Olumiant 2 mg and 4 mg Film-Coated Tablets

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with baricitinib in one or more subsets of the paediatric population in chronic idiopathic arthritis, atopic dermatitis and alopecia 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 (chronic atypical 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 to methodological insufficiencies no definite conclusion could be drawn on the efficacy of baricitinib in these patients. Although safety patterns showed similarities with the adult indications, frequencies of adverse events were generally higher. Three deaths were observed, in the AGS population; it is unclear whether these deaths were related to treatment with baricitinib.

Added (underline) deleted (strikethrough)

4.4          Special warnings and precautions for use

[…]

Hepatic transaminase elevations

Dose dependent increases in blood alanine transaminase (ALT) and aspartate transaminase (AST) activity were reported in patients treated with baricitinib compared to placebo (see section 4.8). Increases in alanine transaminase (ALT) and aspartate transaminase (AST) to ≥ 5 and ≥ 10 x upper limit of normal (ULN) were reported in less than 1 % of patients in clinical trials. In rheumatoid arthritis clinical studies in treatment‑naïve patients, combination with methotrexate resulted in increased frequency of hepatic transaminase elevations compared with baricitinib monotherapy (see section 4.8).

[…]

Diverticulitis

Events of diverticulitis and gastrointestinal perforation have been reported in clinical trials and from postmarketing sources. Baricitinib should be used with caution in patients with diverticular disease and especially in patients chronically treated with concomitant medications 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.

[…]

4.8          Undesirable effects

[…]

Tabulated list of adverse reactions

[…]

Across indications, dose dependent increases in blood ALT and AST activity were also reported in studies extended over week 16. mMost cases of hepatic transaminase elevations were asymptomatic and transient. The pattern and incidence of elevation in ALT/AST remained stable over time including in the long-term extension study.

[…]

10.       DATE OF REVISION OF THE TEXT

             19 October20 November 2020

OL98M

Changes

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2.             What you need to know before you take Olumiant

[…]

Warnings and precautions

[…]

• have had diverticulitis (a type of inflammation of the large intestine) or ulcers in stomach or intestines (see section 4)

If you notice any of the following serious side effects, you need to tell a doctor straight away:

• chest tightness
• wheezing
• severe dizziness or light-headedness
• swelling of the lips, tongue or throat
• hives (itching or skin rash)
• severe abdominal pain especially accompanied with fever, nausea and vomiting.

[…]

Other medicines and Olumiant

[…]

• medicines that may increase your risk of diverticulitis such as a non‑steroidal anti‑inflammatory medicines (usually used to treat painful and/or inflammatory conditions of muscle or joints) and/or opioids (used to treat severe pain), and/or corticosteroids (usually used to treat inflammatory conditions) (see section 4)

[…]

4.         Possible side effects

[…]

Uncommon side effects (may affect up to 1 in 100 people):

[…]

• diverticulitis (painful inflammation of small pockets in the lining of your intestine)

6.             Contents of the pack and other information

This leaflet was last revised in November 2020.  […]

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4.1            Therapeutic indications   

Rheumatoid Arthritis

Olumiant 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. Olumiant 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

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

4.2            Posology and method of administration

Treatment should be initiated by physicians experienced in the diagnosis and treatment of the conditions for which Olumiant is indicatedrheumatoid arthritis.

Posology

Rheumatoid Arthritis

The recommended dose of Olumiant is 4 mg once daily. A dose of 2 mg once daily is appropriate for patients such as those aged ≥ 75 years and may be appropriate for patients with a history of chronic or recurrent infections. A dose of 2 mg once daily may also be considered for patients who have achieved sustained control of disease activity with 4 mg once daily and are eligible for dose tapering (see section 5.1).

Atopic Dermatitis

The recommended dose of Olumiant is 4 mg once daily. A dose of 2 mg once daily is appropriate for patients such as those aged ≥ 75 years and may be appropriate for patients with a history of chronic or recurrent infections. 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).

Olumiant can be used with or without topical corticosteroids. The efficacy of Olumiant 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.

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).

[…]

4.4            Special warnings and precautions for use

Infections

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, in treatment naïve patients, combination with methotrexate resulted in increased frequency of infections compared to baricitinib monotherapy.

Haematological abnormalities

Absolute Neutrophil Count (ANC) < 1 x 10⁹ cells/L, and Absolute Lymphocyte Count (ALC) < 0.5 x 10⁹ cells/L and haemoglobin < 8 g/dL were reported in less than 1 % of patients in clinical trials. Haemoglobin < 8 g/dL was reported in less than 1 % of patients in rheumatoid arthritis clinical trials.

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

Hepatic transaminase elevations

Increases in alanine transaminase (ALT) and aspartate transaminase (AST) to ≥ 5 and ≥ 10 x upper limit of normal (ULN) were reported in less than 1 % of patients in clinical trials. In rheumatoid arthritis clinical studies in treatment‑naïve patients, combination with methotrexate resulted in increased frequency of hepatic transaminase elevations compared with baricitinib monotherapy (see section 4.8).

Immunosuppressive medicinal products

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

In rheumatoid arthritis, dData concerning use of baricitinib with potent immunosuppressive medicinal products (e.g., azathioprine, tacrolimus, ciclosporin) are limited and caution should be exercised when using such combinations (see section 4.5).

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

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e., essentially “sodium-free”.

4.5            Interaction with other medicinal products and other forms of interaction

Immunosuppressive medicinal products

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

4.8            Undesirable effects

Summary of safety profile

In placebo-controlled rheumatoid arthritis clinical trials, for up to 16 weeks, tThe most commonly reported adverse drug reactions (ADRs) occurring in ≥ 2 % of patients treated with Olumiant monotherapy or in combination with conventional synthetic DMARDs were increased LDL cholesterol (33.6 %), upper respiratory tract infections (14.7 %) and nausea headache (23.8 %). Infections reported with Olumiant treatment included hHerpes zoster (1.4 %).

In placebo-controlled atopic dermatitis clinical trials, for up to 16 weeks, the most commonly reported ADRs occurring in ≥ 2 % of patients treated with Olumiant monotherapy or in combination with topical corticosteroids were similar to those observed in rheumatoid arthritis, except for increased LDL cholesterol (13.2 %) and herpes simplex (6.1 %). In patients treated with baricitinib in the atopic dermatitis clinical trials, the frequency of herpes zoster was very rare.

Tabulated list of adverse reactions

Rheumatoid Arthritis

A total of 3,464 3,770 patients were treated with Olumiant in clinical studies in rheumatoid arthritis representing 4214 10,127 patient‑years of exposure. Of these, 2166 2,960 rheumatoid arthritis patients were exposed to Olumiant for at least one year.

SixSeven placebo‑controlled studies were integrated (9971,142 patients on 4 mg once daily and 10701,215 patients on placebo) to evaluate the safety of Olumiant in comparison to placebo for up to 16 weeks after treatment initiation.

Atopic Dermatitis

A total of 2,531 patients were treated with Olumiant in clinical studies in atopic dermatitis representing a total of 2,247 patient‑years of exposure. Of these, 1,106 atopic dermatitis patients were exposed to Olumiant for at least one year.

Five placebo‑controlled studies were integrated (489 patients on 4 mg once daily and 743 patients on placebo) to evaluate the safety of Olumiant in comparison to placebo for up to 16 weeks after treatment initiation.

Table 2. 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 across both rheumatoid arthritis and atopic dermatitis indications unless stated otherwise; where notable differences in frequency are observed in one indication alone, these are presented in the footnotes below the table.

^a Combined term (acute sinusitis, epiglottitis, laryngitis, nasopharyngitis, oropharyngeal pain, pharyngitis, pharyngotonsillitis, rhinitis, sinusitis, tonsillitis, tracheitis, upper respiratory tract infection).

^b Combined term (eczema herpeticum, herpes simplex, ophthalmic herpes simplex, oral herpes).

^ac Includes changes detected during laboratory monitoring (see text below).

^b Frequency for herpes zoster is based on rheumatoid arthritis clinical trials.

^c Frequency for acne and creatine phosphokinase increased > 5 x ULN is based on the pooled rheumatoid arthritis and atopic dermatitis clinical trials. In patients treated with baricitinib in the rheumatoid arthritis clinical trials, the frequency of those events was uncommon.

^d Frequency for pneumonia, thrombocytosis > 600 x 10⁹ cells/L, nausea, and ALT ≥3 x ULN is based on the pooled rheumatoid arthritis and atopic dermatitis clinical trials. In patients treated with baricitinib in the atopic dermatitis clinical trials, the frequency of those events was uncommon.

Description of selected adverse reactions

NauseaGastrointestinal disorders

In rheumatoid arthritis clinical studies, iIn treatment-naïve patients, through 52 weeks, the frequency of nausea was greater for the combination treatment of methotrexate and Olumiant (9.3 %) compared to methotrexate alone (6.2 %) or Olumiant alone (4.4 %). Nausea was most frequent during the first 2 weeks of treatment. In atopic dermatitis clinical studies, for up to 16 weeks, the frequency of nausea with Olumiant was 0.8 %.

In rheumatoid arthritis controlled studies, for up to 16 weeks, abdominal pain occurred in 2.1 % of patients treated with Olumiant 4 mg and 1.4 % of patients treated with placebo. The frequency of abdominal pain in atopic dermatitis clinical studies was similar. The cases were usually mild, transient, not associated with infectious or inflammatory gastrointestinal disorders, and did not lead to treatment interruption..

Infections

Rheumatoid Arthritis

[…]

Atopic Dermatitis

In controlled studies, for up to 16 weeks, the incidence rate of all infections (rate of patients with ≥ 1 event per 100 patient-years of exposure) was 155 with Olumiant 4 mg compared to 118 in the placebo group. Most infections were mild to moderate in severity. Infections were reported in 31.5 %, 29.8 % and 24.2 % of patients up to 16 weeks in the 4 mg, 2 mg and placebo groups, respectively. The percentage of patients reporting infection‑related ADRs for Olumiant 4 mg compared to placebo were: Upper respiratory tract infections (17.5 % vs. 14.1 %), urinary tract infections (2.0 % vs. 0.8 %), gastroenteritis (1.2 % vs. 0.5 %), herpes simplex (6.1 % vs. 2.7 %), herpes zoster (0 % vs. 0.3 %) and pneumonia (0 % vs 0.1 %). In atopic dermatitis clinical studies, the frequency of infections was generally similar to those observed in rheumatoid arthritis patients except for pneumonia which was uncommon and herpes zoster which was very rare. There were less skin infections requiring antibiotic treatment with Olumiant 4 mg (3.4 %) than with placebo (4.4 %). The same percentage of patients with serious infections was observed with Olumiant 4 mg and placebo (0.6 %). The overall incidence rate of serious infections with baricitinib in the atopic dermatitis clinical trial programme was 2.1 per 100 patient-years.

Hepatic transaminase elevations

In rheumatoid arthritis controlled studies, for up to 16 weeks, alanine transaminase (ALT) and aspartate transaminase (AST) elevations ≥ 3 x upper limit of normal (ULN) were observed in 1.4 % and 0.8 % of patients treated with Olumiant, compared to 1.0 % and 0.8 % respectively of patients treated with placebo. Most cases of hepatic transaminase elevations were asymptomatic and transient.

The pattern and incidence of elevation in ALT/AST remained stable over time including in the long-term extension study.

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

Across indications, most cases of hepatic transaminase elevations were asymptomatic and transient. The pattern and incidence of elevation in ALT/AST remained stable over time including in the long-term extension study.

Lipid elevations

In rheumatoid arthritis clinical studies, bBaricitinib treatment was associated with dose-dependent increases in lipid parameters including total cholesterol, triglycerides, LDL cholesterol, and HDL cholesterol. There was no change in the LDL/HDL ratio. Elevations were observed at 12 weeks and remained stable thereafter at a higher value than baseline including in the long-term extension study. In controlled studies, for up to 16 weeks, the following rates were observed for Olumiant vs. placebo:

• Increased total cholesterol ≥ 5.17 mmol/L: 49.1 % vs.15.8 %, respectively
• Increased LDL cholesterol ≥ 3.36 mmol/L: 33.6 % vs. 10.3 %, respectively
• Increased HDL cholesterol ≥ 1.55 mmol/L: 42.7 % vs. 13.8 %, respectively
• Increased triglycerides ≥ 5.65 mmol/L: 0.4 % vs. 0.5 %, respectively

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

In controlled studies, for up to 16 weeks, the following frequencies were observed for Olumiant 4 mg vs. placebo:

• Increased total cholesterol ≥ 5.17 mmol/L:
  • Rheumatoid Arthritis: 49.1 % vs.15.8 %, respectively
  • Atopic Dermatitis: 20.7 % vs. 10.0 %, respectively
• Increased LDL cholesterol ≥ 3.36 mmol/L:
  • Rheumatoid Arthritis: 33.6 % vs. 10.3 %, respectively
  • Atopic Dermatitis: 13.2 % vs. 6.3 %, respectively
• Increased HDL cholesterol ≥ 1.55 mmol/L:
  • Rheumatoid Arthritis: 42.7 % vs. 13.8 %, respectively
  • Atopic Dermatitis: 25.3 % vs. 14.7 %, respectively
• Increased triglycerides ≥ 5.65 mmol/L:
  • Rheumatoid Arthritis: 0.4 % vs. 0.5 %, respectively
  • Atopic Dermatitis: 0.7 % vs. 0.8 %, respectively

Creatine phosphokinase (CPK)

In rheumatoid arthritis controlled studies, for up to 16 weeks, increases in CPK values were uncommon. Significant increases (> 5 x ULN) occurred in 0.8 % of patients treated with Olumiant and 0.3 % of patients treated with placebo. A dose relationship was observed with CPK elevations ≥ 5 x ULN of normal reported in 1.5 %, 0.8 % and 0.6 % of patients at 16 weeks in the 4 mg, 2 mg and placebo groups, respectively. In atopic dermatitis controlled studies, for up to 16 weeks, increases in CPK values were common and occurred in 3.3 %, 2.5 %, and 1.9 % of patients treated with Olumiant 4 mg, 2 mg, and placebo, respectively. Across indications, mMost cases were transient and did not require treatment discontinuation.

In rheumatoid arthritis and atopic dermatitis clinical trials, there were no confirmed cases of rhabdomyolysis. Elevations of CPK were observed at 4 weeks and remained stable at a higher value than baseline thereafter including in the long-term extension study.

Neutropaenia

In rheumatoid arthritis and atopic dermatitis controlled studies, for up to 16 weeks, decreases in neutrophil counts below 1 x 10⁹ cells/L occurred in 0.32 % of patients treated with Olumiant compared to 0 % of patients treated with placebo. […]

Thrombocytosis

In rheumatoid arthritis controlled studies, for up to 16 weeks, increases in platelet counts above 600 x 10⁹ cells/L occurred in 2.0 % of patients treated with Olumiant 4 mg and 1.1 % of patients treated with placebo. In atopic dermatitis controlled studies, for up to 16 weeks, increases in platelet counts above 600 x 10⁹ cells/L occurred in 0.6 % of patients treated with Olumiant 4 mg and 0 % of patients treated with placebo. The frequency of thrombocytosis in atopic dermatitis studies was uncommon and lower than that observed in the rheumatoid arthritis patients.

5.1            Pharmacodynamic properties

Creatinine

In rheumatoid arthritis, bBaricitinib induced a mean increase in serum creatinine levels of 3.8 µmol/L after two weeks of treatment, as compared to placebo, which remained stable thereafter during up to 104 weeks of treatment.  This may be due to inhibition of creatinine secretion by baricitinib in the renal tubules. Consequently, estimates of the glomerular filtration rate based on serum creatinine may be slightly reduced, without actual loss of renal function or the occurrence of renal adverse events.  Similar observations have been made in atopic dermatitis. In atopic dermatitis, baricitinib was associated with a decrease in cystatin C (also used to estimate glomerular filtration rate) of 0.1 mg/L at week 4, with no further decrease noted up to week 16.

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 of filaggrin, a protein that plays a role in skin barrier function and in the pathogenesis of atopic dermatitis.

Clinical efficacy

Rheumatoid Arthritis

The efficacy and safety of Olumiant […]

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 atopic dermatitis defined by Investigator's Global Assessment (IGA) score ≥ 3, an Eczema Area and Severity Index (EASI) score ≥ 16, and a body surface area (BSA) involvement of ≥ 10 %. Eligible patients were over 18 years of age and had previous inadequate response or were intolerant to topical medication. Patients were permitted to receive rescue treatment (which included topical or systemic therapy), at which time they were considered non‑responders. At baseline of study BREEZE-AD7, all patients were on concomitant topical corticosteroids therapy and patients were permitted to use topical calcineurin inhibitors. All patients who completed these studies were eligible to enrol in a long term extension study (BREEZE AD‑3) for up to 2 years of continued treatment.

The Phase III randomised, double‑blind, placebo-controlled BREEZE‑AD4 study evaluated the efficacy of baricitinib in combination with topical corticosteroids over 52 weeks in 463 patients with moderate to severe AD with failure, intolerance, or contraindication to oral ciclosporin treatment.

Baseline Characteristics

In the placebo‑controlled Phase III studies (BREEZE-AD1, -AD2, -AD7, and -AD4), across all treatment 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 for atopic dermatitis. The baseline mean EASI score ranged from 29.6 to 33.5, the baseline weekly averaged 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 Response

16-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 or 1 response (primary outcome), EASI75, or an improvement of ≥ 4 points on the Itch NRS compared to placebo at week 16 (Table 6). Figure 1 shows the mean percent change from baseline in EASI up to week 16.

A significantly greater proportion of patients randomised to baricitinib 4 mg achieved a ≥ 4‑point improvement 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 (FAS^a)

BARI = Baricitinib; PBO = Placebo

* statistically significant vs placebo without adjustment for multiplicity; ** statistically significant vs placebo 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 were considered 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 after permanent study drug discontinuation were considered missing. LS means are from Mixed Model with Repeated Measures (MMRM) analyses.

Maintenance of Response

To evaluate maintenance of response, 1,373 subjects treated with baricitinib for 16 weeks in BREEZE‑AD1 (N = 541), BREEZE‑AD2 (N = 540) and BREEZE‑AD7 (N = 292) were eligible to enrol in a long term extension study BREEZE‑AD3. Data are available up to 68 weeks of cumulative treatment for patients from BREEZE‑AD1 and BREEZE‑AD2, and up to 32 weeks of cumulative treatment for patients from BREEZE‑AD7. Continued response was observed in patients with at least some response (IGA 0, 1 or 2) after initiating baricitinib.

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 and depression (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 and baricitinib in combination with TCS at week 16 (FAS) ^a

BARI = Baricitinib; PBO = Placebo

* statistically significant vs placebo without adjustment for multiplicity; ** statistically significant vs placebo 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 after permanent study drug 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 were considered 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 patients achieving EASI-75 at week 16. The primary and some of the most important secondary endpoints at  week 16 are summarised in Table 8.

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

BARI = Baricitinib; PBO = Placebo

* statistically significant vs placebo without adjustment for multiplicity; ** statistically significant vs placebo with adjustment for multiplicity.

^a All patients were on concomitant topical corticosteroids therapy and patients were permitted to use topical calcineurin inhibitors.

^b Full analysis set (FAS) includes all randomised patients.

^c Non-Responder Imputation: Patients who received rescue treatment or with missing data were considered as non-responders.

^d Data collected after rescue therapy or after permanent study drug discontinuation were considered 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).

Paediatric population

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

5.2            Pharmacokinetic properties

Mean apparent clearance (CL/F) and half-life in patients with atopic dermatitis was 11.2 L/hr (CV = 33.0 %) and 12.9 hrs (CV = 36.0 %), respectively. Cmax and AUC at steady state in patients with atopic dermatitis are 0.8‑fold those seen in rheumatoid arthritis.

8.        MARKETING AUTHORISATION NUMBER(S)

Olumiant 2 mg film‑coated tablets

EU/1/16/1170/001                14 tablets

EU/1/16/1170/002                28 tablets

EU/1/16/1170/003                28 x 1 tablets (unit dose)

EU/1/16/1170/004                35 tablets

EU/1/16/1170/005                56 tablets

EU/1/16/1170/006                84 tablets

EU/1/16/1170/007                84 x 1 tablets (unit dose)

EU/1/16/1170/008                98 tablets

Olumiant 4 mg film‑coated tablets

EU/1/16/1170/009                14 tablets

EU/1/16/1170/010                28 tablets

EU/1/16/1170/011                28 x 1 tablets (unit dose)

EU/1/16/1170/012                35 tablets

EU/1/16/1170/013                56 tablets

EU/1/16/1170/014                84 tablets

EU/1/16/1170/015                84 x 1 tablets (unit dose)

EU/1/16/1170/016                98 tablets

10.      DATE OF REVISION OF THE TEXT

19 October 2020

OL78M

Added (underline) deleted (strikethrough)

1.           What Olumiant is and what it is used for

[…]

Rheumatoid Arthritis

[…]

Atopic Dermatitis

Olumiant is used to treat adults with moderate to severe atopic dermatitis, also known as atopic eczema. Olumiant may be used with eczema medicines that you apply to the skin or it may be used on its own.

Olumiant works by reducing the activity of an enzyme in the body called ‘Janus kinase’, which is involved in inflammation. By reducing the activity of this enzyme, Olumiant helps to improve the condition of your skin and reduce itching. In addition, Olumiant helps improve your sleep disturbance (due to itch) and overall quality of life. Olumiant has also been shown to improve symptoms of skin pain, anxiety, and depression associated with atopic dermatitis.

2.           What you need to know before you take Olumiant

[…]

• injectable medicines that depress the immune system, including so called targeted biologic (antibody) therapies

[…]

Olumiant contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per tablet, i.e., essentially “sodium-free”.

[…]

3.           How to take Olumiant

Treatment should be started by a doctor experienced in the diagnosis and treatment of rheumatoid arthritis of your condition. Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

Rheumatoid Arthritis

[…]

Atopic Dermatitis

The recommended dose is 4 mg once a day. Your doctor may give you a lower dose of 2 mg once a day, particularly if you are over 75 years old or if you have an increased risk of infections. If the medicine is working well, your doctor may decide the dose can be reduced.

If you have reduced kidney function, the recommended dose of Olumiant is 2 mg once a day.

4.        Possible side effects

[…]

painful skin rash with blisters and fever (this was very rare in atopic dermatitis) […]

Common side effects (may affect up to 1 in 10 people):

[…]

• pneumonia (this was uncommon in atopic dermatitis)
• high number of platelets (cells involved in blood clotting), shown by blood test (this was uncommon in atopic dermatitis)
• headache
• feeling sick in the stomach (nausea; this was uncommon in atopic dermatitis)
• stomach pain
• high levels of liver enzymes, shown by blood test (this was uncommon in atopic dermatitis)
• rash
• acne (this was uncommon in rheumatoid arthritis)
• increase in an enzyme called creatine kinase, shown by a blood test (this was uncommon in rheumatoid arthritis)
•  

Uncommon side effects (may affect up to 1 in 100 people):

• low number of white bloods cells (neutrophils), shown by blood test
• increase in an enzyme called creatine kinase, shown by blood test
• high levels of blood fat (triglycerides), shown by blood test
• acne[…]

6.           Contents of the pack and other information

This leaflet was last revised in November 2019October 2020.  […]

Patient Alert Card

Blood clots

Olumiant may cause a condition in which a blood clot forms in your leg that may travel to your lungs. Inform your doctor immediately if you experience any of the following symptoms:

• Swelling or pain in one leg
• Warmth or redness in one leg
• Shortness of breath which is unexpected
• Rapid breathing
• Chest pain

4.4     Special warnings and precautions for use

Venous Thromboembolism

Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving baricitinib. Olumiant should be used with caution in patients with risk factors for DVT/PE, such as older age, obesity, a medical history of DVT/PE, or patients undergoing surgery and immobilisation. If clinical features of DVT/PE occur, Olumiant treatment should be discontinued temporarily interrupted and patients should be evaluated promptly, followed by appropriate treatment.

Hypersensitivity

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

4.8     Undesirable effects

Reporting of suspected adverse reactions

[…] Ireland: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517; website: www.hpra.ie; e-mail: medsafety@hpra.ie, or

10.     DATE OF REVISION OF THE TEXT

22 November 2019 27 September 2018

LEGAL CATEGORY

OL76M

6.3              Shelf life

3 2 years

 10.       DATE OF REVISION OF THE TEXT

  04 September 2018 27 September 2018

4.8          Undesirable effects 

Tabulated list of adverse reactions

10.       DATE OF REVISION OF THE TEXT

25 January 201804 September 2018

Added (underline) deleted (strikethrough)

4.4          Special warnings and precautions for use

Vaccination

No data are available on the response to vaccination with live or inactivated vaccines in patients receiving baricitinib. Use with live, attenuated vaccines during, or immediately prior to, Olumiant therapy is not recommended. International treatment guidelines on vaccination in rheumatoid arthritis patients should be followed when varicella zoster vaccination is considered prior to treatment with Olumiant. Prior to initiating Olumiant, it is recommended that all patients be brought up to date with all immunisations in agreement with current immunisation guidelines.

5.1          Pharmacodynamic properties

Vaccine study

The influence of baricitinib on the humoral response to non-live vaccines was evaluated in 106  RA patients under stable treatment with baricitinib 2 or 4   mg, receiving inactivated pneumococcal or tetanus vaccination. The majority of these patients (n  =  94) were co-treated with methotrexate. For the total population, pneumococcal vaccination resulted in a satisfactory IgG immune response in 68.0  % (95  %  CI: 58.4  %, 76.2  %) of the patients.  In 43.1  % (95  %  CI: 34.0  %, 52.8  %) of the patients, a satisfactory IgG immune response to tetanus vaccination was achieved.

10.       DATE OF REVISION OF THE TEXT

             9 November 201725 January 2018

                                                                                                                                    OL3MOL4M

Changes

Added (underline) deleted (strikethrough)

4.5          Interaction with other medicinal products and other forms of interaction

Transporters

In vitro, baricitinib did inhibitis not an inhibitor of OAT1, OAT2, OAT3, organic cationic transporter (OCT) 1, (OCT)2, OATP1B1, OATP1B3, BCRP, and MATE1 and MATE2 K at clinically relevant concentrations. Clinically meaningful changes in the PK of medicinal products that are substrates for these transporters are unlikely, with the exception of OCT1 substrates. It cannot be ruled out that bBaricitinib is may be a clinically relevant inhibitor of OCT1 inhibitor, 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).

5.2       Pharmacokinetic properties

Biotransformation

Baricitinib metabolism is mediated by CYP3A4, with less than 10 % of the dose identified as undergoing biotransformation. No metabolites were quantifiable in plasma. In a clinical pharmacology study, baricitinib was excreted predominately as the unchanged active substance in urine (69 %) and faeces (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 an may be a clinically relevant inhibitor of the transporters OAT1, OAT3, OCT1, OCT2, OATP1B3, BCRP, MATE1 and MATE2‑K, but clinically meaningful interactions with medicines that are substrates for these transporters are unlikely, with the exception of OCT1 substrates. (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 relevant concentrations.

10.       DATE OF REVISION OF THE TEXT

             20 July 20179 November 2017

                                                                                                                                    OL2MOL3M

OLUMIANT^® (baricitinib)

1.         NAME OF THE MEDICINAL PRODUCT

Olumiant^] 2 mg film-coated tablets

4.4       Special warnings and precautions for use

                         Venous Thromboembolism

Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving baricitinib. Olumiant should be used with caution in patients with risk factors for DVT/PE, such as older age, obesity, a medical history of DVT/PE, or patients undergoing surgery and immobilisation.If clinical features of DVT/PE occur, Olumiant treatment should be temporarily interrupted and patients should be evaluated promptly, followed by appropriate treatment.

4.8       Undesirable effects

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 Ireland: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517; website: www.hpra.ie; e-mail: medsafety@hpra.ie, or United Kingdom: Yellow Card Scheme; website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

10.       DATE OF REVISION OF THE TEXT

20 July 2017

^]OLUMIANT (Baricitinib) is a trademark of Eli Lilly and Company.                                                                              OL12M