Filgotinib

Filgotinib is used for: Rheumatoid arthritis, Ulcerative colitis

Oral 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, 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. 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, 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. 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

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

Can be taken with or without food

Hypersensitivity to the active substance or to any of the excipients. Active tuberculosis (TB) or active serious infections. Pregnancy.

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) Infections Infections, including serious infections, have been reported in patients receiving filgotinib. The most frequent serious infection reported with filgotinib was pneumonia. Among opportunistic infections, TB, oesophageal candidiasis, and cryptococcosis were reported with filgotinib. Tuberculosis Patients should be screened for TB before initiating filgotinib. Filgotinib should not be administered to patients with active TB. In patients with latent TB, standard antimycobacterial therapy should be initiated before administering filgotinib. Viral reactivation Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were reported in 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. Vaccinations Use of live vaccines during, or immediately prior to, filgotinib treatment is not recommended. 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. Major adverse cardiovascular events (MACE) Events of MACE have been observed in patients taking filgotinib. Venous thromboembolism (VTE) Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving JAK inhibitors including filgotinib. 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.

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. Based on findings in animals, filgotinib may cause foetal harm and is therefore contraindicated during pregnancy. 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. 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.

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.

Side effects of Filgotinib : 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 Gastrointestinal disorders Common Nausea Investigations Uncommon Blood creatine phosphokinase increased

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.