4.1. Therapeutic indications

Rheumatoid arthritis

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).

Ulcerative colitis

Jyseleca is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a biologic agent.

4.2. Posology and method of administration

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

Posology

Rheumatoid arthritis

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

In adults at increased risk of VTE, MACE and malignancy (see section 4.4), the recommended dose is 100 mg once daily and may be escalated to 200 mg once daily in case of insufficient disease control. For long term treatment, the lowest effective dose should be used.

Ulcerative colitis

Induction treatment

The recommended dose for induction treatment is 200 mg once daily.

For patients with ulcerative colitis who do not show an adequate therapeutic benefit during the initial 10 weeks of treatment, 12 additional weeks of induction treatment with filgotinib 200 mg once daily may provide additional relief of symptoms (see section 5.1). Patients who have not shown any therapeutic benefit after 22 weeks of treatment should discontinue filgotinib.

Maintenance treatment

The recommended dose for maintenance treatment is 200 mg once daily.

In adults at higher risk of VTE, MACE and malignancy (see section 4.4), the recommended dose for maintenance treatment is 100 mg once daily. In case of flare of the disease, the dose may be escalated to 200 mg once daily. For long term treatment, the lowest effective dose should be used.

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

Laboratory measure

Action

Monitoring guidance

Absolute neutrophil count (ANC)

Treatment should not be initiated, or should be interrupted, if ANC is < 1 × 109 cells/L. Treatment may be restarted once ANC returns above this value

Before treatment initiation and thereafter according to routine patient management

Absolute lymphocyte count (ALC)

Treatment should not be initiated, or should be interrupted, if ALC is < 0.5 × 109 cells/L. Treatment may be restarted once ALC returns above this value

Haemoglobin (Hb)

Treatment should not be initiated, or should be interrupted, if Hb is < 8 g/dL. Treatment may be restarted once Hb returns above this value

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

Special populations

Elderly

Rheumatoid arthritis

In patients with rheumatoid arthritis aged 65 years of age and older, the recommended dose is 100 mg once daily and may be escalated to 200 mg once daily in case of insufficient disease control (see section 4.4). For long term treatment, the lowest effective dose should be used.

Ulcerative colitis

In patients with ulcerative colitis aged 65 years of age and older, the recommended dose is 200 mg once daily for the induction treatment and 100 mg once daily for maintenance treatment (see section 4.4). In case of flare of the disease, the dose may be escalated to 200 mg once daily. For long term treatment, the lowest effective dose should be used. Filgotinib is not recommended in patients aged 75 years and older as there is no data in this population.

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

Filgotinib 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)

Immunosuppressive medicinal products

Combination of filgotinib with other potent immunosuppressants such as ciclosporin, tacrolimus, biologics 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 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 65 years of age and older, filgotinib should only be used if no suitable treatment alternatives are available (see section 4.2).

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). In rheumatoid arthritis clinical studies, the risk of herpes zoster appeared to be higher in female patients, Asian patients, patients ≥ 50 years of age, patients with a medical history of herpes zoster, patients with a medical history of chronic lung disease and patients treated with filgotinib 200 mg once daily. 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

Lymphoma and other malignancies have been reported in patients receiving JAK inhibitors, including filgotinib. In a large randomised 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 65 years of age and older, patients who are current or past long-time smokers, or with other malignancy risk factors (e.g. current malignancy or history of malignancy), filgotinib should only be used if no suitable treatment alternatives are available.

Non-melanoma skin cancer

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

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 the rheumatoid arthritis clinical studies and in < 3% of patients in the ulcerative colitis 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, including prophylactic zoster vaccinations, 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).

Major adverse cardiovascular events (MACE)

Events of MACE have been observed in patients taking filgotinib.

In a large randomised 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 compared to TNF inhibitors.

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

Venous thromboembolism (VTE)

Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving JAK inhibitors including filgotinib.

In a large randomised 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”) filgotinib 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, filgotinib 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, inherited coagulation disorder.

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

Promptly evaluate patients with signs and symptoms of VTE and discontinue filgotinib in patients with suspected VTE, regardless of dose.

Use 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), filgotinib should only be used in these patients if no suitable treatment alternatives are available.

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 data from two dedicated Phase 2 clinical studies (MANTA and MANTA RAy, n=240) to evaluate the human testicular safety in men with inflammatory arthritis diseases and inflammatory bowel diseases did not reveal a difference between treatment groups in the proportion of patients who had a 50% or more decrease from baseline in semen parameters at week 13 (pooled primary endpoint: filgotinib 6.7%, placebo 8.3%) and at week 26. Further, the data did not show any relevant changes in sex hormone levels or change from baseline in semen parameters across treatment groups. Overall, these clinical data were not suggestive of filgotinib-related effects on testicular function.

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

4.7. Effects on ability to drive and use machines

Filgotinib has minor influence on the ability to drive and use machines. Patients should be advised that dizziness and vertigo has been reported during treatment with Jyseleca (see section 4.8).

4.8. Undesirable effects

Summary of the safety profile

Rheumatoid arthritis

The most frequently reported adverse reactions are nausea (3.5%), upper respiratory tract infection (URTI, 3.3%), urinary tract infection (UTI, 1.7%), dizziness (1.2%) and lymphopenia (1.0%).

Ulcerative colitis

In general, the overall safety profile observed in filgotinib-treated patients with ulcerative colitis was generally consistent with the safety profile observed in patients with rheumatoid arthritis.

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

Frequency a

Adverse reaction

Infections and infestations

Common

Urinary tract infection (UTI)

Upper respiratory tract infection (URTI)

Uncommon

Herpes zoster

Pneumonia

Sepsis

Blood and lymphatic system disorders

Common

Lymphopenia

Uncommon

Neutropenia

Metabolism and nutrition disorders

Uncommon

Hypercholesterolaemia

Nervous system disorders

Common

Dizziness

Ear and labyrinth disorders

Uncommon

Vertigo

Gastrointestinal disorders

Common

Nausea

Investigations

Common

Blood phosphorus decreased

Uncommon

Blood creatine phosphokinase increased

a Frequency based on placebo-controlled pre-rescue period (week 12) pooled across FINCH 1 and 2, and DARWIN 1 and 2, for patients with rheumatoid arthritis who received filgotinib 200 mg. Frequencies reported in the SELECTION study in patients with ulcerative colitis who received filgotinib 200 mg were generally consistent with those reported in the rheumatoid arthritis studies.

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.

Serum phosphate

Generally mild, transient or intermittent, and dose-dependent decreases in serum phosphate levels occurred during treatment with filgotinib and resolved without discontinuation of treatment. At week 24 in the Phase 3 studies (FINCH 1, 2, and 3), serum phosphate values of less than 2.2 mg/dL (the lower limit of normal) were reported in 5.3% and 3.8% of subjects receiving filgotinib 200 mg and 100 mg, respectively; no values below 1.0 mg/dL were reported.

In placebo-controlled Phase 3 studies with background DMARDs (FINCH 1 and FINCH 2) through 12 weeks, serum phosphate levels of less than 2.2 mg/dL were reported in 1.6%, 3.1%, and 2.4% in the placebo, filgotinib 200 mg, and filgotinib 100 mg groups, respectively.

Description of selected adverse reactions

Infections

Rheumatoid arthritis

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.

In rheumatoid arthritis clinical studies, there was a higher incidence of serious infections in patients aged 65 years and older.

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. The overall EAIR of herpes zoster across all seven Phase 2 and 3 clinical studies (2 267 and 1 647 total patients for 200 mg and 100 mg, respectively) was 1.6 and 1.1 per 100 PYE in the 200 mg group and 100 mg group, respectively.

Ulcerative colitis

The types of serious infections in the ulcerative colitis clinical studies were generally similar to those reported in the rheumatoid arthritis clinical studies with filgotinib monotherapy treatment groups.

Across the two placebo-controlled induction studies, the frequency of serious infections was 0.6% in the filgotinib 200 mg group, 1.1% in the filgotinib 100 mg group, and 1.1% in the placebo group. In the placebo-controlled maintenance study, the frequency of serious infections in the filgotinib 200 mg group was 1%, compared to 0% in the respective placebo group. In the maintenance study filgotinib 100 mg group, the frequency of serious infections was 1.7%, compared with 2.2% in the respective placebo group.

Opportunistic infections (excluding TB)

In rheumatoid arthritis 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 rheumatoid arthritis 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 × 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 × ULN did not require treatment discontinuation.

Experience from long-term extension studies

Rheumatoid arthritis

In the long-term extension study DARWIN 3, patients enrolled from DARWIN 1 (N = 497) received filgotinib once a day for a median duration of 5.3 years and patients enrolled from DARWIN 2 (N = 242) received filgotinib once a day for a median duration of 5.6 years. In the long-term extension study FINCH 4, 1 530 patients received filgotinib 200 mg once daily and 1 199 patients received filgotinib 100 mg once daily for a median duration of 1.5 years. The safety profile of filgotinib was similar to that in the Phase 2 and Phase 3 studies.

Ulcerative colitis

In the long-term extension study (SELECTION LTE) in patients who participated in the SELECTION study, patients received filgotinib 200 mg (N = 871), filgotinib 100 mg (N = 157), or placebo (N = 133) for median durations of 55, 36, and 32 weeks, respectively. The safety profile of filgotinib was similar to that in the SELECTION induction and maintenance 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.