4.1. Therapeutic indications

Rheumatoid arthritis

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

Atopic dermatitis

Baricitinib is indicated for the treatment of moderate to severe atopic dermatitis in adult and paediatric patients 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).

Juvenile idiopathic arthritis

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

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

- Enthesitis-related arthritis, and

- Juvenile psoriatic arthritis.

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

4.2. Posology and method of administration

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

Posology

Rheumatoid arthritis

The recommended dose of baricitinib is 4 mg once daily. A dose of 2 mg once daily is recommended for 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 or recurrent infections (see section 4.4). A dose of 4 mg once daily may be considered for patients who do not achieve adequate control of disease activity with 2 mg once daily dose. A dose of 2 mg once daily should be considered for patients who have achieved sustained control of disease activity with 4 mg once daily and are eligible for dose tapering (see section 5.1).

Atopic dermatitis

Adults

The recommended dose of baricitinib is 4 mg once daily. A dose of 2 mg once daily is recommended for patients at higher risk of VTE, MACE and malignancy, for patients aged ≥ 65 years and for patients with a history of chronic or recurrent infections (see section 4.4). A dose of 4 mg once daily may be considered for patients who do not achieve adequate control of disease activity with 2 mg once daily dose. A dose of 2 mg once daily should be considered for patients who have achieved sustained control 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 be enhanced when given with topical corticosteroids (see section 5.1). Topical calcineurin inhibitors may be used, but should be reserved for sensitive areas only, such as the face, neck, intertriginous and genital areas.

Consideration should be given to discontinuing treatment in patients who show no evidence of therapeutic 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. For patients weighing 10 kg to less than 30 kg, the recommended dose is 2 mg once daily. A reduction to half the dose should be considered for patients who have achieved sustained control of disease activity with the recommended dose and are eligible for dose tapering.

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

Consideration should be given to discontinuing treatment in patients who show no evidence of therapeutic 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 recommended for patients at higher risk of VTE, MACE and malignancy, for patients aged ≥ 65 years and for patients with a history of chronic or recurrent infections (see section 4.4). A dose of 4 mg once daily may be considered for patients who do not achieve adequate control of disease activity with 2 mg once daily dose. A dose of 2 mg once daily should be considered for patients who have achieved sustained control 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 several months, in order to avoid relapse. The benefit-risk of treatment should be re-assessed at regular intervals on an individual basis.

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

Treatment initiation

Treatment should not be initiated in patients with an absolute lymphocyte count (ALC) less than 0.5 x 109 cells/L, an absolute neutrophil count (ANC) less than 1 x 109 cells/L, or who have a haemoglobin value less than 8 g/dL. Treatment may be initiated once values have improved above these limits (see section 4.4).

Dose reduction

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

Special populations

Renal impairment

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

Hepatic impairment

No dose adjustment is required in patients with mild or moderate hepatic impairment. Baricitinib is not recommended for use in patients with severe hepatic impairment (see section 5.2).

Elderly

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. No data are available. See section 4.2 above for information on posology in children aged 2 years and older.

The safety and efficacy of baricitinib in children less than 18 years of age with alopecia areata have not yet been established. No data are available.

Method of administration

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 the tablets in water. Only water should be used to disperse the tablet. Only the number of tablets needed for the dose should be dispersed.

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

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

4.3. Contraindications

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

Pregnancy (see section 4.6).

4.4. Special warnings and precautions for use

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 in patients 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 are available.

Infections

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 infections compared to placebo (see section 4.8). In rheumatoid arthritis clinical studies, combination with methotrexate resulted in increased frequency of infections compared to baricitinib monotherapy.

The risks and benefits of treatment should be carefully considered prior to initiating baricitinib in patients with active, chronic or recurrent infections (see section 4.2). If an infection develops, the patient should be monitored carefully and therapy should be temporarily interrupted if the patient is not 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 years of age, baricitinib should only be used if no suitable treatment alternatives are available.

Tuberculosis

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

Haematological abnormalities

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 routine patient management (see section 4.2).

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

Viral reactivation

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 zoster was reported more commonly in patients ≥ 65 years of age who had previously been treated with both biologic and synthetic conventional DMARDs. If a patient develops herpes zoster, treatment should be temporarily interrupted until the episode resolves.

Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy with baricitinib. 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 allowed to participate. Patients with hepatitis B surface antibody and hepatitis B core antibody, without hepatitis B surface antigen, were also allowed to participate; such patients should be monitored for expression of hepatitis B virus (HBV) DNA. If HBV DNA is detected, a liver specialist should be consulted to determine if treatment interruption is warranted.

Vaccination

No data are available on the response to vaccination with live vaccines in patients receiving baricitinib. Use with live, attenuated vaccines during or immediately prior to baricitinib therapy is not recommended. Prior to initiating treatment, it is recommended that all patients, and particularly paediatric patients, be brought up to date with all immunisations in agreement with current immunisation guidelines.

Lipids

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

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 clinical trials. In rheumatoid arthritis clinical studies, combination with methotrexate resulted in increased frequency 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 liver injury is suspected, treatment should be temporarily interrupted until this diagnosis is excluded.

Malignancy

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

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

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

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

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

Venous thromboembolism

In a retrospective observational study of baricitinib in rheumatoid arthritis patients, a higher rate of venous 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 rheumatoid arthritis patients 50 years and older with at least one additional cardiovascular risk factor, a dose dependent 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 adverse cardiovascular events (MACE)” and “Malignancy”) baricitinib should only be used if no suitable treatment 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 risk factors include previous VTE, patients undergoing major surgery, immobilisation, use of combined hormonal contraceptives or hormone replacement therapy, and inherited coagulation disorder.

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

Promptly evaluate patients with signs and symptoms of VTE and discontinue baricitinib in patients with 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 rheumatoid arthritis patients 50 years and older with at least one additional cardiovascular risk factor, a higher rate of major adverse cardiovascular events (MACE), defined as cardiovascular death, non-fatal myocardial infarction (MI) and non-fatal stroke ,was observed with tofacitinib (another JAK inhibitor) compared with TNF inhibitors.

Therefore, in patients over 65 years of age, patients who are current or past long-time smokers, and patients 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

Laboratory measure

Action

Monitoring guidance

Lipid parameters

Patients should be managed according to international clinical guidelines for hyperlipidaemia

12 weeks after initiation of treatment and thereafter according to international clinical guidelines for hyperlipidaemia

Absolute Neutrophil Count (ANC)

Treatment should be interrupted if ANC < 1 x 109 cells/L and may be restarted once ANC return above this value

Before treatment initiation and thereafter according to routine patient management

Absolute Lymphocyte Count (ALC)

Treatment should be interrupted if ALC < 0.5 x 109 cells/L and may be restarted once ALC return above this value

Haemoglobin (Hb)

Treatment should be interrupted if Hb < 8 g/dL and may be restarted once Hb return above this value

Hepatic transaminases

Treatment should be temporarily interrupted if drug-induced liver injury is suspected

Immunosuppressive medicinal products

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 potent immunosuppressive 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 potent immunosuppressants has not been studied and is not recommended (see section 4.5).

Hypersensitivity

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

Diverticulitis

Cases of diverticulitis and gastrointestinal perforation have been reported in clinical trials and from postmarketing sources (see section 4.8). Baricitinib should be used with caution in patients with diverticular disease and especially in patients chronically treated with concomitant medicinal products associated with an increased risk of diverticulitis: nonsteroidal anti-inflammatory drugs, corticosteroids, and opioids. Patients presenting with new onset abdominal signs and symptoms should be 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 be necessary in the event that hypoglycaemia occurs.

Excipients

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

4.5. Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactions

Immunosuppressive medicinal products

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

Potential for other medicinal products to affect the pharmacokinetics of baricitinib

Transporters

In vitro, baricitinib is a substrate for organic anionic transporter (OAT)3, P-glycoprotein (Pgp), breast cancer resistance protein (BCRP) and multidrug and toxic extrusion protein (MATE)2-K. In a clinical pharmacology 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 as probenecid, the recommended dose of baricitinib should be reduced by half (see section 4.2). No clinical 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 and therefore may lead to an increase in baricitinib exposure. Since dedicated interaction studies have not been conducted, caution should be used when leflunomide or teriflunomide are given concomitantly with baricitinib. Concomitant use of the OAT3 inhibitors ibuprofen and diclofenac may lead to increased exposure of baricitinib, however their inhibition potential of OAT3 is less compared to probenecid and thus a clinically relevant interaction is not expected. Coadministration of baricitinib with ciclosporin (Pgp/BCRP inhibitor) or methotrexate (substrate of several transporters including OATP1B1, OAT1, OAT3, BCRP, MRP2, MRP3, and MRP4) resulted in no clinically meaningful effects on baricitinib exposure.

Cytochrome P450 enzymes

In vitro, baricitinib is a cytochrome P450 enzyme (CYP)3A4 substrate although less than 10 % of the dose is metabolised via oxidation. In clinical pharmacology studies, coadministration of baricitinib with ketoconazole (strong CYP3A inhibitor) resulted in no clinically meaningful effect on the PK of baricitinib. Coadministration of baricitinib with fluconazole (moderate CYP3A/CYP2C19/CYP2C9 inhibitor) or rifampicin (strong CYP3A inducer) resulted in no clinically meaningful changes to baricitinib 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

Transporters

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 known selective OCT1 substrates for which clinically significant interactions might be predicted. In clinical pharmacology studies there were no clinically meaningful effects on exposure when baricitinib was coadministered with digoxin (Pgp substrate) or methotrexate (substrate of several transporters).

Cytochrome P450 enzymes

In clinical pharmacology studies, coadministration of baricitinib with the CYP3A substrates simvastatin, ethinyl oestradiol, or levonorgestrel resulted in no clinically meaningful changes in the PK of these medicinal products.

4.6. Fertility, pregnancy and lactation

Pregnancy

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

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

Breast-feeding

It is unknown whether baricitinib/metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of baricitinib in milk (see section 5.3).

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

Fertility

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

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

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 %), and urinary tract infections (2.9 %). Serious pneumonia and serious herpes zoster occurred uncommonly in patients with rheumatoid arthritis.

Tabulated list of adverse reactions

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

Table 2. Adverse reactions

System organ class

Very common

Common

Uncommon

Infections and infestations

Upper respiratory tract infections

Herpes zosterb

Herpes simplex

Gastroenteritis

Urinary tract infections Pneumoniad

Folliculitisg

Blood and lymphatic system disorders

Thrombocytosis > 600 x 109 cells/La, d

Neutropaenia < 1 x 109 cells/La

Immune system disorders

Swelling of the face, Urticaria

Metabolism and nutrition disorders

Hypercholesterolaemiaa

Hypertriglyceridaemiaa

Nervous system disorders

Headache

Vascular disorders

Deep vein thrombosisb

Respiratory, thoracic, mediastinal disorders

Pulmonary embolismf

Gastrointestinal disorders

Nausead

Abdominal paind

Diverticulitis

Hepatobiliary disorders

ALT increased ≥ 3 x ULNa, d

AST increased ≥ 3 x ULNa, e

Skin and subcutaneous tissue disorders

Rash

Acnec

Investigations

Creatine phosphokinase increased > 5 x ULNa, c

Weight increased

a 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. In alopecia areata clinical trials, the frequency of abdominal pain was uncommon. In atopic dermatitis and 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 clinical trials.

g Folliculitis was observed in alopecia areata clinical trials. It was usually localized in the scalp region associated with hair regrowth.

Description of selected adverse reactions

Gastrointestinal disorders

In rheumatoid arthritis clinical studies, in treatment-naïve patients, through 52 weeks, the frequency of nausea was greater for the combination treatment of methotrexate and baricitinib (9.3 %) compared to methotrexate alone (6.2 %) or baricitinib alone (4.4 %). In the integrated data from rheumatoid arthritis, atopic dermatitis and alopecia areata clinical trials, nausea was most frequent during the first 2 weeks of treatment.

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

Infections

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, infections were 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 in increased frequency of infections compared to baricitinib monotherapy. Frequency of herpes zoster was 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 with baricitinib than with placebo.

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

Hepatic transaminase elevations

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

In patients with rheumatoid arthritis, the combination of baricitinib with potentially hepatotoxic medicinal 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 total cholesterol, LDL cholesterol, and high density lipoprotein (HDL) cholesterol. There was no change in the LDL/HDL ratio. Elevations were observed at 12 weeks and remained stable thereafter at a higher value 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. In rheumatoid arthritis clinical trials, baricitinib treatment was associated with dose-dependent increases in triglycerides. There was no increase in triglycerides levels in atopic dermatitis and alopecia areata clinical 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 increased at 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 over time. 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 value than baseline over time.

Paediatric population

Juvenile idiopathic arthritis

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

In paediatric patients treated with baricitinib in the placebo-controlled double-blind randomised withdrawal 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 embolism was 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 of baricitinib. Overall, the safety profile in these patients was comparable to that observed in the adult population. Neutropaenia (< 1 x 109 cells/L) was more common (1.7%) compared to adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme; Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Single doses up to 40 mg and multiple doses of up to 20 mg daily for 10 days have been administered to 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 % 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.