Consumer medicine information

Rinvoq

Upadacitinib

BRAND INFORMATION

Brand name

Rinvoq

Active ingredient

Upadacitinib

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Rinvoq.

SUMMARY CMI

Rinvoq®

Consumer Medicine Information (CMI) summary

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

▼ This medicine is new or being used differently. Please report side effects. See the full CMI for further details.

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine.

1. Why am I taking Rinvoq?

Rinvoq contains the active ingredient upadacitinib. Rinvoq is used to treat moderate to severe active rheumatoid arthritis, moderate to severe active psoriatic arthritis, active ankylosing spondylitis, active non-radiographic axial spondyloarthritis, moderate to severe atopic dermatitis, moderate to severe active ulcerative colitis and moderate to severe active Crohn's disease.

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

2. What should I know before I take Rinvoq?

Check the list of ingredients at the end of the CMI. Do not take Rinvoq if you have ever had an allergic reaction to any of them.

Do not take Rinvoq if you are already using a biological medicine or a medicine that depresses or strongly suppresses the immune system including azathioprine, ciclosporin and tacrolimus. Talk to your doctor before you take this medicine if you have any other medical conditions, you are a current or past long-time smoker, take any other medicines or are pregnant or plan to become pregnant or are breastfeeding. For more information, see Section 2. What should I know before I take Rinvoq? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Rinvoq and affect how it works or Rinvoq may interfere with other medicines and affect how they work. A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I take Rinvoq?

  • the usual dose is one tablet once every day.
  • do not split, crush, or chew the tablets. Swallow them whole with a full glass of water with or without food.

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

5. What should I know while taking Rinvoq?

Things you should do
  • remind any doctor, pharmacist or dentist you visit that you are taking Rinvoq.
  • keep all your appointments, including blood tests.
  • tell your doctor if you develop an infection, or pain or swelling in the leg, or pain in your chest and/or have difficulty breathing, or severe stomach pain especially accompanied by fever, nausea and vomiting.
Things you should not do
  • do not stop taking this medicine or change the dose unless your doctor tells you to.
Driving or using machines
  • it is unlikely that Rinvoq will have an effect on your ability to drive or use machines.
Drinking alcohol
  • there is no information on the effects of taking Rinvoq with alcohol.
Looking after your medicine
  • store Rinvoq in a cool dry place, below 30°C, away from moisture, heat and sunlight.
  • keep your tablets in the pack until it is time to take them.

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

6. Are there any side effects?

The more serious side effects include serious infections, e.g., tuberculosis, pneumonia, shingles, and blood clots. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.

WARNINGS: Speak with your doctor and refer to Section 2 for more information if:

• You have a history of cardiovascular disease (such as heart attack, stroke or blood vessel disease) or factors that increase your risk of cardiovascular disease.
• You are a current or past long-time smoker.
• You have or have had cancer including skin cancer and cancer of the lymph glands.
• You are 65 years of age and older.

Your doctor has prescribed RINVOQ because they believe it is the moist suitable option for your condition and they have thought carefully about your specific needs and other ways to treat it.



FULL CMI

Rinvoq® (rin voke)

Active ingredient: upadacitinib (yu-pa-da-si-ti-nib)

Consumer Medicine Information (CMI)

This leaflet provides important information about taking Rinvoq. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Rinvoq.

Where to find information in this leaflet:

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

1. Why am I taking Rinvoq?

Rinvoq contains the active ingredient upadacitinib, which is a Janus Kinase (JAK) inhibitor. JAK enzymes create signals in the body's immune system that result in inflammation. Rinvoq works to block these signals, thereby reducing inflammation and the production of immune cells within the body.

Rinvoq is used to treat:

  • moderate to severe, active rheumatoid arthritis by helping to reduce signs and symptoms of inflammation, including joint pain, tenderness, stiffness and swelling in your joints.
  • moderate to severe, active psoriatic arthritis by helping to reduce pain, stiffness, swelling in and around joints, pain and stiffness in your spine, psoriatic skin rash and tiredness. It helps to slow damage to the bone and cartilage in your joints.
  • active ankylosing spondylitis by helping to reduce back pain including night back pain, stiffness and inflammation in your spine.
  • moderate to severe atopic dermatitis by improving the condition of your skin and reducing itching and flares. Rinvoq has also been shown to improve symptoms of pain, anxiety, and depression associated with atopic dermatitis. Rinvoq can also help improve your sleep disturbance and overall quality of life.
  • active non-radiographic axial spondyloarthritis in adults, a disease that primarily causes inflammation in the spine. Rinvoq helps to reduce back pain including back pain at night, stiffness, and inflammation in your spine. These effects can help you to do normal daily activities and may improve your health-related quality of life.
  • moderate to severe active ulcerative colitis by helping to control inflammation and reduce the signs and symptoms of ulcerative colitis, including bloody stools, abdominal pain and the need to rush to and the number of times you go to the toilet, helping you do normal daily activities, reduce fatigue and improve your health-related quality of life.
  • moderate to severe active Crohn's disease by helping to control inflammation and reduce the signs and symptoms of Crohn's disease, including frequent and loose stools, abdominal pain and the inflammation of your intestinal lining. Rinvoq can also help improve your ability to do your normal daily activities, reduce fatigue and improve your health related quality of life.

2. What should I know before I take Rinvoq?

Warnings

Do not take Rinvoq if:

  1. you are already using a biological medicine, including etanercept, adalimumab
  2. you are taking other medicine used to strongly suppress your immune system, e.g., azathioprine, ciclosporin and tacrolimus
  3. you are allergic to upadacitinib, or any of the ingredients listed at the end of this CMI. Symptoms of an allergic reaction (such as rash (hives), trouble breathing, feeling faint or dizzy, or swelling of your lips, tongue, or throat), have been seen in people taking Rinvoq. Some of these reactions may be serious. If any of these symptoms occur during treatment with Rinvoq, stop taking Rinvoq and get emergency medical help right away.

Check with your doctor if you:

  • have allergies to any other medicines, foods, preservatives, or dyes.
  • take any medicines for any other condition.
  • have an infection or have had an infection that keeps coming back. Rinvoq can reduce your body's ability to fight infections, may make an infection you already have worse, or make it more likely for you to get a new infection. If you have diabetes, or are 65 years of age or older, you may have an increased chance of getting infections.
  • have or have had tuberculosis, have been in close contact with someone who has had tuberculosis, or you have lived or travelled overseas where tuberculosis is a problem. You may need to have a test to check if you have previously been exposed to tuberculosis.
  • have or have had shingles or chicken pox
  • have or have had hepatitis B, are a carrier of the hepatitis B virus or you think you may be at risk of contracting hepatitis B or hepatitis C
  • have been recently vaccinated or are scheduled for any immunisations such as against herpes zoster. Live vaccines should not be given while you are taking Rinvoq.
  • have had blood clots, for example in the legs (deep vein thrombosis, DVT) or lungs (pulmonary embolism) or have an increased risk for developing blood clots (for example: if you had recent major surgery, if you use hormonal contraceptives / hormonal replacement therapy, if a blood clotting disorder is identified in you or your close relative).
  • are a current or past long-time smoker.
  • have or have had cancer including skin cancer and lymphomas (cancer of the lymph glands).
  • If you are at high risk of developing skin cancer, your doctor may recommend preventative measures or monitoring, such as regular skin examinations while taking Rinvoq. Talk to your doctor if you develop a new skin lesion or any change in the appearance of an area on the skin.
  • have or have had an abnormal blood cell count such as low red blood cell count, low haemoglobin, low white cell count.
  • have or have had heart problems, high blood pressure or high cholesterol.
  • have or have had kidney or liver problems.
  • have unexplained stomach (abdominal) pain, have or have had diverticulitis (painful inflammation of small pockets in the lining of your intestine) or ulcers in your stomach or intestines, or are taking non-steroidal anti-inflammatory medicines.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information on side effects including signs and symptoms under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Make sure your doctor is aware if you are pregnant or plan to become pregnant. Use effective contraception to avoid becoming pregnant while taking Rinvoq and for at least 4 weeks after your last dose of Rinvoq. Rinvoq should not be used during pregnancy. Based on animal studies, Rinvoq may harm your unborn baby.

Make sure your doctor is aware if you are breastfeeding or plan to do so. You should not take Rinvoq while you are breastfeeding. It is not known if this medicine passes into your breast milk.

Use in children

Rinvoq is not recommended for use in children under 12 years of age or adolescents weighing less than 40 kg with atopic dermatitis. This is because it has not been studied in this age group.

Rinvoq is not recommended for use in children and adolescents under 18 years of age with rheumatoid arthritis, psoriatic arthritis, non-radiographic axial spondyloarthritis, ankylosing spondylitis, ulcerative colitis, and Crohn's disease. This is because it has not been studied in this age group.

Use in the elderly

Patients 65 years of age and older may be at increased risk of infections, heart problems including heart attack, stroke and some types of cancer.

3. What if I am taking other medicines?

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

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

Do not take Rinvoq if you are taking any of the following medicines:

  • biological medicines.

Medicines that may increase the effect of Rinvoq include:

  • medicines used to treat or prevent fungal infections, e.g., ketoconazole, itraconazole, posaconazole or voriconazole
  • medicines used to treat infections caused by bacteria (antibiotic), e.g., clarithromycin.

Medicines that may reduce the effect of Rinvoq include:

  • medicines used to treat tuberculosis and other bacterial infections, e.g., rifampicin
  • medicines used to treat neurological disorders, e.g., phenytoin.

Medicines that may increase the risk of infection when taken with Rinvoq include:

  • other JAK inhibitors, e.g., tofacitinib and baricitinib
  • biological medicines, e.g., etanercept, adalimumab, see above list of medicines to avoid while taking Rinvoq
  • medicines used for suppressing the immune system, e.g., azathioprine, ciclosporin, tacrolimus.

Medicines that may increase your risk of GI perforations:

  • Medicines that may increase your risk of gastrointestinal perforation such as a non-steroidal anti-inflammatory medicine (usually used to treat painful and/or inflammatory conditions of muscle or joints), and/or opioids (used to treat severe pain), and/or corticosteroids (usually used to treat inflammatory conditions).

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

4. How do I take Rinvoq?

How much to take

If you have rheumatoid arthritis, psoriatic arthritis, non-radiographic axial spondyloarthritis, or ankylosing spondylitis:

  • take one 15 mg tablet once every day.

If you have atopic dermatitis:

  • take one 15mg or 30 mg tablet once every day as prescribed by your doctor.
  • your doctor may increase or decrease your dose depending on how well the medicine is working.
  • if you are 65 years of age or older, the recommended dose is 15 mg a day.
  • if you are an adolescent aged 12 years of age or older, the recommended dose is 15 mg a day.

If you have ulcerative colitis:

When starting treatment (Induction):

  • take one 45 mg tablet once every day for 8 weeks, as prescribed by your doctor. This can be continued for another 8 weeks, for a total of 16 weeks (induction dose).

Continuing treatment (Maintenance):

  • then take one 15 mg or 30 mg tablet once every day, as prescribed by your doctor (maintenance dose).
  • your doctor may increase or decrease your dose depending on how well the medicine is working.
  • if you are 65 years of age or older, the recommended maintenance dose is 15 mg a day.

If you have Crohn's disease:

When starting treatment (Induction):

  • take one 45 mg tablet once every day for 12 weeks, as prescribed by your doctor (induction dose).

Continuing treatment (Maintenance):

  • then take one 15 mg or 30 mg tablet once every day, as prescribed by your doctor (maintenance dose).
  • Your doctor may increase or decrease your dose depending on how well the medicine is working.
  • If you are 65 years of age and older, the recommended maintenance dose is 15 mg a day.

How to take Rinvoq

Do not split, crush or chew the tablets. Swallow them whole with a full glass of water.

  • it does not matter if you take this medicine before or after food.
  • follow the instructions provided and use Rinvoq until your doctor tells you to stop.
  • in some instances, Rinvoq needs to be taken with other medicines. Your doctor will let you know which medicines, how to take them and how long to take them.
  • Avoid food or drink containing grapefruit during treatment with Rinvoq as these may interact and increase the risk of side effects.

When to take Rinvoq

  • take Rinvoq at about the same time each day.

Please look for the QR code on the medicine pack. Scan this code for more information on Rinvoq.

If you forget to take Rinvoq

It is important that you do not skip doses of Rinvoq.

If you miss a dose, take it as soon as you remember as long as it is at least 10 hours before your next dose.

If you forget your dose for an entire day, just skip the missed dose and take only a single dose as usual the following day.

Do not take a double dose to make up for the dose you missed.

If you take too much Rinvoq

You should immediately:

  • phone the Poisons Information Centre in Australia (by calling 13 11 26), in New Zealand the National Poisons Centre (by calling 0800 POISON or 0800 764 766) or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there appear to be no signs of discomfort or poisoning.

5. What should I know while taking Rinvoq?

Things you should do

  • keep all your appointments so your progress can be checked.
  • keep your appointments for blood tests to make sure the medicine is working and as some side effects are seen in blood results before you have any symptoms.
  • get regular skin checks, and wear sunscreen and a hat when outdoors.
  • remind any doctor, pharmacist or dentist you visit that you are taking Rinvoq.

Call your doctor straight away if you:

  • Become pregnant while taking Rinvoq.

Things you should not do

  • do not stop taking this medicine or change the dose without checking with your doctor.

Driving or using machines

It is unlikely that Rinvoq will have an effect on your ability to drive or use machines.

Drinking alcohol

There is no information of the effects of taking Rinvoq with alcohol.

Looking after your medicine

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

Store it in a cool dry place away from moisture, heat or sunlight, for example:

  • do not store it in the bathroom or near a sink, and
  • do not store it in the car or on windowsills.

Do not use this medicine after the expiry date.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

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

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Upper airways:
  • sore or scratchy throat
  • blocked or runny nose
  • flu
Gut:
  • feeling sick in the tummy
  • pain in your belly
Body as a whole:
  • fever
  • weight gain
  • feeling unusually tired or weak
  • anaemia
  • headache
Skin:
  • acne
  • cold sores
  • redness and swelling of the hair follicles
  • hives
  • rash
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Signs of a serious infection:
  • fever, sweating or chills
  • feeling short of breath
  • feeling tired or lacking energy
  • muscle aches
  • diarrhoea
  • tummy pain
  • cough
  • weight loss
  • burning when passing urine or passing urine more often
Signs of a blood disorder:
  • swelling of the glands in your neck, armpits or groin
Skin:
  • painful skin rash with blisters
  • new, or changes to any skin spots, sores, or lesions
  • cluster of warm, red or painful skin sores or blisters on your body
Signs of GI perforation (hole in the bowel):
  • sudden onset of stomach pain
  • fever or chills
  • nausea or vomiting
Call your doctor straight away, if you notice any of these serious side effects.
Signs of an allergic reaction:
  • difficulty breathing or swallowing
  • chest tightness
  • wheezing
  • severe dizziness or light-headedness
  • swelling of face, lips, tongue, or throat
  • severe itching of skin, with a red rash or raised bumps
Signs of tuberculosis:
  • fever, night sweats
  • chills
  • difficulty breathing
  • a bad cough that won't go away
  • blood in your phlegm
  • weight loss
Signs of the effect of a blood clot:
  • leg pain or tenderness
  • redness or discolouration in the leg or arm
  • swelling of the leg or arm
  • chest pain or pain in the upper back
  • sudden shortness of breath or difficulty breathing
Signs of pneumonia:
  • fever, chills
  • cough sometimes with phlegm
  • feeling tired or lacking energy
  • shortness of breath
  • chest pain
Signs of a heart attack:
  • chest pain or discomfort
  • lightheadedness, nausea, or vomiting
  • pain in jaw, neck or back
  • pain or discomfort in arm or shoulder
  • shortness of breath
Signs of a stroke:
  • trouble speaking or difficulty understanding speech
  • sudden numbness, weakness or paralysis in the face, arm or leg of one side of the body
  • problems seeing in one or both eyes
  • headache
  • trouble walking
Go straight to the Emergency Department at your nearest hospital if you notice any of these very serious side effects.

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

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

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What Rinvoq contains

Active ingredient
(main ingredient)		Upadacitinib
Other ingredients
(inactive ingredients)
  • microcrystalline cellulose
  • hypromellose
  • mannitol
  • tartaric acid
  • colloidal anhydrous silica
  • magnesium stearate
  • polyvinyl alcohol
  • macrogol 3350
  • talc
  • titanium dioxide
  • iron oxide red
  • iron oxide black (15 mg only)
  • iron oxide yellow (45 mg only)

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

Rinvoq does not contain gluten or lactose.

What Rinvoq looks like

Rinvoq 15 mg tablets are purple oblong tablets, 14 x 8 mm and marked 'a15' on one side (AUST R 312687).

Rinvoq 30 mg tablets are red oblong tablets, 14 x 8 mm and marked 'a30' on one side (AUST R 346215).

Rinvoq 45 mg tablets are yellow to mottled yellow oblong tablets, 14 x 8 mm and marked ‘a45’ on one side (AUST R 375857).

Rinvoq is supplied in blister packs inside a carton containing 7 or 28 tablets.

Who distributes Rinvoq?

AbbVie Pty Ltd
ABN 48 156 384 262
241 O'Riordan Street
MASCOT NSW 2020

This leaflet was prepared in July 2023.

Version 08

© 2023 AbbVie. All rights reserved. Rinvoq® is a registered trademark of AbbVie Biotechnology Ltd.

Published by MIMS September 2023

BRAND INFORMATION

Brand name

Rinvoq

Active ingredient

Upadacitinib

Schedule

S4

 

1 Name of Medicine

Upadacitinib.

2 Qualitative and Quantitative Composition

Rinvoq contains upadacitinib hemihydrate, equivalent to 15 mg, 30 mg, or 45 mg of upadacitinib, a Janus Kinase (JAK) inhibitor.
The tablets do not contain gluten or lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Rinvoq 15 mg modified release tablets are purple, biconvex oblong, with dimensions of 14 x 8 mm, and debossed with 'a15' on one side.
Rinvoq 30 mg modified release tablets are red, biconvex oblong, with dimensions of 14 x 8 mm, and debossed with 'a30' on one side.
Rinvoq 45 mg modified release tablets are yellow to mottled yellow, biconvex oblong, with dimensions of 14 x 8 mm, and debossed with 'a45' on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

Rheumatoid arthritis.

Rinvoq is indicated for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to, one or more disease-modifying anti-rheumatic drugs (DMARDs).
Rinvoq may be used as monotherapy or in combination with methotrexate or other conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs).

Psoriatic arthritis.

Rinvoq is indicated for the treatment of moderate to severe active psoriatic arthritis in adult patients who have responded inadequately to, or are intolerant to one or more DMARDs.
Rinvoq may be used as monotherapy or in combination with a non-biological DMARD.

Non-radiographic axial spondyloarthritis.

Rinvoq is indicated for the treatment of adults with active non-radiographic axial spondyloarthritis with objective signs of inflammation as indicated by elevated C-reactive protein (CRP) and/or magnetic resonance imaging (MRI) change, who have responded inadequately to, or are intolerant to nonsteroidal anti-inflammatory drugs (NSAIDs).

Ankylosing spondylitis.

Rinvoq is indicated for the treatment of adults with active ankylosing spondylitis.

Atopic dermatitis.

Rinvoq is indicated for use in adults and adolescents aged 12 years and above who weigh at least 40 kg, for the treatment of moderate to severe atopic dermatitis which is inadequately controlled with active topical pharmacotherapies and for whom systemic therapy is indicated.

Ulcerative colitis.

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

Crohn's disease.

Rinvoq 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 biological medicine.

4.2 Dose and Method of Administration

Therapy with Rinvoq should be initiated and monitored by a specialist physician well versed in the use of immunomodulatory therapeutic agents like Rinvoq with expertise in the management of the indicated conditions.
Rinvoq should not be initiated in patients with an absolute lymphocyte count (ALC) less than 500 cells/mm3, an absolute neutrophil count (ANC) less than 1000 cells/mm3 or who have haemoglobin levels less than 8 g/dL (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).
Rinvoq tablets should be taken orally with or without food.
Rinvoq tablets should be swallowed whole. Rinvoq should not be split, crushed, or chewed.

Rheumatoid arthritis.

The recommended dose of Rinvoq is 15 mg once daily.
Rinvoq may be used as monotherapy or in combination with methotrexate or other csDMARDs.

Psoriatic arthritis.

The recommended dose of Rinvoq is 15 mg once daily.
Rinvoq may be used as monotherapy or in combination with a non-biological DMARD.

Non-radiographic axial spondyloarthritis.

The recommended dose of Rinvoq is 15 mg once daily.

Ankylosing spondylitis.

The recommended dose of Rinvoq is 15 mg once daily.

Atopic dermatitis.

Adults.

The recommended starting dose of Rinvoq is 15 mg once daily for adults.
In adults aged less than 65 years, the dose may be increased to 30 mg once daily from 4 weeks after initiation of treatment, if clinically warranted and based on benefit-risk assessment.
The lowest effective dose for maintenance should be considered.

Adolescents (from 12 to 17 years of age).

The recommended dose of Rinvoq is 15 mg once daily for adolescents weighing at least 40 kg. Rinvoq has not been studied in adolescents weighing less than 40 kg.
Rinvoq should be ceased if a satisfactory clinical response is not achieved after 16 weeks.

Ulcerative colitis.

Induction. The recommended induction dose of Rinvoq is 45 mg once daily for 8 weeks. For patients who do not achieve adequate therapeutic benefit by week 8, Rinvoq 45 mg once daily may be continued for an additional 8 weeks. Rinvoq should be ceased if a satisfactory clinical response is not achieved after 16 weeks.
Maintenance. Use the lowest effective dosage needed to maintain response.
The recommended dose of Rinvoq for maintenance treatment is 15 mg once daily. A dose of 30 mg once daily may be considered for patients with refractory, severe or extensive disease. A dose of 30 mg once daily may be appropriate for patients who do not show a satisfactory clinical response to 15 mg once daily.
Rinvoq should be ceased if a satisfactory clinical response is not achieved with the 30 mg dose.
In patients who have responded to treatment with Rinvoq, corticosteroids may be reduced and/or discontinued in accordance with standard of care.

Patients 65 years of age or older.

For patients ≥ 65 years of age, the recommended maintenance dose is 15 mg once daily.

Crohn's disease.

Induction. The recommended induction dose of Rinvoq is 45 mg once daily for 12 weeks.
For patients who have not achieved adequate therapeutic benefit after the initial 12-week induction, Rinvoq may be continued at a dose of 30 mg once daily. If there is no evidence of therapeutic benefit after a further 12 weeks (i.e. 24 weeks in total of treatment) Rinvoq should be discontinued.
Maintenance. Use the lowest effective dosage needed to maintain response.
The recommended dose of Rinvoq for maintenance treatment is 15 mg once daily.
For patients who are not at higher risk of venous thromboembolism (VTE), MACE and malignancy (see Section 4.4), a dose of 30 mg once daily may be appropriate for:
patients with refractory, severe or extensive disease or;
patients who do not show a satisfactory clinical response to 15 mg once daily.
In patients who are responding to induction or maintenance treatment with Rinvoq, corticosteroids may be reduced and/or discontinued in accordance with standard of care.
In line with clinical best practice, ongoing treatment should be reviewed every 3 to 6 months. Rinvoq should be ceased if a satisfactory clinical response is not achieved with the 30 mg dose.

Patients 65 years of age or older.

For patients ≥ 65 years of age, the recommended maintenance dose is 15 mg once daily.

Dose interruption.

Rinvoq treatment should be interrupted if a patient develops a serious infection until the infection is controlled (see Section 4.4 Special Warnings and Precautions for Use).
Interruption of dosing may be needed for management of laboratory abnormalities as described in Table 1.

Missed dose.

If a dose of Rinvoq is missed, and it is more than 10 hours from the next scheduled dose, advise the patient to take a dose as soon as possible and then to take the next dose at the usual time. If a dose is missed and it is less than 10 hours from the next scheduled dose, advise the patient to skip the missed dose and take only a single dose as usual the following day. Advise the patient not to double a dose to make up for a missed dose.

Dosing in special populations.

Paediatric use.

Atopic dermatitis.

The safety and efficacy of Rinvoq in adolescents weighing < 40 kg and in children aged 0 to less than 12 years have not yet been established. No data are available.

Rheumatoid arthritis, psoriatic arthritis, non-radiographic axial spondyloarthritis, ankylosing spondylitis, ulcerative colitis and Crohn's disease.

The safety and efficacy of Rinvoq in children and adolescents aged 0 to less than 18 years have not yet been established. No data are available.

Concomitant use with strong CYP3A4 inhibitors.

See Section 4.5 Interactions with Other Medicines and Other Forms of Interaction, Strong CYP3A4 inhibitors for recommended dose adjustments.
Use in the elderly. Refer to indication specific guidance.
Use in renal impairment. No dose adjustment is recommended for patients with stage 2 kidney disease (glomerular filtration rate (GFR) of 60 mL/min/1.73 m2 or higher). Patients with kidney disease stages 3 to 5 (GFR < 60 mL/min/1.73 m2) may have increased plasma exposures to upadacitinib which may increase potential for adverse events. There are no evaluable data on use of upadacitinib in stage 5 kidney disease (GFR < 15 mL/min/1.73 m2 or on dialysis; see Section 5.2 Pharmacokinetic Properties). While the majority of upadacitinib elimination occurs through non-renal clearance, prudent dosing is recommended in patients with kidney disease stages 3 to 5 (see Table 2 for dosing recommendations).
Rinvoq has not been studied in patients with end stage renal disease (eGFR < 15 mL/min/1.73 m2).
Use in hepatic impairment. No dose adjustment is required in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. Rinvoq is not recommended for use in patients with severe hepatic impairment (Child-Pugh C) (see Section 5 Pharmacological Properties).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.
Rinvoq must not be used in combination with biologic disease-modifying anti-rheumatic drugs (bDMARDs).

4.4 Special Warnings and Precautions for Use

Therapy with Rinvoq should be initiated and monitored by a specialist physician well versed in the use of immunomodulatory therapeutic agents like Rinvoq, with expertise in the management of the indicated conditions.

Mortality.

In a large, randomised, post-marketing safety study of tofacitinib (another JAK inhibitor) in rheumatoid arthritis patients 50 years of age and older with at least one additional cardiovascular risk factor, a higher rate of all-cause mortality, including sudden cardiovascular death, was observed with tofacitinib compared to TNF inhibitors. Mortality was mainly due to cardiovascular events, infections and malignancies.
Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with Rinvoq (see also subsections on Major adverse cardiovascular events (MACE), Thrombosis, Malignancy, Non-melanoma skin cancer and Use in 65 years of age and older).

Major adverse cardiovascular events (MACE).

Events of MACE were observed in clinical studies of Rinvoq.
In a large, randomised, post-marketing safety study of tofacitinib (another JAK inhibitor) in rheumatoid arthritis patients 50 years of age and older with at least one additional cardiovascular risk factor, a higher rate of Major Adverse Cardiovascular Events (MACE), defined as cardiovascular death, non-fatal myocardial infarction (MI) and non-fatal stroke, was observed with tofacitinib compared to TNF inhibitors. MACE, including events of myocardial infarction, were more common in older patients and in patients who were current or past smokers.
In patients 65 years of age and older, patients who are current or past long-time smokers and patients with history of atherosclerotic cardiovascular disease or other cardiovascular risk factors, Rinvoq should only be used if no suitable treatment alternatives are available.

Thrombosis.

Serious and sometimes fatal events of thrombosis, including deep vein thrombosis (DVT), arterial thrombosis and pulmonary embolism (PE), have occurred in patients treated with JAK inhibitors, including upadacitinib.
In a large, randomised, post-marketing safety study of tofacitinib (another JAK inhibitor) in rheumatoid arthritis patients 50 years of age and older with at least one additional cardiovascular risk factor, a dose dependent increased risk for these thrombotic events was observed with tofacitinib compared to TNF inhibitors (see Section 4.8 Adverse Effects (Undesirable Effects)).
In patients with cardiovascular or malignancy risk factors (see also subsections on Major Adverse Cardiovascular Events (MACE) and Malignancy), Rinvoq should only be used if no suitable treatment alternatives are available.
Avoid Rinvoq in patients with an increased risk of thrombosis or in whom risk factors are identified. VTE risk factors include previous VTE, patients undergoing major surgery, immobilisation, use of combined hormonal contraceptives or hormonal therapy, and inherited coagulation disorder. Promptly evaluate patients with signs and symptoms of VTE and discontinue Rinvoq in patients with suspected VTE, regardless of dose or indication.
Patients should be re-evaluated periodically during Rinvoq treatment to assess for changes in VTE risk.

Malignancy.

Lymphoma and other malignancies have been reported in patients receiving JAK inhibitors including Rinvoq. A higher rate of malignancies, driven by non-melanoma skin cancer (NMSC), was observed with Rinvoq 30 mg compared to Rinvoq 15 mg.
In a large, randomised, post-marketing safety study of tofacitinib (another JAK inhibitor) in rheumatoid arthritis patients 50 years of age and older with at least one additional cardiovascular risk factor, a higher rate of malignancies, particularly lung cancer, lymphoma and NMSC, was observed with tofacitinib compared to TNF inhibitors.
In patients 65 years of age and older, patients who are current or past long-time smokers, or patients with other malignancy risk factors (e.g. current malignancy or history of malignancy), Rinvoq should only be use if no suitable treatment alternatives are available.

Non-melanoma skin cancer.

NMSCs have been reported in patients treated with Rinvoq (see Section 4.8 Adverse Effects (Undesirable Effects)). A higher rate of NMSC was observed with Rinvoq 30 mg compared to Rinvoq 15 mg. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

Use in patients 65 years of age and older.

Considering the increased risk of MACE, malignancies, serious infections, and all-cause mortality in patients 65 years of age and older, as observed in a large randomised post-marketing study of tofacitinib (another JAK inhibitor), Rinvoq should only be used in these patients if no suitable treatment alternatives are available.
In patients 65 years of age and older, there is an increased risk of adverse reactions with Rinvoq 30 mg once daily. Consequently, the recommended dose for long-term use in this patient population is 15 mg once daily [see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects)].
Of the 4381 patients treated in the five Phase 3 clinical studies, a total of 906 rheumatoid arthritis patients were 65 years of age or older. Of the 1827 patients treated in the two psoriatic arthritis Phase 3 clinical studies, a total of 274 patients were 65 years of age or older. No differences in effectiveness were observed between these patients and younger patients; however, there was a higher rate of overall adverse events, including serious infections, in the elderly. There are limited data in patients aged 75 years and older.
Of the 2485 patients treated in the atopic dermatitis Phase 3 clinical studies, 115 were 65 years of age or older. In the elderly, a higher rate of overall adverse events was observed compared to younger patients and in the Rinvoq 30 mg dose group compared to the 15 mg dose group.
Of the 576 patients who responded to Rinvoq 45 mg once daily induction treatment and received maintenance treatment in the ulcerative colitis studies, 52 patients were 65 years of age or older. In the elderly, a higher rate of overall adverse events was observed compared to younger patients and in the Rinvoq 30 mg once daily dose group compared to the Rinvoq 15 mg dose once daily group.
Of the 673 patients who responded to Rinvoq 45 mg induction treatment and received maintenance treatment in the Crohn's disease studies, 23 patients were 65 years of age or older. A higher rate of overall adverse events was observed in the elderly with Rinvoq 30 mg compared to younger patients and Rinvoq 15 mg dose.

Immunosuppressive medicinal products.

Combination with other potent immunosuppressants such as azathioprine, cyclosporin, tacrolimus, and biologic DMARDs or other JAK inhibitors has not been evaluated in clinical studies and is not recommended as a risk of additive immunosuppression cannot be excluded (see Section 4.3 Contraindications).

Serious infections.

Serious and sometimes fatal infections have been reported in patients receiving Rinvoq. The most frequent serious infections reported with Rinvoq included pneumonia and cellulitis (see Section 4.8 Adverse Effects (Undesirable Effects)). Cases of bacterial meningitis have been reported in patients receiving upadacitinib. Among opportunistic infections, tuberculosis, multi-dermatomal herpes zoster, oral/oesophageal candidiasis, cryptococcosis, pneumocystosis and eczema herpeticum, were reported with Rinvoq.
Avoid use of Rinvoq in patients with an active, serious infection, including localised infections. Consider the risks and benefits of treatment prior to initiating Rinvoq in patients:
with chronic or recurrent infection;
who have been exposed to tuberculosis;
with a history of a serious or an opportunistic infection;
who have resided or travelled in areas of endemic tuberculosis or endemic mycoses; or
with underlying conditions that may predispose them to infection.
Closely monitor patients for the development of signs and symptoms of infection during and after treatment with Rinvoq. Interrupt Rinvoq if a patient develops a serious or opportunistic infection. A patient who develops a new infection during treatment with Rinvoq should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, the patient should be closely monitored, and Rinvoq should be interrupted if the patient is not responding to antimicrobial therapy. Rinvoq may be resumed once the infection is controlled.
A higher rate of serious infections was observed with Rinvoq 30 mg compared to Rinvoq 15 mg.
As there is a higher incidence of infections in the elderly and in the diabetic populations in general, caution should be used when treating the elderly and patients with diabetes. In patients 65 years of age and older, Rinvoq should only be used if no suitable treatment alternatives are available.

Tuberculosis.

Patients should be screened for tuberculosis (TB) before starting Rinvoq therapy. Rinvoq should not be given to patients with active TB. Anti-TB therapy should be considered prior to initiation of Rinvoq in patients with previously untreated latent TB or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but who have risk factors for TB infection.
Consultation with a physician with expertise in the treatment of TB is recommended to aid in the decision about whether initiating anti-TB therapy is appropriate for an individual patient.
Monitor patients for the development of signs and symptoms of TB, including patients who tested negative for latent TB infection prior to initiating therapy.

Viral reactivation.

Viral reactivation, including cases of herpes virus reactivation (e.g. herpes zoster) and hepatitis B virus reactivation, were reported in clinical studies (see Section 4.8 Adverse Effects (Undesirable Effects)). The risk of herpes zoster appears to be higher in patients treated with Rinvoq in Japan. If a patient develops herpes zoster, consider temporarily interrupting Rinvoq until the episode resolves.
Screening for viral hepatitis and monitoring for reactivation should be performed in accordance with clinical guidelines before starting and during therapy with Rinvoq. Patients who were positive for hepatitis C antibody and hepatitis C virus RNA, were excluded from clinical studies. Patients who were positive for hepatitis B surface antigen or hepatitis B virus DNA were excluded from clinical studies. However, cases of hepatitis B reactivation were still reported in patients enrolled in the Phase 3 studies of Rinvoq. If hepatitis B virus DNA is detected while receiving Rinvoq, a liver specialist should be consulted.

Vaccination.

No data are available on the response to vaccination with live vaccines in patients receiving Rinvoq. Use of live, attenuated vaccines during, or immediately prior to, Rinvoq therapy is not recommended. Prior to initiating Rinvoq, it is recommended that patients be brought up to date with all immunisations, including prophylactic zoster vaccinations and COVID-19 vaccinations, in agreement with current immunisation guidelines.
The influence of Rinvoq on the humoral response following the administration of inactivated pneumococcal 13-valent conjugate vaccine was evaluated in 111 patients with rheumatoid arthritis under stable treatment with upadacitinib 15 mg (N = 87) or 30 mg (N = 24). 97% of patients (N = 108) were on concomitant methotrexate. The primary outcome was the proportion of patients with satisfactory humoral response to inactivated pneumococcal 13-valent conjugate vaccine four weeks post-vaccination. Satisfactory humoral response to inactivated pneumococcal 13-valent conjugate vaccine was defined as ≥ 2-fold increase from baseline in antibody concentration to at least 6 of the 12 pneumococcal antigens (1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F). Results at Week 4 demonstrated a satisfactory humoral response in 67.5% (95% CI: 57.4, 77.5) and 56.5% (95% CI: 36.3, 76.8) of patients treated with upadacitinib 15 mg and 30 mg respectively.

Hypersensitivity reactions.

Serious hypersensitivity reactions such as anaphylaxis and angioedema were reported in patients receiving Rinvoq in clinical trials. If a clinically significant hypersensitivity reaction occurs, discontinue Rinvoq and institute appropriate therapy (see Section 4.8 Adverse Effects (Undesirable Effects)).

Gastrointestinal perforations.

Events of gastrointestinal perforations have been reported in clinical trials (see Section 4.8 Adverse Effects (Undesirable Effects), Specific adverse reactions) and from post-marketing sources. Rinvoq should be used with caution in patients who may be at risk for gastrointestinal perforation (e.g. patients with diverticular disease, a history of diverticulitis, or who are taking nonsteroidal anti inflammatory drugs (NSAIDs), corticosteroids, or opioids). Patients with active Crohn's disease are at increased risk for developing intestinal perforation. Patients presenting with new onset abdominal signs and symptoms should be evaluated promptly for early identification of gastrointestinal perforation.

Embryofetal toxicity.

Rinvoq may cause fetal harm based on animal studies. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception (see Section 4.6 Fertility, Pregnancy and Lactation).

Laboratory tests.

Neutropenia.

Treatment with Rinvoq was associated with an increased incidence of neutropenia (ANC < 1000 cells/mm3).
Evaluate neutrophil counts at baseline and thereafter according to routine patient management. Avoid initiation of or interrupt Rinvoq treatment in patients with a low neutrophil count (i.e. ANC less than 1000 cells/mm3) [see Section 4.2 Dose and Method of Administration].

Lymphopenia.

ALCs < 500 cells/mm3 were reported in Rinvoq clinical studies.
Evaluate lymphocyte counts at baseline and thereafter according to routine patient management. Avoid initiation of or interrupt Rinvoq treatment in patients with a low lymphocyte count (i.e. less than 500 cells/mm3) [see Section 4.2 Dose and Method of Administration].

Anaemia.

Decreases in haemoglobin levels to < 8 g/dL were reported in Rinvoq clinical studies.
Evaluate haemoglobin at baseline and thereafter according to routine patient management. Avoid initiation of or interrupt Rinvoq treatment in patients with a low haemoglobin level (i.e. less than 8 g/dL) [see Section 4.2 Dose and Method of Administration].

Lipids.

Treatment with Rinvoq was associated with increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol (see Section 4.8 Adverse Effects (Undesirable Effects)). Elevations in LDL cholesterol decreased to pre-treatment levels in response to statin therapy. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined.
Patients should be monitored 12 weeks after initiation of treatment and thereafter according to the international clinical guidelines for hyperlipidaemia.

Liver enzyme elevations.

Treatment with Rinvoq was associated with increased incidence of liver enzyme elevation compared to placebo.
Evaluate at baseline and thereafter according to routine patient management. Prompt investigation of the cause of liver enzyme elevation is recommended to identify potential cases of drug-induced liver injury.
If increases in ALT or AST are observed during routine patient management and drug-induced liver injury is suspected, Rinvoq should be interrupted until this diagnosis is excluded.

Use in hepatic impairment.

See Section 4.2 Dose and Method of Administration; Section 5 Pharmacological Properties.

Use in renal impairment.

See Section 4.2 Dose and Method of Administration; Section 5 Pharmacological Properties.

Paediatric use.

Atopic dermatitis.

The safety and efficacy of Rinvoq in adolescents weighing < 40 kg and in children aged 0 to less than 12 years have not yet been established. No data are available.

Rheumatoid arthritis, psoriatic arthritis, non-radiographic axial spondyloarthritis, ankylosing spondylitis, ulcerative colitis, Crohn's disease.

The safety and efficacy of Rinvoq in children and adolescents aged 0 to less than 18 years have not yet been established. No data are available.

Effects on laboratory tests.

No data suggest that Rinvoq will affect the function of any laboratory test.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Strong CYP3A4 inhibitors.

Upadacitinib exposure is increased when co-administered with strong CYP3A4 inhibitors (such as ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin and grapefruit). Rinvoq 15 mg once daily should be used with caution in patients receiving chronic treatment with strong CYP3A4 inhibitors. Rinvoq 30 mg once daily dose is not recommended for patients with atopic dermatitis receiving chronic treatment with strong CYP3A4 inhibitors. For patients with ulcerative colitis using strong CYP3A4 inhibitors, the recommended induction dose is 30 mg once daily (for up to 16 weeks) and the recommended maintenance dose is 15 mg once daily. For patients with Crohn's disease using strong CYP3A4 inhibitors, the recommended induction dose is 30 mg once daily and the recommended maintenance dose is 15 mg once daily.
Food or drink containing grapefruit should be avoided during treatment with upadacitinib.

Strong CYP3A4 inducers.

Upadacitinib exposure is decreased when co-administered with strong CYP3A4 inducers (such as rifampicin and phenytoin), which may lead to reduced therapeutic effect of Rinvoq. Patients should be monitored for changes in disease activity if Rinvoq is co-administered with strong CYP3A4 inducers.

Potential for other drugs to affect the pharmacokinetics of upadacitinib.

Upadacitinib is metabolised in vitro by CYP3A4 with a minor contribution from CYP2D6. The effect of co-administered drugs on upadacitinib plasma exposures is provided in Table 3.
Upadacitinib is a substrate of P-glycoprotein and BCRP. The clinical relevance of this is unknown.
Methotrexate, inhibitors of OATP1B transporters, and pH modifying medications (e.g. antacids or proton pump inhibitors) have no effect on upadacitinib plasma exposures. CYP2D6 metabolic phenotype had no effect on upadacitinib pharmacokinetics, indicating that inhibitors of CYP2D6 have no clinically relevant effect on upadacitinib exposures.

Potential for upadacitinib to affect the pharmacokinetics of other drugs.

In vitro studies indicate that upadacitinib does not inhibit the activity of cytochrome P450 (CYP) enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at clinically relevant concentrations. In vitro studies indicate that upadacitinib induces intestinal CYP3A4 but does not induce CYP2B6 or CYP1A2 at clinically relevant concentrations. In vitro studies indicate that upadacitinib does not inhibit the transporters P-gp, BCRP, BSEP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, and MATE2K at clinically relevant concentrations.
Clinical studies indicate that upadacitinib has no clinically relevant effects on the pharmacokinetics of co-administered drugs. Summary of results from clinical studies which evaluated the effect of upadacitinib on plasma exposures of other drugs is provided in Table 4.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Based on findings in rats, treatment with upadacitinib does not reduce fertility in males or females of reproductive potential.
Upadacitinib had no effect on fertility in male or female rats at doses up to 50 mg/kg/day in males and 75 mg/kg/day in females in a fertility and early embryonic development study, respectively (approximately 46 and 132 times the clinical dose of 15 mg, approximately 24 and 69 times the clinical dose of 30 mg, and 16 and 45 times the clinical dose of 45 mg on an AUC basis for males and females, respectively).
(Category D)
Rinvoq should not be used during pregnancy. There are limited human data on the use of upadacitinib in pregnant women. Based on findings in animal studies, Rinvoq may cause fetal harm when administered to a pregnant woman. Administration of upadacitinib to rats and rabbits during organogenesis caused increases in fetal malformations. Pregnant women should be advised of the potential risk to a fetus.
Advise females of reproductive potential that effective contraception should be used during treatment and for 4 weeks following the final dose of Rinvoq.
Upadacitinib crossed the placenta in both rats (significantly) and rabbits (to a lesser degree). Teratogenicity was seen in both species when pregnant animals received upadacitinib during the period of organogenesis. In rats, an increased incidence of skeletal malformations (misshapen humerus, bent scapula and bent bones of the fore- and hind-limbs) and variations (bent ribs) was seen at doses greater than or equal to 4 mg/kg/day. No adverse embryofetal effects were seen at 1.5 mg/kg/day (exposures below the AUC from a clinical dose of 15 mg, 30 mg or 45 mg). In rabbits, an increased incidence of fetal cardiac malformations (dilated aortic arch, discontinuous interventricular septum, constricted or smaller pulmonary trunk, absent pulmonary valve and a larger ventricle) was seen following maternal exposure to 25 mg/kg/day. Embryofetal lethality and abortions were also seen at this dose. Exposures at the no effect level were marginally above the AUC from a clinical dose of 15 mg, approximately the same as the AUC from a clinical dose of 30 mg, and below the AUC from a clinical dose of 45 mg (exposure margin is 0.8 times the exposure at 45 mg).
 It is unknown whether upadacitinib/metabolites are excreted in human milk. Data in animals have shown excretion of upadacitinib in milk. Following administration of upadacitinib to lactating rats, the concentrations of upadacitinib in milk over time was approximately 30-fold higher exposure in milk relative to maternal plasma. Approximately 97% of drug-related material in milk was parent drug.
A risk to newborns/infants cannot be excluded. Rinvoq should not be used during breast-feeding.

4.7 Effects on Ability to Drive and Use Machines

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

4.8 Adverse Effects (Undesirable Effects)

Adverse events reported in clinical trials.

Rheumatoid arthritis.

A total of 4443 patients with rheumatoid arthritis were treated with upadacitinib in clinical studies representing 5263 patient-years of exposure, of whom 2972 were exposed to upadacitinib for at least one year. In the Phase 3 studies, 2630 patients (2655.1 patient-years of drug exposure) received at least 1 dose of Rinvoq 15 mg, of whom 1607 were exposed for at least one year.
Three placebo-controlled studies were integrated (1035 patients on Rinvoq 15 mg once daily and 1042 patients on placebo) to evaluate the safety of Rinvoq 15 mg in combination with csDMARDs in comparison to placebo for up to 12/14 weeks after treatment initiation. Two methotrexate (MTX)-controlled studies were integrated (534 patients on Rinvoq 15 mg and 530 patients on MTX) to evaluate the safety of Rinvoq 15 mg as monotherapy in comparison to MTX monotherapy for up to 12/14 weeks (see Table 5).
Adverse drug reactions. The frequency of adverse reactions listed below is defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Infections and infestations.

Very common: upper respiratory tract infections (URTI)*.
Uncommon: pneumonia, herpes zoster, herpes simplex**, oral candidiasis.

Blood and lymphatic system disorders.

Common: neutropenia.

Metabolism and nutrition disorders.

Common: hypercholesterolemia.
Uncommon: hypertriglyceridemia.

Respiratory, thoracic and mediastinal disorders.

Common: cough.

Gastrointestinal disorders.

Common: nausea.

General disorders.

Common: pyrexia.

Investigations.

Common: blood creatine phosphokinase (CPK) increased, ALT increased, AST increased, weight increased.
* URTI includes: acute sinusitis, laryngitis, nasopharyngitis, oropharyngeal pain, pharyngitis, pharyngotonsillitis, rhinitis, sinusitis, tonsillitis, viral upper respiratory tract infection.
** Herpes simplex includes: oral herpes.
Specific adverse reactions.

Infections.

In placebo-controlled clinical studies with background DMARDs, the frequency of infection over 12/14 weeks in the Rinvoq 15 mg group was 27.4% compared to 20.9% in the placebo group. In MTX-controlled studies, the frequency of infection over 12/14 weeks in the Rinvoq 15 mg monotherapy group was 19.5% compared to 24.0% in the MTX group. The overall long-term rate of infections for the Rinvoq 15 mg group across all five Phase 3 clinical studies (2630 patients) was 93.7 events per 100 patient-years.
In placebo-controlled clinical studies with background DMARDs, the frequency of serious infection over 12/14 weeks in the Rinvoq 15 mg group was 1.2% compared to 0.6% in the placebo group. In MTX-controlled studies, the frequency of serious infection over 12/14 weeks in the Rinvoq 15 mg monotherapy group was 0.6% compared to 0.4% in the MTX group. The overall long-term rate of serious infections for the Rinvoq 15 mg group across all five Phase 3 clinical studies was 3.8 events per 100 patient-years. The most frequently reported serious infections were pneumonia and cellulitis. The rate of serious infections remained stable with long-term exposure.
There was a higher rate of serious infections in patients ≥ 75 years of age, although data are limited.
The frequencies of infection Adverse Drug Reactions (ADRs) for upadacitinib compared to placebo were: URTI (13.5% vs 9.5%), pneumonia (0.5% vs 0.3%), herpes zoster (0.7% vs 0.2%), herpes simplex (0.8% vs 0.5%), and oral candidiasis (0.4% vs < 0.1%). Most of the herpes zoster events involved a single dermatome and were non-serious.

Tuberculosis.

In placebo-controlled clinical studies with background DMARDs, there were no active cases of TB reported in any treatment group. In MTX-controlled studies, there were no cases over 12/14 weeks in either the Rinvoq 15 mg monotherapy group or the MTX group. The overall long-term rate of active TB for the Rinvoq 15 mg group across all five Phase 3 clinical studies was 0.1 events per 100 patient-years.

Opportunistic infections (excluding tuberculosis).

In placebo-controlled clinical studies with background DMARDs, the frequency of opportunistic infections over 12/14 weeks in the Rinvoq 15 mg group was 0.5% compared to 0.3% in the placebo group. In MTX-controlled studies, there were no cases of opportunistic infection over 12/14 weeks in the Rinvoq 15 mg monotherapy group and 0.2% in the MTX group. The overall long-term rate of opportunistic infections for the Rinvoq 15 mg group across all five Phase 3 clinical studies was 0.6 events per 100 patient-years.

Malignancy.

In placebo-controlled clinical studies with background DMARDs, the frequency of malignancies excluding NMSC over 12/14 weeks in the Rinvoq 15 mg group was < 0.1% compared to < 0.1% in the placebo group. In MTX-controlled studies, the frequency of malignancies excluding NMSC over 12/14 weeks in the Rinvoq 15 mg monotherapy group was 0.6% compared to 0.2% in the MTX group. The overall long-term incidence rate of malignancies excluding NMSC for the Rinvoq 15 mg group in the clinical trial program was 0.8 per 100 patient-years.

Gastrointestinal perforations.

In placebo-controlled clinical studies with background DMARDs, the frequency of gastrointestinal perforations in the Rinvoq 15 mg group was 0.2% compared to 0% in the placebo group. In MTX-controlled studies, there were no gastrointestinal perforations over 12/14 weeks in either the Rinvoq 15 mg monotherapy group or the MTX group. The overall long-term rate of gastrointestinal perforation for the Rinvoq 15 mg group across all five Phase 3 clinical studies was 0.08 events per 100 patient-years.

Thrombosis.

In placebo-controlled studies with background DMARDs, there were two (0.2%) venous thrombosis events (pulmonary embolism or deep vein thrombosis) in the Rinvoq 15 mg group compared to one event (0.1%) in the placebo group. In MTX-controlled studies, there was one venous thrombosis event (0.2%) over 12/14 weeks in the Rinvoq 15 mg monotherapy group and there were no events in the MTX group. The overall long-term incidence rate of venous thrombosis events for the Rinvoq 15 mg group across all five Phase 3 clinical studies was 0.6 per 100 patient-years.

Hepatic transaminase elevations.

In placebo-controlled studies with background DMARDs, for up to 12/14 weeks, alanine transaminase (ALT) and aspartate transaminase (AST) elevations ≥ 3 x upper limit of normal (ULN) in at least one measurement were observed in 2.1% and 1.5% of patients treated with Rinvoq 15 mg, compared to 1.5% and 0.7%, respectively, of patients treated with placebo. Most cases of hepatic transaminase elevations were asymptomatic and transient.
In MTX-controlled studies, for up to 12/14 weeks, ALT and AST elevations ≥ 3 x ULN in at least one measurement were observed in 0.8% and 0.4% of patients treated with Rinvoq 15 mg, compared to 1.9% and 0.9%, respectively, of patients treated with MTX.
The pattern and incidence of elevation in ALT/AST remained stable over time including in long-term extension studies.

Lipid elevations.

Upadacitinib 15 mg treatment was associated with dose-dependent increases in lipid parameters including total cholesterol, triglycerides, LDL cholesterol and HDL cholesterol. There was no change in the LDL/HDL ratio. Elevations were observed at 2 to 4 weeks of treatment and remained stable with longer-term treatment. Among patients in controlled studies with baseline values below the specified limits, the following frequencies of patients were observed to shift above the specified limits on at least one occasion during 12/14 weeks (including patients who had an isolated elevated value):
Total cholesterol ≥ 5.17 mmol/L (200 mg/dL): 62% vs. 31%, in the upadacitinib 15 mg and placebo groups, respectively.
LDL cholesterol ≥ 3.36 mmol/L (130 mg/dL): 42% vs. 19%, in the upadacitinib 15 mg and placebo groups, respectively.
HDL cholesterol ≥ 1.03 mmol/L (40 mg/dL): 89% vs. 61%, in the upadacitinib 15 mg and placebo groups, respectively.
Triglycerides ≥ 2.26 mmol/L (200 mg/dL): 25% vs. 15%, in the upadacitinib 15 mg and placebo groups, respectively.

Creatine phosphokinase elevations.

In placebo-controlled studies with background DMARDs, for up to 12/14 weeks, increases in creatine phosphokinase (CPK) values were observed. CPK elevations > 5 x ULN were reported in 1.0%, and 0.3% of patients over 12/14 weeks in the Rinvoq 15 mg and placebo groups, respectively. Most elevations > 5 x ULN were transient and did not require treatment discontinuation. Mean CPK values increased by 4 weeks with a mean increase of 60 U/L at 12 weeks and then remained stable at an increased value thereafter including with extended therapy.

Neutropenia.

In placebo-controlled studies with background DMARDs, for up to 12/14 weeks, decreases in neutrophil counts, below 1000 cells/mm3 in at least one measurement occurred in 1.1% and < 0.1% of patients in the Rinvoq 15 mg and placebo groups, respectively. In clinical studies, treatment was interrupted in response to ANC < 1000 cells/mm3. The pattern and incidence of decreases in neutrophil counts remained stable at a lower value than baseline over time including with extended therapy.

Lymphopenia.

In placebo-controlled studies with background DMARDs, for up to 12/14 weeks, decreases in lymphocyte counts below 500 cells/mm3 in at least one measurement occurred in 0.9% and 0.7% of patients in the Rinvoq 15 mg and placebo groups, respectively.

Anaemia.

In placebo-controlled studies with background DMARDs, for up to 12/14 weeks, haemoglobin decreases below 8 g/dL in at least one measurement occurred in < 0.1% of patients in both the Rinvoq 15 mg and placebo groups.

Psoriatic arthritis.

A total of 1827 patients with psoriatic arthritis were treated with upadacitinib in clinical studies representing 1639.2 patient-years of exposure, of whom 722 were exposed to upadacitinib for at least one year. In the Phase 3 studies, 907 patients received at least 1 dose of Rinvoq 15 mg, of whom 359 were exposed for at least one year.
Two placebo-controlled studies were integrated (640 patients on Rinvoq 15 mg once daily and 635 patients on placebo) to evaluate the safety of Rinvoq 15 mg in comparison to placebo for up to 24 weeks after treatment initiation.
Overall, the safety profile observed in patients with active psoriatic arthritis treated with Rinvoq 15 mg was consistent with the safety profile observed in patients with rheumatoid arthritis. During the 24-week placebo-controlled period, the frequencies of herpes zoster and herpes simplex were > 1% (1.1% and 1.4%, respectively) with Rinvoq 15 mg and 0.8% and 1.3%, respectively, with placebo. A higher incidence of acne and bronchitis was also observed in patients treated with Rinvoq 15 mg (1.3% and 3.9%, respectively) compared to placebo (0.3% and 2.7%, respectively).

Non-radiographic axial spondyloarthritis.

A total of 286 patients with non-radiographic axial spondyloarthritis were treated with Rinvoq 15 mg in the clinical study representing 269.4 patient-years of exposure, of whom 134 were exposed to Rinvoq 15 mg for at least one year.
Overall, the safety profile observed in patients with active non-radiographic axial spondyloarthritis treated with Rinvoq 15 mg was consistent with the safety profile observed in patients with rheumatoid arthritis. No new safety findings were identified.

Ankylosing spondylitis.

A total of 596 patients with ankylosing spondylitis were treated with Rinvoq 15 mg in the two clinical studies representing 843 patient-years of exposure, of whom 490 were exposed to Rinvoq 15 mg for at least one year.
Overall, the safety profile observed in patients with active ankylosing spondylitis treated with Rinvoq 15 mg was consistent with the safety profile observed in patients with rheumatoid arthritis. No new safety findings were identified.

Atopic dermatitis.

A total of 2893 patients with atopic dermatitis were treated with upadacitinib in clinical studies representing approximately 2096 patient-years of exposure, of whom 614 were exposed to at least one year. In the three global Phase 3 studies, 1238 patients received at least 1 dose of Rinvoq 15 mg, of whom 246 were exposed for at least one year and 1242 patients received at least 1 dose of Rinvoq 30 mg, of whom 263 were exposed for at least one year.
Four global placebo-controlled studies (one Phase 2 study and three Phase 3 studies) were integrated (899 patients on Rinvoq 15 mg once daily, 906 patients on Rinvoq 30 mg once daily and 902 patients on placebo) to evaluate the safety of Rinvoq 15 mg and 30 mg in comparison to placebo for up to 16 weeks after treatment initiation (see Table 6).
The adverse reactions listed below are uncommon (≥ 1/1,000 to < 1/100). Within each grouping, undesirable effects are presented in order of decreasing seriousness.

Infections and infestations.

Uncommon: pneumonia, oral candidiasis.

Neoplasms benign, malignant and unspecified (including cysts and polyps).

Uncommon: non-melanoma skin cancer***.

Metabolism and nutrition disorders.

Uncommon: hypercholesterolemia, hypertriglyceridemia.

Investigations.

Uncommon: ALT increased, AST increased.
*** Presented as a grouped term.
The safety profile of Rinvoq with long term treatment was similar to the safety profile observed at Week 16.
Specific adverse reactions.

Infections.

In placebo-controlled clinical studies, the frequency of infection over 16 weeks in the Rinvoq 15 mg and 30 mg groups was 39% and 43% respectively, compared to 30% in the placebo group. The long-term rate of infections for the Rinvoq 15 mg and 30 mg groups was 123.7 and 139.1 events per 100 patient-years, respectively.
In placebo-controlled clinical studies, the frequency of serious infection over 16 weeks in the Rinvoq 15 mg and 30 mg groups were 0.8% and 0.4% respectively, compared to 0.6% in the placebo group. The long-term rate of serious infections for the Rinvoq 15 mg and 30 mg groups was 2.4 and 3.4 events per 100 patient-years, respectively. The most frequently reported serious infection was pneumonia.

Tuberculosis.

In placebo-controlled clinical studies over 16 weeks, there were no active cases of tuberculosis reported in any treatment group. The overall long-term rate of tuberculosis for both the Rinvoq 15 mg and 30 mg groups was 0.1 events per 100 patient-years.

Opportunistic infections (excluding tuberculosis).

All opportunistic infections (excluding tuberculosis and herpes zoster) reported in the global atopic dermatitis studies were eczema herpeticum. In placebo-controlled clinical studies, the frequency of eczema herpeticum over 16 weeks in the Rinvoq 15 mg and 30 mg groups was 0.7% and 0.8% respectively, compared to 0.4% in the placebo group. The long-term rate of eczema herpeticum for the Rinvoq 15 mg and 30 mg groups was 2.1 and 2.2 events per 100 patient-years, respectively.
The long-term rate of herpes zoster for the Rinvoq 15 mg and 30 mg groups was 3.8 and 5.3 events per 100 patient-years, respectively. Most of the herpes zoster events involved a single dermatome and were non-serious.

Malignancy.

In placebo-controlled clinical studies, the frequency of malignancies excluding NMSC over 16 weeks in the Rinvoq 15 mg and 30 mg groups was 0% and 0.4%, respectively, compared to 0% in the placebo group. The long-term incidence rate of malignancies excluding NMSC for the Rinvoq 15 mg and 30 mg groups was 0 and 0.7 per 100 patient years, respectively.

Gastrointestinal perforations.

There were no cases of gastrointestinal perforations reported in any treatment group.

Thrombosis.

In placebo-controlled studies over 16 weeks, there were no venous thrombosis events (pulmonary embolism or deep vein thrombosis) in the Rinvoq 15 mg and 30 mg groups compared to 1 event (0.1%) in the placebo group. The long-term incidence rate of venous thrombosis for Rinvoq treatment across the atopic dermatitis clinical studies was < 0.1 per 100 patient-years.

Hepatic transaminase elevations.

In placebo-controlled studies, for up to 16 weeks, alanine transaminase (ALT) ≥ 3 x upper limit of normal (ULN) in at least one measurement were observed in 0.7%, 1.4% and 1.1% of patients treated with Rinvoq 15 mg, 30 mg and placebo, respectively. In these trials, aspartate transaminase (AST) elevations ≥ 3 x upper limit of normal (ULN) in at least one measurement were observed in 1.2%, 1.1% and 0.9% of patients treated with Rinvoq 15 mg, 30 mg and placebo, respectively. Most cases of hepatic transaminase elevations were asymptomatic and transient. The pattern and incidence of elevation in ALT/AST remained stable over time including in long-term extension studies.

Lipid elevations.

Rinvoq 15 mg and 30 mg treatment was associated with dose-dependent increases in lipid parameters including total cholesterol, LDL cholesterol and HDL cholesterol. Among patients in the controlled studies with baseline values below the specified limits, the following frequencies of patients were observed to shift to above the specified limits on at least one occasion during 16 weeks (including patients who had an isolated elevated value):
Total cholesterol ≥ 5.17 mmol/L (200 mg/dL): 43.0%, 49.1% and 24.7% in the upadacitinib 15 mg, 30 mg, and placebo groups, respectively.
LDL cholesterol ≥ 3.36 mmol/L (130 mg/dL): 28.1%, 31.6% and 18.9% in the upadacitinib 15 mg, 30 mg, and placebo groups, respectively.
HDL cholesterol ≥ 1.03 mmol/L (40 mg/dL): 90.7%, 93.1% and 69.7% in the upadacitinib 15 mg, 30 mg, and placebo groups, respectively.
Triglycerides ≥ 2.26 mmol/L (200 mg/dL): 19.2%, 19.7% and 17.7% in the upadacitinib 15 mg, 30 mg, and placebo groups, respectively.
Small increases in LDL cholesterol were observed after Week 16.

Creatine phosphokinase elevations.

In placebo-controlled studies, for up to 16 weeks, dose-related increases in creatine phosphokinase (CPK) values were observed. CPK elevations > 5 x ULN were reported in 3.3%, 4.4% and 1.7% of patients over 16 weeks in the Rinvoq 15 mg, 30 mg and placebo groups, respectively. Most elevations > 5 x ULN were transient and did not require treatment discontinuation.

Neutropenia.

In placebo-controlled studies, for up to 16 weeks, dose-related decreases in neutrophil counts, below 1000 cells/mm3 in at least one measurement occurred in 0.4%, 1.3% and 0% of patients in the Rinvoq 15 mg, 30 mg and placebo groups, respectively. In clinical studies, treatment was interrupted in response to ANC < 1000 cells/mm3. The pattern and incidence of decreases in neutrophil counts remained stable at a lower value than baseline over time including with extended therapy.

Lymphopenia.

In placebo-controlled studies, for up to 16 weeks, decreases in lymphocyte counts below 500 cells/mm3 in at least one measurement occurred in 0.1%, 0.3% and 0.1% of patients in the Rinvoq 15 mg, 30 mg and placebo groups, respectively.

Anaemia.

In placebo-controlled studies, haemoglobin decreases below 8 g/dL in at least one measurement occurred in 0%, 0.1% and 0% of patients in the Rinvoq 15 mg, 30 mg and placebo groups, respectively.

Paediatric population.

A total of 343 adolescents aged 12 to 17 years weighing at least 40 kg with atopic dermatitis were enrolled in the Phase 3 studies. The safety profile for Rinvoq 15 mg was similar in adolescents and adults.

Ulcerative colitis.

Rinvoq has been studied in patients with moderately to severely active UC in one phase 2b and three phase 3 (UC-1, UC-2 and UC-3) randomised, double-blind, placebo-controlled clinical studies and a long-term extension study (see Section 5 Pharmacological Properties, Ulcerative colitis) with a total of 1304 patients representing 1821 patient-years of exposure, of whom a total of 721 patients were exposed for at least one year.
In the induction studies (phase 2b, UC-1, and UC-2), 719 patients received at least one dose of Rinvoq 45 mg, of whom 513 were exposed for 8 weeks and 127 subjects were exposed for up to 16 weeks (Table 7).
In the maintenance study UC-3 and the long-term extension study, 285 patients received at least one dose of Rinvoq 15 mg, of whom 131 were exposed for at least one year and 291 patients received at least one dose of Rinvoq 30 mg, of whom 137 were exposed for at least one year (Table 8).
Induction studies (phase 2b, UC-1, UC-2). See Table 7.
Maintenance study (UC-3). See Table 8.
Adverse drug reactions. The frequency of adverse reactions listed below is defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Infections and infestations.

Very common: upper respiratory tract infections (URTI)*.
Common: herpes zoster*, folliculitis, influenza, herpes simplex*.
Uncommon: pneumonia*.

Blood and lymphatic system disorders.

Common: neutropenia*, lymphopenia*.

Metabolism and nutrition disorders.

Common: hypercholesterolemia*, hyperlipidemia*.

Skin and subcutaneous tissue disorders.

Common: acne*, rash*.

General disorders.

Common: pyrexia.

Investigations.

Common: blood creatine phosphokinase (CPK) increased, ALT increased, AST increased.
* Presented as grouped term.
Specific adverse reactions.

Infections.

In the placebo-controlled induction studies, the frequency of infection over 8 weeks in the Rinvoq 45 mg group and the placebo group was 20.7% and 17.5%, respectively. In the placebo-controlled maintenance study, the frequency of infection over 52 weeks in the Rinvoq 15 mg and 30 mg groups was 38.4% and 40.6%, respectively, and 37.6% in the placebo group. The long-term rate of infection for Rinvoq 15 mg and 30 mg was 73.8 and 82.6 events per 100 patient-years, respectively.

Serious infections.

In the placebo-controlled induction studies, the frequency of serious infection over 8 weeks in the Rinvoq 45 mg group and the placebo group was 1.3% and 1.3%, respectively. No additional serious infections were observed over 8-week extended induction treatment with Rinvoq 45 mg. In the placebo-controlled maintenance study, the frequency of serious infection over 52 weeks in the Rinvoq 15 mg and 30 mg groups was 3.2%, and 2.4%, respectively, and 3.3% in the placebo group. The long-term rate of serious infection for the Rinvoq 15 mg and 30 mg groups was 4.1 and 3.9 events per 100 patient-years, respectively. The most frequently reported serious infection in the ulcerative colitis studies was COVID-19 pneumonia.

Tuberculosis.

In the clinical studies for ulcerative colitis, there was 1 case of active tuberculosis reported in a patient receiving Rinvoq 15 mg during the long-term extension study.

Opportunistic infections (excluding tuberculosis).

In the placebo-controlled induction studies over 8 weeks, the frequency of opportunistic infection (excluding tuberculosis and herpes zoster) in the Rinvoq 45 mg group was 0.4% and 0.3% in the placebo group. No additional opportunistic infections (excluding tuberculosis and herpes zoster) were observed over the 8-week extended induction treatment with Rinvoq 45 mg. In the placebo-controlled maintenance study over 52 weeks, the frequency of opportunistic infection (excluding tuberculosis and herpes zoster) in the Rinvoq 15 mg and 30 mg groups was 0.8% and 0.4%, respectively, and 0.8% in the placebo group. The long-term rate of opportunistic infection (excluding tuberculosis and herpes zoster) for the Rinvoq 15 mg and 30 mg groups was 0.6 and 0.3 events per 100 patient-years, respectively.
In the placebo-controlled induction studies over 8 weeks, the frequency of herpes zoster in the Rinvoq 45 mg group was 0.6% and 0% in the placebo group. The frequency of herpes zoster was 3.9% over 16-week treatment with Rinvoq 45 mg. In the placebo controlled maintenance study over 52 weeks, the frequency of herpes zoster in the Rinvoq 15 mg and 30 mg groups was 4.4% and 4.0%, respectively, compared to 0% in the placebo group. The long term rate of herpes zoster for the Rinvoq 15 mg and 30 mg groups was 5.7 and 6.3 events per 100 patient-years, respectively.

Malignancy.

In the placebo-controlled induction studies, there were no reports of malignancy. In the placebo-controlled maintenance study, the frequency of malignancies excluding non-melanoma skin cancer (NMSC) in the Rinvoq 15 mg and 30 mg groups was 0.4%, 0.8%, respectively, and 0.4% in the placebo group. The long-term incidence rate of malignancies excluding NMSC for the Rinvoq 15 mg and 30 mg groups was 0.3 and 1.0 per 100 patient years, respectively.

Gastrointestinal perforations.

In the clinical studies for ulcerative colitis, there was 1 case of gastrointestinal perforation reported in a patient receiving Rinvoq 15 mg during the long-term extension study.

Thrombosis.

In the placebo-controlled induction studies, the frequency of venous thrombosis (pulmonary embolism or deep vein thrombosis) over 8 weeks in the Rinvoq 45 mg group was 0.1% and 0.3% in the placebo group, respectively. No additional events of venous thrombosis were reported with Rinvoq 45 mg extended induction treatment. In the placebo-controlled maintenance study, the frequency of venous thrombosis over 52 weeks in the Rinvoq 15 mg and 30 mg groups was 0.8% and 0.8%, respectively, and 0% in the placebo group. The long-term incidence rate of venous thrombosis for Rinvoq 15 mg and 30 mg was 1.0 and 0.7 per 100 patient-years, respectively.

Hepatic transaminase elevations.

In the placebo-controlled induction studies over 8 weeks, alanine transaminase (ALT) and aspartate transaminase (AST) elevations ≥ 3 x upper limit of normal (ULN) in at least one measurement were observed in 1.5% and 1.5% of patients treated with Rinvoq 45 mg and 0% and 0.3% with placebo, respectively. In the placebo-controlled maintenance study over 52 weeks, ALT elevations ≥ 3 x ULN in at least one measurement were observed in 2.0% and 4.0% of patients treated with Rinvoq 15 mg and 30 mg and 0.8% with placebo, respectively. AST elevations ≥ 3 x ULN in at least one measurement were observed in 1.6% and 2.0% of patients treated with Rinvoq 15 mg and 30 mg and 0.4% with placebo, respectively. Most cases of hepatic transaminase elevations were asymptomatic and transient. The pattern and incidence of ALT/AST elevations remained generally stable over time including in long-term extension studies.

Lipid elevations.

Rinvoq treatment was associated with increases in lipid parameters including total cholesterol, LDL cholesterol, and HDL cholesterol in placebo-controlled induction and maintenance studies over 8 and 52 weeks, respectively. Changes from baseline in lipid parameters are summarised below:
Total cholesterol ≥ 5.17 mmol/L (200 mg/dL): 49% vs. 11%, in the Rinvoq 45 mg and placebo groups, respectively.
LDL cholesterol ≥ 3.36 mmol/L (130 mg/dL): 27% vs. 9%, in the Rinvoq 45 mg and placebo groups, respectively.
HDL cholesterol ≥ 1.03 mmol/L (40 mg/dL): 79% vs. 36%, in the Rinvoq 45 mg and placebo groups, respectively.
Triglycerides ≥ 2.26 mmol/L (200 mg/dL): 6% vs 4% in the Rinvoq 45 mg and placebo groups, respectively.

Creatine phosphokinase elevations.

In the placebo-controlled induction studies over 8 weeks, increases in creatine phosphokinase (CPK) values were observed. CPK elevations > 5 x ULN were reported in 2.2% and 0.3% of patients in the Rinvoq 45 mg and placebo groups, respectively. In the placebo-controlled maintenance study over 52 weeks, CPK elevations > 5 x ULN were reported in 4.0% and 6.4% of patients in the Rinvoq 15 mg and 30 mg groups and 1.2% in the placebo group, respectively. Most elevations > 5 x ULN were transient and did not require treatment discontinuation.

Neutropenia.

In the placebo-controlled induction studies over 8 weeks, decreases in neutrophil counts below 1000 cells/mm3 in at least one measurement occurred in 2.8% of patients in the Rinvoq 45 mg group and 0% in the placebo group, respectively. In the placebo-controlled maintenance study over 52 weeks, decreases in neutrophil counts below 1000 cells/mm3 in at least one measurement occurred in 0.8% and 2.4% of patients in the Rinvoq 15 mg and 30 mg groups and 0.8% in the placebo group, respectively.

Lymphopenia.

In the placebo-controlled induction studies over 8 weeks, decreases in lymphocyte counts below 500 cells/mm3 in at least one measurement occurred in 2.0% of patients in the Rinvoq 45 mg group and 0.8% in the placebo group. In the placebo-controlled maintenance study over 52 weeks, decreases in lymphocyte counts below 500 cells/mm3 in at least one measurement occurred in 1.6% and 0.8% of patients in the Rinvoq 15 mg and 30 mg groups and to 0.8% in the placebo group, respectively.

Anaemia.

In the placebo-controlled induction studies over 8 weeks, hemoglobin decreases below 8 g/dL in at least one measurement occurred in 0.3% of patients in the Rinvoq 45 mg group and 2.1% in the placebo group. In the placebo-controlled maintenance study over 52 weeks, hemoglobin decreases below 8 g/dL in at least one measurement occurred in 0.4% and 0.4% of patients in the Rinvoq 15 mg and 30 mg groups and 1.2% in the placebo group, respectively.

Crohn's disease.

Rinvoq has been studied in patients with moderately to severely active Crohn's disease (CD) in three Phase 3 (CD-1, CD-2, and CD-3) randomised, double-blind, placebo-controlled clinical studies (see Clinical studies) with a total of 833 patients included in two induction studies and in the maintenance/ long term extension study (LTE) representing 1203 patient-years of exposure, of whom a total of 536 patients were exposed for at least one year starting with the dose of induction treatment.
In the induction studies (CD-1 and CD-2), 674 patients received at least one dose of Rinvoq 45 mg during the placebo-controlled period, of whom 592 were exposed for 12 weeks and 142 patients received at least one dose of Rinvoq 30 mg during the extended treatment period. See Table 9.
In the maintenance study CD-3, 221 patients were re-randomised and received at least one dose of Rinvoq 15 mg, of whom 89 were exposed for at least one year and 229 patients were re-randomised and received at least one dose of Rinvoq 30 mg, of whom 107 were exposed for at least one year starting with the first dose of maintenance treatment. See Table 10.
Overall, the safety profile observed in patients with CD treated with Rinvoq was consistent with the known safety profile of Rinvoq.
Maintenance Study (CD-3). See Table 10.
Adverse drug reactions. The frequency of adverse reactions listed below is defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Infections and infestations.

Very common: upper respiratory tract infections (URTI)*.
Common: bronchitis*, herpes zoster*, folliculitis, influenza, herpes simplex*, pneumonia*.
Uncommon: oral candidiasis.

Neoplasms benign, malignant and unspecified (including cysts and polyps).

Uncommon: non-melanoma skin cancer*.

Blood and lymphatic system disorders.

Common: neutropenia*, anaemia*.

Metabolism and nutrition disorders.

Common: hypercholesterolemia*, hyperlipidemia*.

Skin and subcutaneous tissue disorders.

Common: acne*.

General disorders.

Common: pyrexia, fatigue.

Investigations.

Common: blood creatine phosphokinase (CPK) increased, ALT increased, AST increased.

Nervous system disorders.

Common: headache*.
* Presented as grouped term.
Specific adverse reactions.

Serious infections.

In the placebo-controlled induction studies, the frequency of serious infection over 12 weeks in the upadacitinib 45 mg group and the placebo group was 1.9% and 1.7%, respectively. In the placebo-controlled maintenance period, the frequency of serious infection over 52 weeks in the upadacitinib 15 mg and 30 mg groups was 3.2% and 5.7%, respectively, compared to 4.5% in the placebo group. The long-term rate of serious infections for the upadacitinib 15 mg and 30 mg groups in patients who responded to upadacitinib 45 mg as induction treatment was 5.1 and 7.3 events per 100 patient-years, respectively. The most frequently reported serious infection in the induction and maintenance studies was gastrointestinal infections.

Malignancy.

In the placebo-controlled induction studies, there were no reports of malignancy. In the placebo-controlled maintenance period, the frequency of malignancies excluding non-melanoma skin cancer (NMSC) in the Rinvoq 15 mg and 30 mg groups was 0.5%, 1.7%, respectively, and 0.4% in the placebo group. The long-term incidence rate of malignancies excluding NMSC for Rinvoq 15 mg and 30 mg in patients who responded to upadacitinib 45 mg as induction treatment was 0.4 and 1.2 per 100 patient years, respectively.

Gastrointestinal perforations.

During the placebo-controlled period in the Phase 3 induction clinical studies, gastrointestinal perforation was reported in 1 patient (0.1%) treated with Rinvoq 45 mg and no patients on placebo through 12 weeks. In all patients treated with Rinvoq 45 mg (n = 938) during the induction studies, gastrointestinal perforation was reported in 4 patients (0.4%).
In the long-term placebo-controlled maintenance period, gastrointestinal perforation was reported in 1 patient each treated with placebo (0.7 per 100 patient-years), Rinvoq 15 mg (0.4 per 100 patient-years), and Rinvoq 30 mg (0.4 per 100 patient-years). In all patients treated with rescue Rinvoq 30 mg (n = 336), gastrointestinal perforation was reported in 3 patients (0.8 per 100 patient-years) through long-term treatment.

Thrombosis.

In the induction studies, there were no reports of venous thrombosis (pulmonary embolism or deep vein thrombosis) in patients receiving placebo and Rinvoq 45 mg treatment. In the placebo-controlled maintenance period, the frequency of venous thrombosis over 52 weeks in the Rinvoq 15 mg and 30 mg groups was 0% and 0.4%, respectively, and 0% in the placebo group. The long-term incidence rate of venous thrombosis for Rinvoq 15 mg and 30 mg in patients who responded to upadacitinib 45 mg as induction treatment was 0 and 0.6 per 100 patient-years, respectively.

Laboratory abnormalities.

In the induction and maintenance clinical studies, the laboratory changes in ALT increased and/or AST increased (≥ 3 x ULN), CPK values (> 5 x ULN), neutropaenia (ANC < 1 x 109 cells/L), and lipid parameters associated with upadacitinib treatment were generally similar to what was observed in the rheumatologic disease, atopic dermatitis and ulcerative colitis clinical studies. Dose-dependent changes for these laboratory parameters associated with 15 mg and 30 mg upadacitinib treatment were observed.
In the placebo-controlled induction studies for up to 12 weeks, decreases in lymphocyte counts below 0.5 x 109 cells/L in at least one measurement occurred in 2.2% and 2.0% of patients in the upadacitinib 45 mg and placebo groups, respectively. In the placebo-controlled maintenance study, for up to 52 weeks, decreases in lymphocyte counts below 0.5 x 109 cells/L in at least one measurement occurred in 4.6%, 5.2% and 1.8% of patients in the upadacitinib 15 mg, 30 mg and placebo groups, respectively. In clinical studies, treatment was interrupted in response to ALC < 0.5 x 109 cells/L (see Section 4.2). No notable mean changes of lymphocyte counts were observed during upadacitinib treatment over time.
In the placebo-controlled induction studies for up to 12 weeks, decreases in haemoglobin concentration to below 8 g/dL in at least one measurement occurred in 2.7% and 1.4% of patients in the upadacitinib 45 mg and placebo groups, respectively. In the placebo-controlled maintenance study, for up to 52 weeks, decreases in haemoglobin concentration below 8 g/dL in at least one measurement occurred in 1.4%, 4.4% and 2.8% of patients in the upadacitinib 15 mg, 30 mg and placebo groups, respectively. In clinical studies, treatment was interrupted in response to Hb < 8 g/dL (see Section 4.2). No notable mean changes of haemoglobin concentration were observed during upadacitinib treatment over time.

Post marketing experience.

The following adverse reactions have been identified during post-approval use of Rinvoq. Because 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.

Infections and infestations.

Diverticulitis.

Immune system disorders.

Hypersensitivity.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Upadacitinib was administered in clinical trials up to doses equivalent in daily AUC to 60 mg modified release once daily. Adverse events were comparable to those seen at lower doses and no specific toxicities were identified. Approximately 90% of upadacitinib in the systemic circulation is eliminated within 24 hours of dosing (within the range of doses evaluated in clinical studies). In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions. Patients who develop adverse reactions should receive appropriate treatment.
For information on the management of overdose in Australia contact the Poisons Information Centre on 131126.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC code: L04AA44.

Mechanism of action.

Janus Kinases (JAKs) are important intracellular enzymes that transmit cytokine or growth factor signals involved in a broad range of cellular processes including inflammatory responses, haematopoiesis and immune surveillance. The JAK family of enzymes contains four members, JAK1, JAK2, JAK3 and TYK2 which work in pairs to phosphorylate and activate signal transducers and activators of transcription (STATs). This phosphorylation, in turn, modulates gene expression and cellular function. JAK1 is important in inflammatory cytokine signals while JAK2 is important for red blood cell maturation and JAK3 signals play a role in immune surveillance and lymphocyte function.
Upadacitinib is a selective and reversible inhibitor of JAK1. Upadacitinib more potently inhibits JAK1 compared to JAK2 and JAK3. In cellular potency assays that correlated with the in vivo pharmacodynamic responses, upadacitinib demonstrated 33-197-fold greater selectivity for JAK1-associated signalling over JAK2-JAK2 signalling. In enzyme assays, upadacitinib had > 50-fold selectivity for JAK1 over JAK3. Atopic dermatitis pathogenesis is driven by pro-inflammatory cytokines (including IL-4, IL-13, IL-22, TSLP, IL-31 and IFN-γ) that transduce signals via the JAK1 pathway. Inhibiting JAK1 with upadacitinib reduces the signaling of many mediators which drive the signs and symptoms of atopic dermatitis such as eczematous skin lesions and pruritus.
Pro-inflammatory cytokines (including IL-5, IL-7, IL-9, and IL-13) in ulcerative colitis and IL-2, IL-6, IL-7, IL-15, IL-21 and interferon gamma in Crohn's disease) transduce signals via the JAK1 pathway and are involved in pathology of inflammatory bowel disease. JAK1 inhibition with upadacitinib modulates the signalling of the JAK-dependent cytokines underlying the inflammatory burden and signs and symptoms of inflammatory bowel diseases.

Pharmacodynamics.

Inhibition of IL-6 induced STAT3 and IL-7 induced STAT5 phosphorylation.

In healthy volunteers, the administration of upadacitinib (immediate release formulation) resulted in a dose- and concentration-dependent inhibition of IL-6 (JAK1/JAK2)-induced STAT3 and IL-7 (JAK1/JAK3)-induced STAT5 phosphorylation in whole blood. The maximal inhibition was observed 1 hour after dosing which returned to near baseline by the end of dosing interval.

Lymphocytes.

In patients treated with rheumatoid arthritis, treatment with upadacitinib was associated with a small, transient increase in mean ALC from baseline up to Week 36 which gradually returned to, at or near baseline levels with continued treatment.

Immunoglobulins.

In patients with rheumatoid arthritis, small decreases from baseline in mean IgG and IgM levels were observed with upadacitinib treatment in the controlled period; however, the mean values at baseline and at all visits were within the normal reference range.

High-sensitivity (hs) CRP and other markers of inflammation.

In patients with rheumatoid arthritis, treatment with upadacitinib was associated with significant decreases from baseline in mean hsCRP levels as early as Week 1 which were maintained with continued treatment.
In patients with Crohn's disease, reductions in hsCRP and fecal calprotectin (FCP) were observed after treatment with upadacitinib. Decreases in hsCRP and FCP were maintained out to Week 52 in the maintenance study.

Cardiac electrophysiology.

The effect of upadacitinib on QTc interval was evaluated in subjects who received single and multiple doses of upadacitinib. Upadacitinib does not prolong QTc interval at therapeutic or supratherapeutic plasma concentrations.

Clinical trials.

Rheumatoid arthritis.

The efficacy and safety of Rinvoq 15 mg once daily was assessed in five, Phase 3 randomised, double-blind, multicentre studies in patients with moderately to severely active rheumatoid arthritis and fulfilling the ACR/EULAR 2010 classification criteria (see Table 11). Patients 18 years of age and older were eligible to participate. The presence of at least 6 tender and 6 swollen joints and evidence of systemic inflammation based on elevation of hsCRP was required at baseline. Four studies included long-term extensions for up to 5 years and one study (SELECT-COMPARE) included a long-term extension for us to 10 years.
Clinical response. ACR response. In all studies, significantly more patients treated with Rinvoq 15 mg achieved ACR20, ACR50, and ACR70 responses at 12/14 weeks compared to placebo or MTX except for ACR70 in SELECT-BEYOND (Table 12). Time to onset of efficacy was rapid across measures with greater responses seen as early as week 1 for ACR20. Durable response rates were observed (with or without MTX), with ACR20/50/70 responses maintained through 3 years based on available long-term extension study results. In SELECT-COMPARE, a higher proportion of patients treated with Rinvoq 15 mg achieved ACR20 (Figure 1) and ACR70 at Weeks 12 through 48 compared to placebo or adalimumab. In a multiplicity-controlled comparison, Rinvoq was superior to adalimumab for ACR50 at week 12.
Treatment with Rinvoq 15 mg, alone or in combination with csDMARDs, resulted in greater improvements in individual ACR components, including tender and swollen joint counts, patient and physician global assessments, HAQ-DI, pain assessment, and hsCRP, compared to placebo or MTX monotherapy. In SELECT-COMPARE, a higher proportion of patients treated with Rinvoq 15 mg achieved ACR20/50/70 at Weeks 12 through 48 compared to adalimumab. At Week 12, Rinvoq was superior to adalimumab for pain reduction in a multiplicity-controlled comparison. Greater pain reduction was seen as early as week 1 compared to placebo and as early as week 4 compared to adalimumab.

Remission and low disease activity.

In the studies, a significantly higher proportion of patients treated with upadacitinib 15 mg achieved low disease activity (DAS28-CRP ≤ 3.2) and clinical remission (DAS28-CRP < 2.6) compared to placebo, MTX, or adalimumab (Table 12). Overall, both low disease activity and clinical remission rates were consistent across patient populations, with or without MTX and were maintained through 3 years based on available long-term extension study results.
Radiographic response. Inhibition of progression of structural joint damage was assessed using the modified Total Sharp Score (mTSS) and its components, the erosion score, and joint space narrowing score at weeks 26 and 48 (SELECT-COMPARE) and week 24 (SELECT-EARLY).
Treatment with Rinvoq 15 mg resulted in significantly greater inhibition of the progression of structural joint damage compared to placebo at weeks 26 and 48 in SELECT-COMPARE and as monotherapy compared to MTX at week 24 in SELECT-EARLY (Table 13). Analyses of erosion and joint space narrowing scores were consistent with the overall scores. The proportion of patients with no radiographic progression (mTSS change ≤ 0) was significantly higher with Rinvoq 15 mg compared to placebo at Weeks 26 and 48 (SELECT-COMPARE) and compared to MTX at Week 24 (SELECT-EARLY). Inhibition of progression of structural joint damage was maintained through Week 96 in both studies for patients receiving Rinvoq 15 mg.
Physical function response and health-related outcomes. Treatment with upadacitinib 15 mg, alone or in combination with csDMARDs, resulted in a significantly greater improvement in physical function compared to all comparators as measured by HAQ-DI at week 12/14 (Table 14) with Rinvoq being superior to adalimumab in a multiplicity-controlled comparison.
Improvements in HAQ-DI and pain were maintained through 3 years for patients receiving Rinvoq 15 mg based on available results from SELECT-COMPARE and SELECT-EARLY.
In the studies SELECT-MONOTHERAPY, SELECT-NEXT, and SELECT-COMPARE, treatment with upadacitinib 15 mg resulted in a significantly greater improvement in the mean duration of morning joint stiffness compared to placebo or MTX at week 12/14.
In the clinical studies, upadacitinib treated patients reported significant improvements in patient-reported quality of life, as measured by the Short Form (36) Health Survey (SF-36) Physical Component Score compared to placebo and MTX. Moreover, upadacitinib treated patients reported significant improvements in fatigue at week 12, as measured by the Functional Assessment of Chronic Illness Therapy-Fatigue score (FACIT-F) compared to placebo.

Psoriatic arthritis.

The efficacy and safety of Rinvoq 15 mg once daily was assessed in two Phase 3 randomised, double-blind, multicentre, placebo-controlled studies in patients 18 years of age or older with moderately to severely active psoriatic arthritis (Table 15). All patients had active psoriatic arthritis for at least 6 months based upon the Classification Criteria for Psoriatic Arthritis (CASPAR), at least 3 tender joints and at least 3 swollen joints, and active plaque psoriasis or history of plaque psoriasis. In SELECT-PsA 1, 81.7% of participants were taking stable doses of at least one non-biological DMARD (predominantly methotrexate) at baseline. In SELECT-PsA 2, 46.2% of participants were taking stable doses of at least one nonbiological DMARD at baseline. The studies include long-term extensions for up to 5 years (SELECT-PsA 1) and 3 years (SELECT-PsA 2).

Clinical response.

In both studies, a significantly greater proportion of patients treated with Rinvoq 15 mg achieved ACR20 response compared to placebo at Week 12 (Table 16, Figure 2). In SELECT PsA 1, Rinvoq 15 mg achieved non-inferiority compared to adalimumab in the proportion of patients achieving ACR20 response at Week 12. A higher proportion of patients treated with Rinvoq 15 mg achieved ACR50 and ACR70 responses at Week 12 compared to placebo. Time to onset of efficacy was rapid across measures with greater responses seen as early as Week 2 for ACR20.
Treatment with Rinvoq 15 mg resulted in improvements in individual ACR components, including tender/painful and swollen joint counts, patient and physician global assessments, HAQ-DI, pain assessment, and hsCRP compared to placebo (Table 17). Treatment with Rinvoq 15 mg resulted in greater improvement in pain compared to adalimumab at Week 24.
In both studies, consistent responses were observed alone or in combination with nonbiological DMARDs for primary and key secondary endpoints.
The efficacy of Rinvoq 15 mg was demonstrated regardless of subgroups evaluated including baseline BMI, baseline hsCRP, number of prior non-biological DMARDs (≤ 1 or > 1).
In both studies, response rates for ACR20/50/70, MDA, PASI75/90/100, sIGA, enthesitis resolution, and dactylitis resolution in patients treated with Rinvoq 15 mg were maintained through Week 56.

Radiographic response.

In SELECT-PsA 1, inhibition of progression of structural damage was assessed radiographically and expressed as the change from baseline in modified Total Sharp Score (mTSS) and its components, the erosion score and the joint space narrowing score, at Week 24.
Treatment with Rinvoq 15 mg resulted in significantly greater inhibition of the progression of structural joint damage compared to placebo at Week 24 (Table 18). Statistically significant results were also achieved for both erosion and joint space narrowing scores. The proportion of patients with no radiographic progression (mTSS change ≤ 0.5) was higher with Rinvoq 15 mg compared to placebo at Week 24.

Physical function response and health-related outcomes.

In both studies, patients treated with Rinvoq 15 mg showed significant improvement in physical function from baseline compared to placebo as assessed by HAQ-DI at Week 12 (Table 17), which was maintained through Week 56.
The proportion of HAQ-DI responders (≥ 0.35 improvement from baseline in HAQ-DI score) at Week 12 in SELECT-PsA 1 and SELECT-PsA 2 was 58% and 45%, respectively, in patients receiving Rinvoq 15 mg, 33% and 27%, respectively, in patients receiving placebo, and 47% in patients receiving adalimumab (SELECT-PsA 1).
Health-related quality of life was assessed by SF-36. In both studies, patients receiving Rinvoq 15 mg experienced significantly greater improvement from baseline in the Physical Component Summary score compared to placebo at Week 12. Greater improvement was also observed compared to adalimumab. Greater improvement was observed in the Mental Component Summary score and all 8 domains of SF-36 (Physical Functioning, Bodily Pain, Vitality, Social Functioning, Role Physical, General Health, Role Emotional, and Mental Health) compared to placebo. Improvements from baseline were maintained through Week 56 in both studies.
Patients receiving Rinvoq 15 mg experienced significantly greater improvement from baseline in fatigue, as measured by FACIT-F score, at Week 12 compared to placebo in both studies. Improvements from baseline were maintained through Week 56 in both studies.
Greater improvement in patient-reported psoriasis symptoms, as measured by the Self-Assessment of Psoriasis Symptoms (SAPS), was observed in both studies at Week 16 in patients treated with Rinvoq 15 mg compared to placebo and adalimumab. Improvements from baseline were maintained through Week 56 in both studies.
Among patients with psoriatic spondylitis, in both studies patients treated with Rinvoq 15 mg showed improvements from baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Ankylosing Spondylitis Disease Activity Score (ASDAS) compared to placebo at Week 24. Greater improvements were also observed compared to adalimumab. Improvements from baseline were maintained through Week 56 in both studies.

Non-radiographic axial spondyloarthritis.

The efficacy and safety of Rinvoq 15 mg once daily were assessed in a randomised, double-blind, multicenter, placebo-controlled study in patients 18 years of age or older with active non-radiographic axial spondyloarthritis based upon the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥ 4, Patient's Assessment of Total Back Pain score ≥ 4, and objective signs of inflammation (Table 19). The study included a long-term extension for up to 2 years.
Clinical response. In SELECT-AXIS 2 (study 2), a significantly greater proportion of patients treated with Rinvoq 15 mg achieved an ASAS40 response compared to placebo at Week 14 (Table 20, Figure 3). Time to onset of efficacy was rapid with responses seen as early as Week 2 for ASAS40.
Treatment with Rinvoq 15 mg resulted in greater improvement in individual ASAS components (patient global assessment of disease activity, total back pain assessment, inflammation, and function) and other measures of disease activity, including BASDAI compared to placebo at Week 14.
The efficacy of Rinvoq 15 mg was demonstrated across subgroups including gender, baseline BMI, symptom duration of non-radiographic axial spondyloarthritis, baseline hsCRP, MRI sacroiliitis, and prior use of bDMARDs.
In SELECT-AXIS 2 (study 2), efficacy was maintained through Week 52 as assessed by the endpoints presented in Table 20.
Physical function response and health-related outcomes. Patients treated with Rinvoq 15 mg showed significant improvement in physical function from baseline compared to placebo as assessed by the BASFI at Week 14 (Table 21).
Patients treated with Rinvoq 15 mg showed significant improvements in total back pain and nocturnal back pain compared to placebo at Week 14.
Patients treated with Rinvoq 15 mg showed significant improvements in health-related quality of life and overall health as measured by Ankylosing Spondylitis Quality of Life (ASQoL) and ASAS Health Index, respectively, compared to placebo at Week 14.
Improvements in BASFI, total back pain, and ASQoL were maintained through Week 52.

Enthesitis.

Patients with pre-existing enthesitis treated with Rinvoq 15 mg showed greater improvement in enthesitis compared to placebo as measured by change from baseline in Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) at Week 14. Response was maintained through Week 52.

Objective measures of inflammation.

Signs of inflammation were assessed by MRI and expressed as change from baseline in the SPARCC score. Improvement of inflammatory signs in both sacroiliac joints and the spine was observed in patients treated with upadacitinib 15 mg. At Week 14, significant improvement of inflammatory signs in the sacroiliac joints was observed in patients treated with upadacitinib 15 mg compared to placebo.

Ankylosing spondylitis.

The efficacy and safety of Rinvoq 15 mg once daily were assessed in two randomised, double-blind, multicentre, placebo-controlled studies in patients 18 years of age or older with active ankylosing spondylitis based upon the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥ 4 and Patient's Assessment of Total Back Pain score ≥ 4 (Table 22). Both studies included a long-term extension for up to 2 years.
Clinical response. In both studies, a significantly greater proportion of patients treated with Rinvoq 15 mg achieved an ASAS40 response compared to placebo at Week 14 (Table 2, Figures 4 and 5). Time to onset of efficacy was rapid across measures with greater responses seen as early as Week 2 in SELECT-AXIS 1 and Week 4 in SELECT-AXIS 2 (Study 1) for ASAS40.
Treatment with Rinvoq 15 mg resulted in improvements in individual ASAS components (patient global assessment of disease activity, total back pain assessment, inflammation, and function) and other measures of disease activity, including BASDAI at Week 14 compared to placebo (Table 24).
The efficacy of Rinvoq 15 mg was demonstrated regardless of subgroups evaluated including gender, baseline BMI, symptom duration of ankylosing spondylitis, baseline hsCRP, and prior use of bDMARDs (N.B., subjects who had lack of efficacy to both TNFi and IL-17i therapy were not included in the study).
In both studies, efficacy was maintained: through 2 years in SELECT-AXIS 1 and through 52 weeks in SELECT-AXIS 2 (Study 1), as assessed by the endpoints presented in Table 23.
Physical function and health-related outcomes. In both studies, patients treated with Rinvoq 15 mg showed significant improvement in physical function from baseline compared to placebo as assessed by the BASFI at Week 14 (Table 24).
In SELECT-AXIS 1, patients treated with Rinvoq 15 mg showed greater improvement in back pain as assessed by the Total Back Pain component of ASAS response and nocturnal back pain compared to placebo at Week 14.
In SELECT-AXIS 2 (Study 1), patients treated with Rinvoq 15 mg showed significant improvements in total back pain and nocturnal back pain compared to placebo at Week 14.
In both studies, improvement in the overall level of neck, back, or hip pain was demonstrated using BASDAI Question 2. Improvements were also demonstrated for peripheral pain and swelling (assessed by BASDAI question 3 on overall pain in joints other than in the neck, back, or hips).
In SELECT-AXIS 1, improvements in BASFI and pain were maintained through 2 years, and in SELECT-AXIS 2 (STUDY 1) through 52 weeks, for patients receiving Rinvoq 15 mg.
In both studies, patients treated with Rinvoq 15 mg showed improvements in health-related quality of life and overall health as measured by ASQoL and ASAS Health Index, respectively, compared to placebo at Week 14.
In SELECT-AXIS 2 (STUDY 1), patients treated with Rinvoq 15 mg experienced greater improvement from baseline in fatigue as measured by FACIT-F score compared to placebo at Week 14.

Enthesitis.

In SELECT-AXIS 2 (Study 1), patients with pre-existing enthesitis treated with Rinvoq 15 mg showed significant improvement in enthesitis compared to placebo as measured by change from baseline in MASES at week 14, which was maintained through week 52. Improvements in MASES were also observed in SELECT-AXIS 1 compared to placebo at Week 14.

Spinal mobility.

In SELECT-AXIS 2 (Study 1), patients treated with Rinvoq 15 mg showed significant improvement in spinal mobility compared to placebo as measured by change from baseline in Bath Ankylosing Spondylitis Metrology Index (BASMI) at Week 14 which was maintained through week 52. Improvements in BASMI were also observed in SELECT-AXIS 1 compared to placebo at Week 14.

Objective measures of inflammation.

Signs of inflammation were assessed by MRI and expressed as change from baseline in the SPARCC score for spine and sacroiliac joints. In both studies, at Week 14, significant improvement of inflammatory signs in the spine was observed in patients treated with Rinvoq 15 mg compared to placebo. Additionally, patients treated with Rinvoq 15 mg demonstrated greater improvement of inflammatory signs in sacroiliac joints compared to placebo. In SELECT-AXIS 1, improvement in inflammation as assessed by MRI was maintained through 2 years.

Atopic dermatitis.

The efficacy and safety of Rinvoq 15 mg and 30 mg once daily was assessed in three Phase 3 randomised, double-blind, multicentre studies (MEASURE UP 1, MEASURE UP 2 and AD UP) in a total of 2584 patients (12 years of age and older) (Table 25). Rinvoq was evaluated in 344 adolescent and 2240 adult patients with moderate to severe atopic dermatitis, not adequately controlled by topical medication(s). At baseline, patients had to have all the following: an Investigator's Global Assessment (vIGA-AD) score ≥ 3 in the overall assessment of atopic dermatitis (erythema, induration/papulation, and oozing/crusting) on an increasing severity scale of 0 to 4, an Eczema Area and Severity Index (EASI) score ≥ 16 (composite score assessing extent and severity of erythema, edema/papulation, scratches and lichenification across 4 different body sites), a minimum body surface area (BSA) involvement of ≥ 10%, and weekly average Worst Pruritus Numerical Rating Scale (NRS) ≥ 4.
In all three studies, patients received Rinvoq once daily doses of 15 mg, 30 mg or matching placebo for 16 weeks. In the AD UP study, patients also received concomitant topical corticosteroids (TCS).
Following completion of the double-blinded period, patients originally randomised to Rinvoq were to continue receiving the same dose until Week 136. Patients in the placebo group were re-randomised in a 1:1 ratio to receive Rinvoq 15 mg or 30 mg until Week 136.
Clinical response.

Monotherapy studies (MEASURE UP 1 AND MEASURE UP 2).

In the MEASURE UP studies, a significantly greater proportion of patients treated with Rinvoq 15 mg or 30 mg achieved vIGA-AD 0 or 1 response and achieved EASI 75 compared to placebo at Week 16 (Table 26). A rapid improvement in skin clearance (defined as EASI 75 by Week 2) was achieved for both doses compared to placebo (p < 0.001).
A significantly greater proportion of patients treated with Rinvoq 15 mg or 30 mg achieved clinically meaningful improvement in itch (defined as a ≥ 4-point reduction in the Worst Pruritus NRS) compared to placebo at Week 16. Rapid improvement in itch (defined as a ≥ 4-point reduction in Worst Pruritus NRS by Week 1) was achieved for both doses compared to placebo (p < 0.001), with differences observed as early as 1 day after initiating Rinvoq 30 mg (Day 2, p < 0.001) and 2 days after initiating Rinvoq 15 mg (Day 3, p < 0.001).
A significantly smaller proportion of patients treated with Rinvoq 15 mg or 30 mg had a disease flare, defined as a clinically meaningful worsening of disease (increase in EASI by ≥ 6.6), during the initial 16 weeks of treatment compared to placebo (p < 0.001).
Figure 6 and Figure 7 show the proportion of patients achieving an EASI 75 response and the proportion of patients with ≥ 4-point improvement in the Worst Pruritus NRS, respectively up to Week 16.
In both studies, results at Week 16 continued to be observed through Week 52 in patients treated with Rinvoq 15 mg or 30 mg.
Treatment effects in subgroups (weight, age, gender, race, and prior systemic treatment with immunosuppressants) in both studies were consistent with the results in the overall study population.

Concomitant TCS study (AD UP).

In AD UP, a significantly greater proportion of patients treated with Rinvoq 15 mg + TCS or 30 mg + TCS achieved vIGA-AD 0 or 1 response and achieved EASI 75 compared to placebo + TCS at Week 16 (Table 27). A rapid improvement in skin clearance (defined as EASI 75 by Week 2) was achieved for both doses compared to placebo + TCS (p < 0.001). In addition, a higher EASI 90 response rate was achieved at Week 4 for both doses compared to placebo + TCS (p < 0.001).
A significantly greater proportion of patients treated with Rinvoq 15 mg + TCS or 30 mg + TCS achieved a clinically meaningful improvement in itch (defined as a ≥ 4-point reduction in the Worst Pruritus NRS) compared to placebo + TCS at Week 16. A rapid improvement in itch (defined as a ≥ 4-point reduction in Worst Pruritus NRS by Week 1) was achieved for both doses compared to placebo + TCS (p < 0.001).
Figure 8 and Figure 9 show the proportion of patients achieving an EASI 75 response and the proportion of patients with ≥ 4-point improvement in Worst Pruritus NRS, respectively up to Week 16.
Treatment effects in subgroups (weight, age, gender, race, and prior systemic treatment with immunosuppressants) in AD UP were consistent with the results in the overall study population.
Subjects treated with either Rinvoq 15 mg or 30 mg had significantly more days free of TCS use with a concurrent EASI 75 response (mean = 33.5 and 47.5 days, respectively) over the 16-week period, compared to placebo group (mean = 7.9 days).
Results at Week 16 continued to be observed through Week 52 in patients treated with Rinvoq 15 mg or 30 mg.

Quality of life/patient reported outcomes.

In the MEASURE UP studies, a significantly greater proportion of patients treated with Rinvoq 15 mg or 30 mg reported clinically meaningful reductions in the symptoms of atopic dermatitis and the impact of atopic dermatitis on health related quality of life compared to placebo at Week 16 (Table 28). A significantly greater proportion of patients treated with Rinvoq achieved clinically meaningful reductions in atopic dermatitis symptom severity as measured by ADerm SS TSS-7 and ADerm SS Skin Pain compared to placebo at Week 16. A greater proportion of patients treated with Rinvoq achieved clinically meaningful reductions in the patient-reported effects of atopic dermatitis on sleep, daily activities and emotional state as measured by the ADerm IS domain scores compared to placebo at Week 16. Similarly, compared to placebo at Week 16, a greater proportion of patients treated with Rinvoq achieved clinically meaningful improvements in atopic dermatitis symptom frequency and health related quality of life as measured by the POEM and DLQI.
Anxiety and depression symptoms as measured by the HADS score were significantly reduced; in patients with baseline HADS anxiety or HADS depression subscale scores ≥ 8 (the cut-off value for anxiety or depression), a greater proportion of patients in the Rinvoq 15 mg or 30 mg groups achieved HADS-anxiety and HADS-depression scores < 8 at Week 16 compared to placebo (Table 28).

Adolescent population.

A total of 344 adolescents aged 12 to 17 years with moderate-to-severe atopic dermatitis were randomised across the three Phase 3 studies and received either 15 mg (N = 114) or 30 mg (N=114) Rinvoq or matching placebo (N=116), in monotherapy or combination with topical corticosteroids. Efficacy was consistent between the adolescents and adults (Table 29). The adverse event profile in adolescents was generally similar to that in adults. Safety and efficacy of Rinvoq in adolescents weighing less than 40 kg and in patients less than 12 years of age with atopic dermatitis have not been established.

Phase 2b dose-ranging monotherapy study.

Rinvoq 7.5 mg, 15 mg and 30 mg once daily were assessed in a Phase 2b randomised, placebo-controlled, double-blind, dose-ranging, multicenter study (M16-048) of adult patients with moderate to severe atopic dermatitis inadequately controlled by topical medication(s) (Table 30). Based on the results of this study, the 15 mg and 30 mg once daily doses were selected for further investigation in the Phase 3 program.

Ulcerative colitis.

The efficacy and safety of Rinvoq was evaluated in three multicentre, double-blind, placebo-controlled Phase 3 clinical studies: two replicate induction studies, UC-1 and UC-2, and a maintenance study UC-3.
Disease activity was based on the adapted Mayo score (aMS, Mayo scoring system excluding Physician's Global Assessment), which ranged from 0 to 9 and has three subscores that were each scored 0 (normal) to 3 (most severe): stool frequency subscore (SFS), rectal bleeding subscore (RBS), and a centrally-reviewed endoscopy subscore (ES). See Table 31.
Induction studies (UC-1 and UC-2). In studies UC-1 and UC-2, 988 patients (473 and 515 patients, respectively) were randomised to Rinvoq 45 mg once daily or placebo for 8 weeks with a 2:1 treatment allocation ratio and included in the efficacy analysis. All enrolled patients had moderately to severely active ulcerative colitis defined as aMS of 5 to 9 with an ES of 2 or 3 and demonstrated prior treatment failure including inadequate response, loss of response, or intolerance to prior conventional and/or biologic treatment. Prior treatment failure to at least 1 biologic therapy (Prior biologic failure) was seen in 52% (246/473) and 51% (262/515) of patients, respectively. Previous treatment failure to conventional therapy but not biologics (Without prior biologic failure) was seen in 48% (227/473) and 49% (253/515) of patients, respectively.
At Baseline in UC-1 and UC-2 respectively, 39% and 37% of patients received corticosteroids, 1.1% and 0.8% of patients received immunomodulators and 68% and 69% of patients received aminosalicylates. Patient disease activity in UC-1 and UC-2 was moderate (aMS ≤ 7) in 61% of patients and 60% of patients and severe (aMS > 7) in 39% and 40% of patients, in respectively.
Results of the primary endpoint of clinical remission at Week 8 and secondary endpoints are listed in Table 32.

Disease activity and symptoms.

A significantly greater proportion of patients treated with Rinvoq 45 mg once daily compared to placebo had no abdominal pain or no bowel urgency at Week 8 (see Table 32).
For patients with baseline corticosteroid treatment, clinical remission at Week 8 was achieved in 26.5% of patients treated with Rinvoq 45 mg once daily and 4.0% with placebo, and for patients without baseline corticosteroid treatment clinical remission at Week 8 was achieved in 31.9% of patients treated with Rinvoq 45 mg once daily and 4.7% with placebo.
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 pooled results of clinical response over time per paMS in UC-1 and UC-2 are shown in Figure 10. Onset of efficacy was rapid with a greater proportion of patients treated with Rinvoq 45 mg once daily achieving clinical response as early as Week 2 compared to placebo.

Endoscopic and histologic assessment.

Normalisation of the endoscopic appearance of the mucosa (endoscopic remission) was defined as ES of 0. At Week 8, a significantly greater proportion of patients treated with Rinvoq 45 mg once daily compared to placebo achieved endoscopic remission. Histologic improvement was defined as a decrease from Baseline in Geboes score. At Week 8, a significantly greater proportion of patients treated with Rinvoq 45 mg once daily compared to placebo achieved histologic improvement (see Table 32).

Biomarkers of inflammation.

In a pooled analysis of UC-1 and UC-2 at Week 8, high sensitivity CRP (hsCRP) decreased by 6.3 mg/L from Baseline (LS mean) in patients treated with Rinvoq 45 mg once daily vs 1.4 mg/L in patients treated with placebo. The rates of fecal calprotectin below 150 mg/kg for Rinvoq 45 once daily were 46.2% compared to 7.8% for placebo.

Quality of life.

Patients treated with Rinvoq 45 mg once daily compared to placebo demonstrated significantly greater and clinically meaningful improvements in health-related quality of life measured by the inflammatory bowel disease questionnaire (IBDQ) and the Functional Assessment of Chronic Illness Therapy-Fatigue score (FACIT-F), see Table 32.

Extended induction.

A total of 125 patients in UC-1 and UC-2 who did not achieve clinical response after 8 weeks of treatment with Rinvoq 45 mg once daily entered an 8-week open-label extended induction period. After the treatment of an additional 8 weeks (16 weeks total) of Rinvoq 45 mg once daily, 48.3% of patients achieved clinical response per aMS. Among patients who responded to treatment of 16-week Rinvoq 45 mg once daily, 35.7% and 66.7% of patients maintained clinical response per aMS and 19.0% and 33.3% of patients achieved clinical remission per aMS at Week 52 with maintenance treatment of Rinvoq 15 mg and 30 mg once daily, respectively.
Maintenance study (UC-3). The efficacy analysis for UC-3 evaluated 451 patients who achieved clinical response per aMS with 8-week Rinvoq 45 mg once daily induction treatment. Patients were randomised to receive Rinvoq 15 mg, 30 mg or placebo once daily for up to 52 weeks.
The primary endpoint was clinical remission at Week 52. Secondary endpoints are listed in Table 33.

Disease activity and symptoms.

For patients who achieved clinical remission per aMS at induction, it was maintained at Week 52 by a significantly greater proportion of patients treated with Rinvoq 15 mg and 30 mg once daily compared to placebo. At Week 52, a greater proportion of patients treated with Rinvoq 15 mg and 30 mg once daily compared to placebo had no abdominal pain and no bowel urgency (see Table 33).
Clinical remission, defined as Partial Mayo score (consisting of SFS, RBS and PGA) ≤ 2 with no subscore > 1, was achieved over time through Week 52 in more patients treated with both Rinvoq 15 mg and 30 mg once daily compared with placebo (Figure 11).

Endoscopic and histologic assessment.

In UC-3, a significantly greater proportion of patients treated with Rinvoq 15 mg and 30 mg once daily compared to placebo achieved endoscopic remission at Week 52. Maintenance of mucosal healing at Week 52 (ES ≤ 1 without friability) was seen in a significantly greater proportion of patients treated with Rinvoq 15 mg and 30 mg once daily compared to placebo among patients who achieved mucosal healing at the end of induction (see Table 33).
Histologic improvement (decrease from baseline in Geboes score) was seen in a greater proportion of patients treated with Rinvoq 15 mg and 30 mg once daily at Week 52 compared to placebo (42.8% and 56.9% vs 20.6%).

Biomarkers of inflammation.

At Week 52, hsCRP was decreased by 3.9 mg/L and 5.6 mg/L from Baseline (LS mean) in patients treated with Rinvoq 15 mg and 30 mg once daily vs 0.1 mg/L in placebo. The percentage of patients with fecal calprotectin below 150 mg/kg for Rinvoq 15 mg and 30 mg once daily were 43.3% and 46.8%, compared to 12.1% for placebo.

Quality of life.

Patients treated with Rinvoq compared to placebo demonstrated significantly greater and clinically meaningful improvement in health-related quality of life as measured by inflammatory bowel disease questionnaire (IBDQ), Functional Assessment of Chronic Illness Therapy-Fatigue score (FACIT-F). See Table 33.

Crohn's disease.

The efficacy and safety of Rinvoq was evaluated in three multicenter, double-blind, placebo-controlled Phase 3 clinical studies: two induction studies, CD-1 (U-EXCEED) and CD-2 (U-EXCEL), followed by a 52-week maintenance treatment and long-term extension study CD-3 (U-ENDURE). The co-primary endpoints were clinical remission and endoscopic response at Week 12 for CD-1 and CD-2, and at Week 52 for CD-3.
Enrolled patients were 18 to 75 years of age with moderately to severely active CD defined as an average daily very soft or liquid stool frequency (SF) ≥ 4 and/or average daily abdominal pain score (APS) ≥ 2, and a centrally-reviewed Simple Endoscopic Score for CD (SES-CD) of ≥ 6, or ≥ 4 for isolated ileal disease, excluding the narrowing component.
Induction studies (CD-1 and CD-2). In CD-1 and CD-2, 1021 patients (495 and 526, respectively) were randomized to Rinvoq 45 mg once daily or placebo for 12 weeks with a 2:1 treatment allocation ratio.
In CD-1, all patients had an inadequate response or were intolerant to treatment with one or more biologic therapies (prior biologic failure). Of these patients, 61% (301/495) had inadequate response or were intolerant to two or more biologic therapies.
In CD-2, 45% (239/526) patients had an inadequate response or were intolerant to treatment with one or more biologic therapies (prior biologic failure), and 55% (287/526) had an inadequate response or were intolerant to treatment with conventional therapies but not to biologic therapy (without prior biologic failure).
At baseline in CD-1 and CD-2, 34% and 36% of patients received corticosteroids, 7% and 3% of patients received immunomodulators, and 15% and 25% of patients received aminosalicylates.
In both studies, patients receiving corticosteroids at baseline initiated a corticosteroid taper regimen starting at Week 4.
Both studies included a 12 week extended treatment period with Rinvoq 30 mg once daily for patients who received Rinvoq 45 mg once daily and did not achieve clinical response per SF/APS (≥ 30% decrease in average daily very soft or liquid SF and/or ≥ 30% decrease in average daily APS and neither greater than baseline) at Week 12. See Table 34.

Disease activity and symptoms.

In CD-1 and CD-2, a significantly greater proportion of patients treated with Rinvoq 45 mg achieved the co-primary endpoint of clinical remission at Week 12 compared to placebo (Table 34). In both studies, onset of efficacy was rapid, with a significantly greater proportion of patients treated with Rinvoq 45 mg achieving clinical response 100 (CR-100) as early as Week 2 compared to placebo (Table 34). A significantly greater proportion of patients achieved clinical remission at Week 4 compared to placebo (Table 34).

Endoscopic assessment.

In CD-1 and CD-2, a significantly greater proportion of patients treated with Rinvoq 45 mg achieved the co-primary endpoint of endoscopic response at Week 12 compared to placebo (Table 34). Improvements were also observed for ulcer-free endoscopy (mucosal healing) in patients treated with Rinvoq 45 mg.

Quality of life.

In CD-1 and CD-2, patients treated with Rinvoq 45 mg demonstrated significantly greater and clinically meaningful improvement from baseline in fatigue, as measured by FACIT-Fatigue score, and health-related quality of life as measured by the inflammatory bowel disease questionnaire (IBDQ), at Week 12 compared to placebo.
Maintenance study (CD-3). The efficacy analysis for CD-3 evaluated 502 patients who achieved clinical response per SF/APS with the 12-week Rinvoq 45 mg once daily induction treatment. Patients were re-randomised to receive a maintenance regimen of either Rinvoq 15 mg or 30 mg once daily or placebo for 52 weeks, representing a total of at least 64 weeks of therapy.
Results of the co-primary endpoints of clinical remission and endoscopic response at Week 52 and secondary endpoints are listed, see Table 35.

Disease activity and symptoms.

A significantly greater proportion of patients treated with Rinvoq 15 mg and 30 mg achieved the co-primary endpoint of clinical remission at Week 52 compared to placebo (Figure 12, Table 35).
Patients who were not in clinical response per SF/APS to Rinvoq induction at Week 12 in CD-1 and CD-2 (122 patients) received Rinvoq 30 mg once daily for an additional 12 weeks. Of these patients, 53% achieved clinical response at Week 24. Of the patients who responded to the extended treatment period and continued to receive maintenance treatment with Rinvoq 30 mg, 25% achieved clinical remission, and 22% achieved endoscopic response at Week 52.

Endoscopic assessment.

In CD-3, a significantly greater proportion of patients treated with Rinvoq 15 mg and 30 mg achieved the co-primary endpoint of endoscopic response at Week 52 compared to placebo (Table 35). Improvements were also observed for ulcer-free endoscopy (mucosal healing) in patients treated with Rinvoq 15 mg and 30 mg.

Resolution of extra-intestinal manifestations.

Resolution of extra-intestinal manifestations was observed in a significantly greater proportion of patients treated with Rinvoq 30 mg (36%) compared to placebo (15%) at Week 52.

Rescue treatment.

In CD-3, patients who demonstrated inadequate response or lost response during maintenance were eligible to receive rescue treatment with Rinvoq 30 mg. Of the patients who were randomized to Rinvoq 15 mg group and received rescue treatment of Rinvoq 30 mg for at least 12 weeks, 84% achieved clinical response per SF/APS and 48% achieved clinical remission 12 weeks after initiating rescue. Of the patients who were randomized to placebo group and received rescue treatment of Rinvoq 30 mg for at least 12 weeks, 88% achieved clinical response per SF/APS and 53% achieved clinical remission 12 weeks after initiating rescue.

Quality of life.

In CD-3, patients treated with Rinvoq 30 mg demonstrated significantly greater and clinically meaningful improvement from baseline in fatigue, as measured by FACIT-Fatigue score at Week 52 compared to placebo. Patients treated with Rinvoq 15 mg and 30 mg experienced significantly greater improvement from baseline in health-related quality of life as measured by the inflammatory bowel disease questionnaire (IBDQ), at Week 52 compared to placebo.

5.2 Pharmacokinetic Properties

Upadacitinib plasma exposures are proportional to dose over the therapeutic dose range. Steady-state plasma concentrations are achieved within 4 days with minimal accumulation after multiple once-daily administrations. The pharmacokinetic properties of Rinvoq are provided in Table 36.

Pharmacokinetics in special populations.

Renal impairment.

Upadacitinib AUC was 18%, 33%, and 44% higher in subjects with stage 2 (estimated GFR [eGFR] of 60-89 mL/min/1.73 m2), stage 3 (eGFR 30-59 mL/min/1.73 m2) and stage 4 (eGFR 15-29 mL/min/1.73 m2) renal impairment, respectively, compared to subjects with normal renal function (eGFR ≥ 90 mL/min/1.73 m2). Upadacitinib Cmax was similar in subjects with normal and impaired renal function. For dosing in patients with renal impairment, see Section 4.2 Dose and Method of Administration, Use in renal impairment.

Hepatic impairment.

Mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment has no clinically relevant effect on upadacitinib exposure. Upadacitinib AUC was 28% and 24% higher in subjects with mild and moderate hepatic impairment, respectively, compared to subjects with normal liver function. Upadacitinib Cmax was unchanged in subjects with mild hepatic impairment and 43% higher in subjects with moderate hepatic impairment compared to subjects with normal liver function. Upadacitinib was not studied in patients with severe hepatic impairment (Child-Pugh C).

Other intrinsic factors.

Age, sex, body weight, race, and ethnicity did not have a clinically meaningful effect on upadacitinib exposure. Upadacitinib pharmacokinetics are consistent among rheumatoid arthritis, psoriatic arthritis, non-radiographic axial spondyloarthritis, ankylosing spondylitis, atopic dermatitis patients, ulcerative colitis and Crohn's disease patients.

5.3 Preclinical Safety Data

Upadacitinib is teratogenic in both rats and rabbits (see Section 4.6 Fertility, Pregnancy and Lactation).

Genotoxicity.

Upadacitinib was not mutagenic in a bacterial mutagenicity assay or clastogenic in an in vitro chromosomal aberration assay (human peripheral blood lymphocytes) or an in vivo rat bone marrow micronucleus assay.

Carcinogenicity.

The carcinogenic potential of upadacitinib was evaluated in Sprague-Dawley rats and Tg.rasH2 mice. No evidence of tumourigenicity was observed in male or female rats that received upadacitinib for up to 101 weeks at oral doses up to 15 or 20 mg/kg/day, respectively (approximately 5 and 12 times the clinical dose of 15 mg, 2 and 6 times the clinical dose of 30 mg and 1.6 and 4 times the clinical dose of 45 mg on an AUC basis for males and females, respectively). No evidence of tumourigenicity was observed in Tg.rasH2 mice that received upadacitinib for 26 weeks at oral doses up to 20 mg/kg/day in male or female mice (approximately 3 times the clinical dose of 15 mg, 2 times the clinical dose of 30 mg, and at approximately the same exposure as the clinical dose of 45 mg on an AUC basis).

6 Pharmaceutical Particulars

6.1 List of Excipients

Each 15 mg modified release tablet contains the following inactive ingredients: microcrystalline cellulose, hypromellose, mannitol, tartaric acid, colloidal anhydrous silica, and magnesium stearate. Film coating contains polyvinyl alcohol, macrogol 3350, talc, titanium dioxide, ferrosoferric oxide and iron oxide red.
Each 30 mg modified release tablet contains the following inactive ingredients: microcrystalline cellulose, hypromellose, mannitol, tartaric acid, colloidal anhydrous silica, and magnesium stearate. Film coating contains polyvinyl alcohol, macrogol 3350, talc, titanium dioxide, and iron oxide red.
Each 45 mg modified release tablet contains the following inactive ingredients: microcrystalline cellulose, hypromellose, mannitol, tartaric acid, colloidal anhydrous silica and magnesium stearate. Film coating contains polyvinyl alcohol, macrogol 3350, talc, titanium dioxide, iron oxide yellow and iron oxide red.

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 30°C.
Store in the original blister in order to protect from moisture.

6.5 Nature and Contents of Container

Rinvoq 15 mg modified release tablets are purple, biconvex oblong, with dimensions of 14 x 8 mm, and debossed with 'a15' on one side.
Rinvoq 30 mg modified release tablets are red, biconvex oblong, with dimensions of 14 x 8 mm, and debossed with 'a30' on one side.
Rinvoq 45 mg modified release tablets are yellow to mottled yellow, biconvex oblong, with dimensions of 14 x 8 mm, and debossed with 'a45' on one side.
The following presentations are available:

Starter pack (7 tablets).

1 carton containing one PVC/PE/PCTFE/Aluminium blister with 7 tablets.

Monthly pack (28 tablets).

1 carton containing four PVC/PE/PCTFE/Aluminium blisters with 7 tablets in each blister.
Not all presentations may be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Description.

Upadacitinib is a white to light brown powder.

Chemical name.

(3S,4R)-3-Ethyl-4-(3H-imidazo [1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl) pyrrolidine-1-carboxamide hydrate (2:1).

Strength equivalency.

The strength of upadacitinib is based on anhydrous upadacitinib.

Solubility.

The solubility of upadacitinib in water is 38 to less than 0.2 mg/mL across a pH range of 2 to 9 at 37°C.

Molecular weight and formula.

Upadacitinib has a molecular weight of 389.38 g/mol and a molecular formula of C17H19F3N6O.½H2O.

Chemical structure.

The chemical structure of upadacitinib is:

CAS number.

1310726-60-3.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine - Schedule 4.

Summary Table of Changes