantially lower decline from baseline (22.30%; 95% CI: 9.92% to 34.67%) in the mean grip strength in the more affected hand following treatment (see Table 11). The difference in relative change for Kiovig and placebo of 22.94% (95% CI: 10.69 to 35.19) was statistically significant (p < 0.001).
Guy's Neurological Disability Scores (GNDS) for the upper limbs, reflecting both fine motor skills and proximal strength, showed a significant difference in efficacy between Kiovig and placebo at the 2.5% level in favour of Kiovig. GNDS is a patient orientated clinical disability scale designed for multiple sclerosis and is considered appropriate for other neurological disorders.
As determined by GNDS scores for the upper limbs, 35.7% of subjects deteriorated while receiving the placebo, but not during treatment with Kiovig whereas 11.9% of subjects deteriorated during Kiovig but not over the placebo period. This difference was statistically significant (p = 0.021) (see Table 12). 4.8% of subjects showed deterioration with both placebo and Kiovig, while 47.6% showed no deterioration on either.
When data from both treatment sequences were combined, a relative decline of ≥ 30% in grip strength in the more affected hand occurred in 42.9% of subjects during the placebo period, but not during treatment with Kiovig. 4.8% of subjects experienced a ≥ 30% decline during treatment with Kiovig, but not during placebo. A relative decline of ≥ 30% in grip strength in the less affected hand occurred in 31.0% of subjects during the placebo period, but not during treatment with Kiovig. No subject experienced a ≥ 30% decline during treatment with Kiovig.
The Overall Disability Sum Score (ODSS) changed by -7.14% during placebo (indicating worsening of disability), and by -1.11% (indicating no change in disability) during treatment with Kiovig.
At the end of the placebo period, subjects required 17% longer to complete the 9 hole peg test (a measure of dexterity) with the dominant hand, and 33% longer with the nondominant hand, compared to baseline. During Kiovig treatment, dexterity increased by a mean of 1.2% compared to baseline in the dominant hand and 6.7% in the nondominant hand.
Compared to baseline, patients' assessment of physical functioning, as measured by visual analogue scale (VAS), showed a mean change of 290% during placebo compared to baseline. Patient's assessments of physical functioning showed a mean change of 73% during Kiovig treatment. Higher visual analogue scale scores represent more severe disability.

Clinical study of subcutaneous (SC) administration.

A prospective, open label, nonrandomised, multicentre study was conducted to determine the pharmacokinetic equivalence of Kiovig subcutaneous infusion in 49 adult and paediatric subjects with PID. Rates of acute serious bacterial infections, overall infection rate, safety and tolerability were analysed as secondary efficacy endpoints. All subjects were treated for 12 weeks with Kiovig intravenous infusion every 3 or 4 weeks. Subjects who were on intravenous therapy prior to entering the study were switched to Kiovig at the same dose and frequency. Subjects who were receiving subcutaneous immunoglobulin were switched to Kiovig at the intravenous dose they had been given prior to switching to subcutaneous therapy. A PK analysis was performed at the end of the intravenous period in all subjects aged 12 years and older.
One week after the last intravenous infusion, each subject began subcutaneous therapy with Kiovig at 130% of the weekly equivalent of the intravenous dose for a minimum of 12 weeks. PK data from the first 15 adult subjects were used to determine the dose required to ensure that the IgG exposure with subcutaneous therapy was not inferior to that with intravenous therapy. The median dose determined from these subjects was 137% of the intravenous dose, and subsequently all subjects were treated for a minimum of 6 weeks at this dose. After 6 subcutaneous infusions, a trough IgG level was obtained and used to individually adapt the subcutaneous dose of Kiovig to compensate for individual variation from the mean value of 137%. All subjects received a minimum of 12 infusions at this individually adapted dose. Following the formal protocol, all subjects continued to receive subcutaneous treatment with Kiovig until the last subject completed the study. There were 47 subjects treated with 2,294 subcutaneous infusions of Kiovig: 4 subjects treated for up to 29 weeks, 17 subjects for 30 to 52 weeks, and 26 subjects for 53 weeks or longer. The median duration of subcutaneous treatment was 379 days (range: 57 to 477 days).
Efficacy was determined throughout the entire subcutaneous phase. There were 31 adults 16 years or older, 4 adolescents between 12 and < 16 years of age, and 14 children between 2 years and < 12. The volume of Kiovig infused was 30 mL per site for patients weighing 40 kg or more, and 20 mL per site for those weighing less than 40 kg. The total weekly dose was divided by those values to determine the number of sites.
Mean weekly subcutaneous doses ranged from 181.9 mg/kg to 190.7 mg/kg (at 130% to 137% of the intravenous dose). In the study, the number of infusion sites per infusion was dependent on the dose of IgG and in 73% of infusions, the number of infusion sites was 5 or fewer.
There were 3 serious validated bacterial infections, all bacterial pneumonia. None of these subjects required hospitalisation to treat their infection. The annual rate of acute serious bacterial infections while on Kiovig subcutaneous treatment was 0.067, with an upper 99% confidence limit of 0.133, which is lower than the minimal goal of achieving a rate of < 1 bacterial infection per patient year.
The summary of infections and associated events for subjects during subcutaneous therapy with Kiovig is summarised in Table 13. The annual rate of any infection in this study during subcutaneous therapy, including viral and fungal infections, was 4.1 infections per subject per year. This is consistent with the rate of infections observed in other clinical studies of intravenous and subcutaneous immunoglobulin.

5.2 Pharmacokinetic Properties

Intravenous administration.

Normal immunoglobulin (human) is immediately and completely bioavailable in the recipient's circulation after intravenous administration. It is rapidly and nearly evenly distributed between plasma and extravascular fluid; after approximately 3-5 days equilibrium is reached between the intra- and extravascular compartments.
Pharmacokinetic parameters for Kiovig were assessed, in a prospective, open label, noncontrolled, multicenter study design, clinical study 160001, in 22 subjects suffering from primary immunodeficiency (PID) with a clinical condition as hypo- and agammaglobulinemia. Subjects were initially treated with three infusions of Kiovig at a dose of 300 to 450 mg/kg bodyweight/infusion given every 3 weeks to standardise the IgG replacement therapy of all subjects to the same intravenous product and to acquire data with a licensed product. This is followed by treatment with Kiovig of 10% IgG solution with a dose of 300-450 mg/kg bodyweight/3 weeks for the remaining 9 infusions.
These regimens have been shown to be adequate to maintain IgG trough levels at or above the typically accepted threshold of 400 to 600 mg/dL. All pharmacokinetic parameters were calculated for individual subjects for total IgG and IgG subclasses (IgG1, IgG2, IgG3 and IgG4); whilst for the vivo recovery was assessed only on the basis of the total IgG plasma level.
The results of the pharmacokinetic parameters are shown in Table 14. As shown in the table, Kiovig had a half-life of about 30 days. This half-life may vary from patient to patient, in particular, in PID. The values obtained are comparable to parameters reported for other human immunoglobulins.

Subcutaneous administration.

Pharmacokinetic (PK) parameters of subcutaneously administered Kiovig were evaluated in subjects with PID who were 12 years and older during a clinical study (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Clinical study of subcutaneous (SC) administration). Subjects were treated intravenously for 12 weeks with Kiovig and then switched to weekly subcutaneous Kiovig infusions. Initially, all subjects were treated for a minimum of 12 weeks at a subcutaneous dose that was 130% of the intravenous dose. A comparison of the area under the curve (AUC) for intravenous and subcutaneous infusions done on the first 15 adult subjects determined that the subcutaneous dose required to provide an exposure from subcutaneous administration that was not inferior to the exposure from intravenous administration was 137% of the intravenous dose. Subsequently, all subjects were treated with this dose for 6 weeks after which the dose was individualised for all subjects using the trough IgG levels, as described below. After a minimum of 8 weeks at this subcutaneous dose, the PK evaluation was conducted on 32 subjects 12 years of age or older.
The mean adjusted dose at the end of the study was 137.3% (125.7 to 150.8) of the intravenous dose for subjects 12 years and older, and 141.0% (100.5 to 160.0) for subjects under the age of 12. Thus, there was not a significant dosing difference required for children. At this dose adjustment, the geometric mean ratio of the AUC for subcutaneous vs intravenous Kiovig administration was 95.2% (90% confidence limit 92.3 to 98.2). The peak IgG level occurred 2.9 (1.2 to 3.2) days after subcutaneous administration.
The pharmacokinetic parameters of Kiovig administered intravenously compared to subcutaneously in the clinical trial are shown in Table 15. The mean peak IgG levels were lower (1393 ± 289 mg/dL) during subcutaneous treatment with Kiovig compared to when it was administered intravenously (2240 ± 536 mg/dL), consistent with the lower weekly dose compared to the dose administered every 3 or 4 weeks intravenously. In contrast, the mean trough levels were higher with Kiovig given subcutaneously (1202 ± 282 mg/dL), compared to those when given intravenously (1050 ± 260 mg/dL), a result of both higher monthly dose and more frequent dosing.

5.3 Preclinical Safety Data

Genotoxicity.

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

Carcinogenicity.

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

6 Pharmaceutical Particulars

6.1 List of Excipients

Kiovig contains the following excipients: glycine, water for injection.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf-life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store at 2°C to 8°C for up to 36 months from date of manufacture. Refrigerate. Do not freeze.
Do not use after the expiry date. Protect from light.
If Kiovig is diluted, the preparation should be used as soon as practicable as the product does not contain antimicrobial preservative. If storage is necessary, store the diluted preparation at 2°C to 8°C for not more than 24 hours. Product is for a single use in one patient only. Discard any residue.

6.5 Nature and Contents of Container

Kiovig is available in several sizes: 1 g/10 mL, 2.5 g/25 mL, 5 g/50 mL, 10 g/100 mL, 20 g/200 mL and 30 g/300 mL. The product is filled into glass containers of type I, which are closed with bromobutyl rubber stoppers.

Pack size.

1 vial per carton.

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

Chemical name.

Normal immunoglobulin (human).

Chemical structure.

The active ingredient in Kiovig is normal immunoglobulin (human) comprising predominantly of 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 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 liter 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 10% (human): not available.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine (S4).

Summary Table of Changes