Consumer medicine information

Kineret

Anakinra

BRAND INFORMATION

Brand name

Kineret

Active ingredient

Anakinra

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Kineret.

SUMMARY CMI

KINERET®

Consumer Medicine Information (CMI) summary

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

1. Why am I using KINERET?

KINERET contains the active ingredient anakinra. KINERET is used to treat the signs and symptoms associated with Rheumatoid Arthritis (RA), Cryopyrin Associated Periodic Syndromes (CAPS), and Systemic Juvenile Idiopathic Arthritis (SJIA).

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

2. What should I know before I use KINERET?

Do not use if you have ever had an allergic reaction to anakinra or any of the ingredients listed at the end of the CMI.

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

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

3. What if I am taking other medicines?

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

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

4. How do I use KINERET?

  • KINERET is usually given by daily injection under your skin; this is called a subcutaneous injection.
  • Your doctor will decide what dose you or your child needs and how often to give it.

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

5. What should I know while using KINERET?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using KINERET.
  • If you become pregnant while using KINERET, tell your doctor immediately.
  • Attend your scheduled appointments so that your doctor can monitor any changes in certain blood cells and discuss appropriate precautions with you.
Things you should not do
  • Do not try to inject yourself if you have not been trained.
  • Do not stop using this medicine suddenly or change the dose unless your doctor tells you to.
  • Do not use KINERET if you think it has been frozen.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how KINERET affects you.
Looking after your medicine
  • Store KINERET in a refrigerator (2°C to 8°C). Do not freeze. Keep the graduated pre-filled syringe in the original carton in order to protect from light.
  • Once a syringe has been removed from the refrigerator and has reached room temperature (up to 25°C) it must either be used within 72 hours or discarded. Do not place it back in the refrigerator if it has been stored at room temperature.

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

6. Are there any side effects?

Common side effects include headaches, rash and injection site reactions (ISRs). Serious side effects that require urgent medical attention include serious infections, serious allergic reactions and signs and symptoms of a serious drug reaction.

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

KINERET®

Active ingredient(s): anakinra

Consumer Medicine Information (CMI)

This leaflet provides important information about using KINERET. 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 KINERET.

Where to find information in this leaflet:

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

1. Why am I using KINERET?

KINERET contains the active ingredient anakinra. KINERET is a type of cytokine (an immunosuppressive agent).

KINERET is used to treat the signs and symptoms associated with:

  • active Rheumatoid Arthritis (RA) in adults
  • Cryopyrin-Associated Periodic Syndromes (CAPS), including Neonatal-Onset Multisystem Inflammatory Disease (NOMID) / Chronic Infantile Neurological, Cutaneous, Articular Syndrome (CINCA), Muckle-Wells Syndrome (MWS), and Familial Cold Autoinflammatory Syndrome (FCAS) in adults and children (aged 8 months and older)
  • active Systemic Juvenile Idiopathic Arthritis (SJIA) in patients aged 2 years and above.

Cytokines are proteins made by your body that co-ordinate communication between cells and help control cell activity. In people with RA, CAPS and SJIA, your body produces too much of the protein interleukin-1. Too much interleukin-1 causes inflammation contributing to the symptoms of the diseases. Normally, your body blocks this inflammation by producing an interleukin-1-receptor antagonist (IL-1Ra). The active substance of KINERET is anakinra, this works in the same way as your natural interleukin-1 blocking protein.

The time it takes to see an improvement in symptoms varies from person to person; your doctor will monitor your response to KINERET.

In people with RA, KINERET is given in combination with methotrexate.

2. What should I know before I use KINERET?

Warnings

Do not use KINERET if:

  • you are allergic to anakinra, 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 allergic to any other medicines made using E. coli-derived proteins.
  • you are using medicines called tumour necrosis factor (TNF-α) inhibitors, such as etanercept.
    Ask your doctor or pharmacist if you are not sure whether you are taking such a medicine.
  • you have neutropenia (low white blood cell count) determined after a blood test.

Check with your doctor if you:

  • have or have had any of the following medical conditions:
    - history of increased levels of liver enzymes
    - kidney disease
    - cancer
    - infections (ongoing or recent) or a history of frequent infections or any problems that increase your risk of infections
    - diseases that affect your immune response
    - asthma.
  • have had a recent vaccination or require vaccinations.
    Your doctor may ask you to complete all vaccinations before starting KINERET.

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. KINERET has not been tested in pregnant women. Use of KINERET is not recommended during pregnancy and adequate contraception must be used by women of childbearing potential when using KINERET.

Talk to your doctor if you are breastfeeding or intend to breastfeed. You must not breastfeed if you use KINERET. It is not known whether KINERET passes into breast milk.

Children and adolescents

Do not give this medicine to a child with RA or to a child younger than 8 months of age or body weight less than 10 kg with CAPS.

Do not give this medicine to a child younger than 2 years with SJIA.

3. What if I am taking other medicines?

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

Medicines called tumour necrosis factor (TNF-α) inhibitors, such as etanercept should not be used with KINERET because this may increase the risk of infections.

Tell your doctor if you are taking warfarin or phenytoin. Your doctor may need to adjust the dose of your medication.

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

4. How do I use KINERET?

How much to use

  • The recommended dose is either 20 to 90 mg or 100 mg given as an injection under your skin (subcutaneous injection). Your doctor will tell you the dose that you need or whether you need a dose higher than 100 mg.
  • Each KINERET dose comes in a 1 mL graduated pre-filled syringe containing 100 mg KINERET. The graduations are in milligrams (mg) to help you select and inject the right dose.

When to use KINERET

  • KINERET should be used daily. You should try to have the injection at the same time each day.
  • Continue using your medicine for as long as your doctor tells you. KINERET helps control your condition, but it does not cure it. It is important to keep using KINERET even if you feel well.

How to use KINERET

Your doctor may decide that it would be more convenient for you to inject KINERET yourself. Your doctor or nurse will show you how to inject yourself. Do not try to give yourself the injection if you or your carer have not been trained.

  1. Set up the materials needed for the injection:
  • a new graduated pre-filled syringe of KINERET with attached needle
  • alcohol swab
  • a cotton ball.
  1. Take the box out of the refrigerator, and take one KINERET graduated pre-filled syringe from the box and put the remaining graduated pre-filled syringes back in the refrigerator.
  2. Do not shake the graduated pre-filled syringe. If the solution is foamy, allow the graduated pre-filled syringe to sit for a few minutes until it clears.
  3. Check the expiry date (EXP.) on the graduated pre-filled syringe label. Do not use it if the date has passed.
  4. Check the appearance of KINERET. It must be a clear, colourless-to-white solution. It may contain some small translucent-to-white particles of protein. This is expected.
The solution should not be used if discoloured or cloudy or if there are clumps, large or coloured particles present.
Use a new graduated pre-filled syringe.
  1. For a more comfortable injection, take the graduated pre-filled syringe out of the fridge 30 minutes before you intend to use it or hold the graduated pre-filled syringe gently in your hand, warming it for a few minutes.
Do not warm KINERET in a microwave or in hot water or any other way.
  1. Do not remove the needle cover from the graduated pre-filled syringe until you are ready to inject.
  2. Wash your hands thoroughly with soap and water.

Selecting and preparing the injection

Find a comfortable, well-lit, clean, flat, hard surface and put everything you need within reach. Make sure you know what KINERET dose your doctor has prescribed.

How to prepare a 100 mg dose

Before you inject KINERET you must do the following:

  1. Hold the syringe barrel and gently remove the cover from the needle without twisting. Pull straight as shown in Figure A. Do not touch the needle or push the plunger.
Discard the needle cover straight away.

  1. You may notice a small air bubble in the graduated pre-filled syringe. You don't have to remove the air bubble before injecting. Injecting the solution with the air bubble is harmless.
  2. You can now use the pre-filled syringe as described in the "Where should you give your injection?" section and "How do you give your injection?" section.

How to prepare a 20 to 90 mg dose

Before you inject KINERET you must do the following:

  1. Hold the syringe barrel and gently remove the cover from the needle without twisting. Pull straight as shown in Figure A. Do not touch the needle or push the plunger. Discard the needle cover straight away.
  2. Turn the graduated pre-filled syringe so that the needle is now pointing straight upwards as shown in Figure B.
Put your thumb on the plunger rod and push slowly until you see a tiny liquid drop at the tip of the needle.

  1. Turn the syringe so that the needle is now pointing downwards. Place a sterile gauze or tissue on a flat surface and hold the syringe above it with the needle pointing towards the gauze or tissue, as shown in Figure C.
Make sure the needle does not touch the gauze or tissue.

  1. Put your thumb on the plunger rod and push slowly until the front end of the plunger has reached the mark on the graduated scale of the recommended dose.
The extra liquid will be absorbed by the gauze or tissue as shown in Figure C.
  1. If you are not able to set the correct dose or if you drop the syringe, dispose of the syringe and use a new one.
  2. You can now use the graduated pre-filled syringe as described in the "Where should you give your injection?" section and the "How do you give your injection?" section.

Where should you give your injection?

The most suitable places to inject yourself or your child are (see Figure D):

  • the abdomen (except for the area around the navel);
  • the top of the thighs (this is especially good for infants under a year if they have slightly chubby legs);
  • the upper outer areas of the buttocks; and
  • the outer area of the upper arms.

If someone is injecting for you, they can also use the back of your arms.

It is important that you:

  • change the place that you inject each time so you don't become sore in one area.
  • do not injection into skin that is tender, red, bruised, or hard.
  • avoid scars or stretch marks.
  • do not inject close to a vein.

How do you give your injection?

  1. Disinfect the skin with the alcohol wipe and let it dry off naturally in the air (this only takes a few seconds). Then pinch the skin between your thumb and forefinger, without squeezing.
  2. Push the needle fully into the skin as shown by your nurse or doctor.
  3. Inject the liquid slowly and evenly, always keeping the skin pinched as in Figure E.

  1. After injecting the liquid, remove the needle and let go of the skin.

Only use each syringe for one injection. Do not reuse a syringe as this can cause infection. Any unused medicine must be discarded.

If you forget to use KINERET

KINERET should be used regularly at the same time each day. If you miss your dose at the usual time, you should contact your doctor or nurse to discuss when you should use the next dose.

If you use too much KINERET

If you think that you or anyone else have used too much KINERET, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre (in Australia telephone 13 11 26. In New Zealand telephone 0800 POISON or 0800 764 766), 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 while using KINERET?

Things you should do

  • Always follow your doctor's instructions carefully.
  • If you are about to be started on any new medicine, remind your doctor and pharmacist that you are using KINERET.
  • Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.
  • If you become pregnant while using this medicine, tell your doctor immediately.
  • Keep all of your doctor's appointments so that your progress can be checked.
    KINERET may cause a change in certain blood cells. Your doctor will arrange for blood tests before treatment and then periodically during treatment to monitor these changes.

Things you should not do

  • Do not try to inject yourself if you have not been trained.
    For instructions on how to inject yourself or your child with KINERET, please read the “How to use KINERET” section of this leaflet.
  • Do not use KINERET to treat any other complaints unless your doctor tells you to.
  • Do not give your medicine to anyone else, even if they have the same condition as you.
  • Do not use the KINERET graduated pre-filled syringe if it has been frozen.

Helpful hints to manage injection site reactions

  • swelling - apply a cold pack to the injection site before and after injection
  • itching - talk to your doctor or pharmacist. They may recommend a corticosteroid cream or antihistamine
  • bruising - apply a cold pack to the injection site immediately after injection
  • pain during and/or after injection:
    - Try different injection locations, see ‘Where should you give your injection?’. The stomach may be the best site due to the low number of nerve endings.
    - Let the KINERET syringe warm to room temperature before injecting (30 minutes).
    - Allow the alcohol at the injection site to dry before injecting KINERET.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how KINERET affects you.

KINERET may cause dizziness in some people.

Looking after your medicine

  • Keep your KINERET graduated pre-filled syringes in the box until it is time to use them.
  • Keep your graduated pre-filled syringes in the refrigerator where the temperature stays between 2°C and 8°C.
  • You can leave KINERET out of the refrigerator but for no longer than a total of 72 hours at room temperature (up to 25°C).
  • Do not place it back in the refrigerator if it has been stored at room temperature.
  • Do not store KINERET in the freezer.
  • Do not let KINERET freeze.
  • Do not shake KINERET.

Follow the instructions in the carton on how to take care of your medicine properly.

Keep it where young children cannot reach it.

If you drop the syringe, do not use the syringe. This is for your safety in case the syringe is broken, or the needle is bent or dirty.

Getting rid of any unwanted medicine

After injecting KINERET, do not put the cover back on used needles. You should discard the used syringe with any remaining solution immediately into a sharps container. Do not put the used syringe into your normal household or recycling waste.

If you had a dose lower than 100 mg, you will have ejected liquid from the syringe onto a gauze or tissue. Discard the wet gauze or tissue into the sharps container and clean the surface with a fresh tissue.

The needle cover, alcohol swabs and other used supplies can be thrown out with your normal household rubbish.

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

Do not use this medicine after the expiry date stated on the label and carton.

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. However, some side effects may need medical attention.

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
  • headaches
  • rash
  • injection site reactions (ISRs).
ISRs are reactions that occur at the site where KINERET is injected. These reactions include redness, swelling, bruising, itching and pain at the injection site. It is not unusual to experience mild to moderate stinging or injection site reactions, especially when you are beginning therapy.
Most ISRs happen in the first 4 weeks of starting KINERET and usually resolve after about a month during continued use. See “Helpful hints to manage injection site reactions”.		Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Serious infections:
  • a persistent fever, shivers, cough or redness and tenderness of the skin or other signs of infection.
Serious allergic reactions:
  • swelling of the face, tongue or throat
  • trouble swallowing
  • itchy skin or rash
  • wheezing, shortness of breath or difficulty breathing
  • suddenly feeling fast pulse or sweating.
Serious skin reaction:
  • atypical, widespread rash, which may occur in conjunction with high body temperature and enlarged lymph nodes.
    Serious skin reaction, DRESS (drug reaction with eosinophilia and systemic symptoms), has rarely been reported in association with KINERET treatment, predominantly in patients with systemic juvenile idiopathic arthritis (SJIA).
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

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

Other side effects not listed here may occur in some people.

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 KINERET contains

Active ingredient
(main ingredient)		anakinra
Other ingredients
(inactive ingredients)
  • sodium citrate dihydrate
  • sodium chloride
  • disodium edetate
  • polysorbate 80
  • water for injections

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

What KINERET looks like

KINERET is a clear, colourless-to-white solution for injection and is supplied ready for use in a pre-filled syringe. It may contain some translucent-to-white particles of protein. The presence of these particles does not affect the quality of the product.

KINERET is available in packs of 28 syringes. AUST R 82872

Who distributes KINERET

Swedish Orphan Biovitrum Pty Ltd
Floor 22 (Business Sweden Office)
44 Market Street, Sydney NSW 2000
Australia
au.sobi.com

This leaflet was prepared in December 2024.

Published by MIMS February 2025

BRAND INFORMATION

Brand name

Kineret

Active ingredient

Anakinra

Schedule

S4

 

1 Name of Medicine

Anakinra (rbe).

2 Qualitative and Quantitative Composition

Each pre-filled syringe contains 0.67 mL (100 mg) of anakinra.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Kineret is a sterile, clear, colourless-to-white, preservative-free solution for injection in a pre-filled syringe. It may contain some small translucent-to-white particles of protein.

4 Clinical Particulars

4.1 Therapeutic Indications

Kineret (anakinra) is indicated:
for the treatment of active adult rheumatoid arthritis (RA) in patients who have had inadequate response to one or more other Disease Modifying Antirheumatic Drugs (DMARDs). Kineret should be given in combination with methotrexate;
in adult and paediatric patients aged 8 months and older with a body weight of 10 kg or above for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS) including Neonatal-Onset Multisystem Inflammatory Disease (NOMID)/ Chronic Infantile Neurological, Cutaneous, Articular Syndrome (CINCA), Muckle-Wells Syndrome (MWS), and Familial Cold Autoinflammatory Syndrome (FCAS);
for the treatment of active Systemic Juvenile Idiopathic Arthritis (SJIA) in patients 2 years and above who have failed to respond adequately to non-biological DMARDs.

4.2 Dose and Method of Administration

RA.

The recommended dose of Kineret in adults and the elderly is 100 mg/day administered by subcutaneous injection. The dose should be administered at approximately the same time every day.
Alternating the injection site is recommended to avoid discomfort at the site of injection.
Concurrent treatment with Kineret and TNF-alpha antagonists is contraindicated (see Section 4.3 Contraindications).

CAPS.

Starting dose.

The recommended starting dose for both adults and children is 1-2 mg/kg/day by subcutaneous (SC) injection. The therapeutic response is primarily reflected by reduction in clinical symptoms such as fever, rash, joint pain, and headache, but also in inflammatory serum markers (CRP/SAA levels), or occurrence of flares.

Maintenance dose in mild CAPS (FCAS, mild MWS).

Patients are usually well controlled by maintaining the recommended starting dose (1-2 mg/kg/day).

Maintenance dose in severe CAPS (MWS and NOMID/CINCA).

Dose increases may become necessary within 1-2 months based on therapeutic response. The usual maintenance dose in severe CAPS is 3-4 mg/kg/day, which can be adjusted to a maximum of 8 mg/kg/day.
In addition to the evaluation of clinical symptoms and inflammatory markers in severe CAPS, assessments of inflammation of the CNS, including the inner ear (MRI or CT, lumbar puncture, and audiology) and eyes (ophthalmological assessments) are recommended after an initial 3 months of treatment, and thereafter every 6 months, until effective treatment doses have been identified. When patients are clinically well controlled, CNS and ophthalmological monitoring may be conducted yearly.
Once daily administration is generally recommended, but the dose may be split into twice daily administrations. Each syringe is intended for a single use. A new syringe must be used for each dose. Any unused portion after each dose should be discarded.

SJIA.

The recommended dose in SJIA is 2 mg/kg/day up to a maximum of 100 mg/day by SC injection.
Treatment should be undertaken by physicians experienced in the treatment of SJIA. Decisions should be guided by clinical outcomes including laboratory measures. The treating physician should consider whether patients without clinical improvement should continue treatment with anakinra.

Special populations.

Hepatic impairment. No dose adjustment is required for patients with moderate hepatic impairment (Child-Pugh class B). Kineret should be used with caution in patients with severe hepatic impairment.
Renal impairment. Physicians should consider administration of the prescribed dose of Kineret every other day for patients who have severe renal insufficiency (defined as creatinine clearance < 30 mL/min, as estimated from serum creatinine levels), or end stage renal disease. In the absence of adequate data, Kineret should be used with caution in patients with moderate renal impairment (creatinine clearance 30 to 50 mL/minute).
Paediatric use.

CAPS.

Posology and administration in children and infants aged 8 months and older with a body weight of 10 kg or above are the same as for adult CAPS patients, based on body weight. No data are available in children under the age of 8 months.

Preparation and administration of Kineret.

Kineret contains no antimicrobial agent. Kineret is for single use in one patient on one occasion only. Discard any residue.
The graduated pre-filled syringe allows for doses between 20 and 100 mg. As the minimum dose is 20 mg the syringe is not suitable for paediatric patients with a body weight below 10 kg.
Prior to administration, visually inspect the solution for particulate matter and discolouration. There may be small translucent-to-white particles of protein in the solution. This is not unusual for proteins in solution. The solution should not be used if discoloured or cloudy or if foreign particulate matter, i.e. clumps, large or coloured particles, are present.
Avoid shaking. Allow the pre-filled syringe to reach room temperature before injecting. Invert Kineret gently prior to injection.
Alternating the injection site is recommended to avoid discomfort at the site of injection. Cooling of the injection site, warming the injection liquid, use of cold packs (before and after the injection), and use of topical corticosteroids and antihistamines after the injection can alleviate the signs and symptoms of injection site reactions.

4.3 Contraindications

Combination therapy with Kineret (anakinra) and TNF-alpha antagonist drugs is contraindicated.
Kineret (anakinra) is contraindicated in patients with known hypersensitivity to E. coli derived proteins, Kineret or any components of the product.
Kineret treatment must not be initiated in patients with neutropaenia (ANC < 1.5 x 109/L) (see Section 4.4 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

General.

Allergic reactions, including anaphylactic reactions and angioedema, have been reported uncommonly. If a severe hypersensitivity reaction occurs, administration of Kineret should be discontinued and appropriate therapy initiated.
The safety and efficacy of Kineret in patients with cardiac impairment has not specifically been evaluated.

Hepatic events.

In clinical studies in RA and CAPS patients, transient elevations of liver enzymes have been seen uncommonly. These elevations have not been associated with signs or symptoms of damage. During post-marketing use isolated case reports indicating noninfectious hepatitis have been received. Hepatic events during post-marketing use have mainly been reported in patients with predisposing factors, e.g. history of transaminase elevations before start of Kineret treatment. Hepatic events in patients with SJIA predominantly occur during the first month of Kineret treatment.
The efficacy and safety of Kineret in patients with AST/ALT ≥ 1.5 x upper level of normal have not been evaluated.

Serious infections.

Treatment with Kineret should not be initiated in patients with active infections, including chronic or localised infections. Physicians should exercise caution when administering Kineret to, or considering the use of Kineret in, patients with a history of recurring infections or with underlying conditions, such as advanced or poorly controlled diabetes, which may predispose them to infections.
Kineret has been associated with an increased incidence of serious infections (1.8%) compared with placebo (0.7%). In clinical studies the risk for serious infection was higher in patients with a history of asthma compared to patients without a history of asthma.
The safety and efficacy of Kineret in patients with chronic infections have not specifically been evaluated. Patients who develop a new infection while being treated with Kineret should be monitored closely.
In Kineret-treated patients with RA, administration of Kineret should be discontinued if a patient develops a serious infection including sepsis. In two long-term safety studies of RA over 3 years, 4 deaths due to serious infections occurred. These deaths were considered related to Kineret (see Section 4.8 Adverse Effects (Undesirable Effects), Serious infections).
In Kineret-treated patients with SJIA and a concomitant serious infection, there is a risk of Macrophage Activation Syndrome (MAS) if Kineret treatment is discontinued. This should be taken into account when deciding on discontinuing Kineret during a concomitant serious infection. If Kineret treatment is continued during a concomitant serious infection, careful monitoring is required.
In Kineret treated patients with CAPS, there is a risk of disease flares when discontinuing treatment. This should be taken into account when deciding on discontinuing Kineret during a serious infection.
The safety of Kineret in individuals with latent tuberculosis is unknown. There have been reports of tuberculosis in patients receiving several biological anti-inflammatory treatment regimens. Patients should be screened for latent tuberculosis prior to initiating Kineret.
Other anti-rheumatic therapies have been associated with hepatitis B reactivation. Therefore, screening for viral hepatitis should also be performed before starting therapy with Kineret.

Neutropaenia.

Kineret was commonly associated with neutropaenia (ANC < 1.5 x 109/L) in placebo controlled studies in RA and has been observed in CAPS and SJIA patients.
Kineret treatment should not be initiated in patients with neutropaenia (ANC < 1.5 x 109/L). It is recommended that neutrophil counts be assessed prior to initiating Kineret treatment, and while receiving Kineret, monthly during the first 6 months of treatment and quarterly hereafter. In patients who become neutropenic (ANC < 1.5 x 109/L) the ANC should be monitored closely and Kineret treatment should be discontinued. The safety and efficacy of Kineret in patients with neutropaenia have not been evaluated.

Concurrent treatment with Kineret and TNF-alpha antagonists.

Combination therapy with Kineret and TNF-alpha antagonist drugs is contraindicated. Concurrent administration of Kineret with TNF-alpha antagonists has been associated with an increased risk of serious infection and neutropaenia compared to Kineret alone. The combination has not been demonstrated to produce increased clinical benefit. See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, TNF blocking agent.

Pulmonary events.

During postmarketing use, events of interstitial lung disease, pulmonary alveolar proteinosis and pulmonary hypertension have been reported mainly in paediatric patients with SJIA treated with IL-6 and IL-1 inhibitors, including Kineret. Patients with trisomy 21 seem to be overrepresented. In a single company sponsored placebo controlled clinical study of 12 weeks duration followed up to 16 weeks involving 11 patients (6-Kineret, 5-placebo and 8 out of 11 SJIA patients), no such events were reported. In a retrospective safety analysis of registry data involving 306 paediatric patients with SJIA, one patient experienced a serious pulmonary event, an unspecified interstitial lung disease. There was no patient with pulmonary alveolar proteinosis or pulmonary hypertension in the study. A causal relationship between Kineret and pulmonary events has not been established.

Drug reaction with eosinophilia and systemic symptoms (DRESS).

Drug reaction with eosinophilia and systemic symptoms (DRESS) has rarely been reported in patients treated with Kineret, predominantly in patients with systemic juvenile idiopathic arthritis (SJIA). Patients with DRESS may require hospitalisation, as this condition may be fatal. If signs and symptoms of DRESS are present and an alternative aetiology cannot be established, Kineret should be discontinued and a different treatment considered.

Immunosuppression.

It is unknown if chronic exposure to Kineret can increase the incidence of malignancies. The use of Kineret in patients with pre-existing malignancy is not recommended.

Amyloidosis (systemic).

In patients with NOMID/CINCA who received high doses of Kineret over extended periods of time and presented with injection site amyloid deposits [see Section 4.8 Adverse Effects (Undesirable Effects)] isolated cases of systemic AIL1RAP (IL-1 receptor antagonist protein) amyloidosis have been reported during post-marketing use. A causal relationship between Kineret and systemic AIL1RAP amyloidosis has not been established.
In patients with confirmed injection site amyloid deposits, close monitoring for proteinuria is recommended.

Malignancies.

RA patients may be at higher risk (on average 2-3 fold) for the development of lymphoma. In clinical studies, whilst patients treated with Kineret had a higher incidence of lymphoma than the expected rate in the general population, this rate is consistent with rates reported in general for RA patients.
In clinical studies, the incidence of malignancies was the same in Kineret-treated RA patients and placebo treated patients and did not differ from that in the general population. Furthermore, the overall incidence of malignancies was not increased during 3 years of patient exposure to Kineret. In a retrospective safety analysis of registry data involving 306 paediatric patients with SJIA where mean duration of treatment course with Kineret was 17.0 (standard deviation 21.1) months and the median duration was 8.9 months. 306 patients had a total of 360 courses of Kineret treatment, 141 patients (46.1%) were at some point continuously treated for at least 12 months, 104 patients (34.0%) for at least 18 months, and 86 patients (28.1%) for at least 24 months. The shortest treatment course was 0.2 months, whereas the longest course was 109.9 months, there were no reported malignancies.
There is no information available on the incidence of malignancies in CAPS patients receiving Kineret.

Immunisations.

It is recommended that, if possible, paediatric and adult patients should complete all immunisations in accordance with current immunisation guidelines prior to initiating Kineret treatment. It is also recommended that hepatitis B status is confirmed and vaccination completed prior to therapy with Kineret. However, in patients with severe CAPS the risk of not completing all immunisations should be weighed against the risk of not starting Kineret treatment.
In a placebo-controlled clinical study in RA patients (n = 126), no difference was detected in anti-tetanus antibody response between the Kineret and placebo treatment groups when the tetanus/diphtheria toxoids vaccine was administered concurrently with Kineret.
No data are available on either the effects of live vaccination or the secondary transmission of infection by live vaccines in patients receiving Kineret. Live vaccines should not be given concurrently with Kineret. No data are available on the effects of other vaccines, in patients receiving Kineret.

Paediatric use.

The safety and efficacy of Kineret have been demonstrated in 36 paediatric CAPS patients. Overall, the efficacy and safety profile of Kineret is comparable in adult and paediatric CAPS patients.
Kineret was studied in a single randomised, blinded multi-centre study in 86 patients with polyarticular course Juvenile Rheumatoid Arthritis (JRA; ages 2-17 years) receiving a dose of 1 mg/kg subcutaneously daily, up to a maximum dose of 100 mg. The 50 patients who achieved a clinical response after a 12-week-open-label run in were randomised to Kineret (25 patients) or placebo (25 patients), administered daily for an additional 16 weeks. A subset of these patients continued open label treatment with Kineret for up to 1 year in a companion extension study. An adverse event profile similar to that seen in adult RA patients was observed in these studies. These study data are insufficient to demonstrate efficacy and, therefore, Kineret is not recommended for paediatric use in juvenile rheumatoid arthritis.

Use in renal impairment.

Kineret is not recommended for use in patients with severe renal impairment.

Use in the elderly.

A total of 653 patients ≥ 65 years of age, including 135 patients ≥ 75 years of age, were studied in clinical studies in RA. No overall differences in safety or effectiveness were observed between these patients and younger patients. As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly.

Effects on laboratory tests.

In placebo-controlled studies with Kineret, treatment was associated with small reductions in the mean values for total white blood count, platelets and absolute neutrophil blood count and a small increase in the mean eosinophil differential percentage.
In the placebo-controlled studies, 8% of patients receiving Kineret had decreases in neutrophil counts of at least 1 World Health Organisation (WHO) toxicity grade, compared with 2% in the placebo control group. Six Kineret-treated patients (0.3%) experienced neutropaenia (ANC < 1 x 109/L).
Additional patients treated with Kineret plus etanercept (3/139, 2%) developed ANC < 1 x 109/L. While neutropenic, one patient developed cellulitis which recovered with antibiotic therapy.
Blood counts should be assessed prior to initiating Kineret treatment and be monitored on a regular basis while receiving Kineret.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Interactions between Kineret and other medicines have not been investigated in formal studies. In clinical studies, interactions between Kineret and other medicines (including nonsteroidal anti-inflammatory drugs, corticosteroids and DMARDs) have not been observed.

TNF blocking agent.

In two studies in RA, where patients received concurrent etanercept and Kineret therapy and were treated for up to 24 weeks, a 7% rate of serious infections was observed which was higher than when either agent was used alone (also see Section 4.4 Special Warnings and Precautions for Use). Two percent of patients (3/139) treated concurrently with Kineret and etanercept developed neutropaenia (ANC < 1 x 109/L).

Cytochrome P450 substrates.

The formation of CYP450 enzymes is suppressed by increased levels of cytokines (e.g. IL-1) during chronic inflammation. Thus, it may be expected that for an IL-1 receptor antagonist, such as anakinra, the formation of CYP450 enzymes could be normalised during treatment. This would be clinically relevant for CYP450 substrates with a narrow therapeutic index (e.g. warfarin). Upon start or end of Kineret treatment in patients on these types of medicinal products, it may be relevant to consider therapeutic monitoring of the effect or drug concentration of these products and the individual dose of the medicinal product may need to be adjusted.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In rats and rabbits, Kineret at doses of up to 15-30 fold greater than the human dose (based on body surface area adjusted dose) had no adverse effects on male or female fertility.
(Category B1)
Reproductive studies have been conducted with Kineret on rats and rabbits at doses up to 15-30 fold greater (based on body surface area adjusted dose) than the human dose and have revealed no evidence of impaired fertility or harm to the foetus. There are, however, no adequate and well controlled studies in pregnant women. As animal reproduction studies are not always predictive of human response, Kineret should be used during pregnancy only if clearly needed.
 It is not known whether Kineret is secreted in human breast milk. The protein that Kineret mimics (interleukin-1 receptor antagonist) occurs naturally in human breast milk. Should Kineret or antibodies to Kineret be secreted in breast milk, the effect on the immune competence of the neonate is unknown. Exposure of lactating rats to doses of Kineret up to 15-30 fold greater (based on body surface area adjusted dose) than the human dose did not have any apparent effect on the offspring. Caution should be exercised if Kineret is administered to women who are breastfeeding.

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)

In placebo-controlled RA studies, comprising 3330 patients (Kineret: 2372, placebo: 958), the subject incidence of serious adverse reactions at the recommended dose of Kineret (100 mg/day) was comparable with placebo (7.1% compared with 6.5% in the placebo group).
Adverse events data in CAPS patients are based on an open-label study of 43 patients with NOMID/CINCA treated with Kineret for up to 5 years, with a total Kineret exposure of 159.8 patient years. During the 5 year study 14 patients (32.6%) reported 24 serious events. Eleven serious events in 4 (9.3%) patients were considered related to Kineret. No patient withdrew from Kineret treatment due to adverse events.
Adverse events data in SJIA patients is based on a partially open-label and partially blinded, placebo-controlled study of 15 SJIA patients, treated for up to 1.5 years and a randomised double blind placebo controlled study of 11 patients (6-Kineret, 5-placebo and 8 out of 11 SJIA patients) treated for 12 weeks and followed for an additional 4 weeks. In addition, a retrospective safety analysis of registry data involving 306 paediatric patients with SJIA, post-marketing adverse event reports and published studies constitute supporting data.
There are no indications from clinical studies, or from post-marketing adverse event reports and published studies, that the overall safety profile in CAPS or SJIA patients is different from that in RA patients with the exception of the post marketing observation of a higher frequency of reported hepatic events in SJIA patients. During long term treatment of RA, CAPS and SJIA, the safety profile remains unchanged over time. The adverse reactions in Table 1 therefore applies to Kineret treatment in RA, CAPS and SJIA patients.
Adverse reactions are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Serious infections.

The incidence of serious infections in RA studies conducted at the recommended dose (100 mg/day) was 1.8% in Kineret treated patients and 0.7% in placebo-treated patients. In observations up to 3 years, the serious infection rate did not increase over time. Serious infections observed consisted primarily of bacterial events such as cellulitis, pneumonia and bone and joint infections. Most patients continued on the study drug after the infection resolved.
Although the overall rate of serious infections was low, the higher incidence rate in the Kineret-treated group relative to placebo suggests a possible association between Kineret and serious infections.
An increased incidence of serious infections was observed in patients receiving concurrent Kineret and etanercept therapies (see Section 4.4 Special Warnings and Precautions for Use).
In a study with 15 SJIA patients followed for up to 1.5 years, one patient developed serious hepatitis due to a cytomegalovirus infection. In a study with 11 patients (6-Kineret, 5-placebo and 8 out of 11 SJIA patients) followed for 16 weeks, no serious infections were reported. In a retrospective safety analysis of registry data of Kineret use in 306 paediatric patients with SJIA, the mean duration of a treatment course with Kineret was 17.0 (standard deviation 21.1) months and the median duration was 8.9 months. The shortest treatment course was 0.2 months, whereas the longest course was 109.9 months. Among the 306 patients, 141 patients (46.1%) were at some point continuously treated with anakinra for at least 12 months, 104 patients (34.0%) for at least 18 months, and 86 patients (28.1%) for at least 24 months, serious infections were reported in 13 patients. There are no indications from post-marketing adverse event reports and published studies that types and severity of infections in SJIA patients differs from that in RA or CAPS patients.
In clinical studies of RA and SJIA and in the post-marketing experience, rare cases of opportunistic infections have been observed and included fungal, mycobacterial, bacterial, and viral pathogens. Infections have been noted in all organ systems and have been reported in patients receiving Kineret alone or in combination with immunosuppressive agents.
In a study with 43 CAPS patients followed for up to 5 years, 10 patients reported serious infections, the most common being pneumonia and gastroenteritis. Kineret treatment was temporarily stopped in one patient, all other patients continued Kineret treatment during the infections. In a non-interventional long term safety study of Kineret in 12 patients with CAPS with a treatment duration of up to 5 years, serious infections, which did not lead to Kineret discontinuation, were reported in 1 patient.
In two long-term safety studies of RA over 3 years, 4 deaths due to serious infections (1 pneumonia and 3 sepsis) occurred. These deaths were considered related to Kineret (see Section 4.4 Special Warnings and Precautions for Use, Serious infections).

Neutropaenia.

In placebo-controlled studies in RA, treatment was associated with small reductions in the mean values for total white blood count and absolute neutrophil count (ANC). Neutropaenia (ANC < 1.5 x 109/L) was reported in 2.4% of patients receiving Kineret compared with 0.4% of placebo patients.
In a study with 43 CAPS patients followed for up to 5 years neutropaenia was reported in 2 patients. Both episodes of neutropaenia resolved over time with continued Kineret treatment.
In a study with 15 SJIA patients followed for up to 1.5 years, one event of transient neutropaenia was reported. In a study with 11 patients (6-Kineret, 5-placebo and 8 out of 11 SJIA patients) followed for 16 weeks, no neutropenia was reported. In a retrospective safety analysis of registry data of Kineret use in 306 paediatric patients with SJIA, the shortest treatment course was 0.2 months, whereas the longest course was 109.9 months. 5 events of neutropenia including 1 event of febrile neutropenia were reported. There have been isolated reports of neutropaenia during post-marketing use.

Thrombocytopaenia.

In clinical studies in RA patients, thrombocytopaenia has been reported in 1.9% of treated patients compared to 0.3% in the placebo group. The thrombocytopaenias have been mild, i.e. platelet counts have been > 75 x 109/L. Mild thrombocytopaenia has also been observed in CAPS and SJIA patients.
During post-marketing use of Kineret, thrombocytopaenia has been reported, including occasional case reports indicating severe thrombocytopaenia (i.e. platelet counts < 10 x 109/L).

Allergic reactions.

Allergic reactions including anaphylactic reactions, angioedema, urticaria, rash, and pruritus have been reported uncommonly with Kineret.
In a study with 43 CAPS patients followed for up to 5 years, no allergic event was serious and no event required discontinuation of Kineret.
In a study with 15 SJIA patients followed for up to 1.5 years, no allergic event was serious and no event required discontinuation of Kineret. In a study with 11 patients (6-Kineret, 5-placebo and 8 out of 11 SJIA patients) followed for 16 weeks, no allergic reactions were reported.

Hepatic events.

In clinical studies in RA, CAPS and SJIA patients, transient elevations of liver enzymes have been seen uncommonly. These elevations have not been associated with signs or symptoms of hepatocellular damage. During post-marketing use isolated case reports indicating non-infectious hepatitis have been received. Hepatic events during post-marketing use have mainly been reported in patients that have been treated for SJIA in patients with predisposing factors, e.g. history of transaminase elevations before start of Kineret treatment, or in patients that have been treated outside of the approved label.

Injection site reactions (ISR).

In RA patients the most common and consistently reported treatment-related adverse reactions associated with Kineret treatment were ISRs. The majority (95%) of ISRs were reported as mild to moderate. These were typically characterised by 1 or more of the following: erythema, ecchymosis, inflammation, and pain. At a dose of 100 mg/day, 71% of RA patients developed an ISR compared to 28% of the placebo treated patients.
In a study with 43 CAPS patients followed for up to 5 years, no patient permanently or temporarily discontinued Kineret treatment due to ISRs.
In a study with 15 SJIA patients followed for up to 1.5 years, the most common and consistently reported treatment-related adverse reactions associated with Kineret treatment were ISRs. One out of 15 patients discontinued due to ISRs. In a placebo controlled study with 11 patients (6-Kineret, 5-placebo and 8 out of 11 SJIA patients) treated for 12 weeks ISRs occurred in both treatment groups, of which all were mild in severity. No patient discontinued treatment due to ISRs.
ISRs were typically reported within the first 4 weeks of therapy with a median duration in RA studies of 14 to 28 days and resolved during continued Kineret treatment. The development of ISRs in patients who had not previously experienced ISRs was uncommon after the first month of therapy.

Immunogenicity.

In clinical studies, the occurrence of antibodies in RA patients was typically transient and not associated with clinical adverse reactions or diminished efficacy (see Section 5 Pharmacological Properties).
The majority of CAPS patients in study 03-AR-0298 developed anakinra anti-drug antibodies. This was not associated with any clinically significant effects on pharmacokinetics, efficacy, or safety.

Blood cholesterol increase.

In clinical studies of RA, 775 patients treated with daily Kineret doses of 30 mg, 75 mg, 150 mg, 1 mg/kg or 2 mg/kg, there was an increase of 2.4% to 5.3% in total cholesterol levels 2 weeks after start of Kineret treatment, without a dose-response relationship. A similar pattern was seen after 24 weeks of Kineret treatment. Placebo treatment (n = 213) resulted in a decrease of approximately 2.2% in total cholesterol levels at week 2 and 2.3% at week 24. No data are available on LDL or HDL cholesterol.

Paediatric population.

Kineret has been studied in 128 paediatric patients: 36 patients with CAPS, 21 patients with SJIA and 71 patients with other forms of juvenile idiopathic arthritis (JIA) and CAPS patients, aged 8 months to 17 years, for up to 5 years. With the exception of infections and related symptoms that were more frequently reported in patients < 2 years, the safety profile was similar in all paediatric age groups. In addition, in a retrospective safety analysis of registry data of 306 paediatric patients, the shortest treatment course was 0.2 months, whereas the longest course was 109.9 months. The safety profile in paediatric patients was similar to that seen in adult populations and no clinically relevant new adverse reactions were seen.

Other adverse reactions in RA.

Adverse events, reported in at least 2% of patients treated with Kineret who used the 100 mg/day fixed dose, are shown in Table 2.

Other adverse reactions in CAPS.

See Table 3.

Post-marketing experience.

Adverse reactions are listed according to MedDRA system organ class and frequency category (see Table 4). Frequency categories are defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Injection site amyloid deposits.

During post-marketing use, isolated cases of injection site amyloid deposits have been reported in patients with NOMID/CINCA who received high doses of Kineret injected subcutaneously into the same area of skin over long period of time. Rotation of injections is therefore recommended.

Drug reaction with eosinophilia and systemic symptoms (DRESS).

See Section 4.4 Special Warnings and Precautions for Use.

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 www.tga.gov.au/reporting-problems.

4.9 Overdose

There have been no cases of overdose reported with Kineret in clinical studies of RA. In sepsis studies, no serious toxicities attributed to Kineret were seen when it was administered at mean calculated doses of up to 35 times those given to patients with RA over a 72 hour treatment period.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia) or 0800 764 766 (New Zealand).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Anakinra blocks the biological activity of interleukin-1 (IL-1) by competitively inhibiting IL-1 binding to the interleukin-1 type I receptor (IL-1RI), which is expressed in a wide variety of tissues and organs.
IL-1 production is induced in response to inflammatory stimuli and mediates various physiological responses including inflammatory and immunological responses. IL-1 has a broad range of activities including cartilage degradation by its induction of the rapid loss of proteoglycans, as well as stimulation of bone resorption. The levels of the naturally occurring IL-1Ra in synovium and synovial fluid from rheumatoid arthritis (RA) patients are not sufficient to compete with the elevated amount of locally produced IL-1.
Spontaneous mutations in the CIAS1/NLRP3 gene have been identified in a majority of patients with CAPS. CIAS1/NLRP3 encodes for cryopyrin, a component of the inflammasome. The activated inflammasome results in proteolytic maturation and secretion of IL-1β, which has a broad range of effects including systemic inflammation. Untreated CAPS patients are characterised by increased CRP, SAA and IL-6 relative to normal serum levels. Administration of Kineret results in a decrease in the acute phase reactants and a decrease in IL-6 expression level has been observed. Decreased acute phase protein levels are noted within the first weeks of treatment.
In addition to various degrees of arthritis, SJIA is characterised by systemic inflammatory features such as spiking fever, skin rash, hepatosplenomegaly, serositis, and increased acute phase reactants. An important role of IL-1 in the pathogenesis of SJIA has been demonstrated by ex vivo and gene expression studies.

Immunogenicity.

In clinical studies, up to 3% of RA patients tested seropositive at least once during the study for antibodies capable of neutralising the biologic effects of anakinra. The occurrence of antibodies was typically transient and not associated with clinical adverse reactions or diminished efficacy.
In addition, in a clinical study 6% of paediatric JIA patients tested seropositive at least once during the study for antibodies capable of neutralising the biologic effects of anakinra. In a clinical study with 5 patients treated with anakinra for 12 weeks with SJIA, none of the patients tested seropositive for neutralizing anti-anakinra antibodies.
In a clinical study with 43 patients with severe CAPS, the proportion of patients with anti-anakinra antibodies at least once post baseline was 82.5% and the occurrence of anti-anakinra antibodies was highest at month 3. The temporal duration was transient or persistent. Neutralizing anti-anakinra antibodies were not analysed and the impact of anti-anakinra antibodies was not associated with clinical adverse reactions, diminished efficacy or changed pharmacokinetics.

Clinical trials.

RA.

The efficacy of Kineret versus placebo was studied in a phase 3 study in 501 patients with active rheumatoid arthritis who had been on stable doses of methotrexate (10 to 25 mg/week) for at least 8 weeks. In addition, patients had at least 6 swollen/painful joints and 9 tender joints and either a C-reactive protein of ≥ 1.5 mg/dL or an ESR of ≥ 28 mm/hour. The patients were also required to have radiographic evidence of at least one bone erosion. Patients were maintained on methotrexate therapy during the study.
The primary efficacy variable was a 20% improvement in the American College of Rheumatology response criteria (ACR20) (composite score) at 24 weeks. Kineret, administered subcutaneously at a dose of 100 mg daily with background methotrexate, was shown to be more effective in achieving ACR20 (odds ratio = 2.36, 95% CI 1.55, 3.62) compared with placebo plus methotrexate. The results for sustained ACR20 (defined as achieving an ACR20 in at least 4 out of 6 study months with at least one of these ACR20 responses occurring at 12 or 24 weeks) were consistent with the primary analysis. The time course of ACR20 response is shown in Figure 1.
Patients treated with Kineret were more likely to achieve an ACR20 or higher magnitude of response (ACR50 and ACR70) than patients treated with placebo (see Table 5). The treatment response rates did not differ based on gender or ethnic group. Clinical responses to Kineret were seen by week 4 of enrolment.

CAPS.

The safety and efficacy of Kineret have been demonstrated in 43 patients with severe CAPS aged 0.7 to 46 years (36 patients < 18 years) in a prospective, long-term, open-label outcome study with a treatment duration of up to 5 years. Efficacy was demonstrated by decrease in disease specific Diary Symptom Sum Score (DSSS), including the prominent disease symptoms fever, rash, joint pain, vomiting, and headache from baseline to 3-6 months and every 6 months thereafter while on treatment.
A significant improvement in all individual disease symptoms comprising the DSSS was seen, sustained up to month 60. Results were consistent across age, gender, presence of CIAS1 mutation, and disease phenotype. There was also a rapid and sustained decrease in diary symptom score from baseline to month 60 for secondary symptoms (fatigue, eye redness, sleep problems, seizures, and difficulties ambulating).
Levels of the biomarkers of inflammation serum amyloid A (SAA), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) decreased significantly from before to after 3 months of Kineret treatment and were sustained throughout the study.
Disease symptoms worsened and inflammatory serum markers increased during a treatment withdrawal phase and promptly improved again at reinstitution of Kineret therapy.
Indicators of active CNS involvement (including headache, lumbar puncture opening pressure, papilloedema, and CSF pleocytosis) and signs of inflammatory meningeal enhancement on brain MRI decreased during Kineret treatment. Manifestations of eye inflammation decreased, and visual acuity remained stable during the study. Estimated pure tone average (ePTA) data showed stable hearing during long-term treatment, and signs of cochlear inflammation on brain MRI showed significant reductions.
The number of patients on concomitant glucocorticoid treatment decreased during the study, and doses were considerably reduced for patients with continued steroid use.
Haematological lab tests at baseline showed signs of inflammation. Haemoglobin and haematocrit values were low and WBC counts, including neutrophils, were increased, reflecting active disease in the study population. All laboratory values improved after initiation of Kineret treatment.
A non-interventional long term safety study of Kineret in 12 patients with CAPS was designed to evaluate the safety of Kineret in the treatment of CAPS in routine clinical care. Serious infections were reported in 1 patient in this study, which is consistent with the established safety profile of Kineret. No ISRs, allergic reactions, malignancies or medication errors were reported.

SJIA.

Limited evidence of efficacy was available from a study in which 24 SJIA patients were randomised to anakinra (2 mg/kg/day SC to a maximum of 100 mg/day) and placebo groups (12 patients in each group) for a double blind treatment for one month, followed by open label single arm anakinra treatment (N = 24) for 11 months.
Patients eligible for enrolment were aged 2-20 years with a diagnosis of SJIA according to Edmonton's criteria, more than 6 months' disease duration, active systemic disease (disease-related fever and/or C-reactive protein (CRP) > 20 mg/L and/or first hour erythrocyte sedimentation rate (ESR) > 20) and significant overall disease activity at day 1 (D1) defined by at least three of the following Giannini's core-set items: (1) physician global assessment of disease activity ≥ 20/100; (2) parent/patient assessment of disease effect on overall wellbeing ≥ 20/100; (3) Childhood Health Assessment Questionnaire score ≥ 0.375/3; (4) ≥ 2 joints with active arthritis; (5) ≥ 2 joints with non-irreversible limited range of motion and (6) ESR ≥ 30 despite oral prednisone or prednisolone ≥ 0.3 mg/kg or 10 mg/day (whichever was lower). Intravenous or intra-articular steroids, immunosuppressive drugs and disease-modifying antirheumatic drugs (DMARDs) had to be stopped at least 1 month before study onset or for longer periods of time depending on their half-life.
The mean age of patients who participated was 9.5 years (SD 5.19) in the anakinra group vs 7.5 years (SD 3.73) in the placebo group. The mean duration of disease was 4.2 years (SD 3.3) in the anakinra group vs. 3.2 years (SD 1.95) in the placebo group. The mean daily steroid dose was 0.52 mg/kg (SD 0.237) in the anakinra group vs. 0.66 mg/kg (SD 0.373) in the placebo group. A total of 8/12 patients in the anakinra group and 11/12 patients in the placebo group were on methotrexate (MTX) at baseline.
After a one month blinded phase, 8/12 patients in the Kineret treated group were identified as modified ACRpedi30 responders compared to 1/12 in the placebo group. At the same time point, 7/12 were classified as ACRpedi50 and 5/12 as ACRpedi70 responders compared to none in the placebo group. Twenty two patients entered the subsequent open-label phase in the study. Out of the patients randomised to receive Kineret throughout the study, the proportions of responders at months 1, 2, 6 and 12 were 8/12 (67%), 5/12 (42%), 3/8 (38%) and 3/7 (43%), respectively. Out of the patients who initiated the Kineret treatment after month 1, the proportions of responders at months 1, 2, 6 and 12 were 1/11 (9%), 9/10 (90%), 3/9 (33%) and 4/9 (44%), respectively.
Immunogenicity results were not reported in this study.
The efficacy and safety of Kineret for the treatment of SJIA was evaluated in a randomised double bind placebo controlled multicentre study of 11 patients (aged 1 to 51 years) treated for 12 weeks, whereof 6 patients received Kineret, 5 of which were SJIA patients. Kineret was efficacious in the treatment of SJIA as demonstrated by superiority to placebo in the primary endpoint ACR30 response with absence of fever at week 2 (p-value = 0.0022). The efficacy was supported by the superiority to placebo in ACR50, ACR70 and ACR90 responses with absence of fever at week 2. The demonstrated efficacy of Kineret in ACR30, ACR50, ACR70 and ACR90 responses at week 2 were sustained throughout the 12 weeks treatment period. The Kineret treated patients had a prompt decrease in elevated baseline CRP and ferritin levels already at week 1, which was maintained throughout the study, this was not observed in the placebo group. No relevant unexpected safety findings were observed in the study, and the results were in line with the known safety profile of Kineret.
In a retrospective safety analysis of registry data involving 306 paediatric patients with SJIA it appears that the long term safety profile of Kineret did not have any new safety findings. Approximately half (46.1%) of the patients were continuously treated with Kineret for at least 1 year, and 28.1% for at least 2 years. The pattern and frequency of AEs, including SAEs, observed in the study with the confounding factors because the design were in line with the known safety profile of Kineret. In general, the rate of AEs was highest during the first 6 months of treatment and considerably lower during later time periods. There were no deaths during Kineret treatment. Few patients discontinued due to AEs. The main reason for Kineret discontinuation was inefficacy however, the second most common reason for discontinuation was disease remission. Long term treatment with Kineret in SJIA patients was well tolerated, with no overall increase in incidence rate of AEs, including MAS, over time.

5.2 Pharmacokinetic Properties

The absolute bioavailability of the commercial formulation has not been definitively established. However, the absolute bioavailability of development formulations was high (> 80%) for a 70 mg SC bolus injection and the commercial formulation is likely to be comparable. In patients with RA, maximum plasma concentrations of Kineret occurred at 3 to 7 hours after SC administration of Kineret at clinically relevant doses (1 to 2 mg/kg; n = 18); the terminal half-life ranged from 4 to 6 hours. In RA patients, no unexpected accumulation of Kineret was observed after daily SC doses for up to 24 weeks. Evidence suggests that Kineret is predominantly metabolised in proximal renal tubules.
The influence of demographic covariates on the pharmacokinetics of Kineret was studied using population pharmacokinetic analysis encompassing 341 patients receiving daily SC injections of Kineret at doses of 30, 75 and 150 mg for up to 24 weeks. The estimated Kineret clearance increased with increasing creatinine clearance and body weight. After adjusting for creatinine clearance and body weight, gender and age were not significant factors for mean plasma clearance.
When comparing the dose-normalised concentration data in JIA patients with data in adult RA patients no major difference between the age groups was seen when comparing mean estimates, however, the variability was high in the data set (CV% 69-117).
A population PK/PD analysis in patients with SJIA and autoinflammatory syndromes (87 patients aged 8 months to 21 years including 22 SJIA patients aged 2-16 years) based on mean anakinra steady state plasma concentration of 0.4 mg/L required to attain plasma C-reactive protein (CRP) level ≤ 10 mg/L indicated a mean effective anakinra dose of 2 mg/kg/day for body weight 10-50 kg and 1 mg/kg up to a maximum of 100 mg/day for body weight > 50 kg (see Section 4.2 Dose and Method of Administration).
The pharmacokinetics in CAPS patients is similar to that in RA patients. Anakinra exhibits approximate dose linearity with a slight tendency to higher than proportional increase.

Patients with renal impairment.

The mean plasma clearance of Kineret in subjects with mild (creatinine clearance 50-80 mL/min) and moderate (creatinine clearance 30-49 mL/min) renal insufficiency was reduced by 16% and 50%, respectively. The mean plasma clearance of Kineret decreased 70%-75% in normal subjects with severe or end stage renal disease (creatinine clearance < 30 mL/minute). No formal studies have been conducted examining the pharmacokinetics of Kineret administered subcutaneously in rheumatoid arthritis patients with renal impairment. The efficacy of alternative dosing regimens has not been examined in patients with renal impairment.

Patients with hepatic dysfunction.

No formal studies have been conducted examining the pharmacokinetics of Kineret administered subcutaneously in RA patients with hepatic impairment. However, a study including 12 patients with hepatic dysfunction (Child-Pugh class B) given a single 1 mg/kg intravenous dose has been performed. Pharmacokinetic parameters were not substantially different from healthy volunteers, other than a decrease in clearance of approximately 30% in comparison with data from a study with healthy volunteers. A corresponding decrease in creatinine clearance was seen in the hepatic failure population. Accordingly, the decrease in clearance is most likely explained by a decrease in renal function in this population. These data support that no dose adjustment is required for patients with hepatic dysfunction of Child-Pugh class B.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

Kineret has not been evaluated for its carcinogenic potential in animals. It is known that many different types, but not all cancer cells, express the interleukin-1 receptor. Depending on the cancer cell type, activation of the receptor by interleukin-1 can cause a variety of anti-proliferative or proliferative responses. Insufficient data are available on the effect of Kineret on sub-detectable cancer cells in animals or patients. Therefore, Kineret is not recommended for use in patients with pre-existing cancer unless clearly needed.

6 Pharmaceutical Particulars

6.1 List of Excipients

The solution in pre-filled syringes is formulated at pH 6.5 with 0.70 mg polysorbate 80, 1.29 mg sodium citrate dihydrate, 5.48 mg sodium chloride, and 0.12 mg disodium edetate in water for injections.

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. Refrigerate. Do not freeze. Avoid shaking. Protect from light. Allow the pre-filled syringe to reach room temperature before injecting. Kineret may be kept at room temperature up to 25°C for a maximum of 72 hours. After removal from the refrigerator, Kineret must be used within 72 hours or discarded. Once stored at room temperature, Kineret should not be placed back in the refrigerator.

6.5 Nature and Contents of Container

Kineret is supplied in single use pre-filled syringes with a 29 gauge needle.
Kineret is available in packs containing 28 syringes. The pre-filled syringe has an outer rigid plastic needle shield attached to an inner needle cover. None of the syringe or needle shield components are made with natural rubber latex.

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

Kineret (anakinra) is a recombinant, nonglycosylated form of the human interleukin-1 receptor antagonist (IL-1Ra). Kineret differs from native human IL-1Ra in that it has an additional single methionine residue at its amino terminus. Kineret consists of 153 amino acids and has a molecular weight of 17.3 kilodaltons. It is produced by recombinant DNA technology using an E. coli bacterial expression system.

7 Medicine Schedule (Poisons Standard)

Schedule 4 (Prescription Only Medicine).

Summary Table of Changes