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.

What is in this leaflet

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

All medicines have risks and benefits. Your doctor has weighed the risks of you taking RINVOQ against the benefits it is expected to have for you.

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

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

What RINVOQ is used for

RINVOQ contains the active ingredient upadacitinib. It is used to treat moderate to severe active rheumatoid arthritis, which is an autoimmune disease that causes pain and swelling in the joints.

A family of enzymes know as Janus Kinase (JAK) creates signals in the body's immune system that result in inflammation. Upadacitinib belongs to a group of medicines called JAK inhibitors. It works to block these signals, thereby reducing inflammation and the production of immune cells.

In rheumatoid arthritis, RINVOQ helps to reduce signs and symptoms, including joint pain, tenderness, stiffness and swelling in your joints.

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

This medicine is not addictive.

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

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

It is not known if RINVOQ is safe and effective in children under 18 years of age.

Before you take RINVOQ

When you must not take it

Do not take RINVOQ if you are already using any biological (injectable) medicines that depress the immune system or other medicines used to strongly suppress your immune system including azathioprine, cyclosporine and tacrolimus.

Do not take RINVOQ if you have an allergy to:

  • any medicine containing upadacitinib
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

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

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. Return out-of-date or damaged medicines to your pharmacist for disposal.

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

Before you start to take it

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

Tell your doctor if:

  • you have an infection, or if you have ever 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.
  • you have or have had tuberculosis (TB), or you have been in close contact with someone who has had tuberculosis.
    You may need tests to check for TB before you start taking RINVOQ.
    Tell your doctor if you develop a persistent cough, fever, night sweats and weight loss during treatment with RINVOQ as these can be signs of TB.
  • you have or have had a herpes zoster infection (chicken pox/ shingles)
    RINVOQ may allow it to come back.
    Tell your doctor if you develop a painful skin rash with blisters during your treatment with RINVOQ, as these can be signs of shingles.
  • you have or have had hepatitis B or hepatitis C.
  • you have cancer including skin cancer and lymphomas.
  • you have liver problems, or your liver does not work as well as it should.
  • you have recently been vaccinated or are scheduled for any immunisations.
    Some vaccines should not be given while you are taking RINVOQ. Check with your doctor before you receive any immunisations.
  • you have had blood clots in the veins of your legs (deep vein thrombosis) or lungs (pulmonary embolism).
    Tell your doctor if you get a painful swollen leg, chest pain, or shortness of breath as these can be signs of blood clots in the veins.

Tell your doctor if you are pregnant or plan to become pregnant. If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. Your doctor or pharmacist can discuss with you the risks and benefits involved.

You should use effective contraception to avoid becoming pregnant while taking RINVOQ, and for at least 4 weeks after your last dose of RINVOQ. If you become pregnant during this time, you must talk to your doctor.

Tell your doctor if you are breastfeeding or plan to breastfeed. You should not take RINVOQ while you are breastfeeding as it is not known if this medicine passes into breast milk.

You may need blood tests before you start taking RINVOQ, or while you are taking it. This is to check if you have a low red blood cell count (anaemia), low white cell count (neutropaenia or lymphopaenia), high cholesterol or high levels of liver enzymes.

If you have not told your doctor about any of the above, tell them before you start taking RINVOQ.

Taking other medicines

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

RINVOQ should not be used in combination with the following medicines:

  • medicine that affects your immune system (e.g., azathioprine, cyclosporin and tacrolimus)
  • biological medicines that affect your immune system (e.g., etanercept and adalimumab)
  • medicine called JAK inhibitors used to treat rheumatoid arthritis (e.g., baricitinib and tofacitinib)

Some medicines and RINVOQ may interfere with each other. These include:

  • medicines to treat fungal infections (e.g., ketoconazole, itraconazole, posaconazole or voriconazole)
  • antibiotics to treat bacterial infections (e.g., clarithromycin or rifampicin)
  • medicines used to treat neurological disorders (e.g., phenytoin)
  • Some vaccines should not be given while you are taking RINVOQ. Check with your doctor before you receive any immunisations.

These medicines may be affected by RINVOQ or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take RINVOQ

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

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

You may be required to take this medicine together with other medicines to treat your condition.

How much to take

Your doctor will tell you how many tablets to take and when.

The usual dose is one 15 mg RINVOQ tablet once every day with or without food.

How to take it

Swallow the tablets whole with a full glass of water.

Do not split, crush, or chew the tablets.

When to take it

Take your medicine at about the same time each day. It will help you remember when to take it.

It does not matter if you take this medicine before or after food.

How long to take it

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

Your doctor may ask you to temporarily stop your RINVOQ if you develop a serious infection or if your blood tests results are outside of the normal range.

Your doctor will tell you when and how you can restart your medicine.

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

If you forget to take it

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

If you miss a dose and it is less than 10 hours before your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

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

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much RINVOQ.

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

While you are taking RINVOQ

Things you must do

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

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

Tell your doctor if you notice any new spots on your skin, a spot that looks different, a sore that doesn't heal, a mole or freckle that has changed size, shape, colour or bleeds.

Wear sunscreen and a hat when outdoors and avoid getting sunburnt.

Your doctor will conduct regular skin checks for any suspicious spots.

Keep all of your doctor's appointments so that your progress can be checked. Your doctor may do some tests (such as blood tests) from time to time to make sure the medicine is working and to prevent unwanted side effects.

Things you must not do

Do not take RINVOQ to treat any other complaints unless your doctor tells you to.

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

Do not stop taking your medicine or change the dosage without checking with your doctor.

Side effects

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

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

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

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

It can be difficult to tell whether symptoms are effects of your condition, side effects of RINVOQ or side effects from other medicines you may be taking.

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

  • symptoms that may suggest an infection in the nose or throat
  • cough
  • fever
  • feeling sick in the stomach
  • weight gain

The above list includes the more common side effects of your medicine.

Tell your doctor as soon as possible if you notice any of the following:

  • Signs of a serious infection, such as:
    - fever, sweating or chills
    - feeling short of breath
    - warm, red or painful skin sores on your body
    - feeling tired
    - muscle aches
    - blood in your phlegm, or mucous
    - diarrhoea or stomach pain
    - cough
    - weight loss
    - burning when you pass urine or passing urine more often than normal.

The above list includes serious side effects that may require medical attention.

Tell your doctor as soon as possible if you have persistent cough, weight loss, night sweats and fever. These are signs of tuberculosis.

Tell your doctor as soon as possible if you get a painful swollen leg, chest pain, or shortness of breath as these can be signs of blood clots in the veins.

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

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

People with rheumatoid arthritis or problems with their immune system are at increased risk of cancer, including lymphoma (symptoms include swelling of the glands in the neck, armpit or groin).

Some of these side effects (for example, anaemia (low red blood cell count) neutropaenia (low white blood cell count) or high levels of cholesterol in your blood or high levels of liver enzymes) can only be found when your doctor does tests from time to time to check your progress.

Refer to the Product Information for a full list of side effects.

After taking RINVOQ

Storage

Keep your tablets in a cool dry place where the temperature stays below 30°C.

Store your tablets in the original blister in order to protect from moisture.

Do not store RINVOQ or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least 1.5 m above the ground is a good place to store medicines.

Disposal

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

Product description

What it looks like

RINVOQ 15 mg modified release tablets are purple, biconvex oblong tablets, 14 x 8 mm and debossed with 'a15' on one side.

The tablets are provided in blisters. Each blister card contains 7 tablets. Each pack contains 7 or 28 tablets.

Ingredients

RINVOQ contains 15 mg of upadacitinib as the active ingredient.

It also contains the following:

  • microcrystalline cellulose
  • mannitol
  • tartaric acid
  • hypromellose
  • colloidal anhydrous silica
  • magnesium stearate
  • polyvinyl alcohol
  • titanium dioxide
  • macrogol
  • talc
  • ferrosoferric oxide (E172)
  • iron oxide red (E172).

This medicine does not contain gluten or lactose.

Distributor

RINVOQ is distributed in Australia by:

AbbVie Pty Ltd
ABN 48156 384 262
241 O'Riordan Street
MASCOT NSW 2020

This leaflet was prepared in January 2020

AUST R number: 312687

Version 1

Published by MIMS March 2020

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 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.

4 Clinical Particulars

4.1 Therapeutic Indications

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).

4.2 Dose and Method of Administration

Therapy with Rinvoq should be initiated and monitored by a rheumatologist or specialist physician with expertise in the management of rheumatoid arthritis.
The recommended oral dose of Rinvoq is 15 mg once daily with or without food.
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 may be used as monotherapy or in combination with methotrexate or other csDMARDs.
Combination with other JAK inhibitors or potent immunosuppressants has not been studied and is not recommended.
Rinvoq tablets should be swallowed whole. Rinvoq should not be split, crushed, or chewed.

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, it should be taken as soon as possible. The subsequent dose should be taken at the regularly scheduled time.

Dosing in special populations.

Paediatric use.

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.

Use in the elderly.

No dose adjustment is required in patients aged 65 years and older.

Use in renal impairment.

No dose adjustment is required in patients with mild, moderate or severe renal impairment. There are limited data on the use of upadacitinib in subjects with severe renal impairment (see Section 5.2 Pharmacokinetic Properties). Upadacitinib should be used with caution in patients with severe renal impairment. The use of Rinvoq has not been studied in subjects with end stage renal disease. Haemodialysis is not expected to have a clinically relevant effect on upadacitinib plasma exposures due to the major contribution of non-renal clearance to upadacitinib overall elimination (see Section 5 Pharmacological Properties).

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 rheumatologist or specialist physician with expertise in the management of rheumatoid arthritis.
Combination with other potent immunosuppressants such as azathioprine, cyclosporine, 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 and pneumocystosis 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.
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.

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)). 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 or inactivated 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, in agreement with current immunisation guidelines.

Thrombosis.

Thrombosis, including deep venous thrombosis, pulmonary embolism and arterial thrombosis, have occurred in patients treated for inflammatory conditions with Janus kinase (JAK) inhibitors, including Rinvoq. Many of these adverse events were serious and some resulted in death.
Consider the risks and benefits of Rinvoq treatment prior to treating patients who may be at increased risk of thrombosis. If symptoms of thrombosis occur, upadacitinib treatment should be temporarily interrupted and patients should be evaluated promptly, followed by appropriate treatment.

Cardiovascular risk.

Rheumatoid arthritis patients have an increased risk for cardiovascular disorders. Patients treated with upadacitinib should have risk factors (e.g. hypertension, hyperlipidaemia) managed as part of usual standard of care.

Malignancy.

The risk of malignancies including lymphoma is increased in patients with rheumatoid arthritis. Immunomodulatory medications may increase the risk of malignancies including lymphoma. The clinical data are currently limited and long-term studies are ongoing.
Malignancies (including lymphomas) have been observed in clinical studies of Rinvoq (see Section 4.8 Adverse Effects (Undesirable Effects)). Consider the risks and benefits of Rinvoq treatment prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing Rinvoq in patients who develop a malignancy.

Non-melanoma skin cancer.

NMSCs have been reported in patients treated with Rinvoq. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

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.

Use in the elderly.

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. No differences in effectiveness were observed between these patients and younger patients; however, there was a higher rate of overall adverse events in the elderly. There are limited data in patients aged 75 years and older.

Paediatric use.

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.

Neutropaenia.

Treatment with Rinvoq was associated with an increased incidence of neutropaenia (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].

Lymphopaenia.

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.

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 and clarithromycin) (see Section 5 Pharmacological Properties). Rinvoq should be used with caution in patients receiving chronic treatment with strong CYP3A4 inhibitors.

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 (see Section 5 Pharmacological Properties). 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 2.
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 or induce 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 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 3.

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 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 foetal harm when administered to a pregnant woman. Administration of upadacitinib to rats and rabbits during organogenesis caused increases in foetal malformations. Pregnant women should be advised of the potential risk to a foetus.
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 embryofoetal effects were seen at 1.5 mg/kg/day (exposures below the AUC from a clinical dose of 15 mg). In rabbits, an increased incidence of foetal 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. Embryofoetal 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.
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.

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 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 4.

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% v 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 tuberculosis 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 tuberculosis 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 VTE 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 VTE 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.

Neutropaenia.

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.

Lymphopaenia.

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.

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: not yet assigned.

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.

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.

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

High-sensitivity (hs) CRP.

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.

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.

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 5). 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. All studies included long-term extensions (currently ongoing for up to 5 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 6). Time to onset of efficacy was rapid across measures with greater responses seen as early as week 1 for ACR20. In SELECT-COMPARE, a higher proportion of patients treated with Rinvoq 15 mg achieved ACR20 (Figure 1) and ACR70 at week 12 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 at Week 12/14. In SELECT-COMPARE 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, or MTX (Table 6). Overall, both low disease activity and clinical remission rates were consistent across patient populations, with or without MTX.

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 week 26 (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 week 26 in SELECT-COMPARE and as monotherapy compared to MTX at week 24 in SELECT-EARLY (Table 7). 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 in both studies.

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 8) with Rinvoq being superior to adalimumab in a multiplicity-controlled comparison.
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.

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 9.

Pharmacokinetics in special populations.

Renal impairment.

Renal impairment has no clinically relevant effect on upadacitinib exposure. Upadacitinib AUC was 18%, 33%, and 44% higher in subjects with mild, moderate, and severe renal impairment, respectively, compared to subjects with normal renal function. Upadacitinib Cmax was similar in subjects with normal and impaired renal function.

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.

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 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 on an AUC basis).

6 Pharmaceutical Particulars

6.1 List of Excipients

Each 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 (E171), ferrosoferric oxide (E172) and iron oxide red (E172).

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.
The following presentations are available:

Starter pack 15 mg (7 tablets).

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

Monthly pack 15 mg (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

Upadacitinib is a white to light brown powder with the following 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).
The strength of upadacitinib is based on anhydrous upadacitinib. 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.
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)

S4.

Summary Table of Changes