Consumer medicine information

Stelara

Ustekinumab

BRAND INFORMATION

Brand name

Stelara

Active ingredient

Ustekinumab

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Stelara.

What is in this leaflet

This leaflet answers some common questions about STELARA (pronounced stel-ahr-uh). It does not contain all the available information. It does not take the place of talking to your doctor, nurse or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using STELARA against the benefits this medicine is expected to have for you.

If you have any concerns about using STELARA, ask your doctor or pharmacist.

It is important that you read this leaflet.

Keep this leaflet with your medicine. You may need to read it again.

What STELARA is used for

STELARA is a prescription medicine that is used to treat:

  • adults and paediatric patients (children and adolescents) 6 years and older with moderate to severe plaque psoriasis that is chronic (doesn't go away),
  • adults with active psoriatic arthritis, an inflammatory disease of the joints that is usually accompanied by psoriasis,
  • adults with moderately to severely active Crohn’s disease, an inflammatory disease of the bowel.
  • adults with moderate to severe ulcerative colitis, an inflammatory disease of the bowel.

STELARA contains the active ingredient ustekinumab, a monoclonal antibody. Monoclonal antibodies are proteins that recognise and bind to other unique proteins.

Ustekinumab blocks the action of two proteins in your body called interleukin 12 (IL-12) and interleukin 23 (IL-23). IL-12 and IL-23 are made by your body's immune system. In people with psoriasis, psoriatic arthritis, Crohn’s disease or ulcerative colitis, IL-12 and IL-23 can cause their immune system to attack normal healthy parts of their body. Ustekinumab can block IL-12 and IL-23 from causing the immune system to attack.

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.

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

Before you use STELARA

When you must not use it

Do not use STELARA if you have an allergy to:

  • ustekinumab, the active ingredient in the medicine
  • any of the other ingredients in STELARA. See Product Description at the end of this leaflet for a list of ingredients.

Symptoms of an allergic reaction may include rash, itching or hives on the skin, shortness of breath, wheezing or difficulty breathing, swelling of the face, lips, tongue or other parts of the body.

Do not use STELARA if the packaging is torn or shows signs of tampering, or if the liquid is discoloured or cloudy.

Do not use STELARA beyond the expiry date (month and year) printed on the pack.

Do not use STELARA if you know or think that it may have been exposed to extreme temperatures (such as being accidentally frozen or heated).

Before you start to use it

You must tell your doctor about all of your medical conditions before each treatment, including if you:

  • have any kind of infection, even if it is very minor
  • have an infection that won't go away or a history of infection that keeps coming back
  • have had TB (tuberculosis), or if you have recently been near anyone who might have TB
  • have or have had any type of cancer
  • have any new or changing lesions within psoriasis areas or on normal skin
  • have recently received or are scheduled to receive a vaccine. Patients receiving STELARA should not receive live vaccines. Tell your doctor if anyone in your house needs a vaccine. The viruses in some vaccines can spread to people with a weakened immune system, and can cause serious problems
  • are receiving allergy immunotherapy.
  • are pregnant, planning to become pregnant, or breastfeeding. Adequate contraception should be used to avoid falling pregnant. STELARA should only be used during a pregnancy if needed. Women who are breastfeeding should talk to their doctor about whether or not to use STELARA as it might be excreted in breast milk.
  • have an allergy to latex. The needle cover on the pre-filled syringe and the needle cover in the bottom cap of the pre-filled pen contain dry natural rubber (a form of latex). This may cause allergic reactions in people who are sensitive to latex.

Your doctor will examine you for tuberculosis (TB). If your doctor feels that you are at risk for TB, you may be treated with medicine for TB before you begin treatment with STELARA and during treatment with STELARA.

If you have not told your doctor or pharmacist about any of the above, tell them before you start using or are given STELARA.

Taking other medicines

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

Using STELARA

For the treatment of psoriasis or psoriatic arthritis STELARA is given by injection just under the skin (subcutaneously).

For the treatment of Crohn’s Disease and ulcerative colitis, the first dose of STELARA will be given by an intravenous infusion, which means that the medicine will be given to you through a needle placed in a vein. After this starting dose, all future doses of STELARA are given by injection just under the skin (subcutaneously).

All STELARA injections are for single use in one patient only.

STELARA is intended for use under the guidance and supervision of your doctor. In children and adolescents 6 years and older with psoriasis, it is recommended that STELARA be administered by a health care provider. When you start treatment, STELARA may be injected by your healthcare provider. If your doctor determines that it is appropriate, you or your caregiver may be able to administer it under the skin yourself if you wish, after proper training in injection technique. (See How much to use and Injecting STELARA under the skin yourself).

It is important to remember that the first dose of STELARA for the treatment of Crohn’s Disease or ulcerative colitis (intravenous infusion) will always be administered by your healthcare provider.

How much to use

  • Your doctor will determine the correct dose of STELARA for you and how often you should receive it. Make sure to discuss with your doctor when you will receive injections and to come in for all your scheduled follow-up appointments.
  • For children and adolescents aged 6 years or older with psoriasis:
    - The doctor will work out the right dose for you, including the amount (volume) of Stelara to be injected to give the right dose. The right dose for you will depend on your body weight at the time each dose is given. If you weigh less than 60 kg, the recommended dose is 0.75 mg of Stelara per kg body weight.
    - If you weigh 60 kg to 100 kg, the recommended dose is 45 mg Stelara.
    - If you weigh more than 100 kg, the recommended dose is 90 mg Stelara.
    - After the starting dose, you will have the next dose 4 weeks later, and then every 12 weeks.

Injecting STELARA under the skin yourself

Your first STELARA injection may be administered by your healthcare provider. In children and adolescents 6 years and older, it is recommended that all doses of STELARA be administered by a healthcare provider. However, your healthcare provider may decide that it is right for you or your caregiver to learn how to inject STELARA under the skin (subcutaneously) yourself. If you would like to self-inject STELARA under your skin, you or your caregiver must be trained by a healthcare professional to prepare an injection and give it to yourself. If you have not been trained, please contact your healthcare provider to schedule a training session. Call your healthcare provider if you have any questions about giving yourself an injection.

STELARA is given alone and not mixed with other liquids for injection.

STELARA should not be used:

  • after the expiry date on the label;
  • if the seal is broken;
  • if the liquid is discoloured, cloudy or you can see other particulate matter floating in it;
  • if you know, or think that it may have been exposed to extreme temperatures (such as being accidentally frozen or heated).

Do not shake STELARA at any time. Prolonged vigorous shaking may damage the product. If STELARA has been shaken vigorously, don’t use it. STELARA is not to be mixed with other liquids for injection.

STELARA injection under the skin (subcutaneous) is available in vial, pre-filled syringe and pre-filled pen.

Please refer to the 'Instructions for Use' leaflet for the pre-filled pen. Instructions for use for vial and pre-filled syringe are provided below.

How to inject STELARA under the skin from a vial

  1. Check Vials and Assemble materials:
Take the vial(s) out of the refrigerator. Make sure that it is the right dose. If your dose is 45 mg you will receive one 45 mg vial. If your dose is 90 mg, you will receive two 45 mg vials. If you receive two 45 mg vials for a 90 mg dose, you will need to give yourself two injections one right after the other. Check with your healthcare provider.
Children weighing less than 60 kg require a dose lower than 45 mg. Make sure you know the proper amount (volume) and type of syringe needed for dosing. If you don’t know the amount or type of syringe needed, contact your healthcare provider for further instructions.
Check Expiration Date
Open the box and remove the vial. Check the expiration date on the vial and the label of the box. If the expiration date has passed, don’t use it.
Check Solution in Vial
Make sure the vial is not damaged. Look at the solution or liquid in the vial to make sure that it is not cloudy and not frozen.
Assemble Additional Supplies
Assemble the additional supplies you will need for your injection. These include a syringe with a 27 gauge, 1/2 inch needle, an alcohol swab, a cotton ball or gauze, and a sharps container for syringe disposal.

  1. Choose the Injection Site:
Good sites are the top of the thigh and around the tummy (abdomen) but about 5 centimetres away from the belly button (navel). Avoid, if possible, skin involved with psoriasis. If your caregiver is giving you the injection, they may use the upper arms or buttocks as well.

Prepare the Injection Site.
Thoroughly wash your hands with soap and warm water. Wipe the injection site with an alcohol swab. DO NOT touch this area again before giving the injection.
  1. Preparing the dose:
Remove the cap from the top of the vial but do not remove the stopper.

Clean the stopper with an antiseptic swab.
Remove the needle cover from the syringe. Do not touch the needle or allow the needle to touch anything.

Put the vial on a flat surface and push the syringe needle through the rubber stopper.
Turn the vial and the syringe upside down.
For adults and paediatric patients (children and adolescents) 6 years of age and older, who weigh 60 kg or more, pull on the syringe plunger to fill the syringe with the amount of liquid prescribed by your healthcare provider (0.5 mL or 1.0 mL).
For children and adolescents 6 years of age or older who weigh less than 60 kg, the amount of liquid prescribed by your healthcare provider may be less than 0.5 mL. Your healthcare provider will recommend how much liquid is needed.
It is important that the needle is always in the liquid in order to prevent air bubbles from forming in the syringe.
Remove the needle from the vial. Hold the syringe with the needle pointing up to see if it has any air bubbles inside.

If there are air bubbles tap the side gently until the air bubbles go to the top of the syringe and press the plunger until all of the air (but none of the liquid) has been removed. Do not lay the syringe down or allow the needle to touch anything.
  1. Injecting the Medication:
Gently pinch the cleaned skin between your thumb and index finger. Don’t squeeze it.

Push the syringe needle into the pinched skin.
Push the plunger with your thumb as far as it will go to inject all of the liquid. Push it slowly and evenly, keeping the skin gently pinched.
When the plunger is pushed as far as it will go, take out the needle and let go of the skin.
Press an antiseptic swab over the injection site for a few seconds after the injection.

Dispose of the Empty Syringe
Immediately dispose of the empty syringe into the sharps container. For your safety and health and for the safety of others, needles and syringes must NEVER be re-used. Dispose of sharps container according to your local regulations. See "After using STELARA - Disposal".

Use a Cotton Ball or Gauze
There may be a small amount of blood or liquid at the injection site, which is normal. You can press a cotton ball or gauze over the injection site and hold for 10 seconds. Do not rub the injection site. You may cover the injection site with a small adhesive bandage, if necessary.

If your dose amount is 90 mg, and you receive two 45 mg vials you may need to give a second injection right after the first. Use a new needle and syringe. Choose a different site for the second injection.

If you do not understand the instructions provided with this medicine, ask your doctor or pharmacist for help.

How to inject STELARA under the skin from a pre-filled syringe

To reduce the risk of accidental needle stick injuries to users, each pre-filled syringe is equipped with a needle guard that is automatically activated to cover the needle after complete delivery of the syringe content.

  1. Preparing for pre-filled syringe use

Take the syringe(s) out of the refrigerator.
Make sure that it is the right dose.
Check Expiration Date
Open the box and remove the syringe. Check the expiration date on the pre-filled syringe and the label of the box. If the expiration date has passed, don’t use it.
Check Solution in Syringe
Hold the pre-filled syringe with the covered needle pointing upward. Make sure the syringe is not damaged. Look at the solution or liquid in the vial to make sure that it is not cloudy and not frozen.
Assemble Additional Supplies
Assemble the additional supplies you will need for your injection. These include an antiseptic wipe, a cotton ball or gauze, and a sharps container for syringe disposal.
DO NOT remove the needle cover from the pre-filled syringe.
DO NOT pull back on the plunger head at any time.
  1. Choosing and preparing the injection site
Choose the Injection Site*
Good sites are the top of the thigh and around the tummy (abdomen) but about 5 centimetres away from the belly button (navel). Avoid, if possible, skin involved with psoriasis. If your caregiver is giving you the injection, they may use the upper arms or buttocks as well.

Prepare the Injection Site
Thoroughly wash your hands with soap and warm water. Wipe the injection site with an antiseptic wipe. DO NOT touch this area again before giving the injection.
  1. Injecting the medication
Remove the Needle Cover
When you are ready to inject, pick up the pre-filled syringe with one hand and pull the needle cover straight off.
Throw the needle cover into the rubbish.
You may notice a small air bubble in the pre-filled syringe. You do not need to remove the air bubble. You may also see a drop of liquid at the end of the needle – this is normal. Do not touch the needle or allow it to touch any surface.

Note: The needle cover should NOT be removed until you are ready to inject the dose. Do not use the syringe if it is dropped without the needle cover in place. If you drop the syringe without the needle cover in place, please contact your healthcare provider for assistance.
  1. Inject the medication
Gently pinch the cleaned skin between your thumb and index finger.

Don’t squeeze it. Push the syringe needle into the pinched skin.
Push the plunger with your thumb as far as it will go to inject all of the liquid. Push it slowly and evenly, keeping the skin gently pinched.
When the plunger meets the end of the syringe barrel, and all of the medication has been injected, release the pinched skin and gently remove the needle. Following complete injection, the needle guard will automatically extend over the needle and lock as you take your hand off the plunger.

  1. After the injection
Dispose of the Empty Syringe
Immediately dispose of the empty syringe into the sharps container. For your safety and health and for the safety of others, needles and syringes must NEVER be re-used. Dispose of sharps container according to your local regulations. See ‘After using STELARA - Disposal’.
Use a Cotton Ball or Gauze
There may be a small amount of blood or liquid at the injection site, which is normal. You can press a cotton ball or gauze over the injection site and hold for 10 seconds. Do not rub the injection site. You may cover the injection site with a small adhesive bandage, if necessary.

If you do not understand the instructions provided with this medicine, ask your doctor or pharmacist for help.

If you forget to use it

  • Make the next injection as soon as you remember, and then continue to use it as you would normally.
  • Do not administer a double dose to make up for the dose you missed.

If you have missed more than one dose, or are not sure what to do, check with your doctor or pharmacist.

If you have trouble remembering when to use your medicine, ask your pharmacist for some hints.

If you have used too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre for advice or go to Accident and Emergency at your nearest hospital.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Poisons Information Centre telephone numbers:

  • Australia: 13 11 26
  • New Zealand: 0800 POISON or 0800 764 766

Keep these telephone numbers handy.

While you are using STELARA

Things you must do

  • Always follow your doctor’s instructions carefully.
  • Tell your doctor about your medical conditions before each treatment (see Before you use STELARA).
  • Tell your doctor if you become pregnant while using STELARA.
  • If you are about to start taking a new medicine, tell your doctor and pharmacist that you are using STELARA.

Things you must not do

  • You should not receive a live vaccine while taking STELARA.
  • Do not use STELARA to treat any other complaint unless your doctor says so.
  • Do not give this medicine to anyone else, even if their symptoms seem similar to yours.

Side Effects

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some side effects. Do not be alarmed by this list of possible side effects. You may not experience any of them.

In general, the side effects of STELARA in children and adolescents 6 years and older are similar to those in adults. Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you experience any of the following common side effects:

  • Upper respiratory infections such as sinus infection and colds
  • Dizziness, headache
  • Sore throat
  • Diarrhoea
  • Nausea, vomiting
  • Pruritis (itching)
  • Back or muscle pain
  • Joint pain
  • Injection site pain or redness
  • Fatigue (tiredness)
  • Sinus infection

Infusion-related reactions

During infusion of STELARA, the following reactions may occur. Tell your doctor or nurse right away if you get any of the following signs of an infusion-related reaction during, or in the 3 days after, the infusion. You may need other medicines, or the infusion may need to be slowed down or stopped.

  • Fever or chills
  • Itchiness or hives
  • Chest pain
  • Low or high blood pressure

Other uncommonly reported side effects include:

  • Painful skin rash (Herpes Zoster infection) or blister
  • Eczema
  • Cellulitis
  • Dental infections
  • Blisters or sores in the mouth
  • Viral upper respiratory tract infection
  • Vaginal yeast (fungal) infection
  • Depression
  • Blocked or stuffy nose
  • Acne
  • Injection site reactions (including bleeding, bruising, hardness, swelling and itch)
  • Feeling weak
  • A change in psoriasis with redness and new tiny, yellow or white skin blisters, sometimes accompanied by fever (pustular psoriasis)
  • Worsening reddening or shedding/peeling of the skin
  • Lower respiratory tract infections such as bronchitis or pneumonia

Tell your doctor immediately or go to hospital as you need urgent medical attention:

  • A serious allergic reaction. Signs of a serious allergic reaction may include a skin rash, a swollen face, lips, mouth or throat, or wheezing, dizziness, trouble swallowing or breathing.
  • In rare cases, symptoms such as cough, shortness of breath, and fever may also be a sign of an allergic lung reaction to STELARA.

STELARA is a medicine that may decrease the activity of your immune system. It can increase your chances of getting serious side effects. Tell your doctor immediately if you notice any of the following, as you may need urgent medical care:

  • Serious Infections. STELARA may lower your ability to fight infections. Some infections could become serious and lead to hospitalization. If you have an infection, tell your healthcare provider before you start using STELARA. If you get an infection, have any sign of an infection such as fever, feel very tired, cough, flu-like symptoms, or have any open cuts or sores, tell your healthcare provider right away.
  • Cancer. Many drugs such as STELARA that may decrease the activity of the immune system may increase the risk of cancer. Tell your doctor if you have ever had any type of cancer.

Other side effects not listed above may also occur in some people. Tell your doctor if you notice any other side effects, particularly if they bother you or do not go away. In general, the side effects of STELARA in children and adolescents 6 years and older are similar to those in adults. Ask your doctor or pharmacist for more information.

After using STELARA

Storage

Store STELARA between 2°C and 8°C in the refrigerator. Do not freeze. Keep the product in the original carton to protect from light until the time of use. Do not shake.

If needed, you may store STELARA pre-filled syringes and pre-filled pens at room temperature up to 30°C for one period of up to 30 days.

  • Write the date on the carton, when removed from the refrigerator.
  • Once pre-filled syringe or pre-filled pen has been stored at room temperature, do not put it back in the refrigerator.
  • Throw away pre-filled syringe or pre-filled pen if it has been kept for 30 days and has not been used or reached its original expiry.

For pre-filled pen only, before use, remove the carton from the refrigerator and keep the pre-filled pen inside the carton and allow to reach room temperature by waiting for 30 minutes.

Keep your medicines out of reach of children.

Do not store STELARA, or any other medicine, in the bathroom or near a sink. Do not leave medicines in the car or on windowsills. Heat and dampness can destroy some medicines.

Disposal

After injection, used syringes should be placed in a puncture-resistant container, like a sharps container. Dispose of your sharps container according to your state or local regulations. Empty vials, antiseptic wipes, and other supplies can be placed in regular rubbish.

If your doctor tells you to stop using STELARA, or your medicine has passed its expiry date, ask your pharmacist what to do with any medicine that may be left over.

Product Description

What it looks like

STELARA injection for subcutaneous use is a colourless to light yellow solution and may contain a few small translucent or white particles of protein. This appearance is not unusual for solutions containing protein.

STELARA solution for intravenous use is a clear, colourless to light yellow product.

STELARA is available in the following presentations:

For subcutaneous administration

STELARA ustekinumab 45 mg/0.5 mL solution for injection vial (AUST R 149549)

STELARA ustekinumab 45 mg/0.5mL solution for injection prefilled syringe (AUST R 165953)

STELARA ustekinumab 90 mg/1mL solution for injection pre-filled syringe (AUST R 165954)

STELARA ustekinumab 45 mg/0.5 mL solution for injection pre-filled pen (One-Press® patient-controlled injector) (for adult use) (AUST R 400550)

STELARA ustekinumab 90 mg/1 mL solution for injection pre-filled pen (One-Press® patient-controlled injector) (for adult use) (AUST R 400551)

For intravenous infusion

STELARA ustekinumab 130 mg/26 mL (5 mg/1mL) for solution for intravenous infusion injection vial (concentrate). (AUST R 282906)

Each box contains 1 unit.

Ingredients

STELARA 45 mg or 90 mg solution for injection for subcutaneous administration

Each vial contains 45 mg of ustekinumab.

Each pre-filled syringe or pre-filled pen contains 45 mg or 90 mg of ustekinumab.

Inactive ingredients: histidine/histidine hydrochloride monohydrate, sucrose, polysorbate 80, and water for injections.

No preservatives are present.

STELARA 130 mg concentrate for solution for intravenous infusion

Each vial contains 130 mg of ustekinumab.

Inactive ingredients: histidine, histidine hydrochloride monohydrate, sucrose, polysorbate 80, methionine, disodium edetate, and water for injections.

No preservatives are present.

Sponsor

JANSSEN-CILAG Pty Ltd
1-5 Khartoum Road
Macquarie Park NSW 2113 Australia
Telephone: 1800 226 334

NZ Office: Auckland New Zealand
Telephone: 0800 800 806

This leaflet was prepared in November 2023.

Nurse and educational support

The Janssen Immunology Patient Support Program is available to patients prescribed STELARA and offers:

  • starter kit
  • one-to-one nurse support
  • reminder service
  • ongoing education
  • wellbeing support

Call 1800 666 845

Published by MIMS December 2023

BRAND INFORMATION

Brand name

Stelara

Active ingredient

Ustekinumab

Schedule

S4

 

1 Name of Medicine

Ustekinumab.

2 Qualitative and Quantitative Composition

Stelara contains ustekinumab and is available in the following presentations:

Solution for subcutaneous injection.

Pre-filled syringe.

45 mg / 0.5 mL; 90 mg / 1.0 mL.

Pre-filled pen (One-Press patient-controlled injector for adult use).

45 mg / 0.5 mL; 90 mg / 1.0 mL.

Single-use vial.

45 mg / 0.5 mL.

Solution for intravenous infusion.

Single-use vial.

130 mg / 26 mL.
For a full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

For subcutaneous administration.

Solution for subcutaneous injection.
The solution is clear to slightly opalescent, colourless to light yellow.

For intravenous infusion only.

Concentrate for solution for infusion.
The solution is clear, colourless to light yellow.

4 Clinical Particulars

4.1 Therapeutic Indications

Plaque psoriasis.

Adults.

Stelara is indicated for the treatment of adult patients (18 years or older) with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.

Paediatric population, 6 years and older.

Stelara is indicated for the treatment of moderate to severe plaque psoriasis in children and adolescent patients from 6 years of age who are inadequately controlled by, or are intolerant to, other systemic therapies or phototherapies.

Psoriatic arthritis (PsA).

Stelara, alone or in combination with methotrexate, is indicated for the treatment of signs and symptoms of active psoriatic arthritis in adult patients (18 years and older) where response to previous non-biological DMARD therapy has been inadequate.

Crohn's disease.

Stelara is indicated for the treatment of adult patients with moderately to severely active Crohn's disease who have had an inadequate response, lost response, or were intolerant to either conventional therapy or a TNFα antagonist or have medical contraindications to such therapies.

Ulcerative colitis.

Stelara is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis.

4.2 Dose and Method of Administration

Dosing.

Plaque psoriasis.

Adults. For the treatment of plaque psoriasis, Stelara is administered by subcutaneous injection. The recommended dose of Stelara is 45 mg administered at weeks 0 and 4, then every 12 weeks thereafter. Alternatively, 90 mg administered over weeks 0 and 4, then every 12 weeks thereafter may be used in patients with a body weight greater than 100 kg.

Dose adjustment.

For patients who inadequately respond to dosing every 12 weeks, consideration may be given to treating as often as every 8 weeks. Treatment should be discontinued in patients who have shown no response after 28 weeks of treatment.

Re-treatment.

After interruption of therapy, re-treatment with a dosing regimen of weeks 0 and 4, then every 12 weeks thereafter has been shown to be safe and effective.
Paediatric population, 6 years and older. For the treatment of plaque psoriasis, Stelara should be administered by subcutaneous injection. The recommended dose of Stelara based on body weight is shown (Table 1). Stelara should be administered at Weeks 0 and 4, then every 12 weeks thereafter. The pre-filled pen is not recommended for use in paediatric patients.
See Table 2.
Treatment should be discontinued in patients who have shown no response after 28 weeks of treatment.

Psoriatic arthritis.

For the treatment of psoriatic arthritis, Stelara is administered by subcutaneous injection. The recommended dose of Stelara is 45 mg administered at weeks 0 and 4, then every 12 weeks thereafter. Some patients with a body weight greater than 100 kg received a 90 mg dose in clinical trials and observed a clinical benefit.
Treatment should be discontinued in patients who have shown no response after 28 weeks of treatment.

Crohn's disease and ulcerative colitis.

For the treatment of Crohn's disease and ulcerative colitis, the recommended treatment regimen is to initiate Stelara with a single intravenous (IV) tiered dose based on body weight (Table 3). The infusion solution is to be composed of the number of vials of Stelara 130 mg as specified in Table 3.
After the initial IV dose, Stelara should then be administered subcutaneously. The first subcutaneous dose of 90 mg Stelara should be administered 8 weeks after the initial intravenous dose, then every 8 weeks thereafter.
For some patients, the single IV dose followed by a 90 mg subcutaneous dose 8 weeks later, then every 12 weeks thereafter may be acceptable according to clinical judgment. Patients who inadequately respond to 90 mg subcutaneous dosing every 12 weeks may benefit from an increase in dosing frequency to every 8 weeks (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Immunomodulators and/or corticosteroids may be continued during treatment with Stelara. In patients who have responded to treatment with Stelara corticosteroids may be reduced or discontinued in accordance with standard of care.
If therapy in Crohn's disease or ulcerative colitis is interrupted, treatment may be resumed with subcutaneous dosing every 8 weeks (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Consideration should be given to discontinuing treatment in patients who show no evidence of therapeutic benefit by week 16.

Use in patients with hepatic or renal impairment.

Stelara has not been studied in these patient populations. No dose recommendations can be made (see Section 5.2 Pharmacokinetic Properties, Population pharmacokinetic analysis).

Administration.

Subcutaneous administration. Stelara 45 mg vials, 45 mg and 90 mg pre-filled syringes and pre-filled pens are for subcutaneous injection only. Do not inject into areas where the skin is tender, bruised, red, hard, thick, scaly or affected by psoriasis.
Each vial, pre-filled syringe or pre-filled pen is for single use only and any unused medicinal product should be disposed of in accordance with local requirements.
Stelara is intended for use under the guidance and supervision of a health care professional. Patients or their caregivers may inject Stelara if a physician determines that it is appropriate and with medical follow-up as necessary, after proper training in subcutaneous injection technique.
In paediatric patients, it is recommended that Stelara be administered by a health care provider. The pre-filled pen has not been studied in the paediatric population and it not recommended for use in paediatric patient.
Comprehensive instructions for the subcutaneous administration of Stelara are given in the Consumer Medicine Information for the vial and pre-filled syringe or Instructions for Use for the prefilled pen. Patients should be instructed to inject the full amount of Stelara subcutaneously according to the directions provided in the Consumer Medicine Information or Instructions for Use.
Inspect Stelara visually for particulate matter and discolouration prior to administration. Stelara is a colourless to light yellow solution and may contain a few small translucent or white particles. Do not use Stelara if it is discoloured or cloudy, or if other particulate matter is present. Stelara does not contain preservatives; therefore, discard any unused product remaining in the vial, prefilled syringe or pre-filled pen in accordance with local requirements and must never be re-used.

Vials.

When using the single-use vial, a 27 gauge, ½ inch needle is recommended.

Pre-filled syringe or pre-filled pen.

The needle cover on the pre-filled syringe and the needle cover inside the bottom cap of the prefilled pen contain dry natural rubber (a derivative of latex), which may cause allergic reactions in individuals sensitive to latex (see Section 4.4 Special Warnings and Precautions for Use).
Each pre-filled syringe and pre-filled pen is for single dose only. Patients may encounter resistance while injecting. It is important to instruct patients to inject the full amount to receive either 45 mg or 90 mg of Stelara.
For pre-filled pen only, before injection, remove Stelara from the refrigerator and allow it to reach room temperature (30 minutes) inside the carton without removing the pre-filled pen or needle cap.
Intravenous infusion (Crohn's disease and ulcerative colitis). Stelara 130 mg vial is for IV infusion only.

Instructions for dilution and intravenous infusion of Stelara 130 mg for IV infusion (Crohn's disease and ulcerative colitis).

Stelara 130 mg solution must be diluted and prepared for IV infusion by a healthcare professional using aseptic technique. The IV infusion should be administered by qualified healthcare professionals.
1. Calculate the dose and the number of Stelara vials needed based on patient's body weight (see Table 3). Each 26 mL vial of Stelara contains 130 mg of ustekinumab.
2. Withdraw and then discard a volume of the 0.9% w/v sodium chloride solution from the 250 mL infusion bag equal to the volume of Stelara to be added. (Discard 26 mL sodium chloride for each vial of Stelara needed, for 2 vials - discard 52 mL, for 3 vials - discard 78 mL, for 4 vials - discard 104 mL.)
3. Withdraw 26 mL of Stelara from each vial needed and add it to the 250 mL infusion bag. The final volume in the infusion bag should be 250 mL. Gently invert or swirl the bag to mix the solution. Do not shake.
4. Once diluted, the infusion solution may be stored for up to eight hours prior to infusion.
5. Visually inspect the diluted solution before administration. Do not use if visibly opaque particles, discoloration or foreign particles are observed.
6. Administer the diluted solution over a period of at least one hour.
7. Use only an infusion set with an in-line, sterile, non-pyrogenic, low protein-binding filter (pore size 0.2 micrometer).
8. Do not infuse Stelara concomitantly in the same intravenous line with other agents.
9. Each vial is for single use only and any unused medicinal product should be disposed of in accordance with local requirements.

4.3 Contraindications

Severe hypersensitivity to ustekinumab or to any of the excipients (see Section 4.4 Special Warnings and Precautions for Use).
Stelara should not be given to patients with a clinically important, active infection.

4.4 Special Warnings and Precautions for Use

Serious infections.

Stelara is a selective immunosuppressant and may have the potential to increase the risk of infections and reactivate latent infections.
In clinical studies, serious bacterial, fungal, and viral infections have been observed in patients receiving Stelara. Caution should be exercised when considering the use of Stelara in patients with a chronic infection or a history of recurrent infection.
Prior to initiating treatment with Stelara, patients should be evaluated for tuberculosis infection. Stelara should not be given to patients with active tuberculosis. Treatment of latent tuberculosis infection should be initiated prior to administering Stelara. Anti-tuberculosis therapy should also be considered prior to initiation of Stelara in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed. Patients receiving Stelara should be monitored closely for signs and symptoms of active tuberculosis during and after treatment.
Patients should be instructed to seek medical advice if signs or symptoms suggestive of an infection occur. If a patient develops a serious infection they should be closely monitored and Stelara should not be administered until the infection resolves (see Section 4.8 Adverse Effects (Undesirable Effects)).

Non-infectious pneumonia.

Cases of interstitial pneumonia, eosinophilic pneumonia and cryptogenic organizing pneumonia have been reported during post-approval use of Stelara. Clinical presentations included cough, dyspnoea, and interstitial infiltrates following one to three doses. Serious outcomes have included respiratory failure and prolonged hospitalization. Patients improved with discontinuation of therapy and in certain cases administration of corticosteroids. If diagnosis is confirmed, discontinue Stelara and institute appropriate treatment.

Malignancies.

Stelara is a selective immunosuppressant. Immunosuppressive agents have the potential to increase the risk of malignancy. Some patients who received Stelara in clinical studies developed cutaneous and non-cutaneous malignancies (see Section 4.8 Adverse Effects (Undesirable Effects)).
Stelara has not been studied in patients with a history of malignancy. Caution should be exercised when considering the use of Stelara in patients with a history of malignancy or when considering continuing treatment in patients who develop a malignancy.
All patients, in particular those greater than 60 years of age, patients with a medical history of prolonged immunosuppressant therapy or those with a history of PUVA treatment, should be monitored for the appearance of non-melanoma skin cancer (see Section 4.8 Adverse Effects (Undesirable Effects)).

Hypersensitivity and infusion-related reactions.

In post-marketing experience, serious hypersensitivity reactions, including anaphylaxis and angioedema, have been reported. Infusion-related reactions were observed in clinical trials (see Section 4.8 Adverse Effects (Undesirable Effects)). Serious infusion-related reactions including anaphylactic reactions to the infusion have been reported in the post-marketing setting. If an anaphylactic or other serious hypersensitivity or infusion-related reaction occurs, appropriate therapy should be instituted and administration of Stelara should be discontinued immediately (see Section 4.8 Adverse Effects (Undesirable Effects)).

Immunisations.

It is recommended that live viral or live bacterial vaccines (such as Bacillus of Calmette and Guerin [BCG]) not be given concurrently with Stelara.
Before live viral or live bacterial vaccination, treatment with Stelara should be withheld for at least 15 weeks after the last dose and can be resumed at least 2 weeks after vaccination. Prescribers should consult the Product Information for the specific vaccine for additional information and guidance on concomitant use of immunosuppressive agents post vaccination and considering the benefit/risk of ustekinumab treatment in the patient.
No data are available on the secondary transmission of infection by live vaccines in patients receiving Stelara. Caution is advised when administering some live vaccines to household contacts of patients receiving Stelara because of the potential risk for shedding from the household contact and transmission to the patient.
Patients receiving Stelara may receive concurrent inactivated or non-live vaccinations.
Long term treatment with Stelara does not suppress the humoral immune response to pneumococcal polysaccharide or tetanus vaccines (see Section 5.1 Pharmacodynamic Properties).

Infant exposure in utero.

For infants exposed in utero to ustekinumab, a six month waiting period following birth is recommended before the administration of live vaccines. Administration of a live vaccine prior to 6 months of age may be considered if ustekinumab serum levels are undetectable in the infant and the benefit of the vaccination clearly outweighs the theoretical risk of administration of live vaccines to the infant (see Section 4.6 Fertility, Pregnancy and Lactation).

Immunosuppression.

In psoriasis studies, the safety and efficacy of Stelara in combination with immunosuppressive agents or phototherapy have not been evaluated. In psoriatic arthritis studies, concomitant methotrexate (MTX) use did not appear to influence the safety or efficacy of Stelara. In Crohn's disease and ulcerative colitis studies, concomitant use of immunomodulators (6-mercaptopurine (6-MP), azathioprine (AZA), MTX) or corticosteroids did not appear to influence the safety or efficacy of Stelara. Caution should be exercised when considering concomitant use of immunosuppressive agents and Stelara or when transitioning from other biologic agents.

Immunotherapy.

Stelara has not been evaluated in patients who have undergone allergy immunotherapy. Stelara may affect allergy immunotherapy. Caution should be exercised in patients receiving or who have received allergy immunotherapy particularly for anaphylaxis.

Posterior reversible encephalopathy syndrome (PRES).

Posterior reversible encephalopathy syndrome (PRES), also known as reversible posterior leukoencephalopathy syndrome (RPLS), is a neurological disorder, which is not caused by demyelination or a known infectious agent. Conditions with which it has been associated include preeclampsia, eclampsia, acute hypertension, cytotoxic agents and immunosuppressive therapy. Fatal outcomes have been reported in this condition.
Two cases of PRES were reported in clinical trials. Cases have also been reported in postmarketing experience in patients with psoriasis, psoriatic arthritis and Crohn's disease. Clinical presentation included headaches, seizures, confusion, visual disturbances, and imaging changes consistent with PRES a few days to several months after ustekinumab initiation. A few cases reported latency of a year or longer. Patients recovered with supportive care following withdrawal of ustekinumab. Monitor all patients treated with Stelara for signs and symptoms of PRES.
If PRES is suspected, promptly administer appropriate treatment and discontinue Stelara.

Serious skin conditions.

In patients with psoriasis, exfoliative dermatitis has been reported following ustekinumab treatment. Patients with plaque psoriasis may develop erythrodermic psoriasis, with symptoms that may be clinically indistinguishable from exfoliative dermatitis, as part of the natural course of their disease.
As part of the monitoring of the patient's psoriasis, physicians should be alert for symptoms of erythrodermic psoriasis or exfoliative dermatitis. If these symptoms occur, appropriate therapy should be instituted. Stelara should be discontinued if a drug reaction is suspected.

General.

The needle cover on the pre-filled syringe and the needle cover inside the bottom cap of the prefilled pen contain dry natural rubber (a derivative of latex), which may cause allergic reactions in individuals sensitive to latex.

Use in the elderly.

Of the 6709 patients exposed to Stelara, a total of 353 were 65 years or older (183 patients with psoriasis, 69 patients with psoriatic arthritis, 58 with Crohn's disease and 43 patients with ulcerative colitis). No major age-related differences in clearance or volume of distribution were observed in clinical studies. Although no overall differences in efficacy or safety were observed between older and younger patients in clinical studies in approved indications, the number of patients aged 65 and over is not sufficient to determine whether they respond differently from younger patients.

Paediatric use.

Specific studies of Stelara in paediatric patients below 6 years of age have not been conducted. The pharmacokinetics of ustekinumab in paediatric psoriasis patients, 6 to 17 years of age, treated with the recommended dose was generally comparable to that in the adult psoriasis population. No pharmacokinetic, safety or efficacy data are available in paediatric patients with psoriatic arthritis, Crohn's disease or ulcerative colitis.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Specific drug interaction studies have not been conducted with Stelara (see Section 5.2 Pharmacokinetic Properties).
Live vaccines should not be given concurrently with Stelara. Recommendations for infants exposed to ustekinumab in utero are provided (see Section 4.4 Special Warnings and Precautions for Use, Immunisations).

CYP450 substrates.

The formation of CYP450 enzymes can be altered by increased levels of certain cytokines (e.g. IL-1, IL-6, IL-10, TNFα, IFN) during chronic inflammation. Thus, Stelara, an antagonist of IL-12 and IL-23, could normalize the formation of CYP450 enzymes. Upon initiation of Stelara in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, monitoring for therapeutic effect (e.g. for warfarin) or drug concentration (e.g. for ciclosporin) should be considered and the individual dose of the drug adjusted as needed.
The effects of IL-12 or IL-23 on the regulation of CYP450 enzymes were evaluated in an in vitro study using human hepatocytes, which showed that IL-12 and/or IL-23 at levels of 10 nanogram/mL did not alter human CYP450 enzyme activities (CYP1A2, 2B6, 2C9, 2C19, 2D6, or 3A4). However, the clinical relevance of this in vitro data has not been established.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In a male fertility study in cynomolgus monkeys, no ustekinumab-related effects on mating behaviour, sperm parameters or serum concentrations of male hormones were observed following twice weekly subcutaneous administration of ustekinumab at doses up to 45 mg/kg.
The effect of Stelara on female fertility has not been evaluated. A female fertility toxicity study was conducted in mice using an analogous antibody that binds to and inhibits IL-12 and IL-23 activity in mice. Twice weekly subcutaneous administration of the anti-mouse IL-12/23 antibody was well tolerated at doses up to 50 mg/kg and no adverse effects on female fertility parameters were observed.
(Category B1)
It is not known whether Stelara can cause foetal harm when administered to a pregnant woman or can affect reproduction capacity. Stelara should be given to a pregnant woman only if the benefit clearly outweighs the risk.
Women of childbearing potential should use effective methods of contraception during treatment and for at least 15 weeks after treatment.
Developmental toxicity studies of Stelara were conducted in cynomolgus monkeys. No evidence of maternal toxicity, embryotoxicity or teratogenicity was observed at doses up to 45 mg/kg following weekly or twice weekly administration via the IV or SC routes, respectively, during the period of organogenesis. However, animal reproductive and developmental studies are not always predictive of human response.
 Limited data from published literature suggests that ustekinumab is excreted in human breast milk in very small amounts. While systemic exposure to a breastfed infant is expected to be low because ustekinumab is a large molecule and is likely degraded in the gastrointestinal tract, it is not known if Stelara is absorbed systemically after ingestion. Because of the potential for adverse reactions in nursing infants from ustekinumab, a decision on whether to discontinue breast-feeding during treatment and up to 15 weeks after treatment or to discontinue therapy with Stelara must be made, taking into account the benefit of breast-feeding to the child and the benefit of Stelara therapy to the woman.
Maternal treatment of monkeys with Stelara at doses up to 45 mg/kg twice weekly SC from gestation Day 20 to post-partum Day 33 had no adverse effects on offspring development. However, animal reproductive and developmental studies are not always predictive of human response.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Adverse Effects (Undesirable Effects)

Clinical studies experience in adult patients with psoriasis, psoriatic arthritis, Crohn's disease and ulcerative colitis.

The safety data described in Table 4 reflect exposure to Stelara in 14 phase 2 and phase 3 studies in 6709 patients (4135 with psoriasis and/or psoriatic arthritis, 1749 for Crohn's disease, and 825 with ulcerative colitis in UC-1 and UC-2 clinical trials), with duration of exposure to Stelara presented in Table 4.
The most common adverse reactions (> 5%) in controlled periods of the clinical studies with Stelara among all indications were nasopharyngitis and headache. Most were considered to be mild and did not necessitate drug discontinuation. The overall safety profile of Stelara was similar for patients among all indications.
Table 5 provides a summary of adverse drug reactions from the clinical studies. The frequency of these adverse reactions was based on those that occurred during the initial controlled periods of the clinical studies. The adverse drug reactions are ranked by frequency, using the following convention: Very common (> 1/10); Common (frequent) (> 1/100, < 1/10); Uncommon (infrequent) (> 1/1000, < 1/100); Rare (> 1/10,000, < 1/1000).

Infections.

In the placebo-controlled studies of patients with psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis, the rates of infection or serious infection were similar between Stelara-treated patients and those treated with placebo. In the placebo-controlled period of the clinical studies of patients with psoriasis, patients with psoriatic arthritis, patients with Crohn's disease, and patients with ulcerative colitis, the rate of infection was 1.36 per patient-year of follow-up in Stelara-treated patients, and 1.34 per patient-year of follow-up in placebo-treated patients. Serious infections occurred at a rate of 0.03 per patient-year of follow-up in Stelara-treated patients (30 serious infections in 930 patient-years of follow-up) and 0.03 per patient-year of follow-up in placebo-treated patients (15 serious infections in 434 patient-years of follow-up) (see Section 4.4 Special Warnings and Precautions for Use).
In the controlled and non-controlled portions of psoriasis, psoriatic arthritis, Crohn's disease and ulcerative clinical studies representing 11,581 patient-years of exposure in 6709 patients, the median follow-up was 1.0 years; 1.1 years for psoriatic disease studies, 0.6 year for Crohn's disease studies and 1.0 years for ulcerative colitis studies. The rate of infection was 0.91 per patient-year of follow-up in Stelara-treated patients. The incidence of serious infections was 0.02 per patient-year of follow-up in Stelara-treated patients (199 serious infections in 11,581 patient-years of follow-up) and included pneumonia, anal abscess, cellulitis, diverticulitis, osteomyelitis, viral infections, gastroenteritis, and urinary tract infections.
In clinical studies, patients with latent tuberculosis who were concurrently treated with isoniazid did not develop tuberculosis. One case of tuberculosis reactivation occurred in a subject with abnormal baseline chest X-Ray and without treatment for latent TB while on ustekinumab therapy. The subject fully recovered with appropriate treatment.

Malignancy.

In the placebo-controlled period of the psoriasis, psoriatic arthritis, Crohn's disease and ulcerative colitis clinical studies, the incidence of malignancies excluding non-melanoma skin cancer was 0.11 per 100 patient-years of follow-up for Stelara-treated patients (1 patient in 929 patient-years of follow-up) compared with 0.23 per 100 patient-years of follow-up for placebo-treated patients (1 patient in 434 patient-years of follow-up).
The incidence of non-melanoma skin cancer was 0.43 per 100 patient-years of follow-up for Stelara-treated patients (4 patients in 929 patient-years of follow-up) compared with 0.46 per 100 patient-years of follow-up for placebo-treated patients (2 patients in 433 patient-years of follow-up).
In the controlled and non-controlled periods of the psoriasis, psoriatic arthritis, Crohn's disease and ulcerative colitis clinical studies representing 11,561 patient-years of exposure in 6709 patients, the median follow-up was 1.0 years; 1.1 years for psoriatic disease studies, 0.6 years for Crohn's disease studies, and 1.0 years for ulcerative colitis studies. Malignancies excluding non-melanoma skin cancers were reported in 62 patients in 11,561 patient years of follow up (incidence of 0.54 per 100 patient-years of follow-up for Stelara-treated patients). The rate of malignancies reported in Stelara-treated patients was comparable to the rate expected in the general population (standardized incidence ratio = 0.93 [95% confidence interval:0.71,1.20]). The most frequently observed malignancies, other than non-melanoma skin cancer, were prostate, colorectal, melanoma in situ and breast. The incidence of non-melanoma skin cancer was 0.49 per 100 patient-years of follow-up for Stelara treated patients (56 patients in 11,545 patient-years of follow-up). The ratio of patients with basal versus squamous cell skin cancers (3:1) is comparable with the ratio expected in the general population (see Section 4.4 Special Warnings and Precautions for Use).

Hypersensitivity and infusion reactions.

Subcutaneous administration.

During the controlled periods of the psoriasis and psoriatic arthritis clinical studies of Stelara, rash and urticaria have each been observed in < 1% of patients.

IV administration.

In Crohn's disease and ulcerative colitis intravenous induction studies, no events of anaphylaxis or other serious infusion reactions with ustekinumab were reported. In these studies, 2.2% of 785 placebo treated patients and 1.9% of 790 patients treated with the recommended dose of Stelara reported adverse events occurring during or within an hour of the infusion. Serious infusion-related reactions including anaphylactic reactions have been reported in the post-marketing setting (see Section 4.4 Special Warnings and Precautions for Use).

Immunogenicity.

In psoriasis and psoriatic arthritis clinical studies, up to 12.4% of patients treated with Stelara developed antibodies to ustekinumab. Patients positive for antibodies to ustekinumab tended to have lower efficacy, however, antibody positivity did not preclude a clinical response. In psoriasis studies, the majority of patients who were positive for antibodies to ustekinumab had neutralising antibodies.
In Crohn's disease and ulcerative colitis clinical studies, 2.9 and 4.6% of patients, respectively, developed antibodies to ustekinumab when treated with ustekinumab for approximately one year. No apparent association between the development of antibodies to ustekinumab and the development of injection site reactions was observed.

Clinical studies experience in paediatric patients with psoriasis.

The safety of Stelara has been studied in two phase 3 studies of paediatric patients with moderate to severe plaque psoriasis. The first study was in 110 patients from 12 to 17 years of age treated for up to 60 weeks (CADMUS) and the second study was in 44 patients from 6 to 11 years of age treated for up to 56 weeks (CADMUS Jr.). In general, the adverse events reported in these two studies with safety data up to 1 year were similar to those seen in previous studies in adults with plaque psoriasis (see Clinical studies experience in adult patients with psoriasis, psoriatic arthritis, Crohn's disease and ulcerative colitis section above).

Adverse events.

The following adverse events have been reported in patients treated with Stelara. A causal relationship to Stelara is uncertain.
In psoriasis clinical trials of Stelara, serious cardiovascular events, including cardiovascular death, myocardial infarction, and stroke, were reported in 0.3% of patients who received Stelara compared with 0% of patients treated with placebo, during the placebo-controlled period. Individuals with chronic inflammatory diseases, such as psoriasis, have higher rates of cardiovascular risk factors and cardiovascular events. Rates of myocardial infarction and stroke reported in Stelara-treated patients were comparable to rates expected in the general population.
In clinical trials for Crohn's disease, there is no consistent evidence that ustekinumab increases cardiovascular risk in patients treated with Stelara through approximately 1 year of treatment. Results from the Crohn's disease studies, up to 1 year, did not change the previous assessment of the impact of ustekinumab on serious major adverse cardiovascular event (MACE).
Adverse events of depression were reported in some patients who received Stelara in psoriasis clinical trials, including rare events of suicidality. Individuals with psoriasis have higher rates of depression, and it is not known if Stelara may have contributed to these events since Stelara also resulted in improvements of the Hospital Anxiety and Depression Scale (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Post-marketing data.

The adverse drug reactions in Table 6 are ranked by frequency* using the following convention: Very common: ≥ 1/10; Common: ≥ 1/100 and < 1/10; Uncommon: ≥ 1/1,000 and < 1/100; Rare: ≥ 1/10,000 and < 1/1,000; Very rare: < 1/10,000, including isolated reports.
* Post-marketing adverse reaction frequency is derived from clinical trials if the adverse reaction was observed during trials, or is estimated to be lower than a certain frequency given the exposure in adequately designed clinical trials where the adverse reaction was not observed.
There have been reports of rapidly growing and/or multiple squamous cell carcinomas of the skin in patients receiving Stelara who had multiple pre-existing risk factors for developing non-melanoma skin cancer. A causal relationship of these adverse events to Stelara is uncertain.

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

4.9 Overdose

Single doses up to 6 mg/kg intravenously have been administered in clinical studies without dose-limiting toxicity. In case of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment be instituted immediately.
For information on the management of overdose please contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Stelara is a human IgG1 kappa monoclonal antibody that specifically binds to the shared p40 protein subunit of the human cytokines interleukin (IL)-12 and IL-23. Stelara inhibits the bioactivity of human IL-12 and IL-23 by preventing p40 from binding to the IL-12Rbeta1 receptor protein expressed on the surface of immune cells. Stelara cannot bind to IL-12 or IL-23 that is already bound to IL-12Rbeta1 cell surface receptors. Thus, Stelara is not expected to contribute to complement- or antibody-mediated cytotoxicity of cells with IL-12 and/or IL-23 receptors.
IL-12 and IL-23 are heterodimeric cytokines secreted by activated antigen presenting cells, such as macrophages and dendritic cells. IL-12 stimulates natural killer (NK) cells and drives the differentiation of CD4+ T cells toward the T helper 1 (Th1) phenotype and stimulates interferon gamma (IFNγ) production. IL-23 induces the T helper 17 (Th17) pathway and promotes secretion of IL-17A, IL-21, and IL-22. Levels of IL-12 and IL-23 are elevated in the skin and blood of patients with psoriasis, and serum IL12/23p40 distinguishes patients with psoriatic arthritis from healthy individuals, implicating IL-12 and IL-23 in the pathophysiology of psoriatic inflammatory diseases. Genetic polymorphisms in IL23A, IL23R and IL-12B genes confer susceptibility to these disorders. IL-12 and IL-23 are highly expressed in lesional psoriatic skin, and IL-12-mediated induction of IFNγ correlates with psoriasis disease activity. IL-23 responsive T-cells have been found in the enthuses in a mouse model of inflammatory arthritis, where IL-23 drives entheseal inflammation. In addition, there is preclinical evidence implicating IL-23 and downstream pathways in bone erosion and destruction through up-regulation of receptor activator of nuclear factor kB ligand (RANKL), which activates osteoclasts.
In patients with Crohn's disease, IL-12 and IL-23 are elevated in the intestines and lymph nodes. This is accompanied by increases in serum IFNγ and IL-17A levels, suggesting that IL-12 and IL-23 promote Th1 and Th17 activation in Crohn's disease. Both IL-12 and IL-23 can also stimulate TNFα production by T cells, resulting in chronic intestinal inflammation and epithelial cell injury. Significant associations have been found between Crohn's disease and genetic polymorphisms in the IL23R and IL12B genes, suggesting a potential causal role for IL-12/23 signaling in the disease. This is supported by pre-clinical data demonstrating that IL-12/23 signaling is required for intestinal injury in mouse models of inflammatory bowel disease.
By binding the shared p40 subunit of IL-12 and IL-23, Stelara may exert its clinical effects in psoriasis, psoriatic arthritis, Crohn's disease and ulcerative colitis through interruption of the Th1 and Th17 cytokine pathways, which are central to the pathology of these diseases.

Pharmacodynamics.

Treatment with Stelara resulted in significant improvement in histological measures of psoriasis including epidermal hyperplasia and cell proliferation. These results are consistent with the clinical efficacy observed.
In patients with psoriasis and/or psoriatic arthritis, Stelara had no apparent effect on the percentages of circulating immune cell populations including memory and naive T-cell subsets or circulating cytokine levels. Systemic markers of inflammation were measurable in the serum at baseline and 4 markers (MDC, VEGF, MCSF-1 and YKL-40) showed modest differences in concentration post-treatment in Stelara-treated patients as compared to placebo.
In psoriasis and psoriatic arthritis studies, clinical response (improvement in Psoriasis Area and Severity Index [PASI] or ACR measurements, respectively) appeared to be related to serum ustekinumab levels. Patients with psoriasis with PASI response had higher median serum concentrations of ustekinumab than those with lower clinical responses. In psoriasis studies, the proportion of patients with psoriasis who achieved PASI 75 response increased with increasing serum levels of ustekinumab. The proportion of patients who achieved PASI 75 response at week 28 increased with increasing serum ustekinumab trough levels at week 28. In psoriatic arthritis studies, patients achieving an ACR 20 response had higher median serum concentrations of ustekinumab than ACR 20 non-responders. The proportion of patients who achieved ACR 20 and ACR 50 response increased with increasing serum levels of ustekinumab.
In patients with Crohn's disease, treatment with Stelara resulted in a significant decrease in inflammatory markers including C-Reactive Protein (CRP) and faecal calprotectin. CRP was assessed during the study extension and the reductions observed during maintenance were generally sustained through week 252. Reductions in serum IFNγ and IL-17A, which are IL-12 and IL-23 regulated pro-inflammatory cytokines, were achieved and maintained in Stelara treated patients through week 44 compared to placebo (52 weeks since the first dose of Stelara). At week 6, expression of genes such as IL-12Rβ1 and IL-23 were reduced in inflamed colon tissue from Crohn's disease patients, who were responders to Stelara treatment while no significant changes were observed in placebo treated patients.
In patients with ulcerative colitis, treatment with Stelara resulted in a decrease in inflammatory markers including CRP and faecal calprotectin during the induction phase, which were maintained throughout the maintenance phase and study extension through week 200.

Immunisation.

During the long-term extension of a phase 3 psoriasis study (PHOENIX 2), patients treated with Stelara for at least 3.5 years mounted similar antibody responses to both pneumococcal polysaccharide and tetanus vaccines as a non-systemically treated psoriasis control group. Similar proportions of patients developed protective levels of anti-pneumococcal and anti-tetanus antibodies and antibody titres were similar among Stelara-treated and control patients.

Clinical trials.

Plaque psoriasis (adults).

The safety and efficacy of Stelara was assessed in 2 phase 3 studies (A phase 3 multicentre, randomised, double-blind, placebo-controlled trial evaluating the efficacy and safety of CNTO 1275 in the treatment of subjects with moderate to severe plaque-type psoriasis followed by long-term extension [PHOENIX] 1 and PHOENIX 2). A total of 1996 patients were enrolled in these studies. The safety and efficacy of Stelara have not been established beyond 4 years.
The studies enrolled adults (≥ 18 years) with chronic (> 6 months) plaque psoriasis who had a minimum body surface area (BSA) involvement of 10%, and PASI score ≥ 12 and who were candidates for systemic therapy or phototherapy. Patients with guttate, erythrodermic, or pustular psoriasis were excluded from the studies. No concomitant anti-psoriatic therapies were allowed during the study with the exception of low-potency topical corticosteroids on the face and groin after week 12.
The Psoriasis Area and Severity Index (PASI) is a composite score that assesses the fraction of body surface area involved with psoriasis and the severity of psoriatic changes within the affected regions (plaque thickness/induration, erythema, and scaling). PASI numeric scores range from 0 to 72, with higher scores representing more severe disease.
Patients achieving ≥ 75% improvement in PASI from baseline (PASI 75) were considered PASI 75 responders. Patients originally randomised to Stelara who were PASI 75 responders at both weeks 28 and 40 were considered long-term PASI 75 responders. Patients achieving ≥ 90% improvement in PASI from baseline (PASI 90) were considered PASI 90 responders and patients with ≥ 50% improvement in PASI from baseline (PASI 50) were considered PASI 50 responders. Patients who achieved ≥ 50% but less than 75% improvement in PASI from baseline were considered partial responders. Patients with < 50% improvement in PASI from baseline were considered non-responders.
Other key efficacy assessments included:
The Physician's Global Assessment (PGA), a 6-category scale focusing on plaque thickness/induration, erythema, and scaling.
The Dermatology Life Quality Index (DLQI), a dermatology-specific quality of life instrument, with a lower score indicating an improved quality of life.
The SF-36, a health survey questionnaire consisting of multi-item scales measuring 8 health concepts (PHOENIX 1 only).
The Nail Psoriasis Severity Index (NAPSI), a physician-assessed score that measures the severity of nail involvement (PHOENIX 1 only).
The Hospital Anxiety and Depression Scale (HADS), a self-rating tool developed to evaluate psychological measures in patients with physical ailments (PHOENIX 2 only).
The Work Limitations Questionnaire (WLQ), a 25-item, self-administered questionnaire that was used to measure the impact of chronic health conditions on job performance and work productivity among employed populations (PHOENIX 2 only).
The Itch Visual Analogue Scale, (Itch VAS) used to assess the severity of itch at the time of the assessment (PHOENIX 1 only).

PHOENIX 1.

PHOENIX 1 evaluated the safety and efficacy of Stelara versus placebo in 766 patients with plaque psoriasis and the efficacy of every 12 week dosing for patients who were PASI 75 responders. Patients randomised to Stelara received 45 mg or 90 mg doses at weeks 0 and 4 followed by the same doses every 12 weeks. Patients randomised to receive placebo at weeks 0 and 4 crossed over to receive Stelara (either 45 mg or 90 mg) at weeks 12 and 16 followed by the same dose every 12 weeks.

Maintenance dosing (every 12 weeks).

To evaluate the therapeutic benefit of maintenance dosing with Stelara, patients originally randomised to Stelara who were PASI 75 responders at both weeks 28 and 40 were re-randomised to either maintenance dosing of Stelara every 12 weeks or to placebo (i.e. withdrawal of therapy). Patients who were re-randomised to placebo at week 40 reinitiated Stelara at their original dosing regimen when they experienced at least a 50% loss of their PASI improvement obtained at week 40.

Dose adjustment (every 8 weeks).

At week 28, patients who were non-responders discontinued treatment and patients who were partial responders were adjusted to every-8-week dosing. PASI 75 responders at week 28 who became partial responders or non-responders at week 40 were adjusted to every-8-week dosing. All patients were followed for at least 52 weeks following first administration of study treatment.

PHOENIX 2.

PHOENIX 2 evaluated the safety and efficacy of Stelara versus placebo in 1230 patients with plaque psoriasis. Patients randomised to Stelara received 45 mg or 90 mg doses at weeks 0 and 4 followed by an additional dose at week 16. Patients randomised to receive placebo at weeks 0 and 4 crossed over to receive Stelara (either 45 mg or 90 mg) at weeks 12 and 16. Patients were followed for 28 weeks.

Baseline disease characteristics: PHOENIX 1 and 2.

Baseline disease characteristics across PHOENIX 1 and 2 were similar (Table 7).

Efficacy at the primary endpoint, PHOENIX 1 and 2.

In both the PHOENIX 1 and PHOENIX 2 studies, a significantly greater proportion of patients randomised to treatment with Stelara were PASI 75 responders compared with placebo at week 12 (Table 8). In the PHOENIX 1 study, 67% and 66% of patients receiving Stelara 45 mg and 90 mg, respectively, achieved a PASI 75 response at week 12 compared with 3% of patients receiving placebo. In the PHOENIX 2 study, 67% and 76% of patients receiving Stelara 45 mg and 90 mg respectively achieved a PASI 75 response at week 12 compared with 4% of patients receiving placebo.
All 3 components of the PASI (plaque thickness/induration, erythema, and scaling) contributed comparably to the improvement in PASI.
The efficacy of Stelara was significantly superior (p < 0.001) to placebo across all subgroups defined by baseline demographics, clinical disease characteristics (including patients with a history of psoriatic arthritis) and prior medication usage. While pharmacokinetic modelling suggested a trend towards higher CL/F in patients with diabetes, a consistent effect on efficacy was not observed.

Other efficacy measures at week 12.

In both PHOENIX 1 and PHOENIX 2, compared with placebo, significantly greater proportions of patients randomised to 45 mg or 90 mg Stelara achieved a cleared or minimal PGA score, and significantly greater proportions of patients randomised to 45 mg or 90 mg Stelara were PASI 90 and PASI 50 responders at week 12 (Table 8). In the PHOENIX 1 study, 60% and 62% of the patients treated with 45 mg and 90 mg Stelara, respectively, achieved PGA scores of cleared or minimal compared with 4% of placebo-treated patients. In PHOENIX 2, 68% and 73% of patients receiving 45 mg or 90 mg Stelara, respectively, had cleared or minimal PGA scores compared with 5% of the placebo patients. In PHOENIX 1, PASI 90 was achieved by 42% and 37% of the patients treated with 45 mg and 90 mg Stelara, respectively, compared with 2% of placebo-treated patients. In PHOENIX 2, the percentage of patients achieving PASI 90 was 42% in the 45 mg Stelara group, 51% in the 90 mg Stelara group and 1% in the placebo group. The percentage of patients achieving PASI 50 in PHOENIX 1 was 84% and 86% in the 45 mg and 90 mg Stelara groups, respectively, compared with 10% in the placebo group. Similarly, 84% of patients treated with 45 mg Stelara, 89% of patients treated with 90 mg Stelara and 10% of patients treated with placebo reached PASI 50 in PHOENIX 2 (Table 8).

Response over time.

In PHOENIX 1, significantly greater proportions of Stelara-treated patients had PASI 50 responses (9% and 10% for the 45 mg and 90 mg groups, respectively) compared with placebo (2%) by week 2 (p < 0.001). Significantly greater proportions of patients treated with Stelara achieved PASI 75 responses (9% and 12% for the 45 mg and 90 mg Stelara groups, respectively) compared with placebo (0.4%) by week 4 (p < 0.001). Maximum response was generally achieved by week 24 in the 45 mg and 90 mg Stelara treatment groups, and response rates were generally sustained through week 36 (Figure 1). In PHOENIX 1, PASI 75 rates at week 24 were 76% for the 45 mg group, and 85% for the 90 mg group. Higher response rates were observed in patients receiving Stelara 90 mg than in those receiving Stelara 45 mg by week 16 and these higher response rates were sustained through week 36 (Figure 1). Similar results were observed in the PHOENIX 2 study through week 28.
In pre-specified analyses of efficacy by body weight in PHOENIX 1 and PHOENIX 2, no consistent pattern of dose response was seen in patients ≤ 100 kg. In patients who weighed > 100 kg, higher PASI 75 response rates were seen with 90 mg dosing compared with 45 mg dosing, and a higher proportion of patients receiving 90 mg dosing had PGA scores of cleared or minimal compared with patients receiving 45 mg dosing (Table 8). Figure 1 shows PASI 75 response over time in PHOENIX 1 and 2.

Therapeutic benefit of long-term continuous use.

At week 40 in PHOENIX 1, 162 patients were randomised to receive Stelara (maintenance) and 160 were randomised to receive placebo (treatment withdrawal). Maintenance of PASI 75 was significantly superior with continuous treatment compared with treatment withdrawal (p < 0.001). Similar results were seen with each dose of Stelara. At week 52, 89% of patients re-randomised to maintenance treatment were PASI 75 responders compared with 63% of patients re-randomised to placebo (treatment withdrawal) (p < 0.001).

Efficacy of retreatment.

In PHOENIX 1, after withdrawal from therapy, patients re-initiated their original Stelara treatment regimen after loss of ≥ 50% of PASI improvement. Retreatment with Stelara resulted in 76% of evaluated patients regaining PASI 75 response within 8 weeks after reinitiating therapy.

Dosing interval adjustment.

In PHOENIX 1, week 28 and week 40 partial responders and week 40 non-responders were adjusted from every 12-week to every 8-week dosing. Approximately 40%-50% of week 28 partial responders to every 12-week dosing achieved PASI 75 response after adjustment to every 8-week dosing and this proportion of PASI 75 responders was maintained through week-52. A similar proportion of patients who were PASI 75 responders at week 28 and subsequently became partial responders or non-responders at week-40 achieved PASI 75 response following a dosing interval adjustment to every 8 weeks.

Quality of life.

In PHOENIX 1 and 2, the mean baseline DLQI scores ranged from 11 to 12. In PHOENIX 1, the mean baseline SF-36 Physical Component ranged from 47-49 and the mean baseline SF-36 Mental Component was approximately 50. Quality of life improved significantly in patients randomised to 45 mg or 90 mg ustekinumab compared with patients randomised to placebo as evaluated by DLQI in PHOENIX 1 and 2 and SF-36 in PHOENIX 1. Quality of life improvements were significant as early as 2 weeks in patients treated with ustekinumab (p < 0.001) and these improvements were maintained over time with continued dosing.
In PHOENIX 1, 65% and 71% of patients treated with 45 mg and 90 mg of ustekinumab, respectively, showed a clinically meaningful reduction (5 or more points) in DLQI from baseline at week 12 compared to 18% in placebo group (p < 0.001 for both groups compared with placebo). Furthermore, 33% and 34% of patients treated with 45 mg and 90 mg of ustekinumab, respectively, showed a DLQI score of 0 compared to 1% in the placebo group (p < 0.001 for both groups compared with placebo), indicating no impairment in QOL from disease or treatment in these patients. In PHOENIX 2, 72% and 77% of patients treated with 45 mg and 90 mg of ustekinumab, respectively, showed a clinically meaningful reduction (5 or more points) in DLQI from baseline at week 12 compared to 21% in placebo group (p < 0.001 for both groups compared with placebo). In addition, 37% and 39% of patients treated with 45 mg and 90 mg of ustekinumab, respectively, showed a DLQI score of 0 compared to 1% in the placebo group (p < 0.001 for both groups compared with placebo).
In PHOENIX 1, the median baseline NAPSI score for nail psoriasis was 4.0 and the median number of fingernails involved with psoriasis was 8.0. Nail psoriasis improved significantly in patients randomised to 45 mg or 90 mg ustekinumab compared with patients randomised to placebo when measured by the NAPSI score (p ≤ 0.001). Improvements in physical and mental component summary scores of the SF-36 and in the Itch Visual Analogue Scale (VAS) were also significant in each ustekinumab treatment group compared with placebo (p < 0.001). In PHOENIX 2, the Hospital Anxiety and Depression Scale (HADS) and Work Limitations Questionnaire (WLQ) were also significantly improved in each ustekinumab treatment group compared with placebo (p < 0.001).

ACCEPT.

A multicentre, randomised, single-blind, active-controlled study (ACCEPT) compared the safety and efficacy of ustekinumab and etanercept in patients 18 years of age and older with chronic (> 6 months) plaque psoriasis who had a minimum BSA involvement of 10%, PASI score ≥ 12, Physician Global Assessment (PGA) score ≥ 3, who were candidates for phototherapy or systemic therapy, and who had had an inadequate response to, intolerance to, or contraindication to ciclosporin, methotrexate, or PUVA therapy. A total of 903 patients were enrolled in the study.
The ACCEPT trial compared the efficacy of ustekinumab to etanercept and evaluated the safety of ustekinumab and etanercept in moderate to severe psoriasis patients. The active-controlled portion of the study was from week 0 to week 12, during which patients were randomised to receive etanercept (50 mg twice a week) ustekinumab 45 mg at weeks 0 and 4, or ustekinumab 90 mg at weeks 0 and 4. This trial was powered to test the superiority of each ustekinumab dose to etanercept on the primary endpoint of the proportion of patients who achieved a PASI 75 at week 12.
Significantly greater proportions of subjects treated with ustekinumab 45 mg (67%; p = 0.012) or 90 mg (74%; p < 0.001) were PASI 75 responders at week 12 compared with the etanercept group (56.8%). PASI 90 response was observed in 36% and 45% of patients in the ustekinumab 45 mg and 90 mg groups, respectively, compared with 23% of patients receiving etanercept (p < 0.001 for each comparison versus etanercept). PASI 100 response was observed in 12% and 21% of patients in the ustekinumab 45 mg and 90 mg groups, respectively, compared to 6% of patients receiving etanercept. In addition, a greater proportion of patients in the ustekinumab 45 mg and 90 mg treatment groups achieved a PGA score of "cleared" or "minimal" (65% and 71%, respectively) compared with patients in the etanercept treatment group (49%) (p < 0.001 for each comparison versus etanercept).
In pre-specified analyses of efficacy by body weight in ACCEPT, minimal dose response to ustekinumab was evident in patients ≤ 100 kg. In patients who weighed > 100 kg, higher PASI 75 response rates were seen with 90 mg dosing compared with 45 mg dosing, and a higher proportion of patients receiving 90 mg dosing had PGA scores of cleared or minimal compared with patients receiving 45 mg dosing (Table 9).

Plaque psoriasis (adolescent patients - 12 to 17 years of age).

The efficacy of Stelara was studied in 110 paediatric patients 12 to 17 years of age with moderate to severe plaque psoriasis, in a multicentre, Phase 3, randomised, double blind, placebo controlled study (CADMUS). Patients were randomised to receive either placebo (n=37), or the recommended dose of Stelara (n=36) (see Section 4.2 Dose and Method of Administration) or half the recommended dose of Stelara (n=37) by subcutaneous injection at Weeks 0 and 4 followed by every 12 week (q12w) dosing. At Week 12, placebo treated patients crossed over to either receive the recommended dose of Stelara (n=18) or half the recommended dose of Stelara (n=19).
Patients with PASI ≥ 12, PGA ≥ 3 and BSA involvement of at least 10%, who were candidates for systemic or phototherapy, were eligible for the study. Approximately 60% of the patients had prior exposure to conventional systemic therapy or phototherapy. Approximately 11% of the patients had prior exposure to biologics.
The primary endpoint was the proportion of patients who achieved a PGA score of cleared (0) or minimal (1) at Week 12. Secondary endpoints included PASI 75, PASI 90, change from baseline in Children's Dermatology Life Quality Index (CDLQI), and change from baseline in the total score of PedsQL (Paediatric Quality of Life Inventory) at Week 12. At Week 12, subjects treated with Stelara showed significantly greater improvement in their psoriasis and health related quality of life compared with placebo (Table 10).
All patients were followed for efficacy for up to 52 weeks following first administration of study agent. The proportion of patients with a PGA score of cleared (0) or minimal (1) and the proportion achieving PASI 75 showed separation between the Stelara treated group and placebo at the first post-baseline visit at week 4, reaching a maximum by week 12. Improvements in PGA, PASI, CDLQI and PedsQL were maintained through Week 52 (Table 10).
Onset of response was rapid; approximately one-third of patients in the ustekinumab group achieved a PASI 75 response at Week 4 compared with 1 (2.7%) patient in the placebo group. Maximum PASI 75 response rate was achieved by Week 12 and maintained through Week 52, as summarised in Figure 2.
During the placebo controlled period through week 12, the efficacy of both the recommended and half of the recommended dose groups were generally comparable at the primary endpoint (69.4% and 67.6% respectively) although there was evidence of a dose response for higher level efficacy criteria (e.g. PGA of cleared (0), PASI 90). Beyond week 12, efficacy was generally higher and better sustained in the recommended dose group compared with half of the recommended dosage group in which a modest loss of efficacy was more frequently observed toward the end of each 12 week dosing interval. The safety profiles of the recommended dose and half of the recommended dose were comparable.

Plaque psoriasis (children - 6 to 11 years of age).

The efficacy of Stelara was studied in 44 paediatric patients 6 to 11 years of age with moderate to severe plaque psoriasis in an open label, single-arm, multicentre, Phase 3 study (CADMUS Jr.). Patients were treated with the recommended dose of Stelara (n=44) (see Section 4.2 Dose and Method of Administration) by subcutaneous injection at Weeks 0 and 4 followed by every 12 week (q12w) dosing.
Patients with PASI ≥ 12, PGA ≥ 3 and BSA involvement of at least 10%, who were candidates for systemic therapy or phototherapy, were eligible for the study. Approximately 43% of the patients had prior exposure to conventional systemic therapy or phototherapy. Approximately 5% of the patients had prior exposure to biologics.
The primary endpoint was the proportion of patients who achieved a PGA score of cleared (0) or minimal (1) at Week 12. Secondary endpoints included PASI 75, PASI 90, and change from baseline in Children's Dermatology Life Quality Index (CDLQI) at Week 12. At Week 12, patients treated with Stelara showed clinically meaningful improvements in their psoriasis and health related quality of life (Table 11).
All patients were followed for efficacy for up to 52 weeks following first administration of study agent. The proportion of patients with a PGA score of cleared (0) or minimal (1) at week 12 was 77.3%. Efficacy (defined as PGA 0 or 1) was observed as early as the first post-baseline visit at week 4 and the proportion of subjects who achieved a PGA score of 0 or 1 increased through week 16 and then remained relatively stable through week 52. Improvements in PGA, PASI, and CDLQI were maintained through week 52 (Table 11).
See Figure 3.

Psoriatic arthritis (PsA).

The safety and efficacy of Stelara was assessed in two multicentre, randomised, double-blind, placebo-controlled, phase 3 studies PSUMMIT I and PSUMMIT II, in patients with active psoriatic arthritis. Patients were randomised to receive treatment with either Stelara 45 mg, 90 mg, or placebo subcutaneous injections at weeks 0 and 4 followed by every 12 week (q12w) dosing. The primary endpoint in these studies was the reduction in the signs and symptoms of psoriatic arthritis (PsA) as measured by the percentage of ACR 20 responders at week 24. Secondary endpoints included change from baseline in Disability Index of the Health Assessment Questionnaire (HAQ-DI), PASI 75, ACR 50, ACR 70 and change in baseline in total radiographic scores of the hands and feet, at week 24. Efficacy data were collected and analysed through week 52.
These studies included 927 (PSUMMIT I, n = 615; PSUMMIT II, n = 312) adult patients (≥ 18 years) who had active psoriatic arthritis (≥ 5 swollen joints and ≥ 5 tender joints, despite disease modifying antirheumatic (DMARD) and/or nonsteroidal anti-inflammatory (NSAID) therapy). Methotrexate use was allowed during the studies but was not mandatory. Approximately 50% of patients continued on stable doses of MTX (≤ 25 mg/week). In PSUMMIT I and PSUMMIT II, 80% and 86% of the patients, respectively, had been previously treated with DMARDs.
In PSUMMIT I, patients who had been previously treated with anti-TNFα therapy, prior to the first study dose, were excluded. In PSUMMIT II, the majority of patients (58%, n = 180) had been previously treated with one or more anti-TNFα agent(s) for at least 8 weeks (14 weeks with infliximab) or had discontinued anti-TNFα for intolerance at any time. Among the patients who had been previously treated with an anti-TNFα agent, over 70% had discontinued their anti-TNFα treatment for lack of efficacy or intolerance.
Patients with each subtype of psoriatic arthritis were enrolled, including polyarticular arthritis with no evidence of rheumatic nodules (39%, n = 362), spondylitis with peripheral arthritis (28%, n = 255), asymmetrical peripheral arthritis (21%, n = 193), distal interphalangeal (DIP) arthritis (12%, n = 112) and arthritis mutilans (0.5%, n = 5). Over 70% and 40% of the patients in both studies had enthesitis and dactylitis at baseline, respectively.
In both studies, a significantly greater proportion of patients achieved ACR 20 and ACR 50 responses at week 24 in the Stelara 45 mg and 90 mg groups compared to placebo (see Table 12). In PSUMMIT I, a significantly greater proportion of patients and in PSUMMIT II a numerically greater proportion of patients (p = NS) achieved ACR 70 responses in the Stelara 45 mg and 90 mg groups compared to placebo (see Table 12).
In both studies, the proportion of patients achieving a modified PsA response criteria (PsARC) or a Disease Activity Score 28 using C-reactive protein (DAS28-CRP) response was significantly greater in the Stelara 45 mg and 90 mg groups compared to placebo. In PSUMMIT I the proportion of patients achieving DAS28-CRP remission was significantly greater in the Stelara 45 mg and 90 mg groups compared to placebo. In PSUMMIT II, the proportion of patients who achieved DAS28-CRP remission was significantly greater in the Stelara 90 mg group compared to placebo (see Table 12). DAS28-CRP and PsARC responses were maintained through week 52.
The time course for ACR 20 response rates during the first 24 weeks in both studies for patients receiving Stelara or placebo are summarised in Figure 4. ACR 20 responses showed improvement at the first assessment (week 4). ACR 20, 50 and 70 responses continued to improve or were maintained through week 52 (see Table 13).
In PSUMMIT I, of 205 subjects randomised to Stelara 45 mg, 153 continued the same dose and were available for evaluation at week 52. Among those, ACR 20, 50 and 70 responses were achieved by 99 (64.7%), 57 (37.3%) and 34 (22.2%) subjects respectively. Of 204 subjects randomised to Stelara 90 mg, 185 were available for evaluation at week 52. Among those, ACR 20, 50 and 70 responses were achieved by 120 (64.9%), 74 (40%) and 41 (22.2%) subjects respectively.
In PSUMMIT II, of 103 subjects randomised to Stelara 45 mg, 68 continued the same dose and were available for evaluation at week 52. Among those, ACR 20, 50 and 70 responses were achieved by 41 (60.3%), 23 (33.8%) and 11 (16.2%) subjects respectively. Of 105 subjects randomised to Stelara 90 mg, 83 were available for evaluation at week 52. Among those, ACR 20, 50 and 70 responses were achieved by 49 (59%), 26 (31.3%) and 17 (20.5%) subjects respectively.
Additionally, within each weight group, (≤ 100 kg and > 100 kg), ACR 20, ACR 50 and ACR 70 responses were consistently higher in the Stelara 45 mg and 90 mg groups than in the placebo group (see Table 14).
Stelara treatment resulted in significantly greater improvement compared with placebo for each ACR component (see Table 15).

Methotrexate use.

The proportion of patients achieving ACR responses were consistently greater in patients treated with Stelara than those treated with placebo regardless of concomitant MTX use (see Table 16). Responses observed in the Stelara groups were similar in patients receiving or not receiving concomitant MTX. ACR responses were maintained through week 52.

Prior anti-TNFα therapy.

PSUMMIT II evaluated 180 patients who were previously treated with one or more anti-TNFα agents for at least 8 weeks (14 weeks with infliximab), or had documented intolerance of anti-TNFα therapy at any time in the past.
Among patients previously treated with anti-TNFα agents, a significantly greater proportion of Stelara-treated patients achieved an ACR 20 response at week 24 compared to placebo (see Table 17). ACR 20, 50 and 70 responses were generally maintained through week 52.

Enthesitis and dactylitis.

For patients with enthesitis and/or dactylitis at baseline, in PSUMMIT I, a significant improvement in enthesitis and dactylitis score was observed in the Stelara 45 mg and 90 mg groups compared to placebo. In PSUMMIT II, a significant improvement in enthesitis score and numerical improvement in dactylitis score were observed in the 90 mg group (p = NS) compared with the placebo group (see Table 18). In both studies, improvement in enthesitis score and dactylitis score were maintained at week 52.

PASI response.

In PSUMMIT I and PSUMMIT II, the proportion of patients with psoriasis involvement of ≥ 3% BSA at baseline who achieved a ≥ 75% improvement in the PASI assessment at week 24 was significantly greater in the Stelara 45 mg and 90 mg groups compared with the placebo group (see Table 19). In both studies the proportion of patients achieving the PASI 75 response was maintained through week 52 (PSUMMIT I, Stelara 45 mg-70.1% and 90 mg-68.1%; PSUMMIT II, Stelara 45 mg-56.5% and 90 mg-64.4%).
The proportion of patients who achieved both a PASI 75 response and an ACR 20 response was evaluated for those patients with ≥ 3% BSA psoriasis skin involvement at baseline. A significantly higher proportion of patients achieved the combined response in the Stelara 45 mg and 90 mg groups compared with the placebo group at week 24 (see Table 19). In both studies, the proportion of patients achieving both a PASI 75 response and an ACR20 response was maintained through week 52 (PSUMMIT I, Stelara 45 mg-44.8% and 90 mg-44.3%; PSUMMIT II, Stelara 45 mg-36.8% and 90 mg-43.1%).
Additionally, within each weight group (≤ 100 kg and > 100 kg), PASI 75, 90 and 100 responses were consistently higher in the Stelara 45 and 90 mg groups than in the placebo group (see Table 20).

Methotrexate use.

In both studies, the proportion of patients who achieved a PASI 75 response at week 24 was consistently higher in Stelara 45 mg and 90 mg groups compared with placebo regardless of concomitant MTX use. PASI 75 responses were maintained through week 52.

Prior anti-TNFα therapy.

In PSUMMIT II, the proportion of patients who achieved a PASI 75 response at week 24 was significantly greater in Stelara 45 mg and 90 mg groups compared with placebo in patients previously treated with an anti-TNFα agent.

Radiographic response.

Structural damage in both hands and feet was assessed by readers unaware of treatment group and order of visits, and expressed as change in total van der Heijde-Sharp score (vdH-S score), modified for PsA by addition of hand distal interphalangeal (DIP) joints, compared to baseline. A pre-specified integrated analysis combining data from 927 subjects in both PSUMMIT I and II was performed. At week 24, based on this integrated analysis, the Stelara 45 mg or 90 mg treatment significantly inhibited progression of structural damage, when compared to placebo (see Table 21). Beyond week 24, Stelara treatment continued to inhibit the progression of structural damage through week 52. The mean change from week 24 to 52 in total modified vdH-S score (0.18 and 0.26 in the Stelara 45 mg and 90 mg groups respectively) was less than the mean change from week 0 to 24 (see Table 21).
At week 24, patients treated with Stelara demonstrated less progression of structural damage compared to placebo, irrespective of concomitant MTX use.
The effect of Stelara on progression of structural damage in patients with prior anti-TNFα experience has not been established.

Physical function and health-related quality of life.

In PSUMMIT I and PSUMMIT II, physical function and health-related quality of life were assessed using the Disability Index of the Health Assessment Questionnaire (HAQ-DI), Dermatology Life Quality Index (DLQI) and the SF-36 health survey.
Patients treated with Stelara showed significant improvement in physical function as assessed by the HAQ-DI at week 24. The proportion of patients achieving a clinically meaningful ≥ 0.3 improvement in HAQ-DI score from baseline at week 24 was also significantly greater in the Stelara groups when compared with placebo (see Table 22). Improvement was observed at the first assessment (week 4), reached maximum at week 12 and was maintained through week 24. Improvement in HAQ-DI score from baseline was maintained at week 52.
In both studies, the improvement in HAQ-DI at week 24 was consistently greater in the Stelara 45 mg and 90 mg groups compared with placebo regardless of concomitant MTX use.
In PSUMMIT II, the improvement in HAQ-DI at week 24 was significantly greater in the Stelara 45 mg and 90 mg groups compared with placebo in patients previously treated with anti-TNFα agents.
In PSUMMIT I, of 205 subjects randomised to Stelara 45 mg, 153 continued the same dose and were available for evaluation at week 52. Among those, the HAQ-DI response was achieved by 83 (54.2%) subjects. Of 204 subjects randomised to Stelara 90 mg, 185 were available for evaluation at week 52. Among those, HAQ-DI response was achieved by 102 (55.1%) subjects.
In PSUMMIT II, of 103 subjects randomised to Stelara 45 mg, 68 continued the same dose and were available for evaluation at week 52. Among those, the HAQ-DI response was achieved by 29 (42.6%) subjects. Of 105 subjects randomised to Stelara 90 mg, 83 were available for evaluation at week 52. Among those, HAQ-DI response was achieved by 44 (53%) subjects.
The DLQI was assessed by comparing the change in DLQI scores from baseline for those patients with ≥ 3% BSA at baseline. In both studies at week 24, there was a significant improvement from baseline in DLQI scores in both the Stelara 45 mg and 90 mg groups as compared with placebo (see Table 23) and the improvement was maintained at week 52.
In both PSUMMIT I and PSUMMIT II, at week 24, the change from baseline in the SF-36 physical component summary (PCS) scores was significantly greater in the Stelara 45 mg and 90 mg groups compared with the placebo group. In both studies, the change from baseline in the SF-36 mental component summary (MCS) scores at week 24 was greater in both Stelara groups compared with the placebo group (p < 0.001 for PSUMMIT I 90 mg group, p = NS for other groups) (see Table 23). In both studies, the change from baseline in the SF-36 PCS and MCS scores was maintained at week 52.
In PSUMMIT II, a significant change from baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scores was observed at week 24 in the Stelara 45 mg and 90 mg groups compared with the placebo group (median improvement, all 3.0 vs 0.0; p < 0.007). Similarly, the percentage of patients with clinically significant improvement in fatigue from baseline (4 points in FACIT-F) was significantly greater in the Stelara 45 mg (49% [p < 0.001]) and 90 mg groups (49% [p < 0.001]) compared with the placebo group (25.8%). The change from baseline in the FACIT-F scores was maintained at week 52.

Crohn's disease.

The safety and efficacy of Stelara were evaluated in three randomised, double-blind, placebo-controlled clinical trials in adult patients with moderately to severely active Crohn's disease (Crohn's Disease Activity Index [CDAI] score of 220 to 450). The clinical development program consisted of two 8-week IV induction studies (UNITI-1 and UNITI-2) followed by a 44-week subcutaneous randomised withdrawal maintenance study (IM-UNITI) representing 52 weeks of therapy.
Induction of clinical response and remission. UNITI-1 and UNITI-2 studies included 1409 (UNITI-1 n = 769; UNITI-2 n = 640) patients. In both studies, patients were permitted to concomitantly receive oral 5-ASA compounds, immunomodulators, corticosteroids, and/or antibiotics. Patients were randomised to receive a single IV administration of Stelara, designed as a tiered dose based on patient body weight (see Table 3) or placebo at week 0. The primary endpoint was clinical response (defined as a reduction in CDAI score of ≥ 100 points or CDAI score < 150) at week 6. Secondary endpoints included clinical remission at week 8, clinical response at week 8, 70 point response at week 3, and 70 point response at week 6. Efficacy data were collected and analysed through week 8 for both studies.
In UNITI-1, patients had failed or were intolerant to prior anti-TNFα therapy. At baseline, approximately 46% (n = 340) patients were receiving corticosteroids (including budesonide) and 31.4% of patients were receiving immunomodulators. Approximately 48% had failed 1 prior anti-TNFα therapy and 52% had failed 2 or 3 prior anti-TNFα therapies (40.8% and 10.4%, respectively). In this study, 29.1% patients had an inadequate initial response (primary non-responders), 69.4% responded but subsequently lost response (secondary non-responders), and 36.4% were intolerant to anti-TNFα therapies.
Patients in UNITI-2 had failed at least one conventional therapy (corticosteroids or immunomodulators) and were either anti-TNFα naïve (68.6%) or had previously received but not failed anti-TNFα therapy (31.4%). At baseline, approximately 40% patients were receiving corticosteroids (including budesonide) and 35% patients were receiving immunomodulators.
In these induction studies, efficacy was higher and better sustained in the tiered dose (based on weight ranges) group compared to the 130 mg dose group. In both UNITI-1 and UNITI-2, a significantly greater proportion of patients were in clinical response and remission in the group treated with Stelara, compared to placebo (Table 24, Figure 5). Clinical response and remission were significant as early as week 3 in Stelara treated patients and continued to improve through week 8 (Figure 5).
Maintenance of response and remission. The maintenance study (IM-UNITI) evaluated 388 patients who achieved clinical response (≥ 100 point reduction in CDAI score) at week 8 of induction with Stelara in UNITI-1 or UNITI-2. Of those, approximately 60% of the patients entered the maintenance study in remission. Patients were randomised to receive a subcutaneous maintenance regimen of either 90 mg Stelara every 8 weeks, 90 mg Stelara every 12 weeks or placebo for 44 weeks.
Concomitant doses of oral 5-ASA compounds, immunomodulators, corticosteroids and antibiotics were permitted. Corticosteroids were tapered at the start of the maintenance trial. The primary endpoint was clinical remission (CDAI < 150) at week 44. Secondary endpoints assessed at week 44 included clinical response, clinical remission among Stelara treated patients in clinical remission after induction, corticosteroid-free remission, and clinical remission in the subset of patients who were refractory or intolerant to anti-TNFα treatment.
Significantly higher proportions of patients maintained clinical remission and response in the Stelara treated groups as compared to placebo at week 44 (Table 25, Figure 6). A higher proportion of Stelara treated patients compared to placebo achieved sustained clinical remission (clinical remission at week 36, 40 and 44). Clinical remission was achieved in patients who had failed conventional therapy (anti-TNFα naïve) and in patients who had prior treatment experience with an anti-TNFα. A higher rate of clinical remission was observed in the anti-TNFα naïve patients compared to the anti-TNFα refractory/intolerant patients, but the overall treatment effect was consistent in both anti-TNFα refractory/intolerant patients and anti-TNFα naïve patients (Table 25).
Delayed response. Patients who were not in clinical response to Stelara induction (n = 467) received a 90 mg subcutaneous injection of Stelara at week 8 upon entry into the maintenance study. Eight weeks later, 50.5% of the patients achieved clinical response and continued to receive maintenance dosing every 8 weeks; among these patients with continued maintenance dosing, a majority achieved levels of response (68.1%) and remission (50.2%) similar to the patients who initially responded to Stelara induction.
Dosing in patients with a lower inflammatory burden. In patients with a lower inflammatory burden as reflected by CRP ≤ 10 mg/L at initiation of induction or initiation of maintenance therapy, the efficacy of the every 12 week dosing regimen was similar to that of the every 8 week dosing regimen.
Dosing frequency adjustment. In IM-UNITI, 29 of 129 patients (22%) did not maintain response to Stelara when treated every 12 weeks and were allowed to increase the frequency of dosing and receive Stelara every 8 weeks. In these patients, clinical remission was achieved in 41.4% of patients 16 weeks after dosing frequency adjustment.
Resumption of treatment. Of 131 patients that responded to Stelara induction and who were randomised to the placebo group at the start of the maintenance study, 51 subsequently lost response and received 90 mg Stelara subcutaneously every 8 weeks. Of these 51 patients, 70.6% achieved clinical response and 39.2% achieved clinical remission 16 weeks after receiving the first subcutaneous dose of Stelara.
Long-term maintenance. In IM-UNITI, patients who completed the study through week 44 were eligible to continue treatment in a study extension. Among patients who entered the study extension, clinical remission and response were generally maintained through week 252. Results were consistent between patients who failed TNF-therapies versus those who did not.
No new safety concerns were identified in this study extension with up to 5 years of treatment in patients with Crohn's Disease.
Corticosteroid use in maintenance. In patients that were in clinical response to Stelara induction therapy, a greater proportion of patients in the Stelara treated group were in remission and corticosteroid-free compared to the placebo group after 44 weeks of maintenance treatment (Table 25). In addition, a higher proportion of patients were in clinical response and not receiving corticosteroids in the Stelara treated group compared to placebo.
Endoscopic healing of the mucosa. Endoscopic healing of the mucosa was evaluated in 252 patients with baseline endoscopic disease activity in a substudy. At week 8, after a single IV induction dose, reduction in mucosal inflammation, as measured by the Simplified Endoscopic Activity Score for Crohn's Disease (SES-CD), was greater in patients treated with Stelara (n = 83) compared with patients treated with placebo (n = 97) (-2.8 vs -0.7, p = 0.012). Similar reductions in histologic inflammation were also observed.
Fistula response. In patients with draining fistulas at baseline (8.8%), a numerically greater proportion of Stelara treated patients achieved a fistula response (defined as ≥ 50% reduction from baseline of the induction study in the number of draining fistulas) compared with placebo over 44 weeks (p = NS). The proportion of patients in fistula response at week 44 was 45.5% (5/11) for placebo group, 71.4% (5/7) for Stelara 90 mg every 12 week dosing group, and 87.5% (7/8) for Stelara 90 mg every 8 week dosing group.
Health-related quality of life measures. Improvement in general and disease specific health-related quality of life was assessed using the SF-36 and Inflammatory Bowel Disease Questionnaire (IBDQ) respectively.

SF-36.

A higher proportion of patients treated with Stelara showed clinically meaningful improvements in SF-36 Physical Component Summary (PCS) and Mental Component Summary (MCS) scores, and these improvements were significantly greater at week 8 compared with the placebo group in UNITI-1 (MCS) and UNITI-2 (PCS, MCS and all subscores). These improvements in the PCS and MCS scores were maintained in Stelara treated patients in the IM-UNITI maintenance study through week 44.

IBDQ.

At week 8 in UNITI-1 and UNITI-2, significant improvement from baseline in the inflammatory bowel disease questionnaire (IBDQ) total score and all subscales, was observed in the patients treated with Stelara compared to placebo. In both studies, a higher proportion of patients with clinically meaningful improvement in IBDQ total scores were observed in patients treated with Stelara compared to placebo. These improvements in the IBDQ total scores were maintained in Stelara treated patients in the IM-UNITI maintenance study through week 44.

Long-term maintenance of health-related quality of life measures.

The majority of subjects maintained a 16-point improvement in IBDQ score and a 5-point improvement in SF-36 through week 252.

Ulcerative colitis.

The safety and efficacy of Stelara was assessed in two randomised, double-blind, placebo-controlled, multicenter studies in adult patients with moderately to severely active ulcerative colitis (Mayo score 6 to 12; endoscopy subscore ≥ 2 based on central review of the endoscopy). The clinical development program consisted of one intravenous induction study (referred to as UNIFI-induction) with treatment of up to 16 weeks followed by a 44-week subcutaneous randomized withdrawal maintenance study (referred to as UNIFI-maintenance) representing at least 52 weeks of therapy.
Efficacy results presented for UNIFI-induction and UNIFI-maintenance were based on central review of endoscopies.
UNIFI-induction included 961 patients. The primary endpoint for the induction study was the proportion of patients in clinical remission (defined as a Mayo score ≤ 2 points, with no individual subscore > 1) at week 8. Patients were randomized to receive a single intravenous administration of either the recommended tiered dose of approximately 6 mg/kg (see Table 3; Initial IV dosing of Stelaraa), a fixed dose of 130 mg ustekinumab, or placebo at week 0.
Concomitant use of oral corticosteroids, immunomodulators, and aminosalicylates were permitted and 90% of patients continued to receive at least one of these medications. Enrolled patients had to have failed conventional therapy (corticosteroids or immunomodulators) or at least one biologic (a TNFα antagonist and/or vedolizumab). 49% of patients had failed conventional therapy, but not a biologic (of which 94% where biological-naïve). 51% of patients had failed or were intolerant to a biologic. Approximately 50% of the patients had failed at least 1 prior anti-TNFα therapy (of which 48% were primary non-responders) and 17% had failed at least 1 anti-TNFα therapy and vedolizumab.
In UNIFI-induction a significantly greater proportion of patients were in clinical response and remission in the Stelara treated group compared to placebo (Table 26). As early as week 2, the earliest scheduled study visit, and at each visit thereafter, a higher proportion of Stelara patients had no rectal bleeding or achieved normal stool frequency (defined as a stool frequency subscore of 0 or 1) as compared with placebo patients. Significant differences in partial Mayo score and symptomatic remission were observed between Stelara and placebo as early as week 2. Efficacy was higher in the tiered dose group (6 mg/kg) compared to the 130 mg dose group in select endpoints, and tiered dosing is therefore the recommended intravenous induction dose.
UNIFI-maintenance evaluated 523 patients who achieved clinical response with single IV administration of Stelara in UNIFI-induction. Patients were randomized to receive a subcutaneous maintenance regimen of either 90 mg Stelara every 8 weeks, 90 mg Stelara every 12 weeks or placebo for 44 weeks.
Significantly greater proportions of patients were in clinical remission at week 44 and maintained clinical response through week 44 in both Stelara treated groups compared to the placebo group (see Table 27).
The beneficial effect of Stelara on clinical response, mucosal healing and clinical remission was observed in induction and in maintenance both in patients who failed conventional therapy but not a biologic therapy, as well as in those who had failed at least one prior TNFα antagonist therapy, and/or vedolizumab including in patients with a primary non-response to TNFα antagonist therapy.

Delayed responders to Stelara induction.

Stelara treated patients who were not in response at week 8 of UNIFI-induction received an administration of 90 mg SC Stelara at week 8 (36% of patients). Of those patients, 9% of patients who were initially randomized to the recommended induction dose achieved clinical remission and 58% achieved clinical response at week 16. When combining the delayed responders with the initial responders, 80% of subjects randomized to the recommended induction dose in UNIFI-I achieved clinical response and 18% achieved clinical remission within 16 weeks after initiating treatment with ustekinumab.
Patients who were not in clinical response to Stelara induction at week 8 of the UNIFI-induction study but were in response at week 16 (157 patients) entered in the non-randomized portion of UNIFI-maintenance and continued to receive maintenance dosing every 8 weeks; among these patients, a majority (62%) maintained response and 30% achieved remission at week 44.

Long-term maintenance.

In UNIFI (UCO3001), patients who completed the study through week 44 were eligible to continue treatment in a study extension. Among patients who entered the study extension and were treated with ustekinumab, the majority of patients who failed conventional therapy (but not a biologic therapy) and those who failed biologic therapy, including those who failed both anti-TNF and vedolizumab maintained response at week 200. Of those patients who were assessed using the full Mayo score at week 200, mucosal healing and clinical remission were generally maintained.
No new safety concerns were identified in this study extension with up to 4 years of treatment in patients with ulcerative colitis.

Endoscopic normalisation.

Normalization of endoscopic appearance of the mucosa was defined as a Mayo endoscopic subscore of 0 and was observed as early as week 8 of UNIFI-induction. At week 44 of UNIFI-maintenance, it was achieved in 24% and 29% of patients treated with Stelara every 12 or 8 weeks, respectively, as compared to 18% of patients in the placebo group.

Histologic and histo-endoscopic mucosal healing.

Histologic healing (defined as neutrophil infiltration in < 5% of crypts, no crypt destruction, and no erosions, ulcerations, or granulation tissue) was assessed at week 8 of UNIFI-induction and week 44 of UNIFI-maintenance. At week 8, after a single intravenous induction dose, significantly greater proportions of patients in the recommended dose group achieved histologic healing (36%) compared with patients in the placebo group (22%). At week 44 maintenance of this effect was maintained with significantly more patients in histologic healing in the every 12 week (54%) and every 8 week (59%) Stelara groups as compared to placebo (33%).
A combined endpoint of histo-endoscopic mucosal healing defined as subjects having both mucosal healing and histologic healing was evaluated at week 8 of UNIFI-induction and week 44 of UNIFI-maintenance. Patients receiving Stelara at the recommended dose showed significant improvements on the histo-endoscopic mucosal healing endpoint at week 8 in the Stelara group (18%) as compared to the placebo group (9%). At week 44, maintenance of this effect was observed with significantly more patients in histo-endoscopic mucosal healing in the every 12 week (39%) and every 8 week (46%) Stelara groups as compared to placebo (24%).

Health-related quality of life.

Health-related quality of life was assessed by Inflammatory Bowel Disease Questionnaire (IBDQ), SF-36 and EuroQoL-5D (EQ-5D) questionnaires. At week 8 of UNIFI-induction, patients receiving Stelara showed significantly greater and clinically meaningful improvements on IBDQ total score, EQ-5D and EQ-5D VAS, and SF-36 Mental Component Summary Score and SF-36 Physical Component Summary Score when compared to placebo. These improvements were maintained in ustekinumab-treated patients in UNIFI-maintenance through Week 44.
Patients receiving Stelara experienced significantly more improvements in work productivity as assessed by greater reductions in overall work impairment and in activity impairment as assessed by the WPAI-GH questionnaire than patients receiving placebo.

Long-term maintenance of health-related quality of life measures.

Improvement in health-related quality of life as measured by IBDQ and SF-36 was generally maintained during the extension through week 200.

Hospitalisations and ulcerative colitis related surgeries.

Through week 8 of UNIFI-induction, the proportions of subjects with ulcerative colitis disease related hospitalizations were significantly lower for subjects in the Stelara recommended dose group (1.6%, 5/322) compared with subjects in the placebo group (4.4%, 14/319) and no subjects underwent ulcerative colitis disease related surgeries in subjects receiving Stelara at the recommended induction dose compared to 0.6% (2/319) subjects in the placebo group.
Through week 44 of UNIFI-maintenance, a significantly lower number of ulcerative colitis disease related hospitalizations was observed in subjects in the combined Stelara group (2.0%, 7/348) as compared with subjects in the placebo group (5.7%, 10/175). A numerically lower number of subjects in the Stelara group (0.6%, 2/348) underwent ulcerative colitis disease related surgeries compared with subjects in the placebo group (1.7%, 3/175) through week 44.

5.2 Pharmacokinetic Properties

Absorption.

The median time to reach the maximum serum concentration (tmax) was 8.5 days after a single 90 mg subcutaneous administration in healthy subjects. The median tmax values of ustekinumab following a single subcutaneous administration of either 45 mg or 90 mg in patients with psoriasis were comparable to that observed in healthy subjects.
The absolute bioavailability of ustekinumab following a single subcutaneous administration was estimated to be 57.2% in patients with psoriasis. Following the recommended intravenous induction dose, median peak serum ustekinumab concentration was 126.1 microgram/mL in patients with Crohn's disease, and 127.0 microgram/mL in patients with ulcerative colitis.

Distribution.

Median volume of distribution during the terminal phase (Vz) following a single intravenous administration to patients with psoriasis, ranged from 57 to 83 mL/kg. In a population pharmacokinetic analysis of ustekinumab, the volume of distribution at steady-state was 4.62 L in patients with Crohn's disease and 4.44 L in patients with ulcerative colitis.

Metabolism.

The exact metabolic pathway for ustekinumab is unknown.

Excretion.

Median systemic clearance (CL) following a single intravenous administration to patients with psoriasis ranged from 1.99 to 2.34 mL/day/kg. Median half-life (t1/2) of ustekinumab was approximately 3 weeks in patients with ulcerative colitis, Crohn's disease, psoriasis and/or psoriatic arthritis, ranging from 15 to 32 days across all psoriasis and psoriatic arthritis studies. In a population pharmacokinetic analysis of ustekinumab, the clearance was 0.19 L/day while the half-life was approximately 19 days in patients with Crohn's disease and ulcerative colitis.

Dose linearity.

The systemic exposure of ustekinumab (Cmax and AUC) increased in an approximately dose-proportional manner after a single intravenous administration at doses ranging from 0.09 mg/kg to 4.5 mg/kg or following a single subcutaneous administration at doses ranging from approximately 24 mg to 240 mg in patients with psoriasis.

Single dose vs. multiple doses.

Serum concentration-time profiles of ustekinumab were generally predictable after single or multiple subcutaneous dose administrations. In patients with psoriasis, steady-state serum concentrations of ustekinumab were achieved by week 28 after initial subcutaneous doses at weeks 0 and 4, followed by doses every 12 weeks. The median steady-state trough concentration ranged from 0.21 microgram/mL to 0.26 microgram/mL (45 mg dose) and from 0.47 microgram/mL to 0.49 microgram/mL (90 mg dose).
Following the recommended IV induction dose, median peak serum ustekinumab concentration was 126.1 microgram/mL in patients with Crohn's disease and 127.0 microgram/mL in patient with ulcerative colitis. Starting at week 8, subcutaneous maintenance dosing of 90 mg ustekinumab was administered every 8 or 12 weeks. Steady state ustekinumab concentration was achieved by the start of the second maintenance dose. There was no apparent accumulation in serum ustekinumab concentration over time when given subcutaneously every 8 or 12 weeks.
Following subcutaneous maintenance dosing of 90 mg ustekinumab every 8 weeks, median steady-state trough concentrations ranged from 1.97 microgram/mL to 2.24 microgram/mL in patients with Crohn's disease and 2.69 microgram/mL to 3.09 microgram/mL in patients with ulcerative colitis. Following subcutaneous maintenance dosing of 90 mg ustekinumab every 12 weeks, median steady state trough concentrations ranged from 0.61 microgram/mL to 0.76 microgram/mL in patients with Crohn's disease and 0.92 microgram/mL to 1.19 microgram/mL in patients with ulcerative colitis. The steady-state trough ustekinumab levels resulting from 90 mg ustekinumab every 8 weeks were associated with higher clinical remission rates as compared to the steady-state trough levels following 90 mg every 12 weeks.

Dosing frequency adjustment.

In patients with Crohn's disease and ulcerative colitis, based on observed data and population PK analyses, randomised subjects who lost response to treatment had lower serum ustekinumab concentrations over time compared with subjects who did not lose response. In Crohn's disease, dose adjustment from 90 mg every 12 weeks to 90 mg every 8 weeks was associated with an increase in trough serum ustekinumab concentrations and an accompanying increase in efficacy. In ulcerative colitis, population PK model based simulations demonstrated that adjusting dosing from 90 mg every 12 weeks to every 8 weeks would be expected to result in a 3-fold increase in steady-state trough ustekinumab concentrations. Additionally on the basis of clinical trial data in patients with ulcerative colitis, a positive exposure-response relationship was established between trough concentrations and clinical response, clinical remission, and mucosal healing.

Impact of weight on pharmacokinetics.

Serum ustekinumab concentrations were affected by weight in patients with psoriasis and/or psoriatic arthritis. Within each dose (45 or 90 mg), patients of higher weight (> 100 kg) had lower median serum ustekinumab concentrations compared with those in patients of lower weight (≤ 100 kg). However, across doses, the median trough serum concentrations of ustekinumab in patients with higher weight (> 100 kg) in the 90 mg group were comparable to those in patients with lower weight (≤ 100 kg) in the 45 mg group.

Population pharmacokinetic analysis.

In a population pharmacokinetic analysis using data from patients with psoriasis, the apparent clearance (CL/F) and apparent volume of distribution (V/F) were 0.465 L/d and 15.7 L, respectively, and the t1/2 was approximately 3 weeks. The CL/F of ustekinumab was not impacted by sex, age, or race. The CL/F was impacted by body weight, with a trend toward higher CL/F in patients with higher body weight. The median CL/F in patients with weight > 100 kg was approximately 55% higher compared with patients with weight < 100 kg. The median V/F in patients with weight > 100 kg was approximately 37% higher as compared with patients with weight < 100 kg. Similar results were obtained from a confirmatory population pharmacokinetic analysis using data from patients with psoriatic arthritis.
In the population pharmacokinetic analysis using data from patients with psoriasis, the effect of comorbidities (past and current history of diabetes, hypertension, and hyperlipidaemia) on pharmacokinetics of ustekinumab was evaluated. The pharmacokinetics of ustekinumab were impacted by the comorbidity of diabetes, with a trend towards higher CL/F in patients with diabetes. The mean CL/F in patients with diabetes was approximately 29% higher compared with patients without diabetes.
No specific drug-drug interaction studies have been conducted in healthy subjects or patients with psoriasis, psoriatic arthritis, Crohn's disease or ulcerative colitis.
In the population pharmacokinetic analyses, the effect of the most frequently used concomitant medications in patients with psoriasis (including paracetamol/acetaminophen, ibuprofen, acetylsalicylic acid, metformin, atorvastatin, naproxen, levothyroxine, hydrochlorothiazide, and influenza vaccine) on pharmacokinetics of ustekinumab was explored and none of the concomitant medications exerted significant impact. The pharmacokinetics of ustekinumab was not impacted by the prior use of MTX, ciclosporin, or other biological therapeutics for the treatment of psoriasis. The pharmacokinetics of ustekinumab was not impacted by concomitant use of NSAIDs or prior exposure to anti-TNFα agents in patients with psoriatic arthritis; or by the use of MTX, oral corticosteroids, 6MP, AZA in patients with psoriatic arthritis or Crohn's disease, or by prior exposure to biologics (i.e. anti-TNFα agents and/or vedolizumab) in patients with ulcerative colitis.
No pharmacokinetic data are available in patients with renal insufficiency. No pharmacokinetic data are available in patients with impaired hepatic function.
No specific studies have been conducted in elderly patients. The population pharmacokinetic analysis indicated there were no apparent changes in CL/F and V/F estimates in patients > 65 years.
The pharmacokinetics of ustekinumab were not impacted by the use of tobacco or alcohol.

5.3 Preclinical Safety Data

Genotoxicity.

Stelara has not been evaluated for genotoxic potential.

Carcinogenicity.

Stelara has not been evaluated for carcinogenic potential, due to the lack of appropriate models for an antibody with no cross reactivity to rodent IL-12/23 p40. Stelara is a selective immunosuppressant agent. Immunosuppressive agents have the potential to increase the risk of malignancy (see Section 4.4 Special Warnings and Precautions for Use, Malignancies).

6 Pharmaceutical Particulars

6.1 List of Excipients

45 mg vial, 45 mg pre-filled syringe, 45 mg pre-filled pen, 90 mg pre-filled syringe and 90 mg pre-filled pen.

Each mL of Stelara solution for injection for subcutaneous administration contains: ustekinumab 90 mg, histidine/histidine hydrochloride monohydrate 1.0 mg, sucrose 76 mg, polysorbate 80 0.04 mg, water for injection qs.

130 mg vial.

Each mL of Stelara solution for intravenous infusion contains: ustekinumab 5.0 mg, histidine 0.8 mg, histidine hydrochloride monohydrate 1.1 mg, sucrose 85 mg, polysorbate 80 0.40 mg, methionine 0.40 mg, disodium edetate 0.02 mg, water for injection qs.

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Stelara 130 mg concentrate for solution for infusion should only be diluted with sodium chloride 9 mg/mL (0.9%) solution. Stelara 130 mg concentrate for solution for infusion should not be administered concomitantly in the same intravenous line with other medicinal products.

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.
Protect from light by storing in original carton until time of use. Do not shake.
If necessary, the diluted infusion solution may be stored for up to eight hours at room temperature.
Do not freeze. Discard any unused portion of the infusion solution.

Stelara pre-filled syringes and pre-filled pens room temperature storage (excluding vials).

If needed, Stelara pre-filled syringes and pre-filled pens may be stored at room temperature up to a maximum of 30°C for a single period of up to 30 days in the original carton protected from light. Record the date when the pre-filled syringe or pre-filled pen is first removed from the refrigerator on the carton in the space provided. The new expiry date must not exceed the original expiry date printed on the carton. Once the pre-filled syringe or pre-filled pen has been stored at room temperature, it should not be returned to the refrigerator. Discard the pre-filled syringe or pre-filled pen if not used within 30 days at room temperature storage.

6.5 Nature and Contents of Container

For subcutaneous administration.

Stelara is supplied as a sterile solution in a single-use (Type 1) glass vial. The vial is stoppered with a coated stopper.
Stelara is also supplied as a single-use, sterile solution in a Type 1 glass pre-filled syringe with a fixed 27G, half-inch needle and needle cover. The needle cover is manufactured using a dry natural rubber containing latex (see Section 4.4 Special Warnings and Precautions for Use). The syringe is fitted with a passive safety guard. The Stelara pre-filled syringe is also supplied as a pre-filled pen for adult use.
The solution is clear to slightly opalescent, colourless to light yellow with a pH of approximately 6.0.
Stelara does not contain preservatives.
Each vial, pre-filled syringe or pre-filled pen is for single use only and any unused medicinal product should be disposed of in accordance with local requirements.
Stelara for subcutaneous administration is available in two strengths: 45 mg of ustekinumab (rmc) in 0.5 mL in vial, pre-filled syringe and pre-filled pen, or 90 mg of ustekinumab (rmc) in 1.0 mL in pre-filled syringe and pre-filled pen only.
Stelara is available in packs of: 1 single use vial (45 mg), 1 single use pre-filled syringe (45 mg or 90 mg) and 1 single use pre-filled pen (45 mg or 90 mg).
Not all presentations are marketed.

For intravenous infusion only.

Stelara 130 mg vial is supplied as a sterile solution in a single-use (Type 1) glass vial. The vial is stoppered with a coated stopper.
The solution is clear, colorless to light yellow with a pH of approximately 6.0. Stelara does not contain preservatives.
Stelara is available for intravenous infusion in one strength, 130 mg in 26 mL, and packaged as 1 single use vial. Product is for single use in one patient only. Discard any residue.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical structure.


CAS number.

815610-63-0.
Stelara (ustekinumab) is a human IgG1 kappa monoclonal antibody with an approximate molecular weight of 148,600 daltons. Stelara is produced by a recombinant cell line cultured by continuous perfusion and is purified by a series of steps that includes measures to inactivate and remove viruses.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes