Consumer medicine information

Olumiant

Baricitinib

BRAND INFORMATION

Brand name

Olumiant

Active ingredient

Baricitinib

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Olumiant.

What is in this leaflet

This leaflet answers some common questions about OLUMIANT. It does not contain all the available information. It should 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 OLUMIANT against the benefits they expect it will have for you.

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

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

What OLUMIANT is used for

OLUMIANT is used in adults as a treatment for moderate to severe:

  • rheumatoid arthritis
  • atopic dermatitis, also known as atopic eczema.

It can be used alone or with other medicines used to treat rheumatoid arthritis or with eczema medicines that you apply to the skin.

Rheumatoid arthritis is an autoimmune disease which means the body's immune system mistakenly attacks its own tissues. Symptoms include joint pain, tenderness, swelling and stiffness.

Atopic dermatitis is a chronic skin condition marked by intense itching, inflammation and dryness of skin.

OLUMIANT contains the active substance baricitinib. It belongs to a group of medicines called Janus Kinase (JAK) inhibitors.

OLUMIANT works by reducing the activity of an enzyme in the body called Janus Kinase, which is involved in inflammation. By reducing the activity of this enzyme, OLUMIANT helps:

  • block parts of your immune system involved in rheumatoid arthritis and atopic dermatitis.
  • improve the condition of your skin inflammation and reduce itching associated with atopic dermatitis.

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

OLUMIANT is available only with a doctor's prescription.

OLUMIANT is not intended for use by children under the age of 18 years.

Before you take OLUMIANT

When you must not take it

Do not take OLUMIANT if you are taking any biological (injectable) treatment for your condition.

Do not take OLUMIANT if you have an allergy to:

  • 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. If it has expired, return it to your pharmacist for disposal.

Do not take this medicine if the packaging is torn or if the seals over the carton ends are missing or broken. If it is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking OLUMIANT, 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 or have ever had any of the following medical conditions:

  • are being treated for an infection, get a lot of infections or have infections that keep coming back
  • tuberculosis or have been in close contact with someone who has tuberculosis
  • diabetes
  • hepatitis B or C
  • shingles
  • low white or red blood cells
  • recently been vaccinated or plan to get vaccinated
  • kidney problems
  • high cholesterol
  • liver problems
  • cancer
  • blood clots in the blood vessels of your legs (deep vein thrombosis) or lungs (pulmonary embolism).

Tell your doctor if you are pregnant or planning to become pregnant. It is not known if OLUMIANT will harm your unborn baby. You should use an effective method of contraception to avoid becoming pregnant while taking OLUMIANT and for at least one week after your final dose. Your doctor can discuss with you the risks and benefits involved.

Tell your doctor if you are breastfeeding or plan to breast feed. It is not known if OLUMIANT passes into your breast milk. You should not breast feed if you are taking OLUMIANT.

Tell your doctor if you have ever had shingles (herpes zoster virus). OLUMIANT can reactivate shingles in people who have had shingles in the past.

Tell your doctor if you are a carrier of the hepatitis B virus (HBV) or hepatitis C virus (HCV), or if you have hepatitis B or hepatitis C infection. If you have the HBV or HCV in your blood, it may become active while you are taking OLUMIANT. This effect has been reported with other medicines used to treat rheumatoid arthritis.

Make sure you are up to date with all vaccinations before starting OLUMIANT.

Tell your doctor if you are scheduled for any vaccines or have recently been vaccinated. Some vaccines should not be given while you are taking OLUMIANT. Check with your doctor before receiving any vaccines.

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

Taking other medicines

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

Some medicines may be affected by OLUMIANT or may affect how it works. These include:

  • medications used to treat gout such as probenecid.

You may need different amounts of your medicines or you may need to take different medicines.

Tell your doctor or pharmacist if you are already using another medicine for your condition.

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

How to take OLUMIANT

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 pack, ask your doctor or pharmacist for help.

How much to take

Your doctor will tell you how much you need to take each day.

OLUMIANT is supplied as 4 mg and 2 mg tablets.

The usual dose for rheumatoid arthritis is one 4 mg tablet taken once a day. Your doctor may reduce your dose once your condition is under control.

The usual dose for atopic dermatitis is 2 mg once a day. Your doctor may increase your dose to 4 mg once a day if you have not achieved sustained control of your condition with 2 mg and then may reduce your dose to 2 mg once a day once you have achieved sustained control of your condition with 4 mg once a day.

Your doctor may also adjust your dose depending on your condition, for example if you have a kidney problem, or are taking medication to treat gout.

How to take it

Swallow the tablet whole with a glass of water.

When to take it

Take OLUMIANT tablets at about the same time every day. Taking it at the same time every day will help you remember when to take it.

OLUMIANT can be taken with or without food.

How long to take it

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

This medicine helps to control your condition. It is important to keep taking your medicine even if you feel well.

If you forget to take it

If it is close to 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 missed tablets.

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

If you take too much (overdose)

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

While you are taking OLUMIANT

Things you must do

Tell your doctor if you experience signs and symptoms of infection such as:

  • fever, sweating or chills
  • muscle aches
  • cough
  • shortness of breath
  • weight loss
  • warm, red or painful skin or sores on your body
  • burning when you urinate or urinating more often than normal
  • feeling very tired.

OLUMIANT can lower the ability of your body to fight infections.

Tell your doctor if you get a painful swollen leg, chest pain, or shortness of breath as these can be signs of blood clots. Blood clots in the blood vessels of the legs (deep vein thrombosis) or lungs (pulmonary embolism) have been reported in patients taking OLUMIANT.

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

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

You should use an effective method of contraception to avoid becoming pregnant while taking OLUMIANT and for at least one week after your final dose. Your doctor can discuss with you the risks and benefits involved.

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

Keep all of your doctor's appointments so that your progress can be checked.

Your doctors will perform blood tests at regular intervals during your treatment to monitor your blood cells, liver enzymes and cholesterol.

Things you must not do

Do not take OLUMIANT 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.

Things to be careful of

Be careful driving or operating machinery until you know how OLUMIANT affects you.

Side effects

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

OLUMIANT helps people with moderate to severe rheumatoid arthritis and atopic dermatitis, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

It can be difficult to tell whether side effects are the result of taking OLUMIANT, effects of your condition or side effects of other medicines you may be taking. For this reason it is important to tell your doctor of any change in your condition.

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

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

Tell your doctor immediately or go to the Emergency Department at your nearest hospital if you notice any of the following:

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

The above may be signs of an allergic reaction and may require urgent medical attention or hospitalisation.

Tell your doctor as soon as possible if you notice any of the following as they may be serious side effects and require medical attention:

  • signs of an infection, such as fever, sweating or chills; muscle aches; cough; shortness of breath; weight loss; warm, red or painful skin or sores on your body; burning when you urinate or urinating more often than normal; feeling very tired.
  • Signs of blood clots in the blood vessels of the legs (deep vein thrombosis) or lungs (pulmonary embolism) such as painful swollen leg, chest pain or shortness of breath.
  • symptoms of shingles, such as headache; sensitivity to light; tingling, itching or painful skin rash with blisters.

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

  • a cold, sore throat, runny or blocked nose; cough (respiratory tract infection)
  • nausea (feeling sick)
  • cold sore blisters
  • acne (pimples)
  • rash
  • abdominal pain
  • headache

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

Some side effects (for example, changes in cholesterol, liver or other enzymes, and blood cell levels) can only be found when your doctor does tests from time to time to check your progress.

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

This is not a complete list of all possible side effects. Others may occur in some people and there may be side effects not yet known.

Ask your doctor or pharmacist if you don't understand anything on this list.

After taking OLUMIANT

Storage

Keep your tablets in the original pack until it is time to take them. If you take the tablets out of the pack they may not keep as well.

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

Do not store OLUMIANT 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 your medicine where children cannot reach. A locked cupboard at least one-and-a-half metres 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

OLUMIANT 4 mg tablets are pink, round, film-coated tablets, marked with "Lilly" on one side and "4" on the other side.

OLUMIANT 2 mg tablets are pale pink, oblong, film-coated tablets, marked with "Lilly" on one side and "2" on the other side.

Both tablets contain a dent on each face of the tablet to help you with picking them up.

Ingredients

Active Ingredient

  • baricitinib 4 mg or 2 mg

Other Ingredients

  • croscarmellose sodium
  • magnesium stearate
  • mannitol
  • microcrystalline cellulose
  • iron oxide red
  • lecithin
  • macrogol 3350
  • polyvinyl alcohol
  • purified talc
  • titanium dioxide

This medicine does not contain sucrose, gluten, tartrazine or any other azo dyes.

Supplier

OLUMIANT is a product of:

Eli Lilly Australia Pty Limited
112 Wharf Road
West Ryde, NSW 2114
AUSTRALIA

®= Registered Trademark

If you have any questions about OLUMIANT, contact Eli Lilly at 1800 454 559 (Australia) or your healthcare professional for assistance.

Australian Registration Numbers

OLUMIANT 4 mg tablet - AUST R 277917

OLUMIANT 2 mg tablet - AUST R 277905

Further Information

This leaflet was prepared in February 2021

vA-02

Published by MIMS March 2021

BRAND INFORMATION

Brand name

Olumiant

Active ingredient

Baricitinib

Schedule

S4

 

1 Name of Medicine

Baricitinib.

2 Qualitative and Quantitative Composition

Olumiant 2 mg film-coated tablets.

Each film-coated tablet contains 2 mg baricitinib.

Olumiant 4 mg film-coated tablets.

Each film-coated tablet contains 4 mg baricitinib.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Film-coated tablet (tablet).

Olumiant 2 mg film-coated tablets.

Light pink, oblong, debossed with "Lilly" script on one side and "2" on the other.

Olumiant 4 mg film-coated tablets.

Medium pink, round, debossed with "Lilly" script on one side and "4" on the other.
The tablets contain a recessed area on each face of the tablet surface.

4 Clinical Particulars

4.1 Therapeutic Indications

Rheumatoid arthritis.

Olumiant is indicated for the treatment of moderate to severe active rheumatoid arthritis (RA) in adult patients who have responded inadequately, or who are intolerant, to one or more DMARDs.
Olumiant can be taken as monotherapy or in combination with cDMARDs, including methotrexate (MTX).

Atopic dermatitis.

Olumiant is indicated for the treatment of moderate to severe atopic dermatitis in adult patients who are candidates for systemic therapy.

4.2 Dose and Method of Administration

Rheumatoid arthritis.

Therapy with Olumiant should be initiated and monitored by a rheumatologist or specialist physician with expertise in the management of rheumatoid arthritis.
The recommended dose of Olumiant is 4 mg once daily. Olumiant may be used as monotherapy or in combination with cDMARDS.
A dose of 2 mg once daily may be acceptable for patients with an inadequate response to cDMARDs who have moderate disease severity, limited risk of progressive joint damage and moderate impairment of physical function (see Section 5 Pharmacological Properties, Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment, Use in renal impairment, Effects on laboratory tests).
A dose of 2 mg once daily may also be considered for patients who have achieved sustained control of disease activity with 4 mg once daily and are eligible for dose tapering.
Combination with other JAK inhibitors has not been studied and is not recommended.

Atopic dermatitis.

Therapy with Olumiant should be initiated and supervised by a dermatologist or physician with expertise in the management of atopic dermatitis.
The recommended dose of Olumiant is 2 mg once daily (see Section 5 Pharmacological Properties, Section 5.1 Pharmacodynamic Properties, Clinical trials, Atopic dermatitis; Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment, Use in renal impairment, Effects on laboratory tests).
A dose of 4 mg once daily may also be considered for patients who have not achieved sustained control of disease activity with 2 mg once daily. Dose tapering to 2 mg once daily should be considered once the patient has achieved sustained control of disease with 4 mg once daily.
Treatment should be discontinued in patients who show no evidence of therapeutic benefit after 8 weeks of treatment with 4 mg.
Olumiant may be used as monotherapy or in combination with topical corticosteroids. Topical calcineurin inhibitors may be used.
Combination with biologic immunomodulators, other JAK inhibitors, cyclosporine or other potent immunosuppressants has not been studied in patients with atopic dermatitis and is not recommended.
Olumiant is given orally with or without food.

Dose modifications in patients with renal impairment.

The recommended dose of Olumiant in patients with moderate, Stage 3 renal impairment (estimated glomerular filtration rate (GFR) 30 - ≤ 60 mL/min/1.73 m2) is 2 mg once daily. Olumiant is not recommended for use in patients with severe and end stage renal impairment Stage 4 and 5 (estimated GFR of < 30 mL/min/1.73 m2) (see Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment).
Subjects with creatinine clearance of < 40 mL/min at baseline were excluded from participating in the Phase 3 baricitinib studies.

Dose modifications due to drug interactions.

The recommended dose of Olumiant in patients taking OAT3 inhibitors with a strong inhibition potential, such as probenecid, is 2 mg once daily (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Managing dose interruptions or adjustments.

See Table 1.

4.3 Contraindications

Olumiant is contraindicated in patients with known hypersensitivity to baricitinib or any of the excipients in the product.
Olumiant must not be used in combination with bDMARDs.

4.4 Special Warnings and Precautions for Use

Infections.

Olumiant treatment is associated with an increased rate of infections such as upper respiratory tract infections. Olumiant should be used with caution in patients with clinically important chronic, active, or recurrent infection. If an infection develops, monitor carefully and interrupt Olumiant therapy if the patient is not responding to standard therapy; do not resume Olumiant until the infection resolves.

Serious infections.

Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents including Olumiant (see Section 4.8 Adverse Effects (Undesirable Effects), Adverse reactions, Infections).
The most common serious infections reported with Olumiant included herpes zoster and cellulitis. Among opportunistic infections, oesophageal candidiasis and pneumocystis pneumonia were reported with Olumiant.
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with Olumiant.
Caution should be used when treating the elderly and patients with diabetes.
A patient who develops a new infection during treatment with Olumiant should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient, appropriate antimicrobial therapy should be initiated and the patient should be closely monitored.
If a patient develops a serious infection, administration of Olumiant should be interrupted until the infection is controlled.

Tuberculosis.

Patients should be screened for tuberculosis (TB) before starting Olumiant therapy. Olumiant should not be given to patients with active TB. Anti-TB therapy should be considered prior to initiation of Olumiant in patients with previously untreated latent TB.

Viral reactivation.

Viral reactivation, including cases of herpes virus reactivation (e.g. herpes zoster including cases that were disseminated beyond the primary or adjacent dermatomes) were reported in clinical studies with Olumiant. If a patient develops herpes zoster, Olumiant treatment should be interrupted until the episode resolves.
The impact of Olumiant on chronic viral hepatitis reactivation is unknown. Patients with evidence of active hepatitis B or C infection were excluded from clinical trials. Patients who were positive for hepatitis C antibody but negative for hepatitis C virus RNA, were permitted to enrol. Patients with hepatitis B surface antibody and hepatitis B core antibody, without hepatitis B surface antigen, were permitted to enrol; such patients should be monitored for expression of hepatitis B virus (HBV) DNA. Should HBV DNA be detected, consult with a hepatologist.
Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy with Olumiant.

Thrombosis.

Events of deep venous thrombosis (DVT), arterial thrombosis and pulmonary embolism (PE) have been reported in patients receiving Olumiant.
For venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), 5 patients (0.5%) treated with baricitinib 4 mg reported events during the 24-week, randomised, placebo-controlled time period of the 6 Phase 2 and Phase 3 RA studies; no events were reported with the 2 mg dose or placebo during this time period. During the 0 to 52 week treatment period, venous thromboses were reported in 2 patients (0.6 per 100 patient years) treated with baricitinib 2 mg and 7 patients (0.8 per 100 patient-years) treated with baricitinib 4 mg. In an analysis of extended data from the all baricitinib RA exposure population, 3770 patients (12,151 patient-years of observation) with RA, 57 patients experienced a VTE with an exposure-adjusted IR of 0.47 per 100 PY.
During the 16-week placebo-controlled period of atopic dermatitis studies, 1 patient treated with baricitinib 4 mg reported a VTE. In an analysis of extended data from all the baricitinib AD exposure population, including 2531 patients (2247 patient years of observation) with AD, an additional 2 patients reported VTE (one patient receiving 4 mg reported PE and one patient receiving 2 mg reported DVT). The overall IR was 0.13 per 100 PY.
Olumiant should be used with caution in patients with risk factors for deep vein thrombosis or pulmonary embolism (DVT/PE) such as older age, obesity, a medical history of DVT/PE, or patients undergoing surgery and immobilisation. Patients with multiple risk factors should be closely monitored and consideration should be given to appropriate VTE prophylaxis. If clinical features of DVT/PE occur, interrupt Olumiant, evaluate promptly, and institute appropriate treatment. Olumiant should only be recommenced once the patient is established on appropriate treatment. Recurrent events of VTE have been reported in some patients recommencing treatment with Olumiant.

Malignancy.

The risk of malignancy, including lymphoma, is increased in patients with rheumatoid arthritis. Immunomodulatory medicinal products may increase the risk of malignancy.
In the placebo-controlled phase 2/3 clinical studies in rheumatoid arthritis patients, with data up to 24 weeks, 2 malignancies (excluding NMSC) were diagnosed in 2 patients receiving baricitinib 4 mg, compared to 2 malignancies (excluding NMSC) in patients in the placebo group. There were no cases of lymphoma reported during the placebo-controlled studies. In the all baricitinib exposure population of 3464 patients (4214 patient-years of exposure) with RA, 31 patients were diagnosed with malignancies (excluding NMSC), with an exposure-adjusted IR of 0.7 per 100 PY.

Immunisations.

No data are available on the response to vaccination with live vaccines in patients receiving Olumiant.
Use with live, attenuated vaccines during, or immediately prior to, Olumiant therapy is not recommended. Prior to initiating Olumiant, it is recommended that all patients be brought up to date with all immunisations in agreement with current immunisation guidelines. The interval between live vaccinations and initiation of Olumiant therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.
The influence of baricitinib on the humoral response to non-live vaccines was evaluated in 106 RA patients under stable treatment with baricitinib 2 or 4 mg, receiving inactivated pneumococcal 13-valent conjugate vaccine or tetanus vaccination. The majority of these patients (n=94) were co-treated with methotrexate. For the total population, excluding one patient who had pneumococcal 13-valent conjugate vaccine prior to entry to the study, pneumococcal conjugate vaccination resulted in a satisfactory IgG immune response (a ≥ 2-fold increase from baseline in ≥ 6 pneumococcal serotypes) in 68.6% (95% CI: 59.1%, 76.8%) of the patients. In 43.1% (95% CI: 34.0%,52.8%) of the patients, a satisfactory IgG immune response (a ≥ 4-fold increase from baseline in patients with a baseline anti-tetanus IgG concentration ≥ 0.1 IU/mL) to tetanus vaccination was achieved.

Use in hepatic impairment.

No dose adjustment is necessary in patients with mild or moderate hepatic impairment. The use of Olumiant has not been studied in patients with severe hepatic impairment and is therefore not recommended.

Use in renal impairment.

Renal function was found to significantly affect Olumiant exposure. The recommended dose of Olumiant in patients with moderate, Stage 3 renal impairment, (estimated GFR 30 - ≤ 60 mL/min/1.73 m2) is 2 mg once daily. Olumiant is not recommended for use in patients with Stage 4 and 5 severe and end stage renal impairment (estimated GFR of < 30 mL/min/1.73 m2) (see Section 4.2 Dose and Method of Administration, Table 1). Patients with a creatinine clearance < 40 mL/min were excluded from the Phase 3 studies therefore caution is advised in patients with creatinine clearance 30 - < 40 mL/min.

Use in the elderly.

Age of ≥ 65 years or ≥ 75 years has no effect on Olumiant exposure (Cmax and AUC).
Safety information in patients ≥ 75 years is limited compared to younger patients and this should be taken into consideration when choosing the dose for these patients.

Paediatric use.

The safety and effectiveness of Olumiant have not been established in patients under 18 years of age.

Effects on laboratory tests.

Neutropenia.

Absolute neutrophil counts (ANC) < 1000 cells/mm3 were uncommonly reported in clinical trials. Avoid initiation or interrupt Olumiant treatment in patients with an ANC < 1000 cells/mm3 (see Section 4.2 Dose and Method of Administration, Table 1).

Lymphopenia.

Absolute lymphocyte counts (ALC) < 500 cells/mm3 were uncommonly reported in clinical trials. Avoid initiation or interrupt Olumiant treatment in patients with an ALC < 500 cells/mm3 (see Section 4.2 Dose and Method of Administration, Table 1).

Haemoglobin.

Decreases in haemoglobin levels to < 8 g/dL were reported uncommonly with baricitinib treatment. Avoid use of Olumiant treatment in patients with haemoglobin < 8 g/dL (see Section 4.2 Dose and Method of Administration, Table 1).

Lipids.

Increases in lipid parameters were very common in the Olumiant treated patients in clinical trials. Elevations in low-density lipoprotein (LDL) cholesterol decreased to pre-treatment levels in response to statin therapy. Lipid parameters should be assessed approximately 12 weeks following initiation of Olumiant therapy. During 12 weeks of treatment, 33.7% of patients treated with Olumiant 4 mg, 20.3% of patients treated with Olumiant 2 mg and 11.3% of patients treated with placebo developed LDL-C ≥ 3.36 mmol/L (see Section 4.8 Adverse Effects (Undesirable Effects), Adverse reactions, Lipids). Patients should be managed according to local clinical guidelines for hyperlipidaemia (see Section 4.2 Dose and Method of Administration, Table 1). The effect of these lipid parameter elevations on long-term cardiovascular morbidity and mortality has not been determined.

Aminotransferases.

Increases to ≥ 5 and ≥ 10x upper limit of normal (ULN) were uncommonly observed for both alanine transaminase (ALT) and aspartate transaminase (AST) in patients treated with Olumiant in clinical trials. If increases in ALT or AST are observed, and drug induced liver injury is suspected, Olumiant should be interrupted until this diagnosis is excluded (see Section 4.2 Dose and Method of Administration, Table 1).

4.5 Interactions with Other Medicines and Other Forms of Interactions

Potential for Olumiant to affect other drugs.

Cytochrome P450 enzymes.

In vitro, baricitinib did not significantly inhibit or induce the activity of cytochrome P450 enzymes (CYPs 3A, 1A2, 2B6, 2C8, 2C9, 2C19, and 2D6). In clinical pharmacology studies, coadministration of baricitinib with the CYP3A substrates simvastatin, ethinylestradiol, or levonorgestrel resulted in no clinically meaningful changes in the pharmacokinetics (Cmax and AUC(0-∞)) of these drugs.

Transporters.

In vitro, baricitinib did not inhibit the transporters P-glycoprotein (Pgp) or organic anion transporting polypeptide (OATP) 1B1. In vitro, baricitinib does inhibit organic anionic transporter (OAT) 1, OAT2, OAT3, organic cationic transporter (OCT)1, OCT2, OATP1B3, breast cancer resistance protein (BCRP) and multidrug and toxic extrusion protein (MATE)1 and MATE2-K, but clinically meaningful changes to drugs that are substrates for these transporters are unlikely. In clinical pharmacology studies there were no clinically meaningful effects when baricitinib was coadministered with digoxin (Pgp substrate) or methotrexate (substrate of several transporters).

Potential for other drugs to affect Olumiant.

Cytochrome P450 enzymes.

In vitro, baricitinib is a CYP3A4 substrate. In clinical pharmacology studies, coadministration of baricitinib with ketoconazole (CYP3A inhibitor) resulted in no clinically meaningful effect. Coadministration of baricitinib with fluconazole (CYP3A/CYP2C19/CYP2C9 inhibitor) or rifampicin (CYP3A inducer) resulted in no clinically meaningful changes in the pharmacokinetics (Cmax and AUC(0-∞)) of baricitinib.

Transporters.

In vitro, baricitinib is a substrate for OAT3, Pgp, BCRP and MATE2-K. In a clinical pharmacology study, probenecid (OAT3 inhibitor with strong inhibition potential) dosing resulted in approximately a 2-fold increase in AUC(0-∞) with no effect on Cmax or Tmax of baricitinib. Simulations with diclofenac and ibuprofen (OAT3 inhibitors with less inhibition potential) predicted minimal effect on baricitinib exposure. Coadministration of baricitinib with cyclosporine (Pgp/BCRP inhibitor) or methotrexate (substrate of several transporters) resulted in no clinically meaningful effects on baricitinib exposure.

Medicines used for VTE.

No clinical drug-drug interaction (DDI) studies with anticoagulants have been conducted. Based on the low DDI potential of baricitinib via enzymes and transporters, clinically meaningful DDI are not anticipated for coadministration of baricitinib with medicines commonly used for prophylaxis or treatment of VTE.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In a combined male/female rat fertility study, baricitinib decreased overall mating performance and male copulation index following dosing at approximately 56x the maximum recommended human exposure (AUC) and induced a dose-related trend towards reduced male fertility index following dosing at approximately 12x the maximum recommended human exposure (AUC).
Baricitinib treatment also significantly decreased female conception index following dosing at approximately 85x human exposure at the maximum recommended dose (AUC) and induced a dose related trend towards decreased fertility index following dosing at approximately 24x the maximum recommended human exposure (AUC). In female rats there were decreased numbers of corpora lutea and implantation sites and increased pre-implantation loss following dosing at approximately 85x human exposure at the maximum recommended dose (AUC). Following dosing at approximately 24x the maximum recommended human exposure (AUC), reduced mean number of viable embryos/dam, reduced mean viable embryos and increased mean post-implantation loss occurred. The no-observed-effects-level (NOEL) for fertility and impaired early embryonic development was approximately 4x human exposure at the maximum recommended dose (AUC).
Since there were no effects on spermatogenesis (as assessed by histopathology) or semen/sperm endpoints in male rats or mating indices in either sex, the decreased overall mating performance was likely the result of effects on female fertility and/or early pre-implantation embryonic development.
Women of childbearing potential should take appropriate precautions to avoid becoming pregnant during treatment with Olumiant and for at least 1 week after the final treatment.
(Category D)
Effects on human foetal development are not known. Based on limited data in rats, baricitinib-associated radioactivity readily crosses the placenta (foetal:maternal ratio approximately 2; n=1). In a rat embryofoetal development study, dosing with baricitinib at maternotoxic doses (approximately ≥ 10x the human maximum recommended dose; AUC) caused increased incidences of adverse malformations (bent limb bones, rib malformations). An increased incidence of foetal rib variations were also noted at even higher maternal exposures (approximately 55x human exposure at the maximum recommended human dose; AUC). In a rabbit embryofoetal development study, dosing of rabbits at ≤ 30x human exposure at the maximum recommended dose (AUC comparison) was not associated with foetal malformations or variations. However, maternal dosing at approximately 30x human exposure at the maximum recommended dose (AUC comparison) was associated with a decreased mean number of live foetuses/litter (7% decrease), an increased number of late in utero deaths, and decreased foetal weight.
Although the human relevance of the findings in animal studies is uncertain, the JAK/STAT pathway is involved in cell adhesion and cell polarity, which can affect early embryonic development.
Olumiant should only be used during pregnancy if the potential benefit justifies the potential risk to the foetus.
Women of childbearing potential should take appropriate precautions to avoid becoming pregnant during treatment with Olumiant and for at least 1 week after the final treatment.
It is unknown whether baricitinib is present in human milk. Baricitinib was detected in the milk of lactating rats. Following maternal PO dosing at 2-22x human exposure at the maximum recommended dose (AUC), the maximum plasma levels in pups occurred at 8 hours (last time point measured) post-dose of the dam.
Breastfeeding is not recommended during Olumiant treatment.

4.7 Effects on Ability to Drive and Use Machines

No specific studies have been conducted to assess driving ability or sedation. There are no known effects on the ability to drive and use machines associated with the use of Olumiant.

4.8 Adverse Effects (Undesirable Effects)

Adverse events reported in clinical trials.

Rheumatoid arthritis.

The safety of Olumiant in patients with rheumatoid arthritis (RA) was evaluated in a clinical program consisting of one phase 1 multi-dose study (n=53), three phase 2 multi-dose studies (n=573), four phase 3 multicentre, randomised, double-blind, controlled studies (n=3100), and an ongoing long term extension study.
Tables 2 and 3 list the adverse events (regardless of causality) occurring in ≥ 1% of patients treated with Olumiant during the double-blind, RA controlled studies.

Venous thromboembolism.

Events of VTE, including DVT and PE, have been reported in clinical trials (see Section 4.4 Special Warnings and Precautions for Use, Thrombosis).

Treatment-naive patients.

RA-BEGIN evaluated 584 patients with moderate to severe RA who had no or limited exposure to MTX and who were naive to other DMARDs. The safety profile observed in the Olumiant treatment groups was consistent with the overall safety profile of Olumiant across all treatment settings. Up to week 52, similar proportions of patients in each of the 3 treatment groups experienced a treatment-emergent adverse event: MTX alone 71.9%, Olumiant 4 mg monotherapy 71.1%, and Olumiant 4 mg + MTX 77.7%. Likewise, similar proportions of patients experienced serious adverse events (SAEs): MTX alone 9.5%, Olumiant 4 mg monotherapy 7.5%, and Olumiant 4 mg + MTX 7.9%. Adverse events leading to discontinuation of study drug were most frequent in patients taking baricitinib in combination with MTX: MTX alone 5.2%, Olumiant 4 mg monotherapy 5.7%, and Olumiant 4 mg + MTX 10.7%. The most common reason for treatment discontinuation was infections or infestations. Three patient deaths were reported during the study, all in the MTX alone group.

Methotrexate inadequate responders.

RA-BEAM evaluated 1305 patients with moderate to severe RA who had had an inadequate response to methotrexate and had not been treated with biologic DMARDs. Patients in this study were randomised to receive placebo, baricitinib or adalimumab. The safety profile observed in the baricitinib treatment groups was consistent with the overall safety profile of baricitinib across all treatment settings. Up to week 24, a higher proportion of patients in the 2 active treatment groups experienced a treatment-emergent adverse event: placebo 60.5%, baricitinib 4 mg 71.3%, and adalimumab 67.9%. Higher proportions of patients experienced serious adverse events (SAEs) in the placebo (4.5%) and baricitinib 4 mg (4.7%) treatment groups compared to adalimumab (1.8%). Adverse events leading to discontinuation of study drug were most frequent in patients taking baricitinib 4 mg (5.1%) compared to placebo (3.5%) and adalimumab (2.1%). The most common reason for treatment discontinuation was infections or infestations.

Atopic dermatitis.

A total of 2531 patients were treated with Olumiant in clinical studies in atopic dermatitis representing a total of 2247 patient years of exposure. Of these 1106 atopic dermatitis patients were exposed to Olumiant for at least one year.
Five placebo controlled studies were integrated (489 patients on 4 mg once daily, 576 patients on 2 mg once daily and 743 patients on placebo) to evaluate the safety of Olumiant in comparison to placebo for up to 16 weeks after treatment initiation. See Table 4.

Adverse reactions.

Adverse Drug Reactions (ADRs) from clinical studies are presented below by System Organ Class (SOC) and frequency categories, defined using the following convention: very common (≥ 10%); common (≥ 1% to < 10%), uncommon (≥ 0.1% to < 1%); rare (≥ 0.01% to < 0.1%) or very rare (< 0.01%).

Rheumatoid arthritis.

See Table 5.

Atopic dermatitis.

In patients treated with Olumiant in the atopic dermatitis clinical trials, acne and creatine phosphokinase > 5 x ULN were common. The frequency of herpes zoster was very rare and the frequency of thrombocytosis > 600 000 cells/mm3, nausea and ALT ≥ 3 x ULN was uncommon.

Description of selected adverse reactions - rheumatoid arthritis.

Infections.

Events related to upper respiratory tract infections, herpes simplex, and herpes zoster were commonly observed during controlled clinical trials. Most infections (as observed in 95% of patients reporting an infection) were mild to moderate in severity.
Serious infections occurred in 1.0% of patients treated with Olumiant 4 mg (6 study dataset), 1.3% with Olumiant 2 mg (4 study dataset) and 1.0% of patients treated with placebo (6 study dataset) during the initial 12 week period. In RA-BEGIN, the serious infection rate during the 24 week treatment period was 1.3% with Olumiant 4 mg monotherapy, 1.9% with Olumiant 4 mg plus methotrexate, and 1.4% with methotrexate monotherapy. The most common serious infections were herpes zoster and cellulitis.

Nausea.

In treatment-naive patients, through 52 weeks, the frequency of nausea was greater for the combination treatment of methotrexate and Olumiant (9.3%) compared to methotrexate alone (6.2%) or Olumiant alone (4.4%). Nausea was most frequent during the first 2 weeks of treatment.

Laboratory parameters. Neutropenia.

In controlled clinical trials, neutrophil counts below 1000 cells/mm3 occurred in 0.3% of patients treated with Olumiant 4 mg, 0.6% of patients treated with Olumiant 2 mg, and 0% of patients treated with placebo during the initial 12 week treatment period. In RA-BEGIN, decreases in neutrophil counts below 1000 cells/mm3 during the 24 week treatment period did not occur in any patient treated with Olumiant 4 mg monotherapy, with Olumiant 4 mg plus methotrexate, or with methotrexate monotherapy. In the all-exposure population, the pattern and incidence of decreases in neutrophil counts remained consistent with observations in the controlled periods of the studies.
No association was observed between decreases in neutrophil counts and the occurrence of serious infections. In clinical studies, treatment was interrupted in response to absolute neutrophil counts < 1000 cells/mm3 (see Section 4.4 Special Warnings and Precautions for Use).

Thrombocytosis.

In controlled clinical trials, increases in platelet counts above 600,000 cells/mm3 occurred in 1.7% of patients treated with Olumiant 4 mg, 1.1% of patients treated with Olumiant 2 mg, and 0.9% of patients treated with placebo during the 12 week treatment period. In RA-BEGIN, increases in platelet counts above 600,000 cells/mm3 during the 24 week treatment period occurred in 2.6% of patients treated with Olumiant 4 mg monotherapy, 1.9% of patients treated with Olumiant 4 mg plus methotrexate, and 2.4% of patients treated with methotrexate monotherapy.
In the all exposure population, the pattern and incidence of increases in platelet counts remained consistent with observations in the controlled periods of the studies.

Liver enzyme elevations.

Events of increases in liver enzymes ≥ 3 x ULN were observed in patients treated with Olumiant.
ALT elevations ≥ 3 x ULN during the 12 week treatment period occurred in 1.3% of patients treated with Olumiant 4 mg, 1.5% with Olumiant 2 mg, and 1.0% with placebo.
AST elevations ≥ 3 x ULN during the 12 week treatment period occurred in 0.7% of patients treated with Olumiant 4 mg, 1.0% with Olumiant 2 mg, and 0.8% of patients receiving placebo.
In RA-BEGIN, ALT and AST elevations ≥ 3x ULN during the 24 week treatment period occurred in 1.9% and 1.3% of patients treated with Olumiant 4 mg monotherapy, 4.7% and 1.9% of patients treated with Olumiant 4 mg plus methotrexate, and 1.9% and 0% of patients treated with methotrexate monotherapy (see Section 4.4 Special Warnings and Precautions for Use).

Lipids.

In controlled clinical trials, Olumiant treatment was associated with increases in lipid parameters including total cholesterol, triglycerides, LDL cholesterol, and HDL cholesterol. Elevations were observed at 12 weeks and remained stable thereafter. During 12 weeks of treatment, 33.7% of patients treated with Olumiant 4 mg, 20.3% of patients treated with Olumiant 2 mg and 11.3% of patients treated with placebo developed LDL-C ≥ 3.36 mmol/L.
Elevations in LDL cholesterol decreased to pre-treatment levels in response to statin therapy.
While increases were observed in LDL and triglycerides, the mean LDL/HDL ratio remained stable. In the all-exposure population, the pattern and incidence of increases in LDL and triglycerides remained consistent with observations in the controlled periods of the studies (see Section 4.4 Special Warnings and Precautions for Use).

Creatine phosphokinase (CPK).

In controlled clinical trials, Olumiant treatment was associated with CPK elevations > 5 x ULN in 0.7% of patients treated with Olumiant 4 mg, 0.2% of patients treated with Olumiant 2 mg, and 0.3% of patients treated with placebo during the 12 week treatment period. In RA-BEGIN, CPK elevations > 5 x ULN during the 24 week treatment period occurred in 0.6% of patients treated with Olumiant 4 mg monotherapy, 4.3% of patients treated with Olumiant 4 mg plus methotrexate, and 0% of patients treated with methotrexate monotherapy.
In the all exposure population, there were no confirmed cases of rhabdomyolysis. The pattern and incidence of increases in CPK remained consistent with observations in the controlled periods of the studies.

Description of selected adverse reactions - atopic dermatitis.

Infections.

In controlled studies, for up to 16 weeks, the incidence rate of all infections (rate of patients with ≥ 1 event per 100 patient-years of exposure) was 134.5 with Olumiant 4 mg compared to 100.3 in the placebo group. Most infections were mild to moderate in severity. Infections were reported in 31.5%, 29.8% and 24.2% of patients up to 16 weeks in the 4 mg, 2 mg and placebo groups, respectively. The percentage of patients reporting infection related ADRs for Olumiant 4 mg compared to placebo were: Upper respiratory tract infections (17.5% vs. 14.1%), herpes simplex (6.1% vs. 2.7%) and herpes zoster (0% vs. 0.3%). In atopic dermatitis clinical studies, the frequency of infections was generally similar to those observed in RA patients except for herpes zoster which was very rare. There were less skin infections requiring antibiotic treatment with Olumiant 4 mg (3.4%) than with placebo (4.4%). The same percentage of patients with serious infections was observed with Olumiant 4 mg and placebo (0.6%). The overall incidence rate of serious infections with Olumiant in the atopic dermatitis clinical trial programme was 2.1 per 100 patient years.

Nausea.

In atopic dermatitis clinical studies, the frequency of nausea was uncommon with Olumiant treatment (0.8%).

Neutropenia.

In atopic dermatitis controlled studies, for up to 16 weeks, decreases in neutrophil counts below 1 x 109 cells/L occurred in 0.3% of patients treated with Olumiant compared to 0% of patients treated with placebo. There was no clear relationship between decreases in neutrophil counts and the occurrence of serious infections. However, in clinical studies, treatment was interrupted in response to ANC < 1 x 109 cells/L. The pattern and incidence of decreases in neutrophil counts remained stable at a lower value than baseline over time including in the long-term extension study.

Thrombocytosis.

In atopic dermatitis controlled studies, for up to 16 weeks, increases in platelet counts above 600 x 109 cells/L occurred in 0.6% of patients treated with Olumiant 4 mg and 0% of patients treated with placebo. The frequency of thrombocytosis in AD studies was uncommon and lower than that observed in the RA patients.
No association was observed between increased platelet counts and adverse events of a thrombotic nature. The pattern and incidence of increases in platelet counts remained stable at a higher value than baseline over time including in the long term extension study.

Liver enzyme elevations.

In controlled studies, for up to 16 weeks, ALT and AST elevations ≥ 3 x ULN were uncommonly observed in 0.2% and 0.5% of patients treated with Olumiant 4 mg, compared to 0.8% and 0.8% respectively of patients treated with placebo. 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 the long-term extension study.

Lipids.

In atopic dermatitis clinical trials, Olumiant treatment was associated with increases in lipid parameters including total cholesterol, LDL cholesterol, and HDL cholesterol. Elevations were observed at 12 weeks and mean total and LDL cholesterol increased through week 52. There was no increase in the LDL/HDL ratio. No dose relationships were observed in controlled studies, for up to 16 weeks for total cholesterol, LDL cholesterol, or HDL cholesterol. There was no increase in triglycerides levels.

Creatine phosphokinase (CPK).

In atopic dermatitis controlled studies, for up to 16 weeks, increases in CPK values were common. Significant increases (> 5 x ULN) occurred in a dose-dependent manner in 3.3%, 2.5%, and 1.9% of patients treated with Olumiant 4 mg, 2 mg, and placebo, respectively. Most cases were transient and did not require treatment discontinuation.
For atopic dermatitis clinical trials, there were no confirmed cases of rhabdomyolysis. Elevations of CPK were observed at 4 weeks and remained stable at a higher value than baseline thereafter including in the long-term extension study.

4.9 Overdose

Single doses up to 40 mg and multiple doses of up to 20 mg daily for 10 days have been administered in clinical trials without dose-limiting toxicity. Pharmacokinetic data of a single dose of 40 mg in healthy volunteers indicate that more than 90% of the administered dose is expected to be eliminated within 24 hours. 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, contact the Poison Information Centre on 13 11 26.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Janus kinases (JAKs) are enzymes that transduce intracellular signals from cell surface receptors for a number of cytokines and growth factors involved in haematopoiesis, inflammation and immune function. Within the intracellular signalling pathway, JAKs phosphorylate and activate signal transducers and activators of transcription (STATs), which activate gene expression within the cell. Olumiant contains baricitinib which modulates these signalling pathways by partially inhibiting JAK1 and JAK2 enzymatic activity, thereby reducing the phosphorylation and activation of STATs.
Baricitinib is a selective and reversible inhibitor of JAK1 and JAK2. In isolated enzyme assays, baricitinib inhibited the activities of JAK1, JAK2, TYK2 and JAK3 with IC50 values of 5.9, 5.7, 53 and > 400 nanoM, respectively.

Pharmacodynamics.

Olumiant inhibition of IL-6 induced STAT3 phosphorylation.

Olumiant administration resulted in a dose dependent inhibition of IL-6 induced STAT3 phosphorylation in whole blood from healthy subjects with maximal inhibition observed 2 hours after dosing which returned to near baseline by 24 hours. Similar levels of inhibition were observed using either IL-6 or TPO as the stimulus.

Immunoglobulins.

Mean serum IgG, IgM, and IgA values decreased by 12 weeks after starting treatment with Olumiant, and remained stable through at least 52 weeks. For most patients, changes in immunoglobulins occurred within the normal reference range.

Lymphocytes.

Mean absolute lymphocyte count increased by 1 week after starting treatment with Olumiant, returned to baseline by week 24, and then remained stable through at least 104 weeks. For most patients, changes in lymphocyte count occurred within the normal reference range.

C-reactive protein.

In patients with rheumatoid arthritis (RA), decreases in serum C-reactive protein (CRP) were observed as early as 1 week after starting treatment with Olumiant and were maintained throughout dosing.

Creatinine.

In atopic dermatitis, baricitinib induced a mean increase in serum creatinine levels (3.5 micromol/L) after 12 weeks of treatment, which remained stable thereafter during up to 68 weeks of treatment. This may be due to inhibition of creatinine secretion by baricitinib in the renal tubules. Consequently, estimates of the glomerular filtration rate based on serum creatinine may be slightly reduced, without actual loss of renal function or the occurrence of renal adverse events. In atopic dermatitis, baricitinib was associated with decrease in cystatin C (also used to estimate glomerular filtration rate) of 0.1 mg/L at Week 4, with no further decrease noted up to Week 16.

Skin biopsies and in vitro skin models.

Elevated pSTAT3 levels are associated with increased inflammation in atopic dermatitis. In lesional skin of patients with atopic dermatitis, Olumiant reduced phosphorylated STAT3 (pSTAT3) expression in epidermal keratinocytes at week 4 and week 16 reflecting disease improvement.
In a human skin equivalent model treated with pro-inflammatory cytokines (i.e. IL-4, IL-13, IL-31), Olumiant reduced pathological changes consistent with atopic dermatitis, reduced epidermal keratinocyte pSTAT3 expression, and increased the expression of filaggrin, a protein that plays a role in skin barrier function and in the pathogenesis of atopic dermatitis.

Clinical trials.

Rheumatoid arthritis.

The efficacy and safety of Olumiant was assessed in four randomised, double-blind, multicentre studies in patients with active RA (Table 6). The patients were diagnosed according to American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 2010 criteria. Patients over 18 years of age were eligible if at least 6 tender and 6 swollen joints were present at baseline. All patients who completed these studies were eligible to enrol in a long term extension study for up to 4 years continued treatment.

Clinical response.

In all studies, patients treated with Olumiant 4 mg once daily had statistically significantly higher ACR20/50 responses at 12 weeks compared to placebo, methotrexate (MTX) and adalimumab. ACR70 responses in patients treated with Olumiant 4 mg once daily were statistically significantly higher at 12 weeks compared to placebo and MTX (see Table 7 and Table 8). Time to onset of efficacy was rapid across measures with greater responses seen as early as week 1. Continued, durable response rates were observed, with ACR20/50/70 responses maintained for at least 2 years including the long-term extension study.
Treatment with Olumiant 4 mg, alone or in combination with cDMARDs, resulted in significant improvements in all individual ACR components, including tender and swollen joint counts, patient and physician global assessments, HAQ-DI, pain assessment, and CRP, compared to placebo or MTX monotherapy.
In RA-BEAM, treatment with Olumiant 4 mg resulted in improvements in patient and physician global assessments, HAQ-DI, pain assessment and CRP at weeks 12, 24, and 52 compared to adalimumab. The percentage of patients who achieved ACR20 response by visit within this study is shown in Figure 1.
In placebo-controlled trials in which MTX was not required, 501 subjects randomised to Olumiant 2 mg or 4 mg received MTX as background therapy, and 303 received cDMARDs other than MTX (approximately half with MTX and half without). The most common concomitant disease-modifying antirheumatic drugs (DMARDs) in these subjects were MTX (79% of patients), hydroxychloroquine (19%), leflunomide (11%), and sulphasalazine (9%). No relevant differences regarding efficacy and safety were observed in subgroups defined by types of concomitant DMARDs used in combination with Olumiant.

Remission and low disease activity.

A statistically significantly greater proportion of patients treated with Olumiant 4 mg compared to placebo or MTX achieved remission, as defined by Simplified Disease Activity Index (SDAI) ≤ 3.3, at weeks 12 and 24 (see Tables 9 and 10). Similarly, when defined by Clinical Disease Activity Index (CDAI) ≤ 2.8, a greater proportion of patients treated with Olumiant 4 mg compared to placebo or MTX achieved remission at weeks 12 and 24.
In all 4 completed studies, a higher proportion of patients treated with Olumiant 4 mg compared to placebo or MTX achieved low disease activity or remission (Disease Activity Score 28-erythrocyte sedimentation rate [DAS28-ESR] or Disease Activity Score 28-high sensitivity C-reactive protein [DAS28-hsCRP] ≤ 3.2 and DAS28-ESR or DAS28-hsCRP < 2.6) at weeks 12 and 24.
Greater rates of remission compared to placebo were observed as early as week 4. Including data from a long-term extension study, remission and low disease activity rates were maintained for at least 2 years.

Physical function response and health-related outcomes.

Treatment with Olumiant 4 mg, alone or in combination with cDMARDs, resulted in a statistically significant improvement in physical function compared to placebo and MTX as measured by HAQ-DI, at 12, 24 and 52 weeks. Improvements with Olumiant 4 mg treatment were also shown versus adalimumab at these time points. The proportion of patients achieving a clinically significant improvement (HAQ-DI improvement from baseline ≥ 0.30) was also higher with Olumiant compared to placebo or MTX at week 12 (Table 9 and Table 10). Improvements were seen as early as Week 1 and, in RA-BEGIN and RA-BEAM (see Figure 2), these were maintained for up to 52 weeks.
Treatment with Olumiant 4 mg, alone or in combination with cDMARDs, resulted in a significant improvement in pain compared to all comparators (placebo, MTX, and adalimumab), as measured on a 0-100 visual analogue scale, at 12 weeks. Greater pain reduction was seen as early as Week 1 and, in RA-BEGIN and RA-BEAM, this was maintained for up to 52 weeks.
In RA-BEAM and RA-BUILD, treatment with Olumiant 4 mg resulted in an improvement in the mean duration and severity of morning joint stiffness, and mean worst tiredness, compared to placebo or adalimumab as assessed using daily electronic patient diaries for 12 weeks.
In all studies, Olumiant-treated patients reported improvements in patient-reported quality of life, as measured by the Short Form (36) Health Survey (SF36) Physical Component Score, fatigue, as measured by the Functional Assessment of Chronic Illness Therapy-Fatigue score (FACIT-F) and work productivity, as measured by the Work Productivity and Activity Impairment Questionnaire: Rheumatoid Arthritis (WPAI-RA).

Radiographic response.

The effect of Olumiant on progression of structural joint damage was evaluated radiographically in RA-BEGIN, RA-BEAM, and RA-BUILD and assessed using the modified Total Sharp Score (mTSS) and its components, the erosion score and joint space narrowing score.
Treatment with Olumiant 4 mg resulted in a statistically significant inhibition of progression of structural joint damage (Table 11). 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 statistically significantly higher with Olumiant 4 mg compared to placebo at week 24.

Olumiant 4 mg vs. 2 mg.

In clinical trials that included doses of 2 mg and 4 mg Olumiant once daily (RA-BUILD and RA-BEACON), efficacy on signs and symptoms was demonstrated with both doses. However, more consistent improvements in remission and low disease activity were seen with the 4 mg dose. The differences were most notable in the bDMARD-IR population (RA-BEACON), in which statistically significant improvements in the ACR components of swollen joint count, tender joint count and ESR were shown for Olumiant 4 mg compared to placebo at week 24 but not for Olumiant 2 mg compared to placebo. In addition, onset of efficacy was fastest and the effect size was generally largest for the 4 mg dose groups compared to 2 mg.
In a long-term extension study, patients from RA-BEAM, RA-BUILD and RA-BEACON who achieved sustained low disease activity or remission (CDAI ≤ 10) after at least 15 months of treatment with Olumiant 4 mg once daily (N = 502) were re-randomised 1:1 in a double-blind manner to continue 4 mg once daily or reduce dose to 2 mg once daily. A down titration in the baricitinib dose was associated with a significant reduction in efficacy. The majority of patients maintained low disease activity or remission based on CDAI score:
at week 12: 234/251 (93%) continuing 4 mg vs 207/251 (82%) reduced to 2 mg (p ≤ 0.001);
at week 24: 163/191 (85%) continuing 4 mg vs 144/189 (76%) reduced to 2 mg (p ≤ 0.05);
at week 48: 57/73 (78%) continuing 4 mg vs 51/86 (59%) reduced to 2 mg (p ≤ 0.05).
The majority of patients who lost their low disease activity or remission status after dose reduction could regain disease control after the dose was returned to 4 mg.

Olumiant used as monotherapy or in combination with methotrexate.

In RA-BEGIN, Olumiant 4 mg monotherapy was statistically significantly superior to methotrexate monotherapy with respect to ACR20 response rates at 24 weeks (see Table 12). Combination of Olumiant 4 mg with methotrexate therapy was associated with larger improvements in inflammation related measures, including ESR; correspondingly, although most patients did not exhibit radiographic progression across the treatment groups, the lowest radiographic progression rates were seen in the combination group. Olumiant 2 mg was not studied in this trial.
In RA-BUILD, treatment effects compared to placebo were robust whether Olumiant was used as monotherapy, in combination with methotrexate, or in combination with cDMARDs other than methotrexate.

DMARD-naive RA patients.

RA-BEGIN, a 52-week study with the planned primary analysis at week 24, evaluated 584 DMARD-naive adult patients with moderate to severe, active RA (mean disease duration was 1.3 years) and indicators of poor prognosis, such as elevated inflammatory markers (CRP) and the presence of rheumatoid factor or anti-cyclic citrullinated peptides. This study evaluated the efficacy of Olumiant 4 mg monotherapy, Olumiant 4 mg + MTX, and MTX alone in improving the signs and symptoms of RA, physical function, and rate of progression of joint damage. The primary endpoint was the proportion of patients achieving ACR20 at week 24.
A significantly higher proportion of patients in the Olumiant 4 mg and Olumiant 4 mg + MTX groups compared to MTX alone achieved an ACR20 response at week 24: 77% versus 62% (p = 0.003) for Olumiant 4 mg monotherapy and 78% versus 62% (p ≤ 0.001) for Olumiant 4 mg + MTX. The Olumiant 4 mg monotherapy and Olumiant 4 mg + MTX groups also showed statistically significant improvement compared to MTX alone across the key secondary endpoints at week 24 and 52, including ACR20, SDAI remission, and change from baseline in DAS28-hsCRP and HAQ-DI. At 52 weeks, the Olumiant 4 mg + MTX group showed statistically significant improvement compared to MTX as measured by mTSS and a numerically greater response in the Olumiant 4 mg monotherapy group compared with MTX alone. The efficacy results from RA-BEGIN are shown in Table 12.

Atopic dermatitis.

The efficacy and safety of Olumiant as monotherapy or in combination with topical corticosteroids (TCS) were assessed in 3 Phase III randomised, double blind, placebo-controlled, 16 week studies (BREEZE-AD1, -AD2 and -AD7). The outcomes of the primary and key secondary endpoints from these studies were adjusted for multiplicity.
The studies included 1568 patients with moderate to severe atopic dermatitis defined by Investigator's Global Assessment (IGA) score ≥ 3, an Eczema Area and Severity Index (EASI) score ≥ 16, and a body surface area (BSA) involvement of ≥ 10%. Eligible patients were over 18 years of age and had previous inadequate response or were intolerant to topical medication. Patients were permitted to receive rescue treatment (which included topical or systemic therapy), at which time they were considered non-responders. All patients who completed these studies were eligible to enrol in a long term extension study (BREEZE AD-3) for up to 2 years of continued treatment.

Clinical study summary.

See Table 13.

Baseline characteristics.

In the monotherapy studies (BREEZE-AD1 and BREEZE-AD2), across all treatment groups, the mean age was 35.2, the mean weight was 73.3 kg, 37.7% were female, 63.5% were Caucasian, 30% were Asian and 0.2% were black. In these studies, 54% of patients had a baseline IGA score of 3 (moderate AD), 46% of patients had a baseline IGA of 4 (severe AD) and 59.9% of patients had received prior systemic treatment for atopic dermatitis. The baseline mean EASI score was 32.2, the baseline mean BSA score was 52.3, the baseline weekly averaged pruritus NRS was 6.6, the baseline mean SCORAD score was 67.8, the baseline mean POEM score was 20.6, the baseline mean DLQI was 14.0, the baseline mean HADS depression score was 5.0, and the baseline mean HADS anxiety score was 6.1.
In the combination TCS study (BREEZE-AD7), across all treatment groups, the mean age was 33.8, the mean weight was 72.9 kg, 34.3% were female, 45.6% were Caucasian, 51.1% were Asian. In this study, 54.9% of patients had a baseline IGA score of 3, 45.1% of patients had a baseline IGA of 4 and 66.4% of patients received prior systemic treatment. The baseline mean EASI score was 29.6, the baseline mean BSA score was 50.3, the baseline weekly averaged pruritus NRS was 7.1, the baseline mean SCORAD score was 67.2, the baseline mean POEM score was 21.1, the baseline mean DLQI was 14.9, the baseline mean HADS depression score was 5.5, and the baseline mean HADS anxiety score was 6.6.

Clinical response.

16-week monotherapy studies (BREEZE-AD1 and BREEZE-AD2).

In BREEZE-AD1 and BREEZE-AD2, a significantly greater proportion of patients randomised to Olumiant 4 mg achieved an IGA 0 or 1 response, EASI75, or an improvement of ≥ 4 points on the Itch NRS compared to placebo at week 16 (Table 14).
A significantly greater proportion of patients randomised to Olumiant 4 mg achieved a rapid improvement in the Itch NRS compared to placebo (defined as ≥ 4 point improvement as early as Day 2; p ≤ 0.05). The improvement in Itch NRS occurred in conjunction with the improvement of objective skin signs of atopic dermatitis.
Figures 3 and 4 respectively show the mean percent change from baseline in EASI and in Itch NRS, up to week 16.
Treatment effects in subgroups (weight, age, gender, race, disease severity and previous treatment, including immunosuppressants) in BREEZE-AD1 and BREEZE-AD2 were consistent with the results in the overall study population.

16-week combination TCS study (BREEZE-AD7).

In BREEZE-AD7, a significantly greater proportion of patients randomised to Olumiant 4 mg + TCS achieved an IGA 0 or 1 response, EASI-75, or an improvement of ≥ 4 points on the itch NRS compared to placebo at week 16 (Table 15).
A significantly greater proportion of patients randomised to Olumiant 4 mg achieved a rapid improvement in the Itch NRS compared to placebo (defined as ≥ 4 point improvement as early as Week 2; p < 0.001). The improvement in Itch NRS occurred in conjunction with the improvement of objective skin signs of atopic dermatitis.
Figures 5 and 6 respectively show the mean percent change from baseline in EASI and in Itch NRS, up to week 16.
Treatment effects in subgroups (weight, age, gender, race, disease severity and previous treatment, including immunosuppressants) in BREEZE-AD7 were consistent with the results in the overall study population.

Maintenance and durability of response.

To evaluate maintenance of response, subjects treated with Olumiant for 16 weeks in BREEZE-AD1 and BREEZE-AD2 were eligible to enrol in a long term extension study BREEZE-AD3 to an additional 36-weeks of treatment, for a cumulative 52-week study treatment. Continued, durable response was observed. Figure 7 shows the percentage of patients with EASI 75 from baseline in BREEZE-AD3 up to week 52.

Quality of life/patient-reported outcomes in atopic dermatitis.

In both monotherapy studies (BREEZE-AD1 and BREEZE-AD2) and in the concomitant TCS study (BREEZE-AD7), Olumiant 4 mg significantly improved patient-reported outcomes, including itch, sleep (as measured by ADSS, POEM and SCORAD), skin pain (skin pain NRS) and quality of life (DLQI) at 16 weeks compared to placebo. In addition, anxiety and depression symptoms as measured by the HADS total score were significantly reduced in the Olumiant groups compared to placebo at 16 weeks (see Table 16).

5.2 Pharmacokinetic Properties

Absorption.

Following oral administration, baricitinib is rapidly absorbed with a median tmax of approximately 1 hour and an absolute bioavailability of approximately 80%. Administration with meals was not associated with a clinically relevant effect on exposure.

Distribution.

Mean volume of distribution following intravenous infusion administration was 76 L, indicating distribution of baricitinib into tissues. Baricitinib is approximately 50% bound to plasma proteins. Baricitinib is a substrate of the Pgp, BCRP, OAT3 and MATE2-K transporters, which play roles in drug distribution.

Metabolism.

Baricitinib metabolism is mediated by CYP3A4 with approximately 6% of the dose identified as undergoing biotransformation. No metabolites were quantifiable in plasma. Baricitinib was excreted predominately as unchanged drug in urine (69%) and faeces (15%) and only 4 minor oxidative metabolites (3 in urine, 1 in faeces) were identified.

Excretion.

Renal elimination is the principal mechanism for baricitinib clearance through glomerular filtration and active secretion via OAT3, Pgp, BCRP and MATE2-K. In a clinical pharmacology study, approximately 75% of the administered dose was eliminated in the urine, while about 20% of the dose was eliminated in the faeces.
Mean apparent clearance (CL/F) and half-life in patients with rheumatoid arthritis was 9.42 L/hr (CV = 34.3%) and 12.5 hours (CV = 27.4%), respectively. Cmax and AUC at steady state were 1.4- and 2.0 fold higher, respectively, in patients with RA compared to healthy subjects.
Mean apparent clearance (CL/F) and half-life in patients with atopic dermatitis was 11.2 L/hr (CV = 33.0%) and 12.9 hrs (CV = 36.0%), respectively. Cmax and AUC at steady state in patients with atopic dermatitis are 0.8-fold those seen in rheumatoid arthritis.

Other intrinsic factors.

Body weight, sex, race, and ethnicity did not have a clinically relevant effect on the pharmacokinetics (PK) of baricitinib. The mean effects of intrinsic factors on PK parameters (AUC and Cmax) were generally within the intersubject PK variability of baricitinib. Therefore, no dose adjustment is needed based on these patient factors.

Renal impairment.

Renal function was found to significantly affect baricitinib exposure. Subjects with moderate, Stage 3 renal impairment (GFR 30 - ≤ 60 mL/min/1.73 m2) and severe, Stage 4 and 5 renal impairment (GFR < 30 mL/min/1.73 m2) have approximately 2-fold and 4-fold increases, respectively, in baricitinib AUC values compared to subjects with normal renal function.
The recommended dose of Olumiant in patients with estimated GFR of 30 - ≤ 60 mL/min/1.73 m2 is 2 mg once daily. Olumiant is not recommended for use in patients with estimated GFR of < 30 mL/min/1.73 m2.

Hepatic impairment.

There was no clinically relevant effect on the PK of baricitinib in patients with mild or moderate hepatic impairment. No dose adjustment is necessary in these patients. The use of Olumiant has not been studied in patients with severe hepatic impairment and is therefore not recommended.

5.3 Preclinical Safety Data

Genotoxicity.

Baricitinib was not genotoxic in bacterial reverse mutagenicity assays (Ames assay), in the in vitro human peripheral blood lymphocyte chromosomal aberration assay, or in the in vivo micronucleus assay in the rat. All assays were validated by the use of appropriate controls. The overall risk of genotoxicity is considered to be low.

Carcinogenicity.

Baricitinib did not produce neoplastic changes in two year rat and six month transgenic mouse carcinogenicity studies.

6 Pharmaceutical Particulars

6.1 List of Excipients

Croscarmellose sodium, magnesium stearate, mannitol, microcrystalline cellulose, iron oxide red, lecithin, macrogol 3350, polyvinyl alcohol, purified talc, titanium dioxide.

6.2 Incompatibilities

Not applicable.

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

Stored below 30°C. Store in the original package.

6.5 Nature and Contents of Container

Olumiant is available as debossed, film-coated, immediate-release tablets in PVC/PE/PCTFE (Aclar)/Al or PA/Al/PVC/Al blister packs of 7 and 28.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical structure.

The active ingredient in Olumiant tablets is baricitinib. Olumiant is a Janus Kinase (JAK) inhibitor with the chemical name {1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile. The empirical formula is C16H17N7O2S which corresponds to a molecular weight of 371.42 daltons. The chemical structure is:

CAS number.

The CAS number for baricitinib is 1187594-09-7.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Medicine.

Summary Table of Changes