JYSELECA 100 MG FILM-COATED TABLETS - summary of medicine characteristics

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1 NAME OF THE MEDICINAL PRODUCT

Jyseleca 100 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Jyseleca 100 mg film-coated tablets

Each film-coated tablet contains filgotinib maleate equivalent to 100 mg of filgotinib.

Excipient with known effect

Each 100 mg film-coated tablet contains 76 mg of lactose (as monohydrate).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet.

Jyseleca 100 mg film-coated tablets

Beige 12 × 7 mm, capsule-shaped, film-coated tablet debossed with “GSI” on one side and “100” on the other side.

4.1 Therapeutic indications

Jyseleca 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). Jyseleca may be used as monotherapy or in combination with methotrexate (MTX).

4.2 Posology and method of administration

Treatment with filgotinib should be initiated by a physician experienced in the treatment of rheumatoid arthritis.

Posology

The recommended dose of filgotinib for adult patients with rheumatoid arthritis is 200 mg once daily.

Laboratory monitoring, and dose initiation or interruption

Guidance for laboratory monitoring, and dose initiation or interruption is provided in Table 1. Treatment should be interrupted if a patient develops a serious infection until the infection is controlled (see section 4.4).

Table 1: Laboratory measures and monitoring guidance

Special populations

Elderly

A starting dose of 100 mg once daily is recommended for patients aged 75 years and older as clinical experience is limited.

Renal impairment

No dose adjustment is required in patients with mild renal impairment (creatinine clearance [CrCl] > 60 mL/min). A dose of 100 mg of filgotinib once daily is recommended for patients with moderate or severe renal impairment (CrCl 15 to < 60 mL/min). Filgotinib has not been studied in patients with end stage renal disease (CrCl < 15 mL/min) and is therefore not recommended for use in these patients (see section 5.2).

Hepatic impairment

No dose adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh A or B). Filgotinib has not been studied in patients with severe hepatic impairment (Child-Pugh C) and is therefore not recommended for use in these patients (see section 5.2).

Paediatric population

The safety and efficacy of filgotinib in children under the age of 18 years have not yet been established. No data are available.

Method of administration

Oral use.

Jyseleca can be taken with or without food (see section 5.2). It has not been studied if tablets can be split, crushed, or chewed, and it is recommended that tablets are swallowed whole.

4.3 Contraindications

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

Active tuberculosis (TB) or active serious infections (see section 4.4).

Pregnancy (see section 4.6).

4.4 Special warnings and precautions for use

Immunosuppressive medicinal products

Combination of filgotinib with other potent immunosuppressants such as azathioprine, ciclosporin, tacrolimus, biologic DMARDs (bDMARDs) or other Janus kinase (JAK) inhibitors is not recommended as a risk of additive immunosuppression cannot be excluded.

Infections

Infections, including serious infections, have been reported in patients receiving filgotinib. The most frequent serious infection reported with filgotinib was pneumonia (see section 4.8). Among opportunistic infections, TB, oesophageal candidiasis, and cryptococcosis were reported with filgotinib.

The risks and benefits of treatment should be considered prior to initiating filgotinib in patients:

with chronic or recurrent infection

who have been exposed to TB

with a history of a serious or an opportunistic infection

who have resided or travelled in areas of endemic TB or endemic mycoses; or with underlying conditions that may predispose them to infection.

Patients should be closely monitored for the development of signs and symptoms of infections during and after filgotinib treatment. If an infection develops during treatment with filgotinib, the patient should be carefully monitored and filgotinib treatment should be temporarily interrupted if the patient is not responding to standard antimicrobial therapy. Filgotinib treatment may be resumed once the infection is controlled.

As there is a higher incidence of serious infections in the elderly aged 75 years and older, caution should be used when treating this population.

Tuberculosis

Patients should be screened for TB before initiating filgotinib. Filgotinib should not be administered to patients with active TB (see section 4.3). In patients with latent TB, standard antimycobacterial therapy should be initiated before administering filgotinib.

Patients should be monitored for the development of signs and symptoms of TB, including patients who tested negative for latent TB infection prior to initiating treatment.

Viral reactivation

Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were reported in clinical studies (see section 4.8). If a patient develops herpes zoster, filgotinib treatment should be temporarily interrupted until the episode resolves.

Screening for viral hepatitis and monitoring for reactivation should be performed in accordance with clinical guidelines before starting and during treatment with filgotinib. Patients who were positive for both hepatitis C antibody and hepatitis C virus RNA were excluded from clinical studies. Patients who were positive for hepatitis B surface antigen or hepatitis B virus DNA were excluded from clinical studies.

Malignancy

The risk of malignancies is increased in patients with rheumatoid arthritis. Immunomodulatory medicinal products may increase the risk of malignancies. The clinical data are insufficient to assess the potential incidence of malignancies following exposure to filgotinib. Long-term safety evaluations are ongoing.

Malignancies were observed in clinical studies of filgotinib. The risks and benefits of filgotinib treatment should be considered prior to initiating treatment in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing filgotinib treatment in patients who develop a malignancy.

Non-melanoma skin cancer

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

Fertility

In animal studies, decreased fertility, impaired spermatogenesis, and histopathological effects on male reproductive organs were observed (see section 5.3). The potential effect of filgotinib on sperm production and male fertility in humans is currently unknown. The reversibility of these potential effects is unknown. The potential risk of reduced fertility or infertility should be discussed with male patients before initiating treatment.

Haematological abnormalities

ANC < 1 × 109 cells/L (see section 4.8) and ALC < 0.5 × 109 cells/L were reported in < 1% of patients in clinical studies. Treatment should not be initiated, or should be temporarily interrupted, in patients with an ANC < 1 × 109 cells/L, ALC < 0.5 × 109 cells/L or haemoglobin < 8 g/dL observed during routine patient management (see section 4.2).

Vaccinations

Use of live vaccines during, or immediately prior to, filgotinib treatment is not recommended. It is recommended that immunisations be updated in agreement with current immunisation guidelines prior to initiating filgotinib treatment.

Lipids

Treatment with filgotinib was associated with dose-dependent increases in lipid parameters, including total cholesterol, and high-density lipoprotein (HDL) levels, while low-density lipoprotein (LDL) levels were slightly increased (see section 4.8). LDL cholesterol returned to pre-treatment levels in the majority of patients who started statin therapy while taking filgotinib. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined (see section 4.2 for monitoring guidance).

Cardiovascular risk

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

Venous thromboembolism

Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving JAK inhibitors including filgotinib. JAK inhibitors 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 prolonged immobilisation. If clinical features of DVT/PE occur, filgotinib treatment should be discontinued and patients should be evaluated promptly, followed by appropriate treatment.

Lactose content

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

4.5 Interaction with other medicinal products and other forms of interaction

Effect of other medicinal products on filgotinib

Filgotinib is primarily metabolised by carboxylesterase 2 (CES2), which can be inhibited in vitro by medicinal products such as fenofibrate, carvedilol, diltiazem or simvastatin. The clinical relevance of this interaction is unknown.

Effect of filgotinib on other medicinal products

Filgotinib is not a clinically relevant inhibitor or inducer of most enzymes or transporters commonly involved in interactions such as cytochrome P450 (CYP) enzymes and UDP-glucuronosyltran­sferases (UGT).

In vitro studies are inconclusive regarding the potential of filgotinib to induce CYP2B6.

In vivo induction cannot be excluded.

In vitro studies are inconclusive regarding the potential of filgotinib to induce or inhibit CYP1A2. No clinical studies have been performed to investigate interactions with CYP1A2 substrates and therefore the potential in vivo effect of concomitant induction and inhibition of CYP1A2 by filgotinib is unknown. Caution is recommended when filgotinib is co-administered with CYP1A2 substrates with a narrow therapeutic index.

In a clinical pharmacology study, there was no effect on the pharmacokinetics of the combined contraceptive ethinyl estradiol and levonorgestrel when co-administered with filgotinib; thus no dose adjustment of oral contraceptives is required.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential / Contraception

Women of childbearing potential have to use effective contraception during and for at least 1 week after cessation of filgotinib treatment.

Pregnancy

There are no or limited amount of data from the use of filgotinib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).

Based on findings in animals, filgotinib may cause foetal harm and is therefore contraindicated during pregnancy (see section 4.3).

Breast-feeding

It is unknown whether filgotinib is excreted in human milk. A risk to breastfed newborns/infants cannot be excluded. Therefore, Jyseleca should not be used during breast-feeding.

Fertility

In animal studies, decreased fertility, impaired spermatogenesis, and histopathological effects on male reproductive organs were observed (see section 5.3). The potential effect of filgotinib on sperm production and male fertility in humans is currently unknown. The reversibility of these potential effects is unknown (see section 4.4).

Animal studies did not indicate effects with respect to fertility in females

4.7 Effects on ability to drive and use machines

Filgotinib has no or negligible influence on the ability to drive and use machines. However, patients should be advised that dizziness has been reported during treatment with Jyseleca (see section 4.8).

4.8 Undesirable effects

Summary of the safety profile

The most frequently reported adverse reactions are nausea (3.5%), upper respiratory tract infection (URTI, 3.3%), urinary tract infection (UTI, 1.7%) and dizziness (1.2%).

Tabulated list of adverse reactions

The following adverse reactions are based on clinical studies (Table 2). The adverse reactions are listed below by system organ class and frequency. Frequencies are defined as follows: common (> 1/100 to < 1/10) and uncommon (> 1/1,000 to < 1/100).

Table 2: Adverse reactions

a Frequency based on placebo-controlled pre-rescue period (week 12) pooled across FINCH 1 and 2, and DARWIN 1 and 2, for patients who received filgotinib 200 mg.

Laboratory changes

Creatinine

An increase in serum creatinine occurred with filgotinib treatment. At week 24 in the Phase 3 studies (FINCH 1, 2, and 3), the mean (SD) increase from baseline in serum creatinine was 0.07 (0.12) and 0.04 (0.11) mg/dL for filgotinib 200 mg and 100 mg, respectively. Mean creatinine values remained within the normal range.

Lipids

Treatment with filgotinib was associated with dose-dependent increases in total cholesterol and HDL levels, while LDL levels were slightly increased. LDL/HDL ratios were generally unchanged. Lipid changes were observed within the first 12 weeks of filgotinib treatment and remained stable thereafter.

Description of selected adverse reactions

Infections

In placebo-controlled studies with background DMARDs (FINCH 1, FINCH 2, DARWIN 1, and DARWIN 2), the frequency of infection over

12 weeks in the filgotinib 200 mg group was 18.1% compared to 13.3% in the placebo group. In the MTX-controlled study FINCH 3, the frequency of infection over 24 weeks in the filgotinib 200 mg monotherapy and filgotinib 200 mg plus MTX groups was 25.2% and 23.1%, respectively, compared to 24.5% in the MTX group. The overall exposure-adjusted incidence rate (EAIR) of infections for the filgotinib 200 mg group across all seven Phase 2 and 3 clinical studies (2,267 patients) was 26.5 per 100 patient-years of exposure (PYE).

In placebo-controlled studies with background DMARDs, the frequency of serious infection over 12 weeks in the filgotinib 200 mg group was 1.0% compared to 0.6% in the placebo group. In the MTX-controlled study FINCH 3, the frequency of serious infection over 24 weeks in the filgotinib 200 mg monotherapy and filgotinib 200 mg plus MTX groups was 1.4% and 1.0%, respectively, compared to 1.0% in the MTX group. The overall EAIR of serious infections for the filgotinib 200 mg group across all seven Phase 2 and 3 clinical studies (2,267 patients) was 1.7 per 100 PYE. The most common serious infection was pneumonia. The EAIR of serious infections remained stable with long-term exposure.

There was a higher incidence of serious infections in patients aged 75 years and older, although data are limited.

In placebo-controlled studies with background DMARDs, the frequencies of infectious ADRs over 12 weeks for filgotinib 200 mg compared to placebo were: URTI (3.3% versus 1.8%), UTI (1.7% versus 0.9%), pneumonia (0.6% versus 0.4%), and herpes zoster (0.1% versus 0.3%). Most of the herpes zoster events involved a single dermatome and were non-serious.

Opportunistic infections (excluding TB)

In placebo-controlled studies with background DMARDs, there were no opportunistic infections over 12 weeks in the filgotinib 200 mg group or the placebo group. In the MTX-controlled study FINCH 3, the frequency of opportunistic infections over 24 weeks was 0, 0.2%, and 0 in the filgotinib 200 mg monotherapy, filgotinib 200 mg plus MTX, and MTX groups, respectively. The overall EAIR of opportunistic infections for the filgotinib 200 mg group across all seven Phase 2 and 3 clinical studies (2,267 patients) was 0.1 per 100 PYE.

Nausea

Nausea was generally transient and reported during the first 24 weeks of filgotinib treatment.

Creatine phosphokinase

Dose-dependent increases in creatine phosphokinase (CPK) occurred within the first 12 weeks of filgotinib treatment and remained stable thereafter. At week 24 in the Phase 3 studies (FINCH 1, 2, and 3), the mean (SD) increase from baseline in CPK was –16 (449), 61 (260), and 33 (80) U/L for placebo, filgotinib 200 mg and 100 mg, respectively.

In placebo-controlled Phase 3 studies with background DMARDs (FINCH 1 and FINCH 2) through 12 weeks, CPK elevations > 5 x upper limit of normal (ULN) were reported in 0.5%, 0.3%, and 0.3% of patients in the placebo, filgotinib 200 mg, and filgotinib 100 mg groups, respectively. Most elevations > 5 x ULN did not require treatment discontinuation.

Experience from long-term extension studies

In the long-term extension study DARWIN 3, among patients enrolled from DARWIN 1 (N = 497), 238 patients received filgotinib 200 mg once a day for a median duration of 4.4 years; among patients enrolled from DARWIN 2 (N = 242), 234 patients received filgotinib 200 mg once a day for a median duration of 4.4 years. The safety profile of filgotinib was similar to that in the Phase 2 and Phase 3 studies.

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

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

Filgotinib has been administered in clinical studies following single and once daily administration up to 450 mg without dose-limiting toxicity. Adverse reactions were comparable to those seen at lower doses and no specific toxicities were identified. Pharmacokinetic data following a single dose of 100 mg filgotinib in healthy subjects indicate that approximately 50% of the administered dose is eliminated within 24 hours of dosing and 90% of the dose is eliminated within 72 hours. In case of an overdose, it is recommended that a patient be monitored for signs and symptoms of adverse reactions. Treatment of overdose with filgotinib consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. It is unknown whether filgotinib can be removed by dialysis.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants, ATC code: L04AA45

Mechanism of action

Filgotinib is an adenosine triphosphate (ATP)-competitive and reversible inhibitor of the JAK family. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane. JAK1 is important in mediating inflammatory cytokine signals, JAK2 in mediating myelopoiesis and erythropoiesis and JAK3 plays critical roles in immune homeostasis and lymphopoiesis. Within the signalling pathway, JAKs phosphorylate and activate signal transducers and activators of transcription (STATs) which modulate intracellular activity including gene expression. Filgotinib modulates these signalling pathways by preventing the phosphorylation and activation of STATs. In biochemical assays, filgotinib preferentially inhibited the activity of JAK1 and showed > 5-fold higher potency of filgotinib for JAK1 over JAK2, JAK3 and TYK2. In human cellular assays, filgotinib preferentially inhibited JAK1/JAK3-mediated signalling downstream of the heterodimeric cytokine receptors for interleukin (IL)-2, IL-4 and IL-15, JAK1/2-mediated IL-6, and JAK1/TYK2-mediated type I interferons, with functional selectivity over cytokine receptors that signal via pairs of JAK2 or JAK2/TYK2. GS-829845, the primary metabolite of filgotinib, was approximately 10-fold less active than filgotinib in in vitro assays, while exhibiting a similar JAK1 preferential inhibitory activity. In an in vivo rat model, the overall pharmacodynamic effect was predominantly driven by the metabolite.

Pharmacodynamic effects

Inhibition of IL-6 induced STAT1 phosphorylation

Filgotinib administration resulted in a dose-dependent inhibition of IL-6 induced STAT1 phosphorylation in whole blood from healthy subjects. Filgotinib administration did not affect JAK2-associated GM-CSF induced STAT5 phosphorylation.

Immunoglobulins

In FINCH 1, 2, and 3, the median and interquartile ranges for serum IgG, IgM, and IgA values remained largely within the normal reference ranges through 24 weeks of treatment with filgotinib.

Haematologic effects

Treatment with filgotinib was associated with a small, transient increase in mean ALC that remained within normal reference ranges and gradually returned to at or near baseline levels with continued treatment by week 12. In FINCH 1, 2, and 3, median haemoglobin values remained stable within the normal range through 24 weeks of filgotinib treatment. A slight decrease in median platelet counts occurred within the first 4 weeks of filgotinib treatment and remained stable thereafter through 24 weeks. Median platelet counts remained within the normal range.

C-reactive protein

Decreases in serum C-reactive protein (CRP) were observed as early as 2 weeks after starting treatment with filgotinib and were maintained through 24 weeks of treatment.

Clinical efficacy and safety

The efficacy and safety of filgotinib once daily were assessed in three Phase 3 studies (FINCH 1, 2, and 3). These were randomised, double-blind, multicentre studies in patients with moderate to severe active rheumatoid arthritis diagnosed according to American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 2010 criteria.

FINCH 1 was a 52-week study in 1,755 patients with rheumatoid arthritis who had an inadequate response to MTX. Patients received filgotinib 200 mg once daily, filgotinib 100 mg once daily, adalimumab every 2 weeks, or placebo, all added to stable background MTX. At week 24, patients receiving placebo were re-randomised to filgotinib 100 mg or 200 mg once daily through week 52. The primary endpoint was the proportion of patients who achieved an ACR20 response at week 12.

FINCH 2 was a 24-week study in 448 patients with rheumatoid arthritis who had an inadequate response to bDMARDs. Patients received filgotinib 200 mg once daily, filgotinib 100 mg once daily, or placebo, all with a continued stable background dose of conventional synthetic DMARD(s) (csDMARD[s]: MTX, hydroxychloroquine, sulfasalazine, or leflunomide). The primary endpoint was the proportion of patients who achieved an ACR20 response at week 12.

FINCH 3 was a 52-week study in 1,249 patients with rheumatoid arthritis who were naïve to MTX therapy. Patients received filgotinib 200 mg once daily plus MTX once weekly, filgotinib 100 mg once daily plus MTX once weekly, filgotinib 200 mg (monotherapy) once daily, or MTX (monotherapy) once weekly. The primary endpoint was the proportion of patients who achieved an ACR20 response at week 24.

Clinical response

Higher response rates versus placebo or MTX were seen at week 2 for ACR20, and responses were maintained through week 52.

Treatment with filgotinib 200 mg resulted in improvements in all individual ACR components, including tender and swollen joint counts, patient and physician global assessments, Health Assessment Questionnaire Disability Index (HAQ-DI), pain assessment and high sensitivity CRP, compared to placebo or MTX. In two of the Phase 3 studies (FINCH 1 and FINCH 2), the comparison (versus placebo) was carried out on top of MTX or csDMARD(s) (see above).

Low disease activity and remission

Across the Phase 3 studies, a significantly higher proportion of patients treated with filgotinib 200 mg plus MTX or other csDMARD achieved low disease activity and/or remission (DAS28-CRP < 3.2 and DAS28-CRP < 2.6) at weeks 12 and 24 as compared to placebo or MTX. Filgotinib 200 mg was non-inferior to adalimumab at week 12 for DAS28-CRP < 3.2 in FINCH 1 (Table 3).

Table 3: Clinical response at weeks 12, 24 and 52 in FINCH 1, 2, and 3

ADA: adalimumab; bDMARD: biologic DMARD; csDMARD: conventional synthetic DMARD; DMARD: disease-modifying antirheumatic drug; FIL: filgotinib; IR: inadequate responder; mono: monotherapy; MTX:

methotrexate; PBO: placebo.

* p < 0.05; ** p < 0.01; *** p < 0.001 versus placebo (versus MTX for FINCH 3) (statistically significant difference with multiplicity adjustment).

f p < 0.05; ff p < 0.01; fff p < 0.001 versus placebo (versus MTX for FINCH 3) (nominal p-value).

# p < 0.05; ## p < 0.01; ### p < 0.001 versus adalimumab for FINCH 1 (non-inferiority test, statistically significant difference with multiplicity adjustment) (analysed for DAS28-CRP < 3.2 and < 2.6 pairwise comparisons only).

§ p < 0.05; §§ p < 0.01; §§§ p < 0.001 versus adalimumab for FINCH 1 (non-inferiority test, nominal p-value) (analysed for DAS28-CRP < 3.2 and < 2.6 pairwise comparisons only).

T p < 0.05; T[ p <0.01; [[[ p< 0.001 versus adalimumab for FINCH 1 (superiority test, nominal p-value) (analysed for ACR20/50/70, and DAS28-CRP < 3.2 and < 2.6 pairwise comparisons only).

Note: Comparisons were carried out on top of a stable background of MTX (FINCH 1) or csDMARD(s) (FINCH 2).

Radiographic response

Inhibition of progression of structural joint damage was assessed using the modified Total Sharp Score (mTSS) and its components, the erosion score and joint space narrowing score, at weeks 24 and 52 in FINCH 1 and FINCH 3.

In patients who had an inadequate response to MTX, treatment with filgotinib plus MTX resulted in statistically significant inhibition of progression of structural joint damage compared to placebo plus MTX at week 24 (Table 4). Analyses of erosion and joint space narrowing scores were consistent with the overall scores.

Table 4: Radiographic response at weeks 24 and 52 in FINCH 1 and 3

ADA: adalimumab; FIL: filgotinib; IR: inadequate responder; mono: monotherapy; MTX: methotrexate; PBO: placebo.

a No progression defined as mTSS change < 0.

* p < 0.05; ** p < 0.01; *** p < 0.001 versus placebo (statistically significant difference with multiplicity adjustment).

f p < 0.05; ff p < 0.01; fff p < 0.001 versus placebo (versus MTX for FINCH 3) (nominal p-value).

Physical function response and health related outcomes

Treatment with filgotinib 200 mg resulted in a significant improvement in physical function, as measured by change from baseline in HAQ-DI (Table 5).

Table 5: Mean change from baseline in HAQ-DI at weeks 12, 24 and 52 in FINCH 1, 2, and 3

ADA: adalimumab; bDMARD: biologic DMARD; csDMARD: conventional synthetic DMARD; DMARD: disease-modifying antirheumatic drug; FIL: filgotinib; IR: inadequate responder; mono: monotherapy; MTX: methotrexate; PBO: placebo.

* p < 0.05; ** p < 0.01; *** p < 0.001 versus placebo (statistically significant difference with multiplicity adjustment).

f p < 0.05; ff p < 0.01; fff p < 0.001 versus placebo (versus MTX for FINCH 3) (nominal p-value).

Health status outcomes were assessed by the Short Form health survey (SF-36).

Patients treated with filgotinib 200 mg plus MTX or other csDMARD demonstrated numerically greater improvement from baseline in the physical component summary score of SF-36 as well as in the Functional Assessment of Chronic Illness Therapy-Fatigue score (FACIT-F) at weeks 12 and 24 compared to placebo plus MTX/csDMARD or MTX.

Long-term efficacy

In a long-term Phase 2 open-label extension study (DARWIN 3), continued and durable responses were observed, with ACR20/50/70 responses maintained for up to 3 years in patients who received filgotinib 200 mg as monotherapy or with MTX.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with filgotinib in one or more subsets of the paediatric population in the treatment of chronic idiopathic arthritis (including rheumatoid arthritis, ankylosing spondylarthritis, psoriatic arthritis, and juvenile idiopathic arthritis) (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Absorption

Following oral administration, filgotinib was absorbed quickly and its median peak plasma concentration was observed 2 to 3 hours postdose after multiple dosing; the median peak plasma concentrations of its primary metabolite GS-829845 were observed 5 hours postdose after multiple dosing. Filgotinib and GS-829845 exposures (AUC) and Cmax were similar in healthy adult subjects and patients with rheumatoid arthritis. Filgotinib and GS-829845 exposures (AUC) and Cmax are dose-proportional over the therapeutic dose range. Steady-state concentrations of filgotinib are achieved in 2 – 3 days with negligible accumulation after once daily administration. Steady-state concentrations of GS-829845 are achieved in 4 days with approximately 2-fold accumulation after once daily dosing of filgotinib.

There were no clinically relevant differences in exposures when filgotinib was administered with a high-fat or low-fat meal as compared to a fasted state. Filgotinib can be administered with or without food.

The multiple dose pharmacokinetic parameters of filgotinib and GS-829845 are provided in Table 6.

Table 6: Multiple dose pharmacokinetic parameters of filgotinib and GS-829845 following oral administration of filgotinib 200 mg with or without food in adults with moderate to severe active rheumatoid arthritis

CV: coefficient of variation.

a From intensive PK analyses of studies FINCH 1, FINCH 2, and FINCH 3 in rheumatoid

arthritis patients receiving 200 mg filgotinib once daily.

b N = 37

c N = 33

Distribution

Filgotinib and GS-829845 binding to human plasma proteins is low (55 – 59% and 39 – 44% bound, respectively). The blood-to-plasma ratio of filgotinib ranged from 0.85 to 1.1 indicating no preferential distribution of filgotinib and GS-829845 into blood cells. Filgotinib and GS-829845 are substrates of the P-gp transporter.

Biotransformation

Filgotinib is extensively metabolised with approximately 9.4% and 4.5% of an orally administered dose recovered as unchanged filgotinib in urine and faeces, respectively. Filgotinib is primarily metabolised by CES2, and to a lesser extent by CES1. Both CES2 and CES1 form GS-829845, an active circulating metabolite that is approximately 10-fold less potent than the parent compound. In a clinical pharmacology study, filgotinib and GS-829845 accounted for the majority of radioactivity circulating in plasma (2.9% and 92%, respectively). No other major metabolites were identified.

As both filgotinib and GS-829845 contribute to efficacy, their exposures were combined into a single parameter, AUCeff. AUCeff is the sum of the AUC of filgotinib and GS-829845, corrected for their respective molecular weights and potencies.

Elimination

Approximately 87% of the administered dose was eliminated in the urine as filgotinib and its metabolites, while about 15% of the dose was eliminated in the faeces. GS-829845 accounted for approximately 54% and 8.9% of dose recovered in urine and faeces, respectively. The mean terminal half-lives of filgotinib and GS-829845 were approximately 7 and 19 hours, respectively.

Other special populations

Weight, gender, race, and age

Bodyweight, gender, race, and age did not have a clinically relevant effect on the pharmacokinetics (AUC) of filgotinib or GS-829845.

Elderly

There were no clinically relevant differences in mean filgotinib and GS-829845 exposures (AUC and Cmax) between older patients aged > 65 years relative to adult patients aged <65 years.

Renal impairment

The pharmacokinetics of filgotinib and GS-829845 were unaffected in subjects with mild renal impairment (CrCl 60 to < 90 mL/min). Increases in exposures (AUC) of filgotinib, GS-829845, and combined AUCef (< 2-fold), were observed in subjects with moderate renal impairment (CrCl 30 to < 60 mL/min). In subjects with severe renal impairment (CrCl 15 to < 30 mL/min), filgotinib exposure (AUC) increased by 2.2-fold and GS-829845 exposure significantly increased by 3.5-fold leading to a 3-fold increase in AUCeff. The pharmacokinetics of filgotinib has not been studied in subjects with end stage renal disease (CrCl < 15 mL/min).

Hepatic impairment

No clinically relevant changes in the exposures (AUC) of filgotinib and GS-829845 indivi­dually, or their combined exposure (AUCeff), were observed in subjects with moderate hepatic impairment (Child-Pugh B). The pharmacokinetics of filgotinib has not been studied in subjects with severe hepatic impairment (Child-Pugh C).

Effect of filgotinib on other medicinal products

Potential interactions between filgotinib and co-administered medicinal products are listed in Table 7 below (increase is indicated as “f”, decrease as “j”, and no change as “<->”; no effect boundaries are 70 – 143% unless otherwise indicated).

Table 7: Interaction studies with filgotinib 1

GS-829845: primary metabolite of filgotinib.

1 All interaction studies conducted in healthy volunteers.

2 Study conducted with filgotinib 200 mg single dose.

3 Study conducted with filgotinib 100 mg single dose.

4 Study conducted with filgotinib 200 mg once daily.

5 Bioequivalence boundaries are 80 – 125% for midazolam and 1’OH-midazolam.

6 As both filgotinib and GS-829845 contribute to efficacy, their exposures were combined into a single parameter, AUCeff. AUCeff is the combined AUC of filgotinib and GS-829845, adjusted for their respective molecular weights and potencies.

Potential for filgotinib to affect other medicinal products

In vitro data indicate that filgotinib and GS-829845 do not inhibit the activity of the following: CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, UGT1A1, UGT1A4,

UGT1A6, UGT1A9, and UGT2B7 at clinically relevant concentrations. The potential for filgotinib to induce CYP2B6 constitutive androstane receptor (CAR) mediated metabolism in vivo is unknown. No conclusion can be drawn from the in vitro data regarding the potential of filgotinib to inhibit or induce CYP1A2. In vivo data demonstrated no inhibition or induction of CYP3A4 mediated metabolism.

In vitro studies indicate that filgotinib and GS-829845 are not inhibitors of P-gp, BCRP, OCT1, BSEP, OAT1, OAT3 or OAT4 at clinically relevant concentrations.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology.

The carcinogenic potential of filgotinib was evaluated in a 6-month rasH2 transgenic mouse study and a 2-year rat study. Filgotinib was not carcinogenic in mice at up to 150 mg/kg/day, which resulted in exposures of approximately 25 and 12 times the exposures in humans at the 100 mg and 200 mg once daily doses, respectively. In the 2-year rat study, filgotinib treatment resulted in an increase in incidence and decrease in latency of benign Leydig cell tumours at the highest dose of 45 mg/kg/day (exposures of approximately 4.2 times exposures in humans at the 200 mg once daily dose); the clinical relevance of this finding is low.

Filgotinib was not mutagenic or clastogenic in the in vitro bacterial reverse mutation assay, in vitro chromosome aberration assay, and in vivo rat micronucleus assay.

Adverse findings of degeneration/ne­crosis of incisor ameloblasts were observed in rats at exposures 21– to 28-fold greater than clinical exposures at the 200 mg filgotinib dose, with exposure margins at the NOAEL ranging from 3.5– to 8-fold. The human relevance of these dental findings is considered low since in contrast to adult patients, ameloblasts in rats persist into adulthood to support lifelong continuous incisor growth.

Impaired spermatogenesis and histopathological effects on male reproductive organs (testes and epididymis) were observed with filgotinib in rats and dogs. At the no-observed-adverse-effect-levels (NOAELs) in dogs (the most sensitive species), the exposure margin is 2.7-fold at the 200 mg once daily dose in humans. The severity of the histological effects was dose-dependent. Spermatogenic and histopathological effects were not fully reversible at lower exposures and were irreversible at exposure margins of approximately 7– to 9-fold the exposure at the 200 mg once daily dose in humans.

Embryo-foetal development studies in rats and rabbits demonstrated embryolethality and teratogenicity at exposures comparable to 200 mg filgotinib once daily dosing in humans. Visceral and skeletal malformations and/or variations were observed at all dose levels of filgotinib.

Filgotinib was administered to pregnant rats at doses of 25, 50, and 100 mg/kg/day. Dose-related increases in the incidence of internal hydrocephaly, dilated ureters, and multiple vertebral anomalies were seen at all dose levels. At 100 mg/kg/day, an increased number of early and late resorptions were noted together with a decreased number of viable foetuses. In addition, foetal body weights were decreased.

In rabbits, filgotinib caused visceral malformations mainly in the lungs and cardiovascular system, at a dose level of 60 mg/kg/day. Filgotinib caused skeletal malformations affecting the vertebral column region at dose levels of 25 and 60 mg/kg/day, mainly in vertebra, ribs and sternebrae. Fused sternebrae also occurred at 10 mg/kg/day filgotinib. Retarded skeletal ossification was evidenced at 60 mg/kg/day.

No adverse effects on pre-/postnatal development were observed in rats in a pre- and postnatal development study of filgotinib and GS-829845. Filgotinib and GS-829845 were detected in nursing rat pups after administration of filgotinib to lactating female rats from gestation day 6 through 10 days post-partum at dose levels of 2, 5, and 15 mg/kg/day, likely due to the presence of filgotinib in milk. At the highest tested dose, maternal systemic exposure (AUC) to filgotinib in rats was approximately 2 times the exposure in humans at the 200 mg once daily dose; exposures in nursing pups were less than 6% that of maternal exposure on day 10 post-partum. Due to the low exposure of the animals, the pre-/postnatal development study was considered inconclusive.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core

Microcrystalline cellulose

Lactose monohydrate

Pregelatinised starch

Colloidal silicon dioxide

Fumaric acid

Magnesium stearate

Film-coating

Polyvinyl alcohol

Titanium dioxide (E171)

Macrogol

Talc

Iron oxide yellow (E172)

Iron oxide red (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Store in the original package in order to protect from moisture. Keep the bottle tightly closed.

6.5 Nature and contents of container

White, high-density polyethylene (HDPE) bottles, enclosed with a child-resistant polypropylene (PP) screw cap lined with an induction-sealed aluminium foil liner. Each bottle contains either a canister or sachet containing silica gel desiccant and polyester coil.

The following pack sizes are available: outer cartons containing 1 bottle of 30 film-coated tablets and outer cartons containing 90 (3 bottles of 30) film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements

7 MARKETING AUTHORISATION HOLDER

Gilead Sciences Ltd

280 High Holborn

London

WC1V 7EE

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

Jyseleca 100 mg film-coated tablets

PLGB 11972/0033

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

01/01/2021