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.

What is in this leaflet

This leaflet answers some common questions about KINERET. It does not contain all the available information. It does not take the place of talking to your health professional (i.e. doctor, nurse, pharmacist).

All medicines have risks and benefits. Your doctor has weighed the risks of you using KINERET against the benefits he/she expect it will have for you.

If you have any concerns about using this medicine, ask your health professional.

Read this leaflet carefully before you start using KINERET and keep it with the medicine. You may need to read it again.

What KINERET is used for

KINERET contains the active substance anakinra and is used to treat the signs and symptoms associated with:

  • active Rheumatoid Arthritis (RA) in adults in combination with methotrexate;
  • 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.

In people with RA, CAPS and SJIA, the body produces too much of the protein interleukin-1. Too much interleukin-1 causes inflammation contributing to the symptoms of the diseases. The body blocks this inflammation by producing an interleukin-1-receptor antagonist (IL-1Ra). In patients with RA, CAPS and SJIA, the amount of IL-1Ra that the body produces is not enough to counteract the increased amount of interleukin-1. KINERET, which contains anakinra (a man-made protein similar to IL-1Ra), can block the action of interleukin-1 and reduce the signs and symptoms of the disease.

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.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

Before you use KINERET

When you must not use it

Do not use KINERET if you are using a medicine that is a tumour necrosis factor (TNF) antagonist. Ask your doctor or pharmacist if you are not sure whether you are taking such a medicine.

Do not use KINERET if you have an allergy to:

  • any medicine containing anakinra
  • any of the ingredients listed at the end of this leaflet
  • any other medicines made using E. coli-derived proteins.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

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.

Do not use this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

Do not use KINERET if the syringe has been left out of the refrigerator for more than 12 hours.

Do not use KINERET if the syringe has been dropped. This is for your safety in case the syringe is broken or the needle is bent or dirty.

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

KINERET is not recommended for use in patients with pre-existing malignancy.

KINERET should not be used in patients with neutropaenia (low white blood cell count).

If you are not sure whether you should start taking this medicine, talk to your health professional.

Before you start to use it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • 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.

Tell your doctor about your vaccination history and if you have had a recent vaccination. Your doctor may ask you to complete all vaccinations before starting KINERET.

Tell your doctor if you have a history of increased levels of liver enzymes.

Tell your doctor if you are using any other medicines to treat your condition.

Tell your doctor if you are pregnant or plan to become pregnant or are breastfeeding. 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.

You must not breastfeed if you use KINERET. It is not known whether KINERET passes into breast milk.

If you have not told your doctor about any of the above, tell him/her before you start using KINERET. Your doctor can discuss with you the risks and benefits involved.

Taking other medicines

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

Tell your doctor or pharmacist if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop. Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to use KINERET

KINERET is usually given by daily injection under your skin; this is called a subcutaneous injection.

Follow all directions given to you by your health professional carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions in this leaflet, ask your health professional for help. Your health professional will teach you or your carer how to give a subcutaneous injection so that KINERET can be administered at home once you or your carer are confident with the process.

If you are not sure about giving the injection or you have any questions, ask your doctor or nurse for help.

How much to use

Always use this medicine exactly as your doctor has told you.

Your doctor will decide what dose you or your child needs and how often to give it.

Check with your doctor or pharmacist if you are not sure.

Each KINERET dose comes in a 1 mL graduated pre-filled syringe containing 100 mg KINERET.

Graduations are in mg to help you select and inject the right dose.

Use each KINERET graduated pre-filled syringe only once.

If you notice some solution remaining in the syringe, do not re-inject.

You should discard the syringe with any remaining solution in a puncture-proof sharps container.

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.

How to prepare your injection

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.
  1. Check the expiry date (Exp.) on the graduated pre-filled syringe label. Do not use it if the date has passed.
  2. 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: 20 to 90 mg, 100 mg, or higher.

  • If your doctor has prescribed a 100 mg dose you should follow the "How to prepare a 100 mg dose" section;
  • If your doctor has prescribed a lower dose you should follow the "How to prepare a 20 to 90 mg dose" section.

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.

Change the place that you inject each time so you don't become sore in one area.

Do not inject into skin that is tender, red, bruised, or hard.

Avoid scars or stretch marks.

Don't 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.

When to use it

Try to inject KINERET at approximately the same time each day on a schedule that works best for you. Taking it at the same time each day will have the best effect. It will also help you remember when to use it.

Schedule your KINERET injections with another task you do each day, such as getting dressed in the morning.

How long to use it

Continue using your medicine for as long as your doctor tells you.

The medicine helps control your condition, but it does not cure it. It is important to keep using your medicine even if you feel well.

If you forget to use it

If you have forgotten to use a dose of KINERET you should contact your doctor or nurse to discuss when you should use the next dose.

If you use too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre on 13 11 26 (Australia) or 0800 764 766 (New Zealand) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have used too much KINERET. Do this even if there are no signs of discomfort or poisoning.

While you are using KINERET

Things you must 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 must not do

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.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using KINERET, even if you do not think the problems are connected with the medicine or are not listed in this leaflet.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects. Other side effects are minor and are likely to be temporary.

Do not be alarmed by the following list of side effects. You may not experience any of them.

Ask your health professional to answer any questions you may have.

Tell your health professional if you notice any of the following and they worry you:

  • 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.

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. 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.

Other side effects not listed above may also occur in some people. Some of these side effects can only be found when your doctor does tests from time to time to check your progress.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • a fever, a cough or redness and tenderness of the skin or other signs of infection
  • swelling of the face, tongue or throat
  • trouble swallowing
  • itchy skin or rash
  • shortness of breath or difficulty breathing
  • wheezing
  • suddenly feeling fast pulse or sweating.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

These side effects are very rare.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell or worries you.

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

After using KINERET

Storage

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 12 hours at room temperature (up to 25°C).

Do not store KINERET in the freezer.

Do not let KINERET freeze.

Do not use KINERET after the expiry date, which is stamped on the box and syringe label.

Keep it where children cannot reach it.

Disposal

Do not put the cover back on used needles.

Put used syringes into a puncture-proof sharps container and keep it out of the reach and sight of children.

Close the lid of the full puncture-proof sharps container as instructed by your health professional. Contact your local council or the nearest hospital to find out where you can dispose of the sharps container.

Never put the used syringes into your normal household rubbish bin.

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.

Product description

What it looks like

KINERET is supplied in single use graduated pre-filled syringes as a sterile, clear, colourless-to-white, preservative-free solution for subcutaneous administration.

The solution may contain some small translucent-to-white particles of protein.

KINERET is available in packs of 28 syringes.

Ingredients

Each KINERET syringe contains 100 mg of the active ingredient anakinra (100 mg / 0.67 mL).

Other ingredients:

  • sodium citrate dihydrate
  • sodium chloride
  • disodium edetate
  • polysorbate 80
  • water for injections.

Supplier

KINERET is supplied in Australia by:

Swedish Orphan Biovitrum Pty Ltd
Floor 22, 44 Market Street
Sydney NSW 2000

® = Registered Trademark of Swedish Orphan Biovitrum AB (publ).

Australian Registration Number: AUST R 82872

This leaflet was revised in August 2021.

For the most up to date version of this leaflet, please go to https://au.sobi.com

Published by MIMS October 2021

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 (see Section 4.4 Special Warnings and Precautions for Use, Macrophage activation syndrome (MAS)). 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.

Macrophage activation syndrome (MAS).

SJIA patients have an increased risk of spontaneous development of MAS. During post-marketing use case reports of MAS in SJIA patients have been received. No events of MAS were reported in company sponsored clinical studies in SJIA patients. In a retrospective safety analysis of registry data in 306 paediatric patients with SJIA there was no indication that the frequency of MAS increased during, or directly after, Kineret treatment. The incidence rate of MAS was 2.4 events per 100 patient years, which is in line with what is expected for paediatric patients with SJIA. A causal relationship between Kineret and MAS has not been established.

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. A causal relationship between IL-1 inhibitors and DRESS has not been established. 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.

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 the effects of vaccination with other inactivated antigens in patients receiving 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. Therefore, live vaccines should not be given concurrently with 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.

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 removed from storage for a total period of 12 hours at room temperature (up to 25°C).

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