Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Galapagos NV, Generaal De Wittelaan L11 A3, 2800 Mechelen, Belgium
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).
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, 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:
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.
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, 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.
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.
NMSCs have been reported in patients treated with filgotinib. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.
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.
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).
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.
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).
Patients with rheumatoid arthritis and ulcerative colitis have an increased risk for cardiovascular disorders. Filgotinib should be used with caution in patients with cardiovascular risk factors. Patients should have risk factors (e.g., hypertension, hyperlipidaemia) managed as part of usual standard of care.
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.
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
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.
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.
Women of childbearing potential have to use effective contraception during and for at least 1 week after cessation of filgotinib treatment.
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).
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.
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.
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).
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%).
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.
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:
| Frequencya | Adverse reaction |
|---|---|
| Infections and infestations | |
| Common | Urinary tract infection (UTI) Upper respiratory tract infection (URTI) |
| Uncommon | Herpes zoster Pneumonia |
| Blood and lymphatic system disorders | |
| Uncommon | Neutropenia |
| Metabolism and nutrition disorders | |
| Uncommon | Hypercholesterolaemia |
| Nervous system disorders | |
| Common | Dizziness |
| Gastrointestinal disorders | |
| Common | Nausea |
| Investigations | |
| Uncommon | Blood creatine phosphokinase increased |
a 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.
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.
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.
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 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.
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.
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 was generally transient and reported during the first 24 weeks of filgotinib treatment.
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.
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.
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 suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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