Consumer medicine information

Skyrizi

Risankizumab

BRAND INFORMATION

Brand name

Skyrizi

Active ingredient

Risankizumab

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Skyrizi.

What is in this leaflet

This leaflet answers some common questions about SKYRIZI. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using SKYRIZI against the benefits they expect it will have for you.

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

Read this leaflet carefully before you start using this medicine. It includes important information on the safe and effective use of this medicine.

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

What SKYRIZI is used for

SKYRIZI is used to treat adults with moderate to severe plaque psoriasis, an inflammatory condition affecting the skin and nails.

SKYRIZI contains the active ingredient risankizumab, which is a type of protein called a monoclonal antibody. It works by stopping a protein in the body called IL-23 which causes inflammation.

SKYRIZI reduces the inflammation which improves skin clearance and the appearance of the nails. It also reduces symptoms of psoriasis such as burning, itching, pain, redness and scaling.

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 not expected to affect your ability to drive a car or operate machinery.

Before you use SKYRIZI

When you must not use it

Do not use this medicine if you have an allergy to risankizumab or any of the other ingredients listed at the end of this leaflet.

Do not use this medicine if you have an active infection which your doctor thinks is important.

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

If you are not sure whether you should start using this medicine, talk to your doctor.

Before you start to use it

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

Tell your doctor, pharmacist or nurse before and during use of SKYRIZI if you have or have had any of the following medical conditions:

  • you currently have an infection or if you have an infection that keeps coming back.
  • you have tuberculosis (TB).
  • you have recently received or plan to receive an immunisation (vaccine). You should not be given certain types of vaccines while using SKYRIZI.

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding. Your doctor can discuss with you the risks and benefits involved.

If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor for advice before using this medicine. This is because it is not known how this medicine will affect the baby.

If you are breast-feeding or are planning to breast-feed, talk to your doctor before using this medicine.

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

Taking other medicines

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

How to use SKYRIZI

Follow all directions given to you by your doctor, pharmacist or nurse carefully.

If you do not understand the instructions on the box, ask your doctor, pharmacist or nurse for help.

How much to use

SKYRIZI is given as 2 injections under your skin (called 'subcutaneous injections').

The dose is 150 mg given as two 75 mg injections.

  • 1st dose = 150 mg (two 75 mg injections) as directed by your doctor, pharmacist or nurse
  • 2nd dose = 150mg (two 75 mg injections) 4 weeks after the 1st dose
  • Further doses = 150mg (two 75 mg injections) every 12 weeks starting after the 2nd dose

How to use it

You and your doctor, pharmacist or nurse will decide if you should inject SKYRIZI yourself. Do not inject yourself with this medicine unless you have been trained by your doctor, pharmacist or nurse. A caregiver may also give your injections after training.

Special disposal container can be obtained from your local pharmacy.

Read the 'Instructions for Use' before injecting SKYRIZI yourself.

Instructions for Use

Important information to know before you inject SKYRIZI.

  • SKYRIZI is for single use in one patient only. Discard any residue.
  • Receive training on how to inject SKYRIZI before giving an injection. Talk to your doctor, pharmacist or nurse if you need help.
  • Mark the dates on your calendar so you know when to next use SKYRIZI.
  • Keep SKYRIZI in the original carton to protect from light until it is time to use it.
  • Do not inject if the liquid is cloudy or contains flakes or large particles. The liquid should look clear to slightly yellow and may contain tiny white or clear particles.
  • Do not use if the expiration date has passed.
  • Do not use if the liquid has been frozen (even if thawed).
  • Do not shake the syringe.
  • Do not use if the syringe has been dropped or damaged.
  • Do not use if the syringe tray cover is broken or missing. Return this medicine to the pharmacy.
  • Do not remove the needle cover until just before the injection.
    For a more comfortable injection:
    Take the carton out of the refrigerator and leave it at room temperature, out of direct sunlight, for 15 to 30 minutes before injecting.
  • Do not remove the syringes from the carton until ready to inject.
  • Do not warm SKYRIZI in any other way. For example, do not warm it in a microwave or in hot water.

Follow the steps below each time you use SKYRIZI.

STEP 1

Place the following on a clean, flat surface:

  • 2 pre-filled syringes and 2 alcohol pads (provided).
  • 2 cotton balls or gauze pads (not provided).
  • Special disposal container (not provided).

Wash and dry your hands.

Start with one syringe for the first injection.

For a full dose, 2 injections are required, one after the other.

STEP 2

Choose from these 3 areas to inject:

  • Front of left thigh.
  • Front of right thigh.
  • Belly (abdomen) at least 5 cm from the belly button (navel).

For the second syringe, inject at least 3 cm away from the first injection.

  • Do not inject into the same place.
    Before each injection, wipe where you will inject in a circular motion with an alcohol pad.
  • Do not touch or blow on the injection site after it is cleaned. Allow the skin to dry before injecting.
  • Do not inject through clothes.
  • Do not inject into skin that is sore, bruised, red, hard, scarred or has stretch marks.
  • Do not inject into areas affected by psoriasis.

STEP 3

Hold the syringe with covered needle pointing down, as shown.

Check the liquid in the syringe.

  • It is normal to see bubbles in the window.
  • The liquid should look clear to slightly yellow and may contain tiny white or clear particles.
  • Do not use if the liquid is cloudy or contains flakes or large particles.

STEP 4

Removing the needle cover:

  • Hold the syringe in one hand between the finger grip and needle cover.
  • With the other hand, gently pull the needle cover straight off.
  • Do not hold or pull plunger rod when removing the needle cover.
  • You may see a drop of liquid at the end of the needle. This is normal.
  • Throw away the needle cover.
  • Do not touch the needle with your fingers or let the needle touch anything.

STEP 5

Hold the body of the syringe in one hand between the thumb and index finger, like you would a pencil.

Gently pinch the area of cleaned skin with your other hand and hold it firmly.

Insert the needle all the way into the skin at about a 45-degree angle using a quick, short movement. Keep the syringe steady at the same angle.

STEP 6

Slowly push the plunger rod all the way in until all of the liquid is injected.

Pull the needle out of the skin while keeping the syringe at the same angle.

Stop pinching the skin around your injection site.

Slowly take your thumb off the plunger rod. The needle will then be covered by the needle guard.

  • The needle guard will not activate unless all the liquid is injected.
  • Speak to your doctor, pharmacist or nurse if you think you may have not given a full dose.

Press a cotton ball or gauze pad where you have injected and hold for 10 seconds.

Do not rub the skin where you have injected. You may have slight bleeding from where you injected. This is normal.

STEP 7

For a full dose, two injections are needed, one after the other.

  • Repeat Steps 2 through 6 with the second syringe.
  • Inject the second syringe straight after the first injection but at least 3 cm away from the first injection.

STEP 8

Throw away used syringes in a special disposal container right away after use.

  • Do not throw away used syringes in the household waste.
  • Your doctor, pharmacist or nurse will tell you how to return the full special disposal container.

How long to use it

Do not stop using SKYRIZI without talking to your doctor first. If you stop treatment, your symptoms may come back.

If you forget to use it

If you forget to use SKYRIZI, inject a dose as soon as you remember. Talk to your doctor or pharmacist if you are not sure what to do.

If you use too much (overdose)

If you have used more SKYRIZI than you should, or the dose has been given sooner than prescribed, talk to your doctor.

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have used too much SKYRIZI. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are using SKYRIZI

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are using SKYRIZI.

Tell any other doctors, dentists, and pharmacists who treat you that you are using this medicine.

If you become pregnant while using this medicine, tell your doctor immediately.

Things you must not do

You should not receive a live vaccine while taking SKYRIZI. Talk to your doctor, pharmacist or nurse before receiving any vaccination while taking SKYRIZI. Do not use SKYRIZI to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop using your medicine or lower the dosage without checking with your doctor.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using SKYRIZI.

This medicine helps most people, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

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

Ask your doctor or pharmacist to answer any questions you may have.

Talk to your doctor or get medical help as soon as possible if you have symptoms of serious infection such as:

  • Fever, flu-like symptoms, night sweats.
  • Feeling tired or short of breath, cough which will not go away.
  • Warm, red and painful skin, or a painful skin rash with blisters.

Your doctor will decide if you can keep using SKYRIZI.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • Upper respiratory infections with symptoms such as a sore throat and stuffy nose
  • Feeling tired
  • Fungal skin infection
  • Injection site reactions
  • Headache
  • Small raised red bumps on the skin.

The above list includes the more common side effects of SKYRIZI.

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

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

After using SKYRIZI

Storage

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiration date which is stated on the syringe label and outer carton after 'EXP'.

Store SKYRIZI at 2°C to 8°C. Refrigerate. Do not freeze.

Keep the pre-filled syringes in the original carton in order to protect from light.

The liquid should look clear to slightly yellow. The liquid may contain tiny white or clear particles. Do not use if the liquid is cloudy or contains flakes or large particles.

Disposal

After injecting SKYRIZI, immediately throw away the used syringes in a special container as instructed by your doctor, nurse or pharmacist.

If your doctor tells you to stop using this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

SKYRIZI is a clear and colourless to slightly yellow liquid in a pre-filled syringe with needle guard.

Ingredients

SKYRIZI contains 75 mg of risankizumab as the active ingredient in 0.83 mL solution in each pre-filled syringe.

The other ingredients include:

  • Sodium succinate hexahydrate
  • Succinic acid
  • Sorbitol
  • Polysorbate 20
  • Water for injections

Distributor

SKYRIZI is distributed in Australia by:

AbbVie Pty Ltd
241 O'Riordan Street
Mascot NSW 2020
Australia

SKYRIZI is distributed in New Zealand by:

AbbVie Limited
6th Floor, 156 158 Victoria Street
Wellington 6011
New Zealand

This leaflet was prepared in October 2019

AUST R 304226

Version 02

Published by MIMS December 2019

BRAND INFORMATION

Brand name

Skyrizi

Active ingredient

Risankizumab

Schedule

S4

 

1 Name of Medicine

Risankizumab.

2 Qualitative and Quantitative Composition

Each 75 mg/0.83 mL pre-filled syringe contains 75 mg risankizumab in 0.83 mL solution.
Each 150 mg/mL pre-filled pen or pre-filled syringe contains 150 mg risankizumab in 1 mL solution.
Each 180 mg/1.2 mL pre-filled cartridge contains 180 mg risankizumab in 1.2 mL solution.
Each 360 mg/2.4 mL pre-filled cartridge contains 360 mg risankizumab in 2.4 mL solution.
Each 600 mg/10 mL single-dose vial contains 600 mg risankizumab in 10 mL solution.
Skyrizi (risankizumab), an interleukin-23 blocker, is a humanised immunoglobin G1 (IgG1) monoclonal antibody. Risankizumab is produced in a mammalian cell line using recombinant DNA technology.
Skyrizi 75 mg/0.83 mL pre-filled syringe contains 68 mg sorbitol per 150 mg dose.
Skyrizi 150 mg/mL pre-filled pen and pre-filled syringe and Skyrizi 75 mg/0.83 mL pre-filled syringe contain less than 1 mmol sodium (23 mg) per 150 mg dose and are essentially sodium free.
Skyrizi 180 mg/1.2 mL pre-filled cartridge contains less than 1 mmol sodium (23 mg) per 180 mg dose and is essentially sodium-free.
Skyrizi 360 mg/2.4 mL prefilled cartridge contains less than 1 mmol sodium (23 mg) per 360 mg dose and is essentially sodium-free.
Skyrizi 600 mg/10 mL vial contains less than 1 mmol sodium (23 mg) per 600 mg dose and 1200 mg dose and is essentially sodium free.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection in a pre-filled syringe (75 mg/0.83 mL).

The solution is colourless to slightly yellow and clear to slightly opalescent. The solution may contain tiny white or clear particles.

Solution for injection in a pre-filled syringe or pre-filled pen (150 mg/mL).

The solution is colourless to yellow and clear to slightly opalescent. The solution may contain tiny white or clear particles.

Solution for subcutaneous (S.C.) injection in a pre-filled cartridge (180 mg/1.2 mL or 360 mg/2.4 mL) with an on-body injector.

The solution is colourless to yellow and clear to slightly opalescent. The solution may contain tiny white or clear particles.

Concentrate solution for intravenous (I.V.) infusion single dose vial (600 mg/10 mL).

The solution is colourless to slightly yellow and clear to slightly opalescent. The solution may contain tiny white or clear particles.

4 Clinical Particulars

4.1 Therapeutic Indications

Psoriasis.

Skyrizi is indicated for the treatment of moderate to severe plaque psoriasis in adults (18 years or older) who are candidates for phototherapy or systemic therapy.

Psoriatic arthritis.

Skyrizi is indicated for the treatment of active psoriatic arthritis in adult patients who have responded inadequately to or are intolerant to one or more disease-modifying anti-rheumatic drugs (DMARDs).
Skyrizi may be used with or without conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs).

Crohn's disease.

Skyrizi is indicated for the treatment of moderate to severe Crohn's disease in adult patients, who have an inadequate response, a lost response, an intolerance or a contra-indication to either conventional or biologic therapy.

Ulcerative colitis.

Skyrizi is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to, lost response to, or were intolerant to conventional therapy or biologic therapy.

4.2 Dose and Method of Administration

Visually inspect Skyrizi for particulate matter and discolouration prior to administration.
Skyrizi should not be used if the solution is cloudy or discoloured, or contains large particles.

Psoriasis and psoriatic arthritis.

Skyrizi is intended for use under the guidance and supervision of a physician experienced in the diagnosis and treatment of the indicated conditions.
The recommended dose is 150 mg administered by subcutaneous injection at Week 0, Week 4, and every 12 weeks thereafter.
Patients may self-inject Skyrizi after training in subcutaneous injection technique. Patients should read the Instructions for Use before administration.
The injection should be administered in the thigh or abdomen. Patients should not inject into areas where the skin is tender, bruised, erythematous, indurated or affected by psoriasis. Administration of Skyrizi in the upper, outer arm may only be performed by a healthcare professional or caregiver.
If using Skyrizi 75 mg/0.83 mL, patients should be instructed to inject 2 pre-filled syringes for the full 150 mg dose. For the second syringe, inject at least 3 cm away from the first injection.
Before injecting, for a more comfortable injection, patients using the pre-filled syringe may remove the carton from the refrigerator and allow to reach room temperature out of direct sunlight (15 to 30 minutes) without removing the pre-filled syringes from the carton.
Before injecting, for the pre-filled pen, patients should remove the carton from the refrigerator and allow to reach room temperature out of direct sunlight (30 to 90 minutes) without removing the pre-filled pen from the carton.
Skyrizi pre-filled syringe and pre-filled pen are for single use in one patient only. Discard any residue.

Crohn's disease.

For the treatment of Crohn's disease, obtain liver enzymes and bilirubin levels prior to initiating treatment with Skyrizi (see Section 4.4 Special Warnings and Precautions for Use).
Skyrizi induction dose is intended for use under the guidance and supervision of a healthcare professional.
The recommended induction dose is 600 mg administered by I.V. infusion at Week 0, Week 4 and Week 8, followed by a maintenance dose of 360 mg administered by S.C injection at Week 12 and every 8 weeks thereafter.

Ulcerative colitis.

Induction.

The recommended dose is 1200 mg administered by I.V infusion at Week 0, Week 4 and Week 8.

Maintenance.

Starting at Week 12 and every 8 weeks thereafter, the recommended dose is 180 mg or 360 mg based on individual patient presentation:
A dose of 180 mg administered by S.C injection is recommended for patients with adequate improvement in disease activity after induction;
A dose of 360 mg administered by S.C injection is recommended for patients with inadequate improvement in disease activity after induction.
Use the lowest effective dosage needed to maintain therapeutic response.
Consideration should be given to discontinuing treatment in patients who have shown no evidence of therapeutic benefit by Week 24.

Preparation and administration instructions for Crohn's disease and ulcerative colitis.

Intravenous induction-method of administration.

1. Skyrizi should be prepared by a healthcare professional using aseptic technique.
2. Prior to Skyrizi intravenous administration, follow the instructions in Table 1 to dilute Skyrizi to a final drug concentration of approximately 1.2 mg/mL to 6 mg/mL.
3. Prior to the start of the intravenous infusion, the content of the infusion bag or glass bottle should be at room temperature. The utilisation of a 0.2 micrometre infusion in-line filter is not mandatory.
4. Infuse the diluted solution over a period of at least one hour for the Skyrizi 600 mg dose and over a period of at least two hours for the Skyrizi 1200 mg dose.
5. Skyrizi vial solution should not be administered concomitantly in the same intravenous line with other medicinal products.

Handling and storage of the vial and diluted solution.

The solution in the vial and dilutions should not be shaken.
The prepared infusion should be used immediately. If not used immediately, the diluted Skyrizi solution can be stored (protected from light) for up to 20 hours between 2°C to 8°C.
Immediately after preparation or removal from refrigeration, the diluted Skyrizi solution can be stored at room temperature (protected from sunlight) for up to 8 hours. Storage time at room temperature begins once the diluted solution has been prepared.
The infusion should be completed within 8 hours after dilution in the infusion bag.
Exposure to indoor light is acceptable during room temperature storage and administration.
Each vial is for single use only and any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Do not freeze.

Subcutaneous maintenance-method of administration.

Patients should read the instructions for use before administration. The Skyrizi Instructions for Use contains more detailed instructions on the preparation and administration of Skyrizi.
Administer Skyrizi pre-filled cartridge with on-body injector subcutaneously.
Do not inject into areas where the skin is tender, bruised, erythematous, indurated or affected by any lesions.
Patients may self-inject Skyrizi using the pre-filled cartridge with on-body injector after training in subcutaneous injection technique. Provide proper training to patients and/or caregivers on the subcutaneous injection technique of Skyrizi.
Before using the prefilled cartridge with on-body injector, remove the carton from the refrigerator and allow to reach room temperature out of direct sunlight (45 to 90 minutes) without removing the on-body injector or pre-filled cartridge from the carton.

Missed dose.

If a dose is missed, administer the dose as soon as possible. Thereafter, resume dosing at the regular scheduled time.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in Section 6.1.
Clinically important active infections.

4.4 Special Warnings and Precautions for Use

Infections.

Skyrizi may increase the risk of infections.
In patients with a chronic infection or a history of recurrent infection, the risks and benefits should be considered prior to prescribing Skyrizi. Patients should be instructed to seek medical advice if signs or symptoms of clinically important infection occur. If a patient develops such an infection or is not responding to standard therapy for the infection, the patient should be closely monitored and Skyrizi should not be administered until the infection resolves.

Tuberculosis (TB).

Prior to initiating treatment with Skyrizi, patients should be evaluated for TB infection. Skyrizi must not be given to patients with active TB. Patients receiving Skyrizi should be monitored for signs and symptoms of active TB. Anti-TB therapy should be considered prior to initiating Skyrizi in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed.
Across the Phase 3 psoriasis clinical studies, of the 72 subjects with latent TB who were concurrently treated with Skyrizi and appropriate TB prophylaxis during the studies, none developed active TB during the mean follow-up of 61 weeks on Skyrizi.

Immunisations.

Prior to initiating therapy with Skyrizi, completion of all appropriate immunisations should be considered according to current immunisation guidelines. If a patient has received live vaccination (viral or bacterial), it is recommended to wait at least 4 weeks prior to starting treatment with Skyrizi. Patients treated with Skyrizi should not receive live vaccines during treatment and for at least 21 weeks after treatment.

Hypersensitivity.

Serious hypersensitivity reactions, including anaphylaxis, have been reported with the use of risankizumab. If a serious hypersensitivity reaction occurs, administration of risankizumab should be discontinued immediately and appropriate therapy initiated.

Hepatotoxicity in treatment of inflammatory bowel disease.

A serious adverse reaction of drug-induced liver injury was reported in a patient with Crohn's disease (ALT 54 x ULN, AST 30 x ULN, and total bilirubin 2.2 x ULN) following two intravenous doses of Skyrizi 600 mg in conjunction with a rash that required hospitalisation. The liver test abnormalities resolved following administration of steroids. Skyrizi was subsequently discontinued.
For the treatment of Crohn's disease and ulcerative colitis, evaluate liver enzymes and bilirubin at baseline, and during induction at least up to 12 weeks of treatment. Monitor thereafter according to routine patient management.
Consider other treatment options in patients with evidence of liver cirrhosis. Prompt investigation of the cause of liver enzyme elevation is recommended to identify potential cases of drug-induced liver injury. Interrupt treatment if drug-induced liver injury is suspected, until this diagnosis is excluded. Instruct patients to seek immediate medical attention if they experience symptoms suggestive of hepatic dysfunction.

Use in hepatic impairment.

No specific studies were conducted to assess the effect of hepatic impairment on the pharmacokinetics of Skyrizi. This condition is generally not expected to have any significant impact on the pharmacokinetics of monoclonal antibodies and no dose adjustments are considered necessary (see Section 5.2 Pharmacokinetic Properties).

Use in renal impairment.

No specific studies were conducted to assess the effect of renal impairment on the pharmacokinetics of Skyrizi. This condition is generally not expected to have any significant impact on the pharmacokinetics of monoclonal antibodies and no dose adjustments are considered necessary (see Section 5.2 Pharmacokinetic Properties).

Use in the elderly.

No dose adjustment is required (see Section 5.2 Pharmacokinetic Properties). There is limited information in subjects aged ≥ 65 years.

Paediatric use.

The safety and efficacy of Skyrizi in patients younger than 18 years have not yet been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Skyrizi is not expected to undergo metabolism by hepatic enzymes or renal elimination. Drug interactions between Skyrizi and inhibitors/inducers of drug metabolising enzymes are not expected.
Based on results from drug-drug interaction studies in subjects with plaque psoriasis, Crohn's disease or ulcerative colitis, and on population pharmacokinetic analyses in plaque psoriasis, psoriatic arthritis, Crohn's disease and ulcerative colitis, risankizumab is not expected to cause or be impacted by drug-drug interactions (see Section 5.2 Pharmacokinetic Properties, Drug interactions).
No dose adjustment is needed when co-administering risankizumab and cytochrome P450 substrates.
The safety and efficacy of risankizumab in combination with immunosuppressants, including biologics or phototherapy, have not been evaluated.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Studies in male cynomolgus monkeys at doses of up to 50 mg/kg/week (about 70 times the clinical exposures at the maximum recommended human dose (MRHD) for psoriasis and psoriatic arthritis (150 mg S.C.) and about 7 times the clinical exposure during induction (600 mg I.V. every 4 weeks) and about 28 times the clinical exposure during maintenance, (360 mg S.C. every 8 weeks), in Crohn's disease) and 3 and 45 or 23 times the clinical exposures during induction (1200 mg I.V.) and maintenance (180 mg or 360 mg S.C.), respectively, in ulcerative colitis) with risankizumab did not indicate direct or indirect harmful effects on male fertility. The effects of risankizumab were not directly assessed in a dedicated fertility study in female animals. In the 26-week repeat dose toxicology study, histopathology evaluation of reproductive organs from both male and female cynomolgus monkeys did not show any adverse findings.
(Category B1)
Data available with Skyrizi use in pregnant women are insufficient to inform any drug associated risks.
An enhanced pre- and post-natal developmental toxicity study was conducted in cynomolgus monkeys. Pregnant cynomolgus monkeys were administered weekly subcutaneous doses of risankizumab at 5 or 50 mg/kg from gestation day 20 to parturition and the cynomolgus monkeys (mother and infants) were followed for 6 months (180 days) after delivery. These doses produced exposures of up to approximately 99 times the clinical exposure at the MRHD for psoriasis (150 mg S.C.).
For Crohn's disease, these doses produced exposures 10 times the clinical exposures during induction at a dose of 600 mg I.V. every 4 weeks and 39 times the clinical exposures for maintenance when given 360 mg S.C. every 8 weeks. 4.5 times the clinical exposures during induction at a dose of 1200 mg I.V. every 4 weeks and 65 or 32 times the clinical exposures for maintenance when given at 180 mg or 360 mg S.C., respectively, every 8 weeks.
No drug-related fetal/infant deaths and/or malformations were observed. There were no effects on infant growth and development, which included the assessment of external, visceral, skeletal and neurobehavioral parameters and developmental immuno-toxicology endpoints. In the infants, mean serum concentrations increased in a dose-dependent manner and were approximately 17-86% of the respective maternal concentrations. Following delivery, most adult female cynomolgus monkeys and all infants from the risankizumab-treated groups had measurable serum concentrations of risankizumab up to 91 days postpartum. Serum concentrations were below detectable levels at 180 days postpartum.
Skyrizi should be used in pregnancy only if the benefits outweigh the potential risks.
 It is unknown whether risankizumab is excreted in human milk. Human IgGs are known to be excreted in breast milk during the first few days after birth, which decreases to low concentrations soon afterwards; consequently, a risk to the breast-fed infant cannot be excluded during this short period. A decision should be made whether to discontinue/abstain from Skyrizi therapy, taking into account, the benefit of breast-feeding to the child and the benefit of Skyrizi therapy to the woman.

4.7 Effects on Ability to Drive and Use Machines

Skyrizi has no or negligible influence on the ability to drive and use machines.

4.8 Adverse Effects (Undesirable Effects)

Psoriasis.

A total of 2234 subjects were treated with Skyrizi in clinical development studies in plaque psoriasis, representing 2167 subject-years of exposure. Of these, 1208 subjects with psoriasis were exposed to Skyrizi for at least one year.
Data from placebo- and active-controlled studies were pooled to evaluate the safety of Skyrizi for up to 16 weeks. In total, 1306 subjects were evaluated in the Skyrizi 150 mg group. Serious adverse events occurred in 2.4% for the Skyrizi group (9.9 events per 100 subject-years) compared with 4.0% for the placebo group (17.4 events per 100 subject-years), 5.0% for the ustekinumab group (18.4 events per 100 subject-years) and 3.0% for the adalimumab group (14.7 events per 100 subject-years).
Table 2 summarises the adverse reactions that occurred at ≥ 1% and at a higher rate in the Skyrizi group than the placebo group during the 16-week controlled period of pooled clinical studies. Adverse reactions are listed by MedDRA system organ class.

Less common clinical trial adverse drug reactions (< 1%).

Infections and infestations.

Folliculitis.

Specific adverse reactions.

Psoriasis.

Infections.

In the first 16 weeks, infections occurred in 22.1% of the Skyrizi group (90.8 events per 100 subject-years) compared with 14.7% of the placebo group (56.5 events per 100 subject-years), 20.9% of the ustekinumab group (87.0 events per 100 subject-years) and 24.3% of the adalimumab group (104.2 events per 100 subject-years). The majority of cases were non serious and mild to moderate in severity and did not lead to discontinuation of Skyrizi.
Over the entire psoriasis program including long-term exposure to Skyrizi, the rate of infections (75.5 events per 100 subject-years) was similar to that observed during the first 16 weeks of treatment.

Long-term safety.

A total of 1091 patients had received at least 1 year of risankizumab treatment at the proposed dose of 150 mg up to the time of submission. The frequency of adverse reactions was similar over the long term as that observed during the first 16 weeks of treatment. In ULTIMMA-1 and ULTIMMA-2, through Week 52, the exposure-adjusted rates of serious adverse events per 100 subject-years were 9.4 for subjects treated with Skyrizi and 10.9 for those treated with ustekinumab.
Patients who completed some of the Phase 3 plaque psoriasis clinical studies had the opportunity to enrol in the open-label extension study, LIMMITLESS. A total of 2170 subjects in the LIMMITLESS study were treated with Skyrizi, representing 9953 subject-years of exposure. From first exposure to Skyrizi, 2139 subjects with psoriasis were exposed to Skyrizi for at least one year, and 892 subjects were exposed for more than 5 years.
For those subjects exposed to more than 5 years of Skyrizi, no new adverse reactions were identified compared with the first 16 weeks of treatment.
Psoriatic arthritis. Overall, the safety profile observed in patients with psoriatic arthritis treated with Skyrizi was consistent with the safety profile observed in patients with plaque psoriasis.
Crohn's disease. Skyrizi was studied up to 12 weeks in subjects with moderately to severely active Crohn's disease in two randomised, double-blind, placebo-controlled induction studies and a randomised, double-blind, placebo-controlled, dose-finding study. Long-term safety up to 52 weeks was evaluated in subjects who responded to induction therapy in a randomised, double-blind, placebo-controlled maintenance study.
In the two induction studies and the dose finding study, 620 subjects received the Skyrizi intravenous induction regimen at Weeks 0, 4 and 8. In the maintenance study, 142 subjects who achieved clinical response, defined as a reduction in CDAI of at least 100 points from baseline after 12 weeks of induction treatment with intravenous Skyrizi, received a maintenance regimen of Skyrizi 360 mg subcutaneously at Week 12 and every 8 weeks thereafter for up to an additional 52 weeks.
Adverse reactions reported in > 3% of subjects in induction studies and at a higher rate than placebo are shown in Table 3.
Adverse reactions reported in > 3% of subjects in the maintenance study and at a higher rate than placebo are shown in Table 4.

Specific adverse reactions.

Infections.

The majority of infections were non-serious and mild to moderate in severity and did not lead to discontinuation of Skyrizi.

Induction studies.

The rate of infections in the pooled data from the 12-week induction studies was 83.3 events per 100 subject years in subjects treated with Skyrizi 600 mg I.V. compared to 117.7 events per 100 subject-years in placebo. The rate of serious infections was 3.4 events per 100 subject-years in subjects treated with Skyrizi 600 mg I.V. compared to 16.7 events per 100 subject-years in placebo.

Maintenance study - long term safety.

The rate of infections in the 52-week maintenance study was 57.7 events per 100 subject-years in subjects treated with Skyrizi 360 mg S.C. after Skyrizi induction compared to 76.0 events per 100 subject-years in subjects who received placebo after Skyrizi induction. The rate of serious infections was 6.0 events per 100 subject-years in subjects treated with Skyrizi 360 mg S.C. after Skyrizi induction compared to 5.0 events per 100 subject-years in subjects who received placebo after Skyrizi induction.
Ulcerative colitis. Skyrizi was studied up to 12 weeks in subjects with moderately to severely active ulcerative colitis in a randomised, double-blind, placebo-controlled induction study and a randomised, double-blind, placebo-controlled, dose-finding study. Long-term safety up to 52 weeks was evaluated in subjects who responded to induction therapy in a randomised, double-blind, placebo-controlled maintenance study.
In the induction studies, 712 subjects received the Skyrizi 1,200 mg intravenous induction regimen at Weeks 0, 4 and 8. In the maintenance study, 347 subjects who achieved clinical response, defined as a decrease in mMS of ≥ 2 points and ≥ 30% from baseline and a decrease in RBS ≥ 1 from baseline or an absolute RBS ≤ 1, received a maintenance regimen of Skyrizi either 180 mg or 360 mg subcutaneously at Week 12 and every 8 weeks thereafter for up to an additional 52 weeks.
The adverse reaction reported in ≥ 3% subjects treated with Skyrizi in the ulcerative colitis induction studies and at a higher rate than placebo was arthralgia (3% Skyrizi vs 1% placebo).
Adverse reactions reported in ≥ 3% of subjects treated with Skyrizi in the maintenance study and at a higher rate than placebo are shown in Table 5.

Specific adverse reactions.

Infections.

The majority of infections were non-serious and mild to moderate in severity and did not lead to discontinuation of Skyrizi.
The rate of infections in the pooled data from the 12-week induction study was 77.5 events per 100 subject-years in subjects treated with Skyrizi 1200 mg I.V compared to 75.4 events per 100 subject-years in placebo. The rate of serious infections was 2.9 events per 100 subject-years in subjects treated with Skyrizi 1200 mg I.V compared to 5.1 events per 100 subject years in placebo.
The rate of infections in the 52-week maintenance study was 67.4 events per 100 subject-years in subjects treated with Skyrizi 180 mg S.C and 56.5 events per 100 subject-years in subjects treated with Skyrizi 360 mg S.C after Skyrizi induction compared to 64.6 events per 100 subject-years in subjects who received placebo after Skyrizi induction. The rate of serious infections was 1.1 events per 100 subject-years in subjects treated with Skyrizi 180 mg S.C and 0.6 events per 100 subject-years in subjects treated with Skyrizi 360 mg S.C after Skyrizi induction compared to 2.3 events per 100 subject-years in subjects who received placebo after Skyrizi induction.

Post marketing experience.

The following adverse reactions have been identified during post-approval use of Skyrizi. As these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin and subcutaneous tissue disorders.

Eczema, rash, and urticaria.

Immune system disorders.

Anaphylactic reaction.

Immunogenicity.

As with all therapeutic proteins, there is the potential for immunogenicity with Skyrizi. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity (including neutralising antibody) in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to risankizumab with the incidence of antibodies to other products may be misleading.

Psoriasis.

For subjects treated with Skyrizi at the recommended clinical dose for up to 52 weeks in psoriasis clinical trials, treatment-emergent anti-drug antibodies and neutralising antibodies were detected in 24% (263/1079) and 14% (150/1079) of evaluated subjects, respectively.
Among the few subjects (approximately 1%; 7/1000 at Week 16 and 6/598 at Week 52) with high antibody titres (> 128), clinical response appeared to be reduced.
For subjects exposed to long term treatment of Skyrizi (up to 204 weeks in the extension study), the immunogenicity profile observed was consistent compared to the first 52 weeks of treatment.

Psoriatic arthritis.

For subjects treated with Skyrizi at the recommended clinical dose for up to 28 weeks in Phase 3 psoriatic arthritis clinical trials, treatment-emergent anti-drug antibodies and neutralising antibodies were detected in 12.1% (79/652) and 0% (0/652) of evaluated subjects, respectively. Antibodies to risankizumab including neutralising antibodies were not associated with changes in clinical response or safety.

Crohn's disease.

For subjects treated with Skyrizi at the recommended I.V. induction and S.C. maintenance doses for up to 64 weeks in CD clinical trials, treatment-emergent anti-drug antibodies and neutralising antibodies were detected in 3.4% (2/58) and 0% (0/58) of evaluated subjects, respectively.

Ulcerative colitis.

For subjects treated with Skyrizi at the recommended I.V induction and S.C maintenance doses (180 mg or 360 mg) for up to 64 weeks in ulcerative colitis clinical trials, treatment-emergent anti-drug antibodies and neutralising antibodies were detected in 8.9% (8/90) and 6.7% (6/90) for the 180 mg S.C dose, or 4.4% (4/91) and 2.2% (2/91) for the 360 mg S.C. dose, of evaluated subjects, respectively.
Across all approved indications, available data suggest there are no clear associations between development of antibodies to risankizumab, including neutralising antibodies, on clinical response or safety.

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. In Australia, healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems. In New Zealand, healthcare professionals are asked to report any suspected adverse reactions at https://nzphvc.otago.ac.nz/reporting/.

4.9 Overdose

In the event of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment be instituted immediately.
For information on the management of overdose in Australia contact the Poisons Information Centre on 131126.
For advice on the management of overdose in New Zealand, please contact the National Poisons Centre on 0800 POISON (0800 764 766).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC code: L04AC18.
In a study of subjects with psoriasis, expression of genes associated with the IL-23/IL-17 axis was decreased in the skin after single doses of risankizumab. Reductions in epidermal thickness, infiltration of inflammatory cells, and expression of psoriatic disease markers were also observed in psoriatic lesions.
In a study of subjects with psoriatic arthritis, reductions from baseline were observed at Week 24 in IL-23- and IL-17-associated biomarkers, including serum IL-17A, IL-17F, and IL-22, following treatment with risankizumab at 150 mg administered subcutaneously at Week 0, Week 4, and every 12 weeks thereafter. These results are based on exploratory analysis of limited pharmacodynamic data. The relationship between these pharmacodynamic activities and the mechanism(s) by which risankizumab exerts its clinical effects is unknown.
In a Phase 2 study of subjects with Crohn's disease, expression of genes associated with the IL-23/Th17 axis was decreased in gut tissue after multiple doses of risankizumab. Reductions in faecal calprotectin (FCP), serum C reactive protein (CRP) and IL-22 were also observed after multiple doses in Phase 3 induction studies in Crohn's patients. Decreases in FCP, CRP and serum IL-22 were maintained out to Week 52 of the maintenance study.
In a Phase 2b/3 study of subjects with ulcerative colitis, statistically significant and clinically meaningful reduction from baseline was observed in the inflammatory biomarkers, FCP and CRP, and in the IL-23 pathway-associated biomarker, serum IL-22, at Week 12 of the induction study. Decreases in FCP, CRP and serum IL-22 were maintained out to Week 52 of the maintenance study.

Mechanism of action.

Risankizumab is a humanised immunoglobulin G1 (IgG1) monoclonal antibody that selectively binds with high affinity to the p19 subunit of human interleukin 23 (IL-23) cytokine and inhibits its interaction with the IL-23 receptor complex. IL-23 is a naturally occurring cytokine that is involved in inflammatory and immune responses. IL-23 supports the development, maintenance and activation of Th17 cells, which produces IL-17A, IL-17F, and IL-22, as well as other pro-inflammatory cytokines, and plays a key role in driving inflammatory autoimmune diseases, such as psoriasis, Crohn's disease, and ulcerative colitis. IL-23 is up-regulated in lesional skin in comparison to non-lesional skin of patients with plaque psoriasis. IL-23 is elevated in inflamed colonic mucosa from Crohn's disease and ulcerative colitis patients compared to colonic mucosa from healthy individuals. By blocking IL-23 from binding to its receptor, risankizumab inhibits IL-23-dependent cell signalling and release of pro-inflammatory cytokines.
Risankizumab does not bind to human IL-12, which shares the p40 subunit with IL-23.

Clinical trials.

Psoriasis. The efficacy and safety of Skyrizi was assessed in 2109 subjects with moderate to severe plaque psoriasis in four multicentre, randomised, double-blind studies (ULTIMMA-1, ULTIMMA-2, IMMHANCE, and IMMVENT). Patients who completed these studies had the opportunity to enrol in the open-label extension study, LIMMITLESS. Enrolled subjects were 18 years of age and older with plaque psoriasis who had a body surface area (BSA) involvement of ≥ 10%, a static Physician Global Assessment (sPGA) score of ≥ 3 in the overall assessment (plaque thickness/induration, erythema, and scaling) of psoriasis on a severity scale of 0 to 4, and a Psoriasis Area and Severity Index (PASI) score ≥ 12 and were candidates for systemic therapy or phototherapy.
Overall, subjects had a median baseline PASI score of 17.8 and a median BSA of 20.0%. Baseline sPGA score was severe in 19.3% of subjects. A total of 9.8% of study subjects had a history of diagnosed psoriatic arthritis.
Across all studies, 30.9% of subjects were naïve to both non-biologic systemic and biologic therapy, 31.3% of subjects had received prior phototherapy, 9.9% of subjects had received prior photochemotherapy, 48.3% had received prior non-biologic systemic therapy, 42.1% had received prior biologic therapy, and 23.7% had received at least one anti-TNF alpha agent for the treatment of psoriasis.

ULTIMMA-1 and ULTIMMA-2.

ULTIMMA-1 and ULTIMMA-2 enrolled 997 subjects (598 randomised to Skyrizi 150 mg, 199 to ustekinumab 45 mg or 90 mg, and 200 to placebo). Subjects received treatment at Week 0, Week 4, and every 12 weeks thereafter. The results are presented in Table 6 and Figure 1.
Examination of age, gender, race, body weight, baseline PASI score, concurrent psoriatic arthritis, previous non-biologic systemic treatment, previous biologic treatment, and previous failure of a biologic did not identify differences in response to Skyrizi among these subgroups.
Improvements were observed in psoriasis involving the scalp, the nails, and the palms and soles at Week 16 and Week 52 in subjects treated with Skyrizi.

IMMHANCE.

IMMHANCE enrolled 507 subjects (407 randomised to Skyrizi 150 mg and 100 to placebo). Subjects received treatment at Week 0, Week 4 and every 12 weeks thereafter.
At Week 16, Skyrizi was superior to placebo on the co-primary endpoints of sPGA of clear or almost clear (83.5% Skyrizi vs 7.0% placebo) and PASI 90 (73.2% Skyrizi vs 2.0% placebo). More subjects on Skyrizi had clear skin [sPGA 0 (46.4% Skyrizi vs 1.0% placebo) or PASI 100 (47.2% Skyrizi vs 1.0% placebo)] at Week 16. Subjects receiving Skyrizi were also more likely to have a PASI 75 response compared with placebo (88.7% Skyrizi vs 8.0% placebo).
Of the 31 subjects from the IMMHANCE study with latent tuberculosis (TB) who did not receive prophylaxis during the study, none developed active TB during the mean follow-up of 55 weeks on Skyrizi.

IMMVENT.

IMMVENT enrolled 605 subjects (301 randomised to Skyrizi and 304 to adalimumab). Subjects randomised to Skyrizi received 150 mg of treatment at Week 0, Week 4 and every 12 weeks thereafter. Subjects randomised to adalimumab received 80 mg at Week 0, 40 mg at Week 1 and 40 mg fortnightly through Week 15. Starting at Week 16, subjects who were receiving adalimumab continued or switched treatment based on response:
< PASI 50 were switched to Skyrizi;
PASI 50 to < PASI 90 were re-randomised to either continue adalimumab or switch to Skyrizi;
PASI 90 continued to receive adalimumab.
Similar results for Skyrizi at Week 16 were seen in IMMVENT as in other clinical studies (Table 7 and Figure 2).
For subjects who had PASI 50 to < PASI 90 with adalimumab at Week 16 and were re-randomised, differences in PASI 90 response rates between switching to Skyrizi and continuing adalimumab were noted as early as 4 weeks after re-randomisation (49.1% vs 26.8%, respectively). 66.0% (35/53) of subjects achieved PASI 90 following 28 weeks of Skyrizi, compared with 21.4% (12/56) who continued to receive adalimumab. Other levels of response were also higher following Skyrizi: 39.6% PASI 100, 39.6% sPGA of clear, and 73.6% sPGA of clear or almost clear had response after switching to Skyrizi, compared with 7.1% PASI 100, 7.1% sPGA of clear, and 33.9% sPGA of clear or almost clear who continued to receive adalimumab.

Maintenance and durability of response.

In an integrated analysis of subjects receiving Skyrizi in ULTIMMA-1 and ULTIMMA-2 for PASI 100 responders at Week 16, 79.8% (206/258) of the subjects who continued on Skyrizi maintained the response at Week 52. For PASI 90 responders at Week 16, 88.4% (398/450) of subjects maintained the response at Week 52.
IMMHANCE subjects originally on Skyrizi who achieved sPGA of clear or almost clear at Week 28 were re-randomised to continue Skyrizi every 12 weeks through Week 88 (n = 111) or were withdrawn from therapy (n = 225). At Week 52 and Week 104 (16 weeks after last Skyrizi dose), 87.4% and 81.1% of the subjects continuing Skyrizi achieved sPGA of clear or almost clear compared to 61.3% and 7.1% for those withdrawn from Skyrizi. sPGA clear response rates at Week 52 and Week 104 were 64.9% and 63.1% for subjects continuing Skyrizi compared to 30.7% and 2.2% for those withdrawn from Skyrizi. Among subjects who achieved sPGA of clear or almost clear at Week 28 and relapsed (sPGA ≥ 3) following withdrawal from Skyrizi, 83.7% (128/153) regained sPGA of clear or almost clear response after 16 weeks of retreatment.
In LIMMITLESS, for subjects who completed ULTIMMA-1 and ULTIMMA-2 and continued Skyrizi treatment, rates of PASI 90 and sPGA response of clear or almost clear were maintained through Week 160. For subjects who switched from ustekinumab to Skyrizi at Week 52, rates of PASI 90 and sPGA of clear or almost clear increased from Week 52 through Week 76 which were maintained through Week 160 (Figure 3 and 4).

Quality of life/patient-reported outcomes.

Significantly more subjects treated with Skyrizi achieved a Dermatology Life Quality Index (DLQI) score of 0 or 1 [no impact on health-related quality of life] at Week 16 compared with placebo, adalimumab, or ustekinumab (Table 8). Improvement in health-related quality of life continued through Week 52 (ULTIMMA-1 and ULTIMMA-2). These improvements were maintained in patients receiving continuous risankizumab treatment through Week 280 in the open label extension study LIMMITLESS.
In ULTIMMA-1 and ULTIMMA-2, significantly greater improvements in psoriasis symptoms (itch, pain, redness and burning, as measured by the Psoriasis Symptom Score [PSS]) were demonstrated with Skyrizi compared with placebo at Week 16. A significantly greater proportion of subjects on Skyrizi achieved a PSS of 0 (symptom-free) at Week 16 compared with ustekinumab and with placebo. By Week 52, 55.7% (333/598) of subjects on Skyrizi reported no itch, pain, redness or burning.
Anxiety and depression, as measured by the Hospital Anxiety and Depression Scale (HADS) improved in the Skyrizi group at Week 16 compared with those receiving placebo in ULTIMMA-1 and ULTIMMA-2.
A greater improvement in the Work Limitations Questionnaire (WLQ) at Week 16 was achieved in subjects receiving Skyrizi compared with those receiving adalimumab in IMMVENT.
Psoriatic arthritis. The safety and efficacy of Skyrizi were assessed in 1407 subjects in 2 randomised, double blind, placebo-controlled studies (964 in KEEPsAKE1 and 443 in KEEPsAKE2) in subjects 18 years and older with active PsA.
Subjects in these studies had a diagnosis of PsA for at least 6 months based on the Classification Criteria for Psoriatic Arthritis (CASPAR), a median duration of PsA of 4.9 years at baseline, ≥ 5 tender joints and ≥ 5 swollen joints, and active plaque psoriasis or nail psoriasis at baseline. 55.9% of subjects had ≥ 3% BSA with active plaque psoriasis. 63.4% and 27.9% of subjects had enthesitis and dactylitis, respectively. In KEEPsAKE1 where nail psoriasis was further assessed, 67.3% had nail psoriasis.
In KEEPsAKE1, all subjects had a previous inadequate response or intolerance to csDMARD therapy and were biologic disease-modifying anti-rheumatic drug (bDMARD) naïve. In KEEPsAKE2, 53.5% of subjects had a previous inadequate response or intolerance to csDMARD therapy and 46.5% of subjects had a previous inadequate response or intolerance to one or two bDMARDs (anti-TNFs, abatacept, rituximab).
In both studies, subjects were randomised to receive Skyrizi 150 mg or placebo at Weeks 0, 4, and 16. Starting from Week 28, all subjects received Skyrizi every 12 weeks. Both studies include a long-term extension for up to an additional 204 weeks. At baseline 59.6% of subjects from both studies were receiving concomitant methotrexate (MTX), 11.6% were receiving concomitant csDMARDs other than MTX including 5.3% on leflunomide and 1.9% on apremilast, and 28.9% were receiving no concomitant csDMARD.
For both studies, the primary endpoint was the proportion of subjects who achieved an American College of Rheumatology (ACR) 20 response at Week 24.

Clinical response.

In both studies, treatment with Skyrizi resulted in significant improvement in measures of disease activity compared to placebo at Week 24. See Table 6 for key efficacy results.
Time to onset of efficacy was rapid across measures with greater responses versus placebo seen as early as Week 4 in 25.7% and 19.6% of subjects for ACR20, for KEEPsAKE1 and KEEPsAKE2, respectively.
Treatment with Skyrizi resulted in statistically significant improvement in dactylitis and enthesitis in patients with pre-existing dactylitis or enthesitis at Week 24 (see Table 9).
In both studies, efficacy was observed regardless of concomitant csDMARD use, number of prior csDMARDs, age, gender, race, and BMI. In KEEPsAKE2, responses were seen regardless of prior bDMARD therapy.
The percent of subjects achieving ACR20 responses in study KEEPsAKE1 through Week 24 is shown in Figure 5.
In both studies, improvements were shown in all components of the ACR scores including subject's assessment of pain (see Table 10). These responses were maintained through Week 52.
Treatment with Skyrizi resulted in statistically significant improvement in the skin manifestations of psoriasis in subjects with psoriatic arthritis.
Treatment with Skyrizi resulted in statistically significant improvement in nail psoriasis as measured by modified Nail Psoriasis Severity Index (mNAPSI) and the 5-point Physician's Global Assessment of Fingernail Psoriasis (PGA-F) in subjects with nail psoriasis at baseline (67.3%) in KEEPsAKE1 (Table 11).

Radiographic response.

In Study KEEPsAKE1, inhibition of progression of structural damage was assessed radiographically and expressed as the change in modified Total Sharp Score (mTSS) at Week 24, compared with baseline. The mTSS score was modified for psoriatic arthritis by addition of hand distal interphalangeal (DIP) joints. Skyrizi numerically reduced the mean progression of structural damage at Week 24 compared with placebo (mean change from baseline in mTSS score was 0.23 in the Skyrizi group compared with 0.32 in the placebo group [not statistically significant]). The proportion of subjects with no radiographic progression (defined as a change from baseline in mTSS ≤ 0) was higher with Skyrizi (92.4%) compared with placebo (87.7%) at Week 24 (nominal p-value = 0.016).

Physical function and health related quality of life.

In KEEPsAKE1 and KEEPsAKE2, physical function and disability were assessed by the Health Assessment Questionnaire-Disability Index (HAQ-DI), 36-Item Short Form Health Survey (SF-36) V2. Fatigue was assessed using Functional Assessment of Chronic Illness Therapy Fatigue Scale (FACIT-Fatigue).
In KEEPsAKE1, subjects treated with Skyrizi showed statistically significant improvement from baseline in physical function as assessed by HAQ-DI at Week 24 (-0.31) compared with placebo (-0.11) (p-value ≤ 0.001). In KEEPsAKE2, subjects treated with Skyrizi showed statistically significant improvement from baseline in HAQ-DI at Week 24 (-0.22) compared with placebo (-0.05) (p-value ≤ 0.001). Improvements in physical function were maintained through Week 52 in both studies.
In both studies at Week 24, subjects treated with Skyrizi demonstrated improvements in the SF-36 V2 physical component summary scores and in FACIT-Fatigue scores compared with subjects who received placebo. Improvements in SF-36 physical component as well as FACIT Fatigue scores were maintained through Week 52 in both studies.
Crohn's disease. Skyrizi has been shown to improve signs and symptoms, as well as decrease mucosal inflammation as measured by endoscopy.
The efficacy and safety of Skyrizi was assessed in 1419 subjects with moderate to severe active Crohn's disease in three multicentre, randomised, double-blind, placebo-controlled clinical studies. Enrolled subjects were 16 years of age or older with a Crohn's Disease Activity Index (CDAI) of 220 to 450, an average daily stool frequency (SF) ≥ 4 and/or average daily abdominal pain score (APS) ≥ 2, and a Simple Endoscopic Score for CD (SES-CD) of ≥ 6, or ≥ 4 for isolated ileal disease, excluding the narrowing component and confirmed by a central reviewer.
There were two 12-week intravenous induction studies (ADVANCE and MOTIVATE), which included a 12-week extension period for subjects who did not achieve SF/APS clinical response (≥ 30% decrease in SF and/or ≥ 30% decrease in APS and both not worse than baseline) at Week 12. ADVANCE and MOTIVATE were followed by a 52-week subcutaneous randomised withdrawal maintenance study (FORTIFY) that enrolled subjects with SF/APS clinical response to I.V. induction treatment, representing at least 64 weeks of therapy.

ADVANCE and MOTIVATE.

In studies ADVANCE and MOTIVATE, subjects were randomised to receive either Skyrizi 600 mg I.V. (recommended dose), Skyrizi 1200 mg I.V., or placebo, at Week 0, Week 4, and Week 8.
In ADVANCE, 58% (491/850) subjects had failed or were intolerant to treatment with one or more biologic therapies (prior biologic failure), and 42% (359/850) had failed or were intolerant to treatment with conventional therapy but not to biologic therapy (without prior biologic failure). In ADVANCE, among the subjects without prior biologic failure, (87%) 314/359 were naïve to biologic therapy and the remaining 13% had received biologic therapy but never failed nor demonstrated intolerance. All subjects in MOTIVATE had prior biologic failure.
The co-primary endpoints were clinical remission based on SF and APS (average daily SF ≤ 2.8 and not worse than baseline and average daily AP score ≤ 1 and not worse than baseline) at Week 12, and endoscopic response (greater than 50% decrease in SES-CD from baseline, or a decrease of at least 2 points for subjects with a baseline score of 4 and isolated ileal disease) at Week 12. In both studies, a greater proportion of subjects treated with Skyrizi achieved clinical remission at Week 12 and endoscopic response at Week 12 compared to placebo (Table 12). Enhanced SF/APS clinical response and clinical remission were significant as early as Week 4 in subjects treated with Skyrizi and continued to improve through Week 12.
Additional secondary endpoints measured at Week 12 included the proportion of subjects with enhanced SF/APS clinical response (with ≥ 60% decrease in average daily SF and/or ≥ 35% decrease in average daily AP score and both not worse than Baseline, and/or clinical remission), endoscopic remission (SES-CD ≤ 4 at least a 2 point reduction versus Baseline and no subscore greater than 1 in any individual variable), mucosal healing (SES-CD ulcerated surface subscore of 0 in subjects with a subscore of ≥ 1 at Baseline), a decrease of least 100 points in baseline CDAI, and a CDAI < 150 at Week 12.
At Week 4, a higher proportion of subjects treated with Skyrizi achieved a CDAI < 150 compared to placebo (ADVANCE, Skyrizi = 18%, placebo = 10%, p ≤ 0.05; MOTIVATE, Skyrizi = 21%, placebo = 11%, p ≤ 0.01).
At Week 12, a higher proportion of subjects treated with Skyrizi achieved a CDAI < 150 compared to placebo (ADVANCE, Skyrizi = 45%, placebo = 25%, p < 0.001; MOTIVATE, Skyrizi = 42%, placebo = 20%, p < 0.001).
At Week 12, a higher proportion of subjects treated with Skyrizi achieved a decrease of at least 100 points in baseline CDAI compared to placebo (ADVANCE, Skyrizi = 60%, placebo = 37%, p < 0.001; MOTIVATE, Skyrizi = 60%, placebo = 30%, p < 0.001).
At Week 12, a higher proportion of subjects treated with Skyrizi achieved mucosal healing compared to placebo (ADVANCE, Skyrizi = 21% (N = 336), placebo = 8% (N = 173), p < 0.001; MOTIVATE, Skyrizi = 14% (N = 190), placebo = 4% (N = 186), p = 0.001).
At Week 12, a higher proportion of subjects treated with Skyrizi achieved both enhanced SF/APS clinical response and endoscopic response at Week 12 compared to placebo (ADVANCE, Skyrizi = 31%, placebo = 8%, p < 0.001; MOTIVATE, Skyrizi = 21%, placebo = 7%, p < 0.001).

CD-related hospitalisations.

Rates of CD-related hospitalisations through Week 12 were lower in subjects treated with Skyrizi compared to placebo (ADVANCE, Skyrizi = 3%, placebo = 12%, p < 0.001, MOTIVATE, Skyrizi = 3%, placebo = 11%, p ≤ 0.01).
In ADVANCE, subjects treated with Skyrizi who had prior biologic failure and subjects without prior biologic failure achieved clinical remission and endoscopic response at higher rates than subjects who received placebo (Table 13).
In ADVANCE, a higher proportion of subjects treated with Skyrizi with and without prior biologic failure achieved CDAI < 150 compared to placebo (with prior biologic failure, Skyrizi = 42%, placebo = 26%; Without prior biologic failure, Skyrizi = 49%, placebo = 23%).

Health-related and quality of life outcomes.

Health-related quality of life was assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ), 36-Item Short Form Health Survey (SF-36), and the European Quality of Life 5 Dimensions (EQ-5D). Improvement in fatigue was evaluated by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) scale.
At Week 12 of ADVANCE and MOTIVATE, subjects treated with Skyrizi achieved clinically meaningful improvements from baseline in IBDQ total score, all IBDQ domain scores (bowel symptoms, systemic function, emotional function, and social function), SF-36 Physical and Mental Component Summary Score, EQ-5D VAS, and FACIT-Fatigue compared to placebo.
Subjects treated with Skyrizi experienced more improvements in work productivity compared to placebo, as assessed by the WPAI-CD questionnaire at Week 12. Specifically, greater reductions in impairment while working, overall work impairment, and activity impairment was demonstrated in ADVANCE; and greater reduction in activity impairment was demonstrated in MOTIVATE.
Compared to placebo, subjects treated with Skyrizi achieved clinically meaningful improvements from baseline in Crohn's-related symptoms and sleep impact as assessed by Crohn's Symptom Severity (CSS) questionnaire at Week 12. These improvements were maintained in subjects treated with Skyrizi I.V./Skyrizi S.C. in FORTIFY through Week 52.

FORTIFY.

The maintenance study FORTIFY evaluated 462 subjects with SF/APS clinical response to 12 weeks of Skyrizi I.V. induction treatment in studies ADVANCE and MOTIVATE. Subjects were randomised to continue to receive a maintenance regimen of Skyrizi 360 mg S.C. (recommended dose), or Skyrizi 180 mg S.C. every 8 weeks, or to withdraw from Skyrizi induction and receive placebo S.C. every 8 weeks for up to 52 weeks.
The co-primary endpoints were clinical remission at Week 52 and, endoscopic response at Week 52. Co-primary endpoints were also measured in subjects with and without prior biologic failure (Table 14).
Secondary endpoints measured at Week 52 included enhanced SF/APS clinical response, maintenance of clinical remission (clinical remission at Week 52 in subjects with clinical remission at Week 0), mucosal healing, endoscopic remission, deep remission (clinical remission and endoscopic remission), and CDAI < 150.
Deep remission at Week 52 was observed at higher rates in subjects treated with Skyrizi I.V./Skyrizi S.C. compared to subjects who received Skyrizi I.V./placebo S.C. (28% vs. 10%, respectively, p < 0.001).
At Week 52, a higher proportion of subjects treated with Skyrizi I.V./Skyrizi S.C. achieved CDAI < 150 compared to Skyrizi IV/placebo S.C. (52% vs. 41%, respectively, p ≤ 0.01). A higher proportion of subjects treated with Skyrizi I.V./Skyrizi S.C. achieved a decrease of at least 100 points in baseline CDAI score compared to subjects treated with Skyrizi I.V./placebo S.C. (62% vs. 48%, respectively, p ≤ 0.01).
91 subjects who did not demonstrate SF/APS clinical response 12 weeks after Skyrizi induction in studies ADVANCE and MOTIVATE received subcutaneous 360 mg dose of Skyrizi at Week 12 and Week 20. Of these subjects, 64% (58/91) achieved SF/APS clinical response at Week 24.
During FORTIFY, 30 subjects had loss of response to Skyrizi 360 mg S.C. treatment and received rescue treatment with Skyrizi (1200 mg I.V. single dose, followed by 360 mg S.C. every 8 weeks). Of these subjects, 57% (17/30) achieved SF/APS clinical response at Week 52. In addition, 20% (6/30) and 34% (10/29) of subjects achieved clinical remission and endoscopic response at Week 52, respectively.
Ulcerative colitis. Skyrizi has been shown to improve signs and symptoms and health related quality of life, as well as decreased mucosal inflammation as measured by endoscopy.
The efficacy and safety of Skyrizi was assessed in subjects with moderately to severely active ulcerative colitis in two multicentre, randomised, double-blind, placebo-controlled clinical studies. Enrolled subjects were ≥ 18 and ≤ 80 years of age with modified Mayo Score (mMS) of 5 to 9 (using the Mayo scoring system, excluding Physician's Global Assessment) with an endoscopic subscore (ES) of 2 or 3 on screening endoscopy, confirmed by central review.
The 12-week intravenous induction study (INSPIRE) included a 12-week extension period for subjects who did not achieve clinical response [defined as a decrease from baseline in the mMS ≥ 2 points and ≥ 30% from baseline, and a decrease in rectal bleeding subscore (RBS) ≥ 1 or an absolute RBS ≤ 1] at Week 12. INSPIRE was followed by a 52-week randomised withdrawal study of subcutaneous maintenance treatment (COMMAND) that enrolled subjects with clinical response to 12 weeks of Skyrizi intravenous induction treatment, representing at least 64 weeks of therapy.
INSPIRE. In study INSPIRE, 975 subjects were randomised and receive either Skyrizi 1200 mg or placebo, at Week 0, Week 4, and Week 8.
In INSPIRE, 52% (503/975) of subjects had failed (inadequate response or intolerance) one or more advanced therapies. Of these 503 subjects, 488 (97%) failed biologics and 90 (18%) failed JAK inhibitors.
Enrolled subjects were permitted to use a stable dose of oral corticosteroids (up to 20 mg/day prednisone or equivalent), immunomodulators, and aminosalicylates. At baseline in INSPIRE, 36% of subjects received corticosteroids, 17% of subjects received immunomodulators and 73% of subjects received aminosalicylates. Patient disease activity was moderate (mMS ≤ 7) in 58% of subjects and severe (mMS > 7) in 42% of subjects.
In INSPIRE, a significantly greater proportion of subjects treated with Skyrizi achieved the primary endpoint of clinical remission per mMS [defined as stool frequency subscore (SFS) ≤ 1, and not greater than baseline, RBS = 0, and ES ≤ 1 without evidence of friability] at Week 12 compared to placebo (Table 15). Results of the primary endpoint and key secondary endpoints are listed in Table 15.

Clinical disease activity and symptoms.

The partial adapted Mayo score (paMS) is composed of SFS and RBS. Clinical response per paMS is defined as a decrease of ≥ 1 point and ≥ 30% from baseline and a decrease in RBS ≥ 1 or an absolute RBS ≤ 1. The results of clinical response per paMS over time in INSPIRE are shown in Figure 6. Onset of efficacy was rapid with a greater proportion of subjects treated with Skyrizi achieving clinical response as early as Week 4 compared to placebo (52% vs 31%, respectively, p < 0.00001).
A significantly greater proportion of subjects treated with Skyrizi compared to placebo had no abdominal pain (36% vs 26%, respectively, p < 0.01) and no bowel urgency (44% vs 28%, respectively, p < 0.00001) at Week 12.

Other ulcerative colitis symptoms.

Number of faecal incontinence episodes per week was reduced by a significantly greater amount in subjects treated with Skyrizi compared to placebo at Week 12 (change from baseline in Skyrizi = -3.8, placebo = -2.2, p = 0.00003).
The proportion of subjects who had no nocturnal bowel movements was significantly greater in subjects treated with Skyrizi compared to placebo at Week 12 (67% vs 43%, respectively, p < 0.00001).
The proportion of subjects who had no tenesmus was significantly greater in subjects treated with Skyrizi compared to placebo at Week 12 (49% vs 30%, respectively, p < 0.00001).
Number of days with sleep interruption due to ulcerative colitis symptoms per week were reduced by a significantly greater amount in subjects treated with Skyrizi compared to placebo at Week 12 (change from baseline in Skyrizi = -2.5, placebo = -1.5, p < 0.00001).

Ulcerative colitis-related hospitalisations.

Rates of ulcerative colitis-related hospitalisations through Week 12 were significantly lower in subjects treated with Skyrizi compared to placebo (1% vs 6%, respectively, p < 0.00001).

Extended treatment in Week 12 non-responders.

A total of 141 subjects who did not demonstrate clinical response at Week 12 of Skyrizi induction in INSPIRE received either subcutaneous 180 mg or 360 mg dose of Skyrizi at Week 12 and Week 20. Of the 71 subjects who received Skyrizi 180 mg S.C and 70 subjects who received Skyrizi 360 mg S.C, 56% and 57% achieved clinical response at Week 24, respectively.
COMMAND. The maintenance study COMMAND evaluated 548 subjects with clinical response after 12 weeks of Skyrizi I.V induction treatment in study INSPIRE. Subjects were randomised to receive a maintenance regimen of Skyrizi 180 mg S.C or 360 mg S.C every 8 weeks, or to withdraw from Skyrizi induction and receive placebo S.C every 8 weeks for up to 52 weeks.
In COMMAND, 75% (411/548) of subjects had failed (inadequate response or intolerance) one or more advanced therapies prior to induction baseline. Of these 411 subjects, 407 (99%) failed biologics and 78 (19%) failed JAK inhibitors.
In COMMAND, a significantly greater proportion of the above 548 subjects treated with Skyrizi 180 mg S.C or Skyrizi 360 mg S.C achieved the primary endpoint of clinical remission per mMS at Week 52 compared to placebo (see Table 16). Results of the primary endpoint and key secondary endpoints are listed in Table 16.

Clinical disease activity and symptoms.

A significantly greater proportion of subjects treated with Skyrizi I.V/Skyrizi 180 mg S.C compared to Skyrizi I.V/placebo had no abdominal pain (47% vs 30%, respectively, p < 0.001) and no bowel urgency (54% vs 31%, respectively, p < 0.00001) at Week 52. A greater proportion of subjects treated with Skyrizi I.V/Skyrizi 360 mg S.C compared to Skyrizi I.V/placebo had no bowel urgency (49% vs 31%, p < 0.001) at Week 52, and a numerically higher proportion of subjects had no abdominal pain compared to Skyrizi I.V/placebo (38% vs 30%, respectively, p = 0.0895) at Week 52.

Other ulcerative colitis symptoms.

The proportion of subjects who had no nocturnal bowel movements was greater in subjects treated with Skyrizi I.V/Skyrizi 180 mg S.C and Skyrizi I.V/Skyrizi 360 mg S.C compared to Skyrizi I.V/placebo at Week 52 (42% and 43% vs 30%, p < 0.01 and p < 0.001, respectively).
The proportion of subjects who had no tenesmus was greater in subjects treated Skyrizi I.V/Skyrizi 180 mg S.C and Skyrizi I.V/Skyrizi 360 mg S.C compared to Skyrizi I.V/placebo at Week 52 (37% and 37% vs 23%, respectively, p < 0.01).

Ulcerative colitis-related hospitalisations.

Occurrence of ulcerative colitis-related hospitalisations through Week 52 were numerically lower in subjects treated with Skyrizi I.V/Skyrizi 180 mg S.C and Skyrizi I.V/Skyrizi 360 mg S.C compared to Skyrizi I.V/placebo (0.6 per 100 subject years and 1.2 per 100 subject years vs 3.1 per 100 subject years, p = 0.0949 and p = 0.2531, respectively).

Endoscopic and histologic assessment.

Endoscopic remission (normalisation of the endoscopic appearance of the mucosa) was defined as ES of 0. At Week 12 of INSPIRE, a significantly greater proportion of subjects treated with Skyrizi compared to placebo achieved endoscopic remission (11% vs 3%, respectively, p < 0.00001). At Week 52 of COMMAND, a significantly greater proportion of subjects treated with Skyrizi I.V/Skyrizi 180 mg S.C and Skyrizi I.V/Skyrizi 360 mg S.C compared to Skyrizi I.V/placebo achieved endoscopic remission (23% and 24% vs 15%, respectively, p < 0.05).
Mucosal healing was defined as ES of 0 and Geboes score < 2.0 (indicating no neutrophil in crypts or lamina propria and no increase in eosinophil, no crypt destruction, and no erosions, ulcerations or granulation tissue). At Week 12 of INSPIRE, a significantly greater proportion of subjects treated with Skyrizi compared to placebo achieved mucosal healing (6% vs 1%, respectively, p < 0.00001). At Week 52 of COMMAND, a numerically higher proportion of subjects treated Skyrizi I.V/Skyrizi 180 mg S.C and Skyrizi I.V/Skyrizi 360 mg S.C compared to Skyrizi I.V/placebo achieved mucosal healing (13% and 16% vs 10%, p = 0.2062 and p = 0.0618, respectively).
In COMMAND, maintenance of endoscopic improvement at Week 52 (ES ≤ 1 without friability) was seen in a greater proportion of subjects treated with Skyrizi I.V/Skyrizi 180 mg S.C and numerically higher proportion of subjects treated with Skyrizi I.V/Skyrizi 360 mg S.C compared to Skyrizi I.V/placebo among subjects who achieved endoscopic improvement at the end of induction (74% and 54% vs 47%, p < 0.01 and p = 0.5629, respectively).

Rescue treatment.

During COMMAND, subjects who had loss of response to Skyrizi S.C treatment received rescue treatment with Skyrizi (a single I.V induction dose, followed by 360 mg S.C every 8 weeks). Among these subjects, in the Skyrizi180 mg S.C and Skyrizi 360 mg S.C treatment group, 85% (17/20) and 74% (26/35) achieved clinical response at Week 52, respectively. In addition, 24% (6/25) and 35% (13/37) of subjects achieved clinical remission per mMS, and 38% (10/26) and 45% (17/38) of subjects achieved endoscopic improvement at Week 52 in the Skyrizi 180 mg S.C and Skyrizi 360 mg S.C treatment group, respectively.

Week 24 responders.

A total of 100 subjects did not demonstrate clinical response after 12 weeks of induction treatment, received either subcutaneous 180 mg (N=56) or 360 mg (N=44) dose of Skyrizi at Week 12 and Week 20, demonstrated clinical response at Week 24, and continued receiving Skyrizi 180 mg or 360 mg S.C every 8 weeks for up to 52 weeks in COMMAND. Among these subjects, 46% and 45% achieved clinical response per mMS at Week 52, and 18% and 23% achieved clinical remission per mMS at Week 52, for Skyrizi 180 mg and 360 mg S.C respectively.

Health-related and quality of life outcomes.

Subjects treated with Skyrizi achieved clinically meaningful improvements from baseline in the Inflammatory Bowel Disease Questionnaire (IBDQ) (bowel symptoms, systemic function, emotional function, and social function) compared to placebo. Changes from baseline in IBDQ total score at Week 12 with Skyrizi compared to placebo were 42.6 and 24.3, respectively. Changes from baseline in IBDQ total score at Week 52 were 52.6, 50.3 and 35.0 in subjects treated with Skyrizi I.V/Skyrizi 180 mg S.C, Skyrizi I.V/Skyrizi 360 mg S.C and Skyrizi I.V/placebo, respectively.
Subjects receiving Skyrizi experienced significantly greater improvement from baseline in fatigue, as measured by FACIT-F score at Week 12 compared to placebo. Changes from baseline in FACIT-F score at Week 12 with Skyrizi compared to placebo were 7.9 and 3.3, respectively. Changes from baseline in FACIT-F score at Week 52 were 10.9, 10.3 and 7.0 in subjects treated with Skyrizi I.V/Skyrizi 180 mg S.C, Skyrizi I.V/Skyrizi 360 mg S.C and Skyrizi I.V/placebo, respectively.
At Week 12 of INSPIRE, subjects treated with Skyrizi achieved greater improvements from baseline in WPAI-UC and SF-36 Physical and Mental Component Summary Score compared to placebo. For WPAI-UC greater reductions in impairment while working, overall work impairment, and activity impairment were observed in INSPIRE. These improvements were maintained in subjects treated with Skyrizi I.V/ Skyrizi S.C in COMMAND through Week 52.

5.2 Pharmacokinetic Properties

The pharmacokinetics of risankizumab was similar between subjects with plaque psoriasis and psoriatic arthritis, and between subjects with Crohn's disease and ulcerative colitis.

Absorption.

Risankizumab exhibited linear pharmacokinetics with dose-proportional increase in exposure across dose ranges of 18 to 360 mg and 0.25 to 1 mg/kg administered subcutaneously, and 200 to 1800 mg and 0.01 to 5 mg/kg administered intravenously.
Following subcutaneous dosing of risankizumab, peak plasma concentrations were achieved between 3 - 14 days after dosing with an estimated absolute bioavailability of 74-89%. With the dosing regimen in subjects with psoriasis (150 mg at Week 0, Week 4, and every 12 weeks thereafter), estimated steady-state peak and trough plasma concentrations are 12 and 2 microgram/mL, respectively.
In subjects with Crohn's disease treated with 600 mg I.V. induction dose at Weeks 0, 4, and 8 followed by 360 mg S.C. maintenance dose at Week 12 and every 8 weeks thereafter, maximum median peak and trough concentrations are estimated to be 156 and 38.8 microgram/mL respectively during the induction period (Weeks 8-12) and steady state median peak and trough concentrations are estimated to be 28.0 and 8.13 microgram/mL respectively during the maintenance period (Weeks 40-48).
In subjects with ulcerative colitis treated with 1200 mg I.V induction dose at Weeks 0, 4, and 8 followed by 180 mg or 360 mg S.C maintenance dose at Week 12 and every 8 weeks thereafter, maximum median peak and trough concentrations are estimated to be 350 and 87.7 microgram/mL respectively during the induction period (Weeks 8-12) and steady state median peak and trough concentrations are estimated to be 19.6 and 4.64 microgram/mL for 180 mg S.C dose and 39.2 and 9.29 microgram/mL for 360 mg S.C dose respectively during the maintenance period (Weeks 40-48).
Bioequivalence was demonstrated between a single risankizumab 150 mg/mL injection and two risankizumab 75 mg/0.83 mL injections in pre-filled syringes. Bioequivalence was also demonstrated between risankizumab 150 mg/mL pre-filled syringe and pre-filled pen.

Distribution.

In a typical 90 kg subject with psoriasis, the steady-state volume of distribution (Vss) was 11.2 L, indicating that the distribution of risankizumab is primarily confined to the vascular and interstitial spaces. In a typical 70 kg subject with Crohn's disease, Vss was 7.68 L.

Metabolism.

Therapeutic IgG monoclonal antibodies are typically degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgGs. Risankizumab is not expected to be metabolised by cytochrome P450 enzymes.

Excretion.

The systemic clearance (CL) of risankizumab was 0.31 L/day and terminal elimination half-life was 28 days for a typical 90 kg subject with psoriasis. For a typical 70 kg subject with Crohn's disease, CL was 0.30 L/day and terminal elimination half-life was 21 days.
As an IgG1 monoclonal antibody, risankizumab is not expected to be filtered by glomerular filtration in the kidneys or to be excreted as an intact molecule in the urine.

Drug interactions.

Drug interaction studies were conducted in subjects with plaque psoriasis, Crohn's disease or ulcerative colitis to assess the effect of repeated administration of risankizumab on the pharmacokinetics of cytochrome P450 (CYP) sensitive probe substrates. The exposure of caffeine (CYP1A2 substrate), warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate), metoprolol (CYP2D6 substrate) and midazolam (CYP3A substrate) following risankizumab treatment were comparable to their exposures prior to risankizumab treatment, indicating no clinically meaningful drug interactions through these enzymes.
Population pharmacokinetic analyses indicated that risankizumab exposure was not impacted by concomitant medications (such as metformin, atorvastatin, lisinopril, amlodipine, ibuprofen, acetylsalicylate and levothyroxine) used by some subjects with plaque psoriasis during the clinical studies. Similar lack of impact was observed for concomitant use of methotrexate in psoriatic arthritis, concomitant use of corticosteroids in Crohn's disease and with concomitant medications (amino salicylates, immunomodulators and ulcerative colitis-related antibiotics) used by some patients with ulcerative colitis based on population pharmacokinetic analyses (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Paediatrics.

The pharmacokinetics of risankizumab in paediatric subjects under 16 years of age has not been established. Risankizumab exposures in 16- to 17-year-old subjects with Crohn's disease were similar to those in adults. Age was not found to have any significant impact on risankizumab exposure based on the population pharmacokinetic analyses.

Use in the elderly.

Of the 2234 subjects with plaque psoriasis exposed to Skyrizi, 243 were 65 years or older and 24 subjects were 75 years or older. Of the 1574 subjects with Crohn's disease exposed to Skyrizi, 72 were 65 years or older. Of the 1512 subjects with ulcerative colitis exposed to Skyrizi, 103 were 65 years or older No overall differences in risankizumab exposure, safety and effectiveness were observed between older and younger subjects who received Skyrizi (see Section 4.4 Special Warnings and Precautions for Use, Use in the elderly).

Renal or hepatic impairment.

No specific studies have been conducted to determine the effect of renal or hepatic impairment on the pharmacokinetics of risankizumab. Based on population pharmacokinetic analyses, serum creatinine levels, and/or creatinine clearance, or hepatic function markers (ALT/AST/bilirubin) did not have a meaningful impact on risankizumab clearance in subjects with psoriasis, psoriatic arthritis, Crohn's disease or ulcerative colitis.
As an IgG1 monoclonal antibody, risankizumab is mainly eliminated via intracellular catabolism and is not expected to undergo metabolism via hepatic cytochrome P450 enzymes or renal elimination (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment, Use in renal impairment).

Body weight.

Risankizumab clearance and volume of distribution increase as body weight increases. However, clinically meaningful changes in efficacy and safety of risankizumab were not observed with increased body weight, therefore no dose adjustment is necessary based on body weight.

Gender or race.

The clearance of risankizumab was not significantly influenced by gender or race (Asian subjects compared to non-Asian subjects including Caucasians) in adult subjects with plaque psoriasis, psoriatic arthritis, Crohn's disease or ulcerative colitis based on population pharmacokinetic analyses. No clinically meaningful differences in risankizumab exposure were observed after accounting for body weight differences in Chinese or Japanese subjects compared to Caucasian subjects in clinical pharmacokinetic studies in healthy volunteers.

5.3 Preclinical Safety Data

Genotoxicity.

Genotoxicity studies have not been conducted with risankizumab.

Carcinogenicity.

Carcinogenicity studies have not been conducted with risankizumab. In a 26-week chronic toxicology study in cynomolgus monkeys at doses of up to 50 mg/kg/week (about 70 times the clinical exposure at the MRHD for psoriasis), there were no pre-neoplastic or neoplastic lesions observed.
For Crohn's disease, these doses in cynomolgus monkeys produced exposures about 7 times the clinical exposures during induction (600 mg I.V. every 4 weeks) and about 28 times the clinical exposures for maintenance (360 mg S.C. every 8 weeks).
For ulcerative colitis, these doses in the 26-week chronic study in cynomolgus monkeys produced exposures 3 times the clinical exposures during induction at a dose of 1200 mg I.V every 4 weeks and 45 or 23 times the clinical exposures for maintenance when given 180 mg or 360 mg S.C, respectively, every 8 weeks.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each Skyrizi 75 mg/0.83 mL pre-filled syringe contains sodium succinate hexahydrate, succinic acid, sorbitol, polysorbate 20 and water for injections.
Each Skyrizi 150 mg/mL pre-filled syringe or pre-filled pen contains sodium acetate trihydrate, glacial acetic acid, trehalose dihydrate, polysorbate 20 and water for injections.
Each Skyrizi 180 mg/1.2 mL or 360 mg/2.4 mL pre-filled cartridge contains sodium acetate trihydrate, glacial acetic acid, trehalose dihydrate, polysorbate 20 and water for injections.
Each Skyrizi 600 mg/10 mL single-dose vial contains, sodium acetate trihydrate, glacial acetic acid, trehalose dihydrate, polysorbate 20 and water for injections.

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed 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. Keep in the original carton in order to protect from light. Discard after use. Do not reuse.
Skyrizi 150 mg/mL pre-filled pen or pre-filled syringe, Skyrizi 180 mg/1.2 mL or Skyrizi 360 mg/2.4 mL pre-filled cartridge with on-body injector may be stored one time out of the refrigerator (up to a maximum of 25°C) for up to 24 hours in the original carton to protect from light.
If unopened and stored below 25°C for less than 24 hours, the Skyrizi 150 mg/mL pen or 150 mg/mL pre-filled syringe or Skyrizi 180 mg/1.2 mL or 360 mg/2.4 mL pre-filled cartridge with on-body injector may be returned to the refrigerator.

6.5 Nature and Contents of Container

Skyrizi 75 mg/0.83 mL pre-filled syringe.

Skyrizi 75 mg/0.83 mL is supplied as a sterile solution for subcutaneous injection.
Each pre-filled syringe with needle guard contains 75 mg of risankizumab in 0.83 mL in the following packaging configuration:
Each carton contains 2 pre-filled syringes and 2 alcohol pads.

Skyrizi 150 mg/mL pre-filled syringe.

Skyrizi 150 mg/mL is supplied as a sterile solution for subcutaneous injection.
Each pre-filled syringe with needle guard contains 150 mg of risankizumab in 1.0 mL in the following packaging configuration:
Each carton contains 1 pre-filled syringe.

Skyrizi 150 mg/mL pre-filled pen.

Skyrizi 150 mg/mL is supplied as a sterile solution for subcutaneous injection.
Each pre-filled pen contains 150 mg of risankizumab in 1.0 mL in the following packaging configuration:
Each carton contains 1 pre-filled pen.

Skyrizi 180 mg/1.2 mL pre-filled cartridge.

Skyrizi 180 mg/1.2 mL is supplied as a solution for subcutaneous injection in a pre-filled cartridge with an on-body injector.
Each pre-filled cartridge contains 180 mg of risankizumab in 1.2 mL in the following packaging configuration:
Each carton contains 1 pre-filled cartridge with 1 on-body injector.

Skyrizi 360 mg/2.4 mL pre-filled cartridge.

Skyrizi 360 mg/2.4 mL is supplied as a solution for subcutaneous injection in a pre-filled cartridge with an on-body injector.
Each pre-filled cartridge contains 360 mg of risankizumab in 2.4 mL in the following packaging configuration:
Each carton contains 1 pre-filled cartridge with 1 on-body injector.

Skyrizi 600 mg/10 mL vial.

Skyrizi 600 mg/10 mL is supplied as a concentrate solution for infusion in a single-dose vial.
Each vial contains 600 mg of risankizumab in 10 mL in the following packaging configuration:
Each carton contains 1 vial.
Not all presentations may be marketed.

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

CAS number.

CAS registry number: 1612838-76-2.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes