OLUMIANT 4mg tablets medication leaflet

Olumiant 1 mg film-coated tablets

Olumiant 2 mg film-coated tablets

Olumiant 4 mg film-coated tablets

Olumiant 1 mg film-coated tablets

Each film-coated tablet contains 1 mg baricitinib.

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.

Film-coated tablet (tablet)

Olumiant 1 mg film-coated tablets

Very light pink, 6.75 mm round tablets, debossed with “Lilly” on one side and “1” on the other.

Olumiant 2 mg film-coated tablets

Light pink, 9 x 7.5 mm oblong tablets, debossed with “Lilly” on one side and “2” on the other.

Olumiant 4 mg film-coated tablets

Medium pink, 8.5 mm round tablets, debossed with “Lilly” on one side and “4” on the other.

The tablets contain a recessed area on each side.

Baricitinib is indicated for the treatment of moderate to severe active rheumatoid arthritis in adultpatients who have responded inadequately to, or who are intolerant to one or more disease-modifyinganti-rheumatic drugs (DMARDs). Baricitinib may be used as monotherapy or in combination withmethotrexate (see sections 4.4, 4.5 and 5.1 for available data on different combinations).

Baricitinib is indicated for the treatment of moderate to severe atopic dermatitis in adult and paediatricpatients 2 years of age and older who are candidates for systemic therapy.

Alopecia areata

Baricitinib is indicated for the treatment of severe alopecia areata in adult patients (see section 5.1).

Baricitinib is indicated for the treatment of active juvenile idiopathic arthritis in patients 2 years of ageand older who have had an inadequate response or intolerance to one or more prior conventionalsynthetic or biologic DMARDs:

- Polyarticular juvenile idiopathic arthritis (polyarticular rheumatoid factor positive [RF+] ornegative [RF-], extended oligoarticular),

- Enthesitis-related arthritis, and

- Juvenile psoriatic arthritis.

Baricitinib may be used as monotherapy or in combination with methotrexate.

Treatment should be initiated by physicians experienced in the diagnosis and treatment of theconditions for which this medicinal product is indicated.

The recommended dose of baricitinib is 4 mg once daily. A dose of 2 mg once daily is recommendedfor patients at higher risk of venous thromboembolism (VTE), major adverse cardiovascular events(MACE) and malignancy, for patients aged ≥ 65 years and for patients with a history of chronic orrecurrent infections (see section 4.4). A dose of 4 mg once daily may be considered for patients whodo not achieve adequate control of disease activity with 2 mg once daily dose. A dose of 2 mg oncedaily should be considered for patients who have achieved sustained control of disease activity with4 mg once daily and are eligible for dose tapering (see section 5.1).

The recommended dose of baricitinib is 4 mg once daily. A dose of 2 mg once daily is recommendedfor patients at higher risk of VTE, MACE and malignancy, for patients aged ≥ 65 years and forpatients with a history of chronic or recurrent infections (see section 4.4). A dose of 4 mg once dailymay be considered for patients who do not achieve adequate control of disease activity with 2 mg oncedaily dose. A dose of 2 mg once daily should be considered for patients who have achieved sustainedcontrol of disease activity with 4 mg once daily and are eligible for dose tapering (see section 5.1).

Baricitinib can be used with or without topical corticosteroids. The efficacy of baricitinib can beenhanced when given with topical corticosteroids (see section 5.1). Topical calcineurin inhibitors maybe used, but should be reserved for sensitive areas only, such as the face, neck, intertriginous andgenital areas.

Consideration should be given to discontinuing treatment in patients who show no evidence oftherapeutic benefit after 8 weeks of treatment.

Children and adolescents (2 years of age and older)

The recommended dose of baricitinib is 4 mg once daily for patients weighing 30 kg or more. Forpatients weighing 10 kg to less than 30 kg, the recommended dose is 2 mg once daily. A reduction tohalf the dose should be considered for patients who have achieved sustained control of disease activitywith the recommended dose and are eligible for dose tapering.

Baricitinib can be used with or without topical corticosteroids. Topical calcineurin inhibitors may beused, but should be reserved for sensitive areas only, such as the face, neck, intertriginous and genitalareas.

Consideration should be given to discontinuing treatment in patients who show no evidence oftherapeutic benefit after 8 weeks of treatment.

Alopecia areata

The recommended dose of baricitinib is 4 mg once daily. A dose of 2 mg once daily is recommendedfor patients at higher risk of VTE, MACE and malignancy, for patients aged ≥ 65 years and forpatients with a history of chronic or recurrent infections (see section 4.4). A dose of 4 mg once dailymay be considered for patients who do not achieve adequate control of disease activity with 2 mg oncedaily dose. A dose of 2 mg once daily should be considered for patients who have achieved sustainedcontrol of disease activity with 4 mg once daily and are eligible for dose tapering (see section 5.1).

Once a stable response has been achieved, it is recommended to continue treatment for at least severalmonths, in order to avoid relapse. The benefit-risk of treatment should be re-assessed at regularintervals on an individual basis.

Consideration should be given to discontinuing treatment in patients who show no evidence oftherapeutic benefit after 36 weeks of treatment.

Juvenile idiopathic arthritis (from 2 to less than 18 years of age)

The recommended dose of baricitinib is 4 mg once daily for patients weighing 30 kg or more. Forpatients weighing 10 kg to less than 30 kg, the recommended dose is 2 mg once daily.

Consideration should be given to discontinuing treatment in patients who show no evidence oftherapeutic benefit after 12 weeks of treatment.

Treatment initiation

Treatment should not be initiated in patients with an absolute lymphocyte count (ALC) less than0.5 x 109 cells/L, an absolute neutrophil count (ANC) less than 1 x 109 cells/L, or who have ahaemoglobin value less than 8 g/dL. Treatment may be initiated once values have improved abovethese limits (see section 4.4).

In patients taking strong Organic Anion Transporter 3 (OAT3) inhibitors such as probenecid, or withcreatinine clearance between 30 and 60 mL/min the recommended dose should be reduced by half forpaediatric patients and the recommended dose is 2 mg for adult patients (see section 4.5).

The recommended dose is 2 mg once daily in adult patients with creatinine clearance between 30 and60 mL/min. In paediatric patients with creatinine clearance between 30 and 60 mL/min, therecommended dose of baricitinib should be reduced by half. Baricitinib is not recommended for use inpatients with creatinine clearance < 30 mL/min (see section 5.2).

No dose adjustment is required in patients with mild or moderate hepatic impairment. Baricitinib is notrecommended for use in patients with severe hepatic impairment (see section 5.2).

Clinical experience in patients aged ≥ 75 years is very limited.

Paediatric population (less than 2 years)

The safety and efficacy of baricitinib in children less than 2 years have not yet been established. Nodata are available. See section 4.2 above for information on posology in children aged 2 years andolder.

The safety and efficacy of baricitinib in children less than 18 years of age with alopecia areata havenot yet been established. No data are available.

Oral use.

Baricitinib is to be taken once daily with or without food and may be taken at any time of the day.

Alternative administration for children

For paediatric patients who are unable to swallow whole tablets, it may be considered to disperse thetablets in water. Only water should be used to disperse the tablet. Only the number of tablets neededfor the dose should be dispersed.

If for any reason the entire suspension is not administered, do not disperse and administer anothertablet but wait until the next scheduled dose.

For instructions on dispersion of the medicinal product before administration, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Pregnancy (see section 4.6).

Baricitinib should only be used if no suitable treatment alternatives are available in patients:

- 65 years of age and older;

- patients with history of atherosclerotic cardiovascular disease or other cardiovascular risk factors(such as current or past long-time smokers);

- patients with malignancy risk factors (e.g. current malignancy or history of malignancy)

Use of JAK inhibitors in patients 65 years of age and older

Considering the increased risk of MACE, malignancies, serious infections, and all-cause mortality inpatients 65 years of age and older, as observed in a large randomised study of tofacitinib (another

JAK inhibitor), baricitinib should only be used in these patients if no suitable treatment alternatives areavailable.

Serious and sometimes fatal infections have been reported in patients receiving other JAK inhibitors.

Baricitinib is associated with an increased rate of infections such as upper respiratory tract infectionscompared to placebo (see section 4.8). In rheumatoid arthritis clinical studies, combination withmethotrexate resulted in increased frequency of infections compared to baricitinib monotherapy.

The risks and benefits of treatment should be carefully considered prior to initiating baricitinib inpatients with active, chronic or recurrent infections (see section 4.2). If an infection develops, thepatient should be monitored carefully and therapy should be temporarily interrupted if the patient isnot responding to standard therapy. Treatment should not be resumed until the infection resolves.

As there is a higher incidence of infections in the elderly and in the diabetic populations in general,caution should be used when treating the elderly and patients with diabetes. In patients over 65 yearsof age, baricitinib should only be used if no suitable treatment alternatives are available.

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

Absolute Neutrophil Count (ANC) < 1 x 109 cells/L, Absolute Lymphocyte Count(ALC) < 0.5 x 109 cells/L, and haemoglobin < 8 g/dL were reported in clinical trials.

Treatment should not be initiated, or should be temporarily interrupted, in patients with an

ANC < 1 x 109 cells/L, ALC < 0.5 x 109 cells/L or haemoglobin < 8 g/dL observed during routinepatient management (see section 4.2).

The risk of lymphocytosis is increased in elderly patients with rheumatoid arthritis. Rare cases oflymphoproliferative disorders have been reported.

Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster, herpes simplex),were reported in clinical studies (see section 4.8). In rheumatoid arthritis clinical studies, herpes zosterwas reported more commonly in patients ≥ 65 years of age who had previously been treated with bothbiologic and synthetic conventional DMARDs. If a patient develops herpes zoster, treatment should betemporarily interrupted until the episode resolves.

Screening for viral hepatitis should be performed in accordance with clinical guidelines before startingtherapy with baricitinib. Patients with evidence of active hepatitis B or C infection were excluded fromclinical trials. Patients, who were positive for hepatitis C antibody but negative for hepatitis C virus

RNA, were allowed to participate. Patients with hepatitis B surface antibody and hepatitis B coreantibody, without hepatitis B surface antigen, were also allowed to participate; such patients should bemonitored for expression of hepatitis B virus (HBV) DNA. If HBV DNA is detected, a liver specialistshould be consulted to determine if treatment interruption is warranted.

No data are available on the response to vaccination with live vaccines in patients receivingbaricitinib. Use with live, attenuated vaccines during or immediately prior to baricitinib therapy is notrecommended. Prior to initiating treatment, it is recommended that all patients, and particularlypaediatric patients, be brought up to date with all immunisations in agreement with currentimmunisation guidelines.

Dose dependent increases in blood lipid parameters were reported in paediatric and adult patientstreated with baricitinib (see section 4.8). Elevations in low density lipoprotein (LDL) cholesteroldecreased to pre-treatment levels in response to statin therapy in adults. In both paediatric and adultpatients, lipid parameters should be assessed approximately 12 weeks following initiation of therapyand thereafter patients should be managed according to international clinical guidelines forhyperlipidaemia.

Hepatic transaminase elevations

Dose dependent increases in blood alanine transaminase (ALT) and aspartate transaminase (AST)activity were reported in patients treated with baricitinib (see section 4.8).

Increases in ALT and AST to ≥ 5 and ≥ 10 x upper limit of normal (ULN) were reported in clinicaltrials. In rheumatoid arthritis clinical studies, combination with methotrexate resulted in increasedfrequency of hepatic transaminase elevations compared with baricitinib monotherapy (see section 4.8).

If increases in ALT or AST are observed during routine patient management and drug-induced liverinjury is suspected, treatment should be temporarily interrupted until this diagnosis is excluded.

Immunomodulatory medicinal products may increase the risk of malignancies including lymphoma.

Lymphoma and other malignancies have been reported in patients receiving JAK inhibitors, includingbaricitinib.

In a large randomized active-controlled study of tofacitinib (another JAK inhibitor) in rheumatoidarthritis patients 50 years and older with at least one additional cardiovascular risk factor, a higher rateof malignancies, particularly lung cancer, lymphoma and non-melanoma skin cancer (NMSC) wasobserved with tofacitinib compared to TNF inhibitors.

In patients over 65 years of age, patients who are current or past long-time smokers, or with othermalignancy risk factors (e.g. current malignancy or history of malignancy) baricitinib should only beused if no suitable treatment alternatives are available.

Periodic skin examination is recommended for all patients, particularly those with risk factors for skincancer.

In a retrospective observational study of baricitinib in rheumatoid arthritis patients, a higher rate ofvenous thromboembolic events (VTE) was observed compared to patients treated with TNF inhibitors(see section 4.8).

In a large randomized active-controlled study of tofacitinib (another JAK inhibitor) in rheumatoidarthritis patients 50 years and older with at least one additional cardiovascular risk factor, a dosedependent higher rate of VTE including deep venous thrombosis (DVT) and pulmonary embolism(PE) was observed with tofacitinib compared to TNF inhibitors.

In patients with cardiovascular or malignancy risk factors (see also section 4.4 “Major adversecardiovascular events (MACE)” and “Malignancy”) baricitinib should only be used if no suitabletreatment alternatives are available.

In patients with known VTE risk factors other than cardiovascular or malignancy risk factors,baricitinib should be used with caution. VTE risk factors other than cardiovascular or malignancy riskfactors include previous VTE, patients undergoing major surgery, immobilisation, use of combinedhormonal contraceptives or hormone replacement therapy, and inherited coagulation disorder.

Patients should be re-evaluated periodically during baricitinib treatment to assess for changes in VTErisk.

Promptly evaluate patients with signs and symptoms of VTE and discontinue baricitinib in patientswith suspected VTE, regardless of dose or indication.

Major adverse cardiovascular events (MACE)

In a retrospective observational study of baricitinib in rheumatoid arthritis patients, a higher rate of

MACE was observed compared to patients treated with TNF inhibitors.

In a large randomized active-controlled study of tofacitinib (another JAK inhibitor) in rheumatoidarthritis patients 50 years and older with at least one additional cardiovascular risk factor, a higher rateof major adverse cardiovascular events (MACE), defined as cardiovascular death, non-fatalmyocardial infarction (MI) and non-fatal stroke ,was observed with tofacitinib (another JAK inhibitor)compared with TNF inhibitors.

Therefore, in patients over 65 years of age, patients who are current or past long-time smokers, andpatients with history of atherosclerotic cardiovascular disease or other cardiovascular risk factors,baricitinib should only be used if no suitable treatment alternatives are available.

Laboratory monitoring

Table 1. Laboratory measures and monitoring guidance

Laboratorymeasure Action Monitoring guidance

Patients should be managed 12 weeks after initiation of

Lipid parameters according to international clinical treatment and thereafter accordingguidelines for hyperlipidaemia to international clinical guidelinesfor hyperlipidaemia

Treatment should be interrupted if

Absolute Neutrophil ANC < 1 x 109 cells/L and may be

Count (ANC) restarted once ANC return abovethis value

Absolute Treatment should be interrupted if

Lymphocyte Count ALC < 0.5 x 109 cells/L and may be(ALC) restarted once ALC return above Before treatment initiation andthis value thereafter according to routine

Treatment should be interrupted if patient management

Haemoglobin (Hb) Hb < 8 g/dL and may be restartedonce Hb return above this value

Hepatic Treatment should be temporarilytransaminases interrupted if drug-induced liverinjury is suspected

Combination with biological DMARDs, biological immunomodulators or other Janus kinase (JAK)inhibitors is not recommended, as a risk of additive immunosuppression cannot be excluded.

In rheumatoid arthritis and juvenile idiopathic arthritis, data concerning use of baricitinib with potentimmunosuppressive medicinal products other than methotrexate (e.g., azathioprine, tacrolimus,ciclosporin) are limited. Caution should be exercised when using such combinations (see section 4.5).

In atopic dermatitis and alopecia areata, combination with ciclosporin or other potentimmunosuppressants has not been studied and is not recommended (see section 4.5).

In post-marketing experience, cases of hypersensitivity associated with baricitinib administration havebeen reported. If any serious allergic or anaphylactic reaction occurs, treatment should be discontinuedimmediately.

Diverticulitis

Cases of diverticulitis and gastrointestinal perforation have been reported in clinical trials and frompostmarketing sources (see section 4.8). Baricitinib should be used with caution in patients withdiverticular disease and especially in patients chronically treated with concomitant medicinal productsassociated with an increased risk of diverticulitis: nonsteroidal anti-inflammatory drugs,corticosteroids, and opioids. Patients presenting with new onset abdominal signs and symptoms shouldbe evaluated promptly for early identification of diverticulitis or gastrointestinal perforation.

Hypoglycaemia in patients treated for diabetes

There have been reports of hypoglycaemia following initiation of JAK inhibitors, including baricitinib,in patients receiving medication for diabetes. Dose adjustment of anti-diabetic medication may benecessary in the event that hypoglycaemia occurs.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially“sodium-free”.

Combination with biological DMARDs, biological immunomodulators or other JAK inhibitors has notbeen studied. In rheumatoid arthritis and juvenile idiopathic arthritis, use of baricitinib with potentimmunosuppressive medicinal products such as azathioprine, tacrolimus, or ciclosporin was limited inclinical studies, and a risk of additive immunosuppression cannot be excluded. In atopic dermatitis andalopecia areata, combination with ciclosporin or other potent immunosuppressants has not beenstudied and is not recommended (see section 4.4).

Potential for other medicinal products to affect the pharmacokinetics of baricitinib

In vitro, baricitinib is a substrate for organic anionic transporter (OAT)3, P-glycoprotein (Pgp), breastcancer resistance protein (BCRP) and multidrug and toxic extrusion protein (MATE)2-K. In a clinicalpharmacology study, dosing of probenecid (an OAT3 inhibitor with strong inhibition potential)resulted in approximately a 2-fold increase in AUC(0-∞) with no change in tmax or Cmax of baricitinib.

Consequently, in patients taking OAT3 inhibitors with a strong inhibition potential, such asprobenecid, the recommended dose of baricitinib should be reduced by half (see section 4.2). Noclinical pharmacology study has been conducted with OAT3 inhibitors with less inhibition potential.

The prodrug leflunomide rapidly converts to teriflunomide which is a weak OAT3 inhibitor andtherefore may lead to an increase in baricitinib exposure. Since dedicated interaction studies have notbeen conducted, caution should be used when leflunomide or teriflunomide are given concomitantlywith baricitinib. Concomitant use of the OAT3 inhibitors ibuprofen and diclofenac may lead toincreased exposure of baricitinib, however their inhibition potential of OAT3 is less compared toprobenecid and thus a clinically relevant interaction is not expected. Coadministration of baricitinibwith ciclosporin (Pgp/BCRP inhibitor) or methotrexate (substrate of several transporters including

OATP1B1, OAT1, OAT3, BCRP, MRP2, MRP3, and MRP4) resulted in no clinically meaningfuleffects on baricitinib exposure.

Cytochrome P450 enzymes

In vitro, baricitinib is a cytochrome P450 enzyme (CYP)3A4 substrate although less than 10 % of thedose is metabolised via oxidation. In clinical pharmacology studies, coadministration of baricitinibwith ketoconazole (strong CYP3A inhibitor) resulted in no clinically meaningful effect on the PK ofbaricitinib. Coadministration of baricitinib with fluconazole (moderate CYP3A/CYP2C19/CYP2C9inhibitor) or rifampicin (strong CYP3A inducer) resulted in no clinically meaningful changes tobaricitinib exposure.

Gastric pH modifying agents

Elevating gastric pH with omeprazole had no clinically significant effect on baricitinib exposure.

Potential for baricitinib to affect the pharmacokinetics of other medicinal products

In vitro, baricitinib is not an inhibitor of OAT1, OAT2, OAT3, organic cationic transporter (OCT) 2,

OATP1B1, OATP1B3, BCRP, MATE1 and MATE2-K at clinically relevant concentrations.

Baricitinib may be a clinically relevant inhibitor of OCT1, however there are currently no knownselective OCT1 substrates for which clinically significant interactions might be predicted. In clinicalpharmacology studies there were no clinically meaningful effects on exposure when baricitinib wascoadministered with digoxin (Pgp substrate) or methotrexate (substrate of several transporters).

Cytochrome P450 enzymes

In clinical pharmacology studies, coadministration of baricitinib with the CYP3A substratessimvastatin, ethinyl oestradiol, or levonorgestrel resulted in no clinically meaningful changes in the

PK of these medicinal products.

The JAK/STAT pathway has been shown to be involved in cell adhesion and cell polarity which canaffect early embryonic development. There are no adequate data from the use of baricitinib in pregnantwomen. Studies in animals have shown reproductive toxicity (see section 5.3). Baricitinib wasteratogenic in rats and rabbits. Animal studies indicate that baricitinib may have an adverse effect onbone development in utero at higher doses.

Baricitinib is contraindicated during pregnancy (see section 4.3). Women of childbearing potentialhave to use effective contraception during and for at least 1 week after treatment. If a patient becomespregnant while taking baricitinib the parents should be informed of the potential risk to the foetus.

It is unknown whether baricitinib/metabolites are excreted in human milk. Availablepharmacodynamic/toxicological data in animals have shown excretion of baricitinib in milk (seesection 5.3).

A risk to newborns/infants cannot be excluded and baricitinib should not be used duringbreast-feeding. A decision must be made whether to discontinue breast-feeding or to discontinuetherapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for thewoman.

Studies in animals suggest that treatment with baricitinib has the potential to decrease female fertilitywhile on treatment, but there was no effect on male spermatogenesis (see section 5.3).

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

The most commonly reported adverse reactions with baricitinib are increased LDL cholesterol(26.0 %), upper respiratory tract infections (16.9 %), headache (5.2 %), herpes simplex (3.2 %), andurinary tract infections (2.9 %). Serious pneumonia and serious herpes zoster occurred uncommonly inpatients with rheumatoid arthritis.

Frequency estimate: Very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000). The frequencies in Table 2 arebased on integrated data from clinical trials in adults and/or postmarketing setting across rheumatoidarthritis, atopic dermatitis, and alopecia areata indications unless stated otherwise; where notabledifferences in frequency between indications are observed, these are presented in the footnotes belowthe table.

Table 2. Adverse reactions

System organ Very common Common Uncommonclass

Infections and Upper respiratory tract Herpes zosterbinfestations infections Herpes simplex

Gastroenteritis

Urinary tract infections

Pneumoniad

Folliculitisg

Blood and Thrombocytosis Neutropaenialymphatic > 600 x 109 cells/La, d < 1 x 109 cells/Lasystem disorders

Immune system Swelling of the face,disorders Urticaria

Metabolism and Hypercholesterolaemiaa Hypertriglyceridaemiaanutritiondisorders

Nervous system Headachedisorders

Vascular Deep vein thrombosisbdisorders

Respiratory, Pulmonary embolismfthoracic,mediastinaldisorders

Gastrointestinal Nausead Diverticulitisdisorders Abdominal paind

Hepatobiliary ALT increased AST increased ≥ 3 x ULNa, edisorders ≥ 3 x ULNa, d

Skin and Rashsubcutaneous Acnectissue disorders

Investigations Creatine phosphokinase Weight increasedincreased > 5 x ULNa, ca Includes changes detected during laboratory monitoring (see text below).b Frequency for herpes zoster and deep vein thrombosis is based on rheumatoid arthritis clinical trials.c In rheumatoid arthritis clinical trials, the frequency of acne and creatine phosphokinase increased> 5 x ULN was uncommon.d In atopic dermatitis clinical trials, the frequency of nausea, and ALT ≥3 x ULN was uncommon. Inalopecia areata clinical trials, the frequency of abdominal pain was uncommon. In atopic dermatitisand alopecia areata clinical trials, the frequency of pneumonia and thrombocytosis> 600 x 109 cells/L was uncommon.

e In alopecia areata clinical trials, the frequency of AST ≥ 3 x ULN was common.f Frequency for pulmonary embolism is based on rheumatoid arthritis and atopic dermatitis clinicaltrials.g Folliculitis was observed in alopecia areata clinical trials. It was usually localized in the scalp regionassociated with hair regrowth.

In rheumatoid arthritis clinical studies, in treatment-naïve patients, through 52 weeks, the frequency ofnausea was greater for the combination treatment of methotrexate and baricitinib (9.3 %) compared tomethotrexate alone (6.2 %) or baricitinib alone (4.4 %). In the integrated data from rheumatoidarthritis, atopic dermatitis and alopecia areata clinical trials, nausea was most frequent during the first2 weeks of treatment.

Cases of abdominal pain were usually mild, transient, not associated with infectious or inflammatorygastrointestinal disorders, and did not lead to treatment interruption.

In the integrated data from rheumatoid arthritis, atopic dermatitis and alopecia areata clinical trials,most infections were mild to moderate in severity. In studies which included both doses, infectionswere reported in 31.0 %, 25.7 % and 26.7 % of patients in the 4 mg, 2 mg and placebo groups,respectively. In rheumatoid arthritis clinical studies, combination with methotrexate resulted inincreased frequency of infections compared to baricitinib monotherapy. Frequency of herpes zosterwas common in rheumatoid arthritis, very rare in atopic dermatitis and uncommon in alopecia areata.

In atopic dermatitis clinical trials, there were less skin infections requiring antibiotic treatment withbaricitinib than with placebo.

The incidence of serious infections with baricitinib was similar to placebo. The incidence of seriousinfections remained stable during long term exposure. The overall incidence rate of serious infectionsin the clinical trial programme was 3.2 per 100 patient-years in rheumatoid arthritis, 2.1 in atopicdermatitis and 0.8 in alopecia areata. Serious pneumonia and serious herpes zoster occurreduncommonly in patients with rheumatoid arthritis.

Hepatic transaminase elevations

Dose dependent increases in blood ALT and AST activity were reported in studies extended overweek 16. Elevations in mean ALT/AST remained stable over time. Most cases of hepatic transaminaseelevations ≥ 3 x ULN were asymptomatic and transient.

In patients with rheumatoid arthritis, the combination of baricitinib with potentially hepatotoxicmedicinal products, such as methotrexate, resulted in increased frequency of these elevations.

Lipid elevations

In the integrated data from rheumatoid arthritis, atopic dermatitis and alopecia areata clinical trials,baricitinib treatment was associated with dose-dependent increases in lipid parameters including totalcholesterol, LDL cholesterol, and high density lipoprotein (HDL) cholesterol. There was no change inthe LDL/HDL ratio. Elevations were observed at 12 weeks and remained stable thereafter at a highervalue than baseline including in the long-term extension study in rheumatoid arthritis. Mean total and

LDL cholesterol increased through week 52 in patients with atopic dermatitis and alopecia areata. Inrheumatoid arthritis clinical trials, baricitinib treatment was associated with dose-dependent increasesin triglycerides. There was no increase in triglycerides levels in atopic dermatitis and alopecia areataclinical trials.

Elevations in LDL cholesterol decreased to pre-treatment levels in response to statin therapy.

Creatine phosphokinase (CPK)

Baricitinib treatment was associated with dose-dependent increases in CPK. Mean CPK was increasedat week 4 and remained at a higher value than baseline thereafter. Across indications, most cases of

CPK elevations > 5 x ULN were transient and did not require treatment discontinuation.

In clinical trials, there were no confirmed cases of rhabdomyolysis.

Neutropaenia

Mean neutrophil counts decreased at 4 weeks and remained stable at a lower value than baseline overtime. There was no clear relationship between neutropaenia and the occurrence of serious infections.

However, in clinical studies, treatment was interrupted in response to ANC < 1 x 109 cells/L.

Thrombocytosis

Dose-dependent increases in mean platelet counts were observed and remained stable at a higher valuethan baseline over time.

A total of 220 patients from 2 to less than 18 years of age were exposed to any dose of baricitinib inthe juvenile idiopathic arthritis clinical trial programme, representing 326 patient years’ exposure.

In paediatric patients treated with baricitinib in the placebo-controlled double-blind randomisedwithdrawal period of the juvenile idiopathic arthritis clinical trial (n=82), headache was very common(11 %), neutropenia < 1 000 cells/mm3 was common (2.4 %, one patient) and pulmonary embolismwas common (1.2 %, one patient).

Paediatric atopic dermatitis

The safety assessment in children and adolescents is based on the safety data of the phase III trial

BREEZE-AD-PEDS in which 466 patients between 2 and 18 years of age received any dose ofbaricitinib. Overall, the safety profile in these patients was comparable to that observed in the adultpopulation. Neutropaenia (< 1 x 109 cells/L) was more common (1.7%) compared to adults.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Single doses up to 40 mg and multiple doses of up to 20 mg daily for 10 days have been administeredto adult patients in clinical trials without dose-limiting toxicity. No specific toxicities were identified.

Pharmacokinetic data of a single dose of 40 mg in healthy volunteers indicate that more than 90 % ofthe administered dose is expected to be eliminated within 24 hours. In case of an overdose, it isrecommended that the patient be monitored for signs and symptoms of adverse reactions. Patients whodevelop adverse reactions should receive appropriate treatment.

Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants, ATC code:

L04AF02

Baricitinib is a selective and reversible inhibitor of Janus kinase (JAK)1 and JAK2. In isolated enzymeassays, baricitinib inhibited the activities of JAK1, JAK2, Tyrosine Kinase 2 and JAK3 with IC50values of 5.9, 5.7, 53 and > 400 nM, respectively.

Janus kinases (JAKs) are enzymes that transduce intracellular signals from cell surface receptors for anumber of cytokines and growth factors involved in haematopoiesis, inflammation and immunefunction. Within the intracellular signalling pathway, JAKs phosphorylate and activate signaltransducers and activators of transcription (STATs), which activate gene expression within the cell.

Baricitinib modulates these signalling pathways by partially inhibiting JAK1 and JAK2 enzymaticactivity, thereby reducing the phosphorylation and activation of STATs.

Inhibition of IL-6 induced STAT3 phosphorylation

Administration of baricitinib resulted in a dose dependent inhibition of IL-6 induced STAT3phosphorylation in whole blood from healthy subjects with maximal inhibition observed 2 hours afterdosing which returned to near baseline by 24 hours.

Immunoglobulins

Mean serum IgG, IgM, and IgA values decreased by 12 weeks after starting treatment, and remainedstable at a lower value than baseline through at least 104 weeks. For most patients, changes inimmunoglobulins occurred within the normal reference range.

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

C-reactive protein

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

Creatinine

In clinical trials, baricitinib induced a mean increase in serum creatinine levels of 3.8 µmol/L after twoweeks of treatment, which remained stable thereafter. This may be due to inhibition of creatininesecretion by baricitinib in the renal tubules. Consequently, estimates of the glomerular filtration ratebased on serum creatinine may be slightly reduced, without actual loss of renal function or theoccurrence of renal adverse reactions. In alopecia areata, mean serum creatinine continued to increaseup to week 52. In atopic dermatitis and alopecia areata, baricitinib was associated with a decrease incystatin C (also used to estimate glomerular filtration rate) at week 4, with no further decreasesthereafter.

In vitro skin models

In an in vitro human skin model treated with pro-inflammatory cytokines (i.e., IL-4, IL-13, IL-31),baricitinib reduced epidermal keratinocyte pSTAT3 expression, and increased the expression offilaggrin, a protein that plays a role in skin barrier function and in the pathogenesis of atopicdermatitis.

Vaccine study

The influence of baricitinib on the humoral response to non-live vaccines was evaluated in106 rheumatoid arthritis patients under stable treatment with baricitinib 2 or 4 mg, receiving inactivatedpneumococcal or tetanus vaccination. The majority of these patients (n = 94) were co-treated withmethotrexate. For the total population, pneumococcal vaccination resulted in a satisfactory IgG immuneresponse in 68 % (95 % CI: 58.4 %, 76.2 %) of the patients. In 43.1 % (95 % CI: 34 %, 52.8 %) of thepatients, a satisfactory IgG immune response to tetanus vaccination was achieved.

The efficacy and safety of baricitinib once daily were assessed in 4 Phase III randomised,double-blind, multicentre studies in adult patients with moderate to severe active rheumatoid arthritisdiagnosed according to the ACR/EULAR 2010 criteria (Table 3). The presence of at least 6 tender and6 swollen joints was required at baseline. All patients who completed these studies were eligible toenrol in a long term extension study for up to 7 years additional treatment.

Table 3. Clinical trial summary

Study name Population Treatment arms Summary of key outcome measures(Duration) (Number)

RA-BEGIN MTX-naïve1 * Baricitinib 4 mg QD * Primary endpoint: ACR20 at week 24(52 weeks) (584) * Baricitinib 4 mg QD + MTX * Physical function (HAQ-DI)

* MTX * Radiographic progression (mTSS)

* Low disease activity and Remission (SDAI)

RA-BEAM MTX-IR2 * Baricitinib 4 mg QD * Primary endpoint:ACR20 at week 12(52 weeks) (1305) * Adalimumab 40 mg SC Q2W * Physical function (HAQ-DI)

* Placebo * Radiographic progression (mTSS)

* Low disease activity and Remission (SDAI)

All patients on background MTX * Morning Joint Stiffness

RA-BUILD cDMARD-IR3 * Baricitinib 4 mg QD * Primary endpoint: ACR20 at week 12(24 weeks) (684) * Baricitinib 2 mg QD * Physical function (HAQ-DI)

* Placebo * Low disease activity and remission (SDAI)

* Radiographic progression (mTSS)

On background cDMARDs5 if on * Morning Joint Stiffnessstable cDMARD at study entry

RA- TNF-IR4 * Baricitinib 4 mg QD * Primary endpoint: ACR20 at week 12

BEACON (527) * Baricitinib 2 mg QD * Physical function (HAQ-DI)(24 weeks) * Placebo * Low disease activity and Remission (SDAI)

On background cDMARDs5

Abbreviations: IR = inadequate responder; QD = Once daily; Q2W = Once every 2 weeks;

SC = Subcutaneously; ACR = American College of Rheumatology; SDAI = Simplified Disease

Activity Index; HAQ-DI = Health Assessment Questionnaire-Disability Index; mTSS = modified

Total Sharp Score1 Patients who had received less than 3 doses of Methotrexate (MTX); naïve to other conventional orbiologic DMARDs2 Patients who had an inadequate response to MTX (+/- other cDMARDs); biologic-naïve3 Patients who had an inadequate response or were intolerant to ≥ 1 cDMARDs; biologic- naïve4 Patients who had an inadequate response or were intolerant to ≥ 1 bDMARDs; including at least one

TNF inhibitor5 Most common concomitant cDMARDs included MTX, hydroxychloroquine, leflunomide andsulfasalazine

In all studies, patients treated with baricitinib 4 mg once daily had statistically significantly higher

ACR20, ACR50 and ACR70 response at 12 weeks compared to placebo, methotrexate (MTX) oradalimumab (Table 4). Time to onset of efficacy was rapid across measures with significantly greaterresponses 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 baricitinib 4 mg, alone or in combination with cDMARDs, resulted in significantimprovements in all individual ACR components, including tender and swollen joint counts, patientand physician global assessments, HAQ-DI, pain assessment and CRP, compared to placebo, MTX oradalimumab.

No relevant differences regarding efficacy and safety were observed in subgroups defined by types ofconcomitant DMARDs used in combination with baricitinib.

Remission and low disease activity

A statistically significantly greater proportion of patients treated with baricitinib 4 mg compared toplacebo or MTX achieved remission (SDAI ≤ 3.3 and CDAI ≤ 2.8) or low disease activity orremission (DAS28-ESR or DAS28-hsCRP ≤ 3.2 and DAS28-ESR or DAS28-hsCRP < 2.6), atweeks 12 and 24 (Table 4).

Greater rates of remission compared to placebo were observed as early as week 4. Remission and lowdisease activity rates were maintained for at least 2 years. Data from the long-term extension study upto 6 years follow-up indicate durable low disease activity/remission rates.

Table 4: Response, remission and physical function

Study RA-BEGIN RA-BEAM RA-BUILD RA-BEACON

MTX-naïve patients MTX-IR patients cDMARD-IR patients TNF-IR patients

Treatment MTX BARI BARI PBO BARI ADA PBO BARI BARI PBO BARI BARIgroup 4 mg 4 mg 4 mg 40 mg 2 mg 4 mg 2 mg 4 mg+ MTX Q2W

N 210 159 215 488 487 330 228 229 227 176 174 177

ACR20:

Week 12 59 % 79 %*** 77 %*** 40 % 70 %***† 61 %*** 39 % 66 %*** 62 %*** 27 % 49 %*** 55 %***

Week 24 62 % 77 %** 78 %*** 37 % 74 %***† 66 %*** 42 % 61 %*** 65 %*** 27 % 45 %*** 46 %***

Week 52 56 % 73 %*** 73 %*** 71 %†† 62 %

ACR50:

Week 12 33 % 55 %*** 60 %*** 17 % 45 %***†† 35 %*** 13 % 33 %*** 34 %*** 8 % 20 %** 28 %***

Week 24 43 % 60 %** 63 %*** 19 % 51 %*** 45 %*** 21 % 41 %*** 44 %*** 13 % 23 %* 29 %***

Week 52 38 % 57 %*** 62 %*** 56 %† 47 %

ACR70:

Week 12 16 % 31 %*** 34 %*** 5 % 19 %***† 13 %*** 3 % 18 %*** 18 %*** 2 % 13 %*** 11 %**

Week 24 21 % 42 %*** 40 %*** 8 % 30 %***† 22 %*** 8 % 25 %*** 24 %*** 3 % 13 %*** 17 %***

Week 52 25 % 42 %*** 46 %*** 37 % 31 %

DAS28-hsCRP ≤ 3.2:

Week 12 30 % 47 %*** 56 %*** 14 % 44 %***†† 35 %*** 17 % 36 %*** 39 %*** 9 % 24 %*** 32 %***

Week 24 38 % 57 %*** 60 %*** 19 % 52 %*** 48 %*** 24 % 46 %*** 52 %*** 11 % 20 %* 33 %***

Week 52 38 % 57 %*** 63 %*** 56 %† 48 %

SDAI ≤ 3.3:

Week 12 6 % 14 %* 20 %*** 2 % 8 %*** 7 %*** 1 % 9 %*** 9 %*** 2 % 2 % 5 %

Week 24 10 % 22 %** 23 %*** 3 % 16 %*** 14 %*** 4 % 17 %*** 15 %*** 2 % 5 % 9 %**

Week 52 13 % 25 %** 30 %*** 23 % 18 %

CDAI ≤ 2.8:

Week 12 7 % 14 %* 19 %*** 2 % 8 %*** 7 %** 2 % 10 %*** 9 %*** 2 % 3 % 6 %

Week 24 11 % 21 %** 22 %** 4 % 16 %*** 12 %*** 4 % 15 %*** 15 %*** 3 % 5 % 9 %*

Week 52 16 % 25 %* 28 %** 22 % 18 %

HAQ-DI Minimum Clinically Important Difference (decrease in HAQ-DI score of ≥ 0.30):

Week 12 60 % 81 %*** 77 %*** 46 % 68 %*** 64 %*** 44 % 60 %*** 56 %** 35 % 48 %* 54 %***

Week 24 66 % 77 %* 74 % 37 % 67 %***† 60 %*** 37 % 58 %*** 55 %*** 24 % 41 %*** 44 %***

Week 52 53 % 65 %* 67 %** 61 % 55 %

Note: Proportions of responders at each time point based on those initially randomised to treatment(N). Patients who discontinued or received rescue therapy were considered as non-respondersthereafter.

Abbreviations: ADA = adalimumab; BARI = baricitinib; IR = inadequate responder;

MTX = methotrexate; PBO = Placebo

* p ≤ 0.05; ** p ≤ 0.01; *** p ≤ 0.001 vs. placebo (vs. MTX for study RA-BEGIN)† p ≤ 0.05; †† p ≤ 0.01; ††† p ≤ 0.001 vs. adalimumab

The effect of baricitinib on progression of structural joint damage was evaluated radiographically instudies 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 baricitinib 4 mg resulted in a statistically significant inhibition of progression ofstructural joint damage (Table 5). Analyses of erosion and joint space narrowing scores wereconsistent with the overall scores. The proportion of patients with no radiographic progression (mTSSchange ≤ 0) was significantly higher with baricitinib 4 mg compared to placebo at weeks 24 and 52.

Table 5. Radiographic changes

Study RA-BEGIN RA-BEAM RA-BUILD

MTX-naïve patients MTX-IR patients cDMARD-IR patients

Treatment MTX BARI4 BARI4 PBOa BARI4 ADA PBO BARI2 BARI4group mg mg mg 40 mg mg mg+ MTX Q2W

Modified Total Sharp Score, mean change from baseline:

Week 24 0.61 0.39 0.29* 0.90 0.41*** 0.33*** 0.70 0.33* 0.15**

Week 52 1.02 0.80 0.40** 1.80 0.71*** 0.60***

Proportion of patients with no radiographic progressionb:

Week 24 68 % 76 % 81 %** 70 % 81 %*** 83 %*** 74 % 72 % 80 %

Week 52 66 % 69 % 80 %** 70 % 79 %** 81 %**

Abbreviations: ADA = adalimumab; BARI = baricitinib; IR = inadequate responder;

MTX = methotrexate; PBO = Placeboa Placebo data at week 52 derived using linear extrapolationb No progression defined as mTSS change ≤ 0.

* p ≤ 0.05; ** p ≤ 0.01; *** p ≤ 0.001 vs. placebo (vs. MTX for study RA-BEGIN)

Physical function response and health-related outcomes

Treatment with baricitinib 4 mg, alone or in combination with cDMARDs, resulted in a significantimprovement in physical function (HAQ-DI) and pain (0-100 visual analogue scale) compared to allcomparators (placebo, MTX, adalimumab). Improvements were seen as early as week 1 and, instudies RA-BEGIN and RA-BEAM, this was maintained for up to 52 weeks.

In RA-BEAM and RA-BUILD, treatment with baricitinib 4 mg resulted in a significant improvementin the mean duration and severity of morning joint stiffness compared to placebo or adalimumab asassessed using daily electronic patient diaries.

In all studies, baricitinib-treated patients reported improvements in patient-reported quality of life, asmeasured by the Short Form (36) Health Survey (SF-36) Physical Component Score and fatigue, asmeasured by the Functional Assessment of Chronic Illness Therapy-Fatigue score (FACIT-F).

Baricitinib 4 mg vs. 2 mg

Differences in efficacy between the 4 mg and the 2 mg doses were most notable in thebDMARD-inadequate responder (IR) population (RA-BEACON), in which statistically significantimprovements in the ACR components of swollen joint count, tender joint count and ESR were shownfor baricitinib 4 mg compared to placebo at week 24 but not for baricitinib 2 mg compared to placebo.

In addition, for both study RA-BEACON and RA-BUILD, onset of efficacy was faster and the effectsize was generally larger for the 4 mg dose groups compared to 2 mg.

In a long-term extension study, patients from Studies RA-BEAM, RA-BUILD and RA-BEACON whoachieved sustained low disease activity or remission (CDAI ≤ 10) after at least 15 months of treatmentwith baricitinib 4 mg once daily were re-randomised 1:1 in a double-blind manner to continue 4 mgonce daily or reduce dose to 2 mg once daily. The majority of patients maintained low disease activityor remission based on CDAI score:

* At week 12: 451/498 (91 %) continuing 4 mg vs. 405/498 (81 %) reduced to 2 mg (p ≤ 0.001)

* At week 24: 434/498 (87 %) continuing 4 mg vs. 372/498 (75 %) reduced to 2 mg (p ≤ 0.001)

* At week 48: 400/498 (80 %) continuing 4 mg vs. 343/498 (69 %) reduced to 2 mg (p ≤ 0.001)

* At week 96: 347/494 (70 %) continuing 4 mg vs. 297/496 (60 %) reduced to 2 mg (p ≤ 0.001)

The majority of patients who lost their low disease activity or remission status after dose reductioncould regain disease control after the dose was returned to 4 mg.

Adults with atopic dermatitis

The efficacy and safety of baricitinib 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 studies included 1 568 patients with moderate to severe atopicdermatitis 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 patientswere over 18 years of age and had previous inadequate response or were intolerant to topicalmedicinal products. Patients were permitted to receive rescue treatment (which included topical orsystemic therapy), at which time they were considered non-responders. At baseline of study BREEZE-

AD7, all patients were on concomitant topical corticosteroids therapy and patients were permitted touse topical calcineurin inhibitors. All patients who completed these studies were eligible to enrol in along term extension study (BREEZE AD-3) for up to 4 years of continued treatment.

The Phase III randomised, double-blind, placebo-controlled BREEZE-AD4 study evaluated theefficacy of baricitinib in combination with topical corticosteroids over 52 weeks in 463 patients withmoderate to severe atopic dermatitis with failure, intolerance, or contraindication to oral ciclosporintreatment.

Baseline characteristics

In the placebo-controlled Phase III studies (BREEZE-AD1, -AD2, -AD7, and -AD4), across alltreatment groups, 37 % were female, 64 % were Caucasian, 31 % were Asian and 0.6 % were Black,and the mean age was 35.6 years. In these studies, 42 % to 51 % of patients had a baseline IGA of 4(severe atopic dermatitis), and 54 % to 79 % of patients had received prior systemic treatment foratopic dermatitis. The baseline mean EASI score ranged from 29.6 to 33.5, the baseline weeklyaveraged Itch Numerical Rating Scale (NRS) ranged from 6.5 to 7.1, the baseline mean Dermatology

Life Quality Index (DLQI) ranged from 13.6 to 14.9, and the baseline mean Hospital Anxiety and

Depression Scale (HADS) Total score ranged from 10.9 to 12.1.

Clinical response16-week monotherapy (BREEZE-AD1, -AD2) and TCS combination (BREEZE-AD7) studies

A significantly larger proportion of patients randomised to baricitinib 4 mg achieved an IGA 0 or1 response (primary outcome), EASI75, or an improvement of ≥ 4 points on the Itch NRS compared toplacebo at week 16 (Table 6). Figure 1 shows the mean percent change from baseline in EASI up toweek 16.

A significantly greater proportion of patients randomised to baricitinib 4 mg achieved a ≥ 4-pointimprovement in the Itch NRS compared to placebo (within the first week of treatment for

BREEZE-AD1 and AD2, and as early as week 2 for BREEZE-AD7; p < 0.002).

Treatment effects in subgroups (weight, age, gender, race, disease severity, and previous treatment,including immunosuppressants) were consistent with the results in the overall study population.

Table 6. Efficacy of baricitinib at week 16 (FASa)

Monotherapy TCS Combination

Study BREEZE- AD1 BREEZE-AD2 BREEZE- AD7

Treatment PBO BARI BARI PBO BARI BARI PBO + BARI BARI

Group 2 mg 4 mg 2 mg 4 mg TCS 2 mg + 4 mg +

TCS TCS

N 249 123 125 244 123 123 109 109 111

IGA 0 or 1, 4.8 11.4** 16.8** 4.5 10.6** 13.8** 14.7 23.9 30.6**% respondersb, c

EASI-75, 8.8 18.7** 24.8** 6.1 17.9** 21.1** 22.9 43.1* 47.7**% respondersc

Itch NRS 7.2 12.0 21.5** 4.7 15.1** 18.7** 20.2 38.1* 44.0**(≥ 4 pointimprovement),% respondersc, d

BARI = Baricitinib; PBO = Placebo

* statistically significant vs placebo without adjustment for multiplicity; ** statistically significant vsplacebo with adjustment for multiplicity.a Full analysis set (FAS) including all randomised patients.b Responder was defined as a patient with IGA 0 or 1 (“clear” or “almost clear”) with a reduction of≥ 2 points on 0-4 IGA scale.c Non-Responder Imputation: Patients who received rescue treatment or with missing data wereconsidered as non-responders.d Results shown in subset of patients eligible for assessment (patients with itch NRS ≥ 4 at baseline).

Figure 1. Mean percent change from baseline in EASI (FAS)a

LS = Least squares; * statistically significant vs placebo without adjustment for multiplicity; **statistically significant vs placebo with adjustment for multiplicity.a Full analysis set (FAS) including all patients randomised. Data collected after rescue therapy or afterpermanent medicinal product discontinuation were considered missing. LS means are from Mixed

Model with Repeated Measures (MMRM) analyses.

To evaluate maintenance of response, 1 398 subjects treated with baricitinib for 16 weeks in

BREEZE-AD1 (N = 566), BREEZE-AD2 (N = 540) and BREEZE-AD7 (N = 292) were eligible toenrol in a long term extension study BREEZE-AD3. Data are available up to 4 years (216 weeks) ofcumulative treatment. Continued response was observed in patients with at least some response (IGA0, 1 or 2) after initiating baricitinib.

Dose tapering

In the long-term extension study BREEZE-AD3, patients who had clear, almost clear skin, or milddisease (i.e., IGA 0, 1, or 2) with baricitinib 4 mg once daily were re-randomised at Week 52 tocontinue 4 mg once daily or reduce the dose to 2 mg once daily. Among patients who reduced the doseto 2 mg, 37 % had an IGA 0, 1, or 2 response and 52 % had an EASI75 response at Week 200. 47 %of patients in this group had an Itch NRS ≥ 4-point improvement at Week 52, and 40 % had thisimprovement at Week 68. The proportion of patients with a relapse (IGA ≥ 3) was lower in thesubgroup of patients with clear, or almost clear skin (IGA 0 or 1) at start of dose reduction. For thosepatients who experienced a relapse (IGA ≥ 3) after dose reduction, the majority regained diseasecontrol upon retreatment with baricitinib 4 mg.

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), baricitinib 4 mg significantly improved patient-reported outcomes, including itch

NRS, sleep (ADSS), skin pain (skin pain NRS), quality of life (DLQI) and symptoms of anxiety anddepression (HADS) that were uncorrected for multiplicity, at 16 weeks compared to placebo (See

Table 7).

Table 7. Quality of life/patient-reported outcomes results of baricitinib monotherapy andbaricitinib in combination with TCS at week 16 (FAS) a

Monotherapy TCS Combination

Study BREEZE-AD1 BREEZE-AD2 BREEZE-AD7

Treatment group PBO BARI BARI PBO BARI BARI PBO + BARI BARI2 mg 4 mg 2 mg 4 mg TCS 2 mg + 4 mg +

TCS TCS

N 249 123 125 244 123 123 109 109 111

ADSS Item 2 12.8 11.4 32.7* 8.0 19.6 24.4* 30.6 61.5* 66.7*≥ 2-pointimprovement,% respondersc,d

Change in Skin -0.84 -1.58 -1.93** -0.86 -2.61** -2.49** -2.06 -3.22* -3.73*

Pain NRS, (0.24) (0.29) (0.26) (0.26) (0.30) (0.28) (0.23) (0.22) (0.23)mean(SE)b

Change in DLQI, -2.46 -4.30* -6.76* -3.35 -7.44* -7.56* -5.58 -7.50* -8.89*mean(SE)b (0.57) (0.68) (0.60) (0.62) (0.71) (0.66) (0.61) (0.58) (0.58)

Change in -1.22 -3.22* -3.56* -1.25 -2.82 -3.71* -3.18 -4.75* -5.12*

HADS, (0.48) (0.58) (0.52) (0.57) (0.66) (0.62) (0.56) (0.54) (0.54)mean(SE)b

BARI = Baricitinib; PBO = Placebo

* statistically significant vs placebo without adjustment for multiplicity; ** statistically significant vsplacebo with adjustment for multiplicity.a Full analysis set (FAS) including all randomised patients.b Results shown are LS mean change from baseline (SE). Data collected after rescue therapy or afterpermanent medicinal product discontinuation were considered missing. LS means are from Mixed

Model with Repeated Measures (MMRM) analyses.c ADSS Item 2: Number of night time awakenings due to itch.d Nonresponder imputation: patients who received rescue treatment or with missing data wereconsidered as nonresponders. Results shown in subset of patients eligible for assessment (patients with

ADSS Item 2 ≥ 2 at baseline).

Clinical response in patients with experience with or a contra-indication to ciclosporin treatment(BREEZE-AD4 study)

A total of 463 patients were enrolled, who had either failed (n = 173), or had an intolerance (n = 75),or contraindication (n = 126) to oral ciclosporin. The primary endpoint was the proportion of patientsachieving EASI-75 at week 16. The primary and some of the most important secondary endpoints atweek 16 are summarised in Table 8.

Table 8: Efficacy of baricitinib in combination with TCSa at week 16 in BREEZE-AD4 (FAS)b

Study BREEZE- AD4

Treatment PBOa BARI 2 mga BARI 4 mgagroup

N 93 185 92

EASI-75, 17.2 27.6 31.5**% respondersc

IGA 0 or 1, 9.7 15.1 21.7*% respondersc, e

Itch NRS (≥ 4 point 8.2 22.9* 38.2**improvement), % respondersc, f

Change in DLQI mean (SE)d -4.95 -6.57 -7.95*(0.752) (0.494) (0.705)

BARI = Baricitinib; PBO = Placebo

* statistically significant vs placebo without adjustment for multiplicity; ** statistically significant vsplacebo with adjustment for multiplicity.a All patients were on concomitant topical corticosteroids therapy and patients were permitted to usetopical calcineurin inhibitors.b Full analysis set (FAS) includes all randomised patients.c Non-Responder Imputation: Patients who received rescue treatment or with missing data wereconsidered as non-responders.d Data collected after rescue therapy or after permanent medicinal product discontinuation wereconsidered missing. LS means are from Mixed Model with Repeated Measures (MMRM) analyses.e Responder was defined as a patient with IGA 0 or 1 (“clear” or “almost clear”) with a reduction of≥ 2 points on 0-4 IGA scale.f Results shown in subset of patients eligible for assessment (patients with itch NRS ≥ 4 at baseline).

Alopecia areata

The efficacy and safety of baricitinib once daily were assessed in one adaptive Phase II/III study(BRAVE-AA1) and one Phase III study (BRAVE-AA2). The Phase III portion of BRAVE-AA1 studyand the Phase III BRAVE-AA2 study were randomised, double blind, placebo-controlled, 36-weekstudies with extension phases up to 200 weeks. In both phase III studies, patients were randomised toplacebo, 2 mg or 4 mg baricitinib in a 2:2:3 ratio. Eligible patients were adults between 18 years and60 years of age for male patients, and between 18 years and 70 years of age for female patients, with acurrent episode of more than 6 months of severe alopecia areata (hair loss encompassing ≥ 50 % of thescalp). Patients with a current episode of more than 8 years were not eligible unless episodes ofregrowth had been observed on the affected areas of the scalp over the past 8 years. The onlypermitted concomitant alopecia areata therapies were finasteride (or other 5 alpha reductaseinhibitors), oral or topical minoxidil and bimatoprost ophthalmic solution for eyelashes, if at a stabledose at study entry.

Both studies assessed as primary outcome the proportion of subjects who achieved a SALT (Severityof Alopecia Tool) score of ≤ 20 (80 % or more scalp coverage with hair) at week 36. Additionally,both studies evaluated clinician assessment of eyebrow and eyelash hair loss using a 4-point scale(ClinRO Measure for Eyebrow Hair Loss™, ClinRO Measure for Eyelash Hair Loss™).

Baseline characteristics

The Phase III portion of BRAVE-AA1 study and the Phase III BRAVE-AA2 study included1 200 adult patients. Across all treatment groups, the mean age was 37.5 years, 61 % of patients werefemale. The mean duration of alopecia areata from onset and the mean duration of current episode ofhair loss were 12.2 and 3.9 years, respectively. The median SALT score across the studies was 96 (thisequals 96 % scalp hair loss), and approximately 44 % of patients were reported as alopecia universalis.

Across the studies, 69 % of patients had significant or complete eyebrow hair loss at baseline and58 % had significant or complete eyelash hair loss, as measured by ClinRO Measures for eyebrow andeyelash scores of 2 or 3. Approximately 90 % of patients had received at least one treatment foralopecia areata at some point before entering the studies, and 50 % at least one systemicimmunosuppressant. The use of authorised concomitant alopecia areata treatments was reported byonly 4.3 % of patients during the studies.

In both studies, a significantly greater proportion of patients randomised to baricitinib 4 mg once dailyachieved a SALT ≤ 20 at week 36 compared to placebo, starting as early as week 8 in study

BRAVE-AA1 and week 12 in study BRAVE-AA2. Consistent efficacy was seen across most of thesecondary endpoints (Table 9). Figure 2 shows the proportion of patients achieving SALT ≤ 20 up toweek 36.

Treatment effects in subgroups (gender, age, weight, eGFR, race, geographic region, disease severity,current alopecia areata episode duration) were consistent with the results in the overall studypopulation at week 36.

Table 9. Efficacy of baricitinib through week 36 for pooled studies (Pooled Week 36 Efficacy

Populationa)

BRAVE-AA1 (phase III part of a phase II/III study) and

BRAVE-AA2 (phase III study) Pooled Data*

Placebo Baricitinib 2 mg Baricitinib 4 mg

N=345 N=340 N=515

SALT ≤ 20 at week 36 4.1 % 19.7 %** 34.0 %**

SALT ≤ 20 at week 24 3.2 % 11.2 % 27.4 %**

ClinRO Measure for 3.8 % 15.8 % 33.0 %**

Eyebrow Hair Loss of0 or 1 at week 36 witha ≥ 2 pointimprovement frombaselineb

ClinRO Measure for 4.3 % 12.0 % 33.9 %**

Eyelash Hair Loss of 0or 1 at week 36 with a≥ 2 point improvementfrom baselineb

Change in Skindex-16 -11.33 (1.768) -19.89 (1.788) -23.81 (1.488)adapted for alopeciaareata emotionsdomain, mean (SE)c

Change in Skindex-16 -9.26 (1.605) -13.68 (1.623) -16.93 (1.349)adapted for alopeciaareata functioningdomain, mean (SE)c

ClinRO = clinician-reported outcome; SE = standard errora Pooled Week 36 Efficacy Population: All patients enrolled in the Phase III portion of Study

BRAVE-AA1 and in Study BRAVE-AA2.

* The results of the pooled analysis are in line with those of the individual studies

** Statistically significant with adjustment for multiplicity in the graphical testing scheme within eachindividual study.b Patients with ClinRO Measure for Eyebrow Hair loss score of ≥ 2 at baseline: 236 (Placebo),240 (Baricitinib 2 mg), 349 (Baricitinib 4 mg). Patients with ClinRO Measure for Eyelash Hair lossscore of ≥ 2 at baseline: 186 (Placebo), 200 (Baricitinib 2 mg), 307 (Baricitinib 4 mg). Both ClinRO

Measures use a 4-point response scale ranging from 0 indicating no hair loss to 3 indicating no notableeyebrow/eyelashes hair.c Sample sizes for analysis on Skindex-16 adapted for alopecia areata at week 36 are n= 256 (Placebo),249 (Baricitinib 2 mg), 392 (Baricitinib 4 mg).

Figure 2: Proportion of patients with SALT ≤ 20 through week 36

**p-value for baricitinib versus placebo ≤ 0.01; ***p-value for baricitinib versus placebo ≤ 0.001.

Efficacy up to week 52

The proportion of patients treated with baricitinib achieving a SALT ≤ 20 continued to increase afterweek 36, reaching 39.0 % of patients on baricitinib 4 mg at week 52. The results for the baselinedisease severity and episode duration subpopulations at week 52 were consistent with those observedat week 36 and with the results in the overall study population.

Dose tapering substudy

In the study BRAVE-AA2, patients who had received baricitinib 4 mg once daily since the initialrandomization and achieved SALT ≤ 20 at week 52 were re-randomised in a double-blind manner tocontinue 4 mg once daily or reduce dose to 2 mg once daily. The results show that 96 % of the patientswho remained on baricitinib 4 mg and 74 % of the patients who were re-randomised tobaricitinib 2 mg maintained their response at week 76.

The baricitinib clinical development programme for juvenile idiopathic arthritis consisted of onecompleted pivotal Phase III study (JUVE-BASIS) and one ongoing long-term open label safetyextension study (JUVE-X).

JUVE-BASIS was a double-blind randomised withdrawal (DBW), up to 44-week placebo-controlledstudy to evaluate the efficacy and safety of baricitinib when administered once daily to patients from2 years to less than 18 years of age with juvenile idiopathic arthritis who have had an inadequateresponse or intolerance to treatment with at least 1 conventional synthetic or biologic DMARD. Thisincluded patients with polyarticular juvenile idiopathic arthritis (rheumatoid factor positive orrheumatoid factor negative), extended oligoarticular course juvenile idiopathic arthritis,enthesitis-related juvenile idiopathic arthritis, and juvenile psoriatic arthritis as defined by the

International League of Associations for Rheumatology (ILAR) criteria. Patients who participated in

JUVE-BASIS were eligible for enrollment into study JUVE-X.

In JUVE-BASIS, patients received open-label once daily baricitinib for approximately 12 weeks frombaseline. Patients 2 to less than 9 years received 2 mg daily and patients 9 to less than 18 yearsreceived 4 mg daily, to attain an equivalent exposure to a 4 mg dose in adults. At week 12, treatmentresponse (based on PedACR30 criteria) was reviewed for each patient. Patients who achieved at least a

PedACR30 response were randomised (1:1 ratio) to receive placebo or to remain on the samebaricitinib dose in the 32-week double-blind, placebo-controlled phase. Patients who did not achieve

PedACR30 were given the option of enrolling to JUVE-X.

The primary efficacy endpoint of JUVE-BASIS was time to disease flare from the initiation of the

DBW period to the end of the DBW period.

Baseline characteristics

A total of 220 patients enrolled JUVE-BASIS. Of these, 163 (74.4 %) patients were eligible to berandomised into the DBW period to either baricitinib (n=82) or placebo (n=81). There were144 patients with polyarticular juvenile idiopathic arthritis, 16 with extended oligoarticular coursejuvenile idiopathic arthritis, 50 with enthesitis-related juvenile idiopathic arthritis and 10 with juvenilepsoriatic arthritis.

In JUVE-BASIS, the mean age was 13 years (standard deviation 3.0) and 69.1 % were female. Patientnumbers per age group were as follows: 2 to <6 years: n=6; 6 to <9 years: n=9; 9 to <12 years: n=30;and 12 to <18 years: n=175.

The average time reported by all patients in the study since juvenile idiopathic arthritis diagnosis was4 years. Use of concomitant therapies was similar across treatment groups in the DBW period (mostcommon concomitant csDMARDs included MTX, sulfasalazine and leflunomide). A total of127 (57.7 %) patients were on MTX at baseline.

In JUVE-BASIS, the group of baricitinib treated patients had a significantly longer time to diseaseflare compared to those receiving placebo (Figure 3). In addition, more patients treated with baricitinibachieved a PedACR value of 30/50/70/90/100 throughout the DBW period, as compared to placebo.

Figure 3. Time to disease flare during the DBW period

CI = confidence interval; HR = hazard ratio; NA = not applicable; No. = number

*a HR - stratified by juvenile idiopathic arthritis categories (polyarticular and extended oligoarticularversus enthesitis-related arthritis and juvenile psoriatic arthritis).

*b P-value is from logrank test stratified by juvenile idiopathic arthritis categories (polyarticular andextended oligoarticular versus enthesitis-related arthritis and juvenile psoriatic arthritis).

Time to disease flare and PedACR score results were overall consistent across juvenile idiopathicarthritis subtypes and background characteristics (including age, geography, weight, prior use ofbiologic, concomitant use of MTX or corticosteroids), and were consistent with those for the overallstudy population.

Paediatric atopic dermatitis

The efficacy and safety of baricitinib in combination with TCS were assessed in a single Phase IIIrandomised, double-blind, placebo-controlled, 16 week study (BREEZE-AD-PEDS). The studyincluded 483 patients with moderate to severe atopic dermatitis defined by IGA score ≥ 3, an EASIscore ≥ 16, and a BSA involvement of ≥ 10 %. Eligible patients were 2 to less than 18 years of age andhad previous inadequate response or were intolerant to topical medications and were candidates forsystemic therapy. All patients were prescribed concomitant low or medium potency topicalcorticosteroids and patients were permitted to use topical calcineurin inhibitors during the study.

Patients were randomised to placebo or baricitinib low, medium or high dose tested (resulting inequivalent exposure to 1 mg, 2 mg or 4 mg in adult AD patients, respectively) in a 1:1:1:1 ratio. Thestudy includes an ongoing long-term extension for up to 4 years.

Baseline characteristics

Across all treatment groups, 76 % were Caucasian, 15% were Asian and 3 % were Black, 50 % werefemale and mean age was 12 years with 72 % at least 10 years of age and 28 % less than 10 years ofage. Patients 6 years and younger comprised 14% of the population (6 years [N=28], 5 years [N=11], 4years [N=16], 3 years [N=8], 2 years [N=5]). In this study, 38 % of patients had a baseline IGA of 4(severe atopic dermatitis), and 42 % of patients had received prior systemic treatment for atopicdermatitis. The baseline EASI score ranged from 12.2 to 70.8, the baseline weekly averaged Itch

Numeric Rating Scale (NRS) in patients at least 10 years of age was 5.5 (SD = 2.6).

A statistically significant larger proportion of patients randomised to the baricitinib 4 mg equivalentdose achieved an IGA 0 or 1 response (primary outcome), EASI75, or an improvement of ≥ 4 pointson the Itch NRS compared to placebo at week 16 (Table 10). Figure 4 shows the time course ofachieving IGA 0 or 1.

Treatment effects in subgroups (weight, age, gender, race, disease severity, and previous treatment,including immunosuppressants) were consistent with the results in the overall study population.

Table 10. Efficacy of baricitinib in paediatric patients at week 16a

Study BREEZE-AD-PEDS

Treatment group PBO BARI 4 mgequivalent

N 122 120

IGA 0 or 1, 16.4 41.7**% respondersb,c

EASI75, 32.0 52.5**% respondersc

Itch NRS (≥4 point 16.4 35.5**improvement),% responders c,d

BARI = Baricitinib; PBO = Placebo

** Statistically significant vs placebo with adjustment for multiplicity.a Intent to Treat (ITT) population (all randomized patients)b Responder was defined as a patient with IGA 0 or 1 (“clear” or “almost clear”) with a reduction of≥ 2 points on 0-4 IGA scale.c Non-Responder Imputation: Patients who received rescue treatment or with missing data wereconsidered as non-responders.d Results shown in subset of patients eligible for assessment (patients aged ≥ 10 years with Itch NRS≥ 4 at baseline, BARI 4 mg equivalent N=62; Placebo, N = 55).

Figure 4. Time course for achieving IGA 0 or 1 with ≥ 2 points improvement in paediatricpatients through week 16

BARI=baricitinib; NRI=non-responder imputation; PBO=placebo* p< 0.05; ** p< 0.01; *** p< 0.001vs. PBO (nominal p-value; logistic regression analysis); † Statistically significant with multiplicityadjustment

A significantly greater proportion of patients randomised to the baricitinib 4 mg equivalent doseachieved a ≥ 4-point improvement in the Itch NRS compared to placebo as early as week 4 (adjustedfor multiplicity).

The need for concomitant TCS use was reduced as demonstrated by a median reduction in gramquantity of TCS use for the baricitinib 4 mg equivalent dose versus placebo over 16 weeks and agreater median number of TCS-free days for the baricitinib 4 mg equivalent dose (25 days) versusplacebo (11 days) over 16 weeks.

The European Medicines Agency has deferred the obligation to submit the results of studies withbaricitinib in one or more subsets of the paediatric population in chronic idiopathic arthritis andalopecia areata (see section 4.2 for information on paediatric use).

The efficacy of baricitinib up to 12 mg/day has been evaluated in 71 patients with CANDLE (chronicatypical neutrophilic dermatosis with lipodystrophy and elevated temperature, n=10),

CANDLE-related conditions (CANDLE-RC, n=9), SAVI (Stimulator of interferon gene-Associated

Vasculopathy with onset during Infancy, n=8), Juvenile DermatoMyositis (JDM, n=5), and

Aicardi-Goutières syndrome (AGS, n=39). Total patient-years of exposure (PYE) was 251. Due tomethodological insufficiencies no definite conclusion could be drawn on the efficacy of baricitinib inthese patients. Although safety patterns showed similarities with the adult indications, frequencies ofadverse events were generally higher. Three deaths were observed, in the AGS population; it isunclear whether these deaths were related to treatment with baricitinib.

The efficacy and safety of baricitinib were evaluated in 29 patients from 2 to < 18 years of age withactive JIA-associated uveitis or chronic anterior antibody positive uveitis. MTX-IR (n = 10) wereassigned to baricitinib (n = 5) or adalimumab (n = 5); bDMARD-IR (n = 19) were all assigned tobaricitinib. Baricitinib was dosed 2 mg once daily for patients 2 to < 9 years old and 4 mg once dailyfor those 9 to < 18 years old, adalimumab dosing was 20 mg (if < 30 kg), or 40 mg (if ≥ 30 kg) onceevery two weeks.

The primary endpoint was the proportion of patients with a 2 step decrease in the level ofinflammation (anterior chamber cells) according to the SUN (standardisation of uveitis nomenclature)criteria or decrease to zero through week 24, in the eye most severely affected at baseline. Eight(33.3 %) patients were baricitinib responders (7 bDMARD-IR and 1 MTX-IR), but the response ratebetween the two cohorts did not show a statistical significance.

Following oral administration of baricitinib, a dose-proportional increase in systemic exposure wasobserved in the therapeutic dose range. The PK of baricitinib is linear with respect to time.

Following oral administration, baricitinib is rapidly absorbed with a median tmax of approximately1 hour (range 0.5 - 3.0 h) and an absolute bioavailability of approximately 79 % (CV = 3.94 %). Foodintake led to a decreased exposure by up to 14 %, a decrease in Cmax by up to 18 % and delayed tmax by0.5 hours. Administration with meals was not associated with a clinically relevant effect on exposure.

Mean volume of distribution following intravenous infusion administration was 76 L, indicatingdistribution of baricitinib into tissues. Baricitinib is approximately 50 % bound to plasma proteins.

Baricitinib metabolism is mediated by CYP3A4, with less than 10 % of the dose identified asundergoing biotransformation. No metabolites were quantifiable in plasma. In a clinical pharmacologystudy, baricitinib was excreted predominately as the unchanged active substance in urine (69 %) andfaeces (15 %) and only 4 minor oxidative metabolites were identified (3 in urine; 1 in faeces)constituting approximately 5 % and 1 % of the dose, respectively. In vitro, baricitinib is a substrate for

CYP3A4, OAT3, Pgp, BCRP and MATE2-K, and may be a clinically relevant inhibitor of thetransporter OCT1 (see section 4.5). Baricitinib is not an inhibitor of the transporters OAT1, OAT2,

OAT3, OCT2, OATP1B1, OATP1B3, BCRP, MATE1 and MATE2-K at clinically relevantconcentrations.

Renal elimination is the principal mechanism for baricitinib’s clearance through glomerular filtrationand 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 thedose 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 hrs (CV = 27.4 %), respectively. Cmax and AUC at steady state are 1.4- and2.0-fold higher, respectively, in subjects with rheumatoid arthritis 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 patientswith atopic dermatitis are 0.8-fold those seen in rheumatoid arthritis.

Mean apparent clearance (CL/F) and half-life in patients with alopecia areata was 11.0 L/hr(CV = 36.0 %) and 15.8 hrs (CV = 35.0 %), respectively. Cmax and AUC at steady state in patientswith alopecia areata are 0.9-fold those seen in rheumatoid arthritis.

Renal function was found to significantly affect baricitinib exposure. The mean ratios of AUC inpatients with mild and moderate renal impairment to patients with normal renal function are 1.41(90 % CI: 1.15-1.74) and 2.22 (90 % CI: 1.81-2.73), respectively. The mean ratios of Cmax in patientswith mild and moderate renal impairment to patients with normal renal function are 1.16(90 %CI: 0.92-1.45) and 1.46 (90 %CI: 1.17-1.83), respectively. See section 4.2 for doserecommendations.

There was no clinically relevant effect on the PK of baricitinib in patients with mild or moderatehepatic impairment. The use of baricitinib has not been studied in patients with severe hepaticimpairment.

Age ≥ 65 years or ≥ 75 years has no effect on baricitinib exposure (Cmax and AUC).

The half-life in paediatric patients from 2 to less than18 years was 8 to 9 hours.

Exposure in paediatric patients weighing <30 kg and ≥ 30 kg: In patients < 30 kg with a mean age andrange of 8.1 (2.0-16.0) years, the mean and CV% for AUC and Cmax was 381 h*ng/mL (76%) and62.1 ng/mL (39%), respectively. In patients ≥ 30 kg with mean age and range of 14.1 (9.0 - 17.0), themean and CV% for AUC and Cmax was 438 h*ng/mL (68%) and 60.7 ng/mL (30%), respectively.

Exposure in paediatric patients weighing 10 to <20 kg and 20 to <30 kg: In patients 10 to < 20 kg witha mean age and range of 5.1 (2.0-8.0) years, the mean and CV% for AUC and Cmax was 458h*ng/mL (81%) and 77.6 ng/mL (38%), respectively . In patients 20 to < 30 kg with mean age andrange of 10.3 (6.0 - 16.0), the mean and CV% for AUC and Cmax was 327 h*ng/mL (66%) and 51.2ng/mL (22%), respectively.

Pharmacokinetics in paediatric patients with atopic dermatitis

The mean half-life in paediatric patients from 2 to less than 18 years was 13 to 18 hours.

Exposure in paediatric patients weighing < 30 kg and ≥ 30 kg: In patients < 30 kg with a mean age andrange of 6.4 (2.0-11.1) years, the mean and CV% for AUC and Cmax was 404 h*ng/mL (78%) and60.4 ng/mL (28%), respectively. In patients ≥ 30 kg with mean age and range of 13.5 (6.2 - 17.9), themean and CV% for AUC and Cmax was 529 h*ng/mL (102%) and 57.0 ng/mL (42%), respectively.

Exposure in paediatric patients weighing 10 to < 20 kg and 20 to <30 kg: In patients 10 to < 20 kgwith a mean age and range of 4.8 (2.0-6.9) years, the mean and CV% for AUC and Cmax was 467h*ng/mL (80%) and 73.4 ng/mL (21%), respectively . In patients 20 to < 30 kg with mean age andrange of 7.5 (4.8 - 11.1), the mean and CV% for AUC and Cmax was 363 h*ng/mL (72%) and 52.0ng/mL (21%), respectively

Other intrinsic factors

Body weight, age, sex, race, and ethnicity did not have a clinically relevant effect on the PK ofbaricitinib in adult patients. The mean effects of intrinsic factors on PK parameters (AUC and Cmax)were generally within the inter-subject PK variability of baricitinib. Therefore, no dose adjustment isneeded based on these patient factors.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, genotoxicity and carcinogenic potential.

Decreases in lymphocytes, eosinophils and basophils as well as lymphoid depletion in organs/tissuesof the immune system were observed in mice, rats and dogs. Opportunistic infections related todemodicosis (mange) were observed in dogs at exposures approximately 7 times the human exposure.

Decreases in red blood cell parameters were observed in mice, rats and dogs at exposuresapproximately 6 to 36 times the human exposure. Degeneration of the sternal growth plate wasobserved in some dogs, at low incidence and also in control animals, but with a dose-effectrelationship regarding severity. At present it is not known whether this is clinically relevant.

In rat and rabbit reproductive toxicology studies, baricitinib was shown to reduce foetal growth/weightand produce skeletal malformations (at exposures of approximately 10 and 39 times the humanexposure, respectively). No adverse foetal effects were observed at exposures 2 times the humanexposure based on AUC.

In a combined male/female rat fertility study, baricitinib decreased overall mating performance(decreased fertility and conception indices). In female rats there were decreased numbers of corporalutea and implantation sites, increased pre-implantation loss, and/or adverse effects on intrauterinesurvival of the embryos. Since there were no effects on spermatogenesis (as assessed byhistopathology) or semen/sperm endpoints in male rats, the decreased overall mating performance waslikely the result of these female effects.

Baricitinib was detected in the milk of lactating rats. In a pre- and postnatal development study,decreased pup weights and decreased postnatal survival were observed at exposures 4 and 21 times,respectively, the human exposure.

Tablet corescellulose, microcrystallinecroscarmellose sodiummagnesium stearatemannitol

Film coatingiron oxide red (E172)lecithin (soya) (E322)macrogolpoly (vinyl alcohol)talctitanium dioxide (E171)

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

Olumiant 1 mg film-coated tablets

Polyvinylchloride/polyethylene/polychlorotrifluoroethylene - aluminium blisters in cartons of 14 or28 film-coated tablets.

Polyvinylchloride/aluminium/oriented polyamide - aluminium perforated unit dose blisters in cartonsof 28 x 1 film-coated tablets.

Olumiant 2 mg and 4 mg film-coated tablets

Polyvinylchloride/polyethylene/polychlorotrifluoroethylene - aluminium blisters in cartons of 14, 28,35, 56, 84 or 98 film-coated tablets.

Polyvinylchloride/aluminium/oriented polyamide - aluminium perforated unit dose blisters in cartonsof 28 x 1 or 84 x 1 film-coated tablets.

Not all pack sizes may be marketed.

For paediatric patients who are unable to swallow whole tablets, it may be considered to disperse thetablets in water. Only water should be used to disperse the tablet. Only the number of tablets neededfor the dose should be dispersed.

- Place whole tablet in a container with 5-10 mL of water at room temperature and gently swirl todisperse. It may take up to 10 minutes for the tablet to disperse into a cloudy pale pinksuspension. Some settling may occur.

- After the tablet is dispersed, gently swirl again and administer the entire suspensionimmediately.

- Rinse the container with 5-10 mL of water at room temperature and administer the entirecontents immediately.

The tablet dispersed in water is stable for up to 4 hours at room temperature.

If for any reason the entire suspension is not administered, do not disperse and administer anothertablet but wait until the next scheduled dose.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Eli Lilly Nederland B.V., Papendorpseweg 83, 3528BJ Utrecht, The Netherlands.

Olumiant 1 mg film-coated tablets

EU/1/16/1170/017

EU/1/16/1170/018

EU/1/16/1170/019

Olumiant 2 mg film-coated tablets

EU/1/16/1170/001

EU/1/16/1170/002

EU/1/16/1170/003

EU/1/16/1170/004

EU/1/16/1170/005

EU/1/16/1170/006

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EU/1/16/1170/008

Olumiant 4 mg film-coated tablets

EU/1/16/1170/009

EU/1/16/1170/010

EU/1/16/1170/011

EU/1/16/1170/012

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Date of first authorisation: 13 February 2017

Date of latest renewal: 12 November 2021

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.