Filgotinib

In vitro studies indicate that filgotinib and its primary metabolite GS-829845 are inhibitors of OATP1B1 and OATP1B3. No clinical studies have been performed to investigate interactions with OATP1B1 and OATP1B3 substrates. Therefore, it cannot be excluded that co-administration of filgotinib with OATP1B1 or OATP1B3 substrates may increase their exposure and the risk of adverse events. Co-administration with sensitive OATP1B1 or OATP1B3 substrates (e.g., valsartan, statins) is therefore not recommended.

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.

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 vitro studies are inconclusive regarding the potential of the primary metabolite of filgotinib, GS-829845 to inhibit P-gp or BCRP. In vivo inhibition of these transporters cannot be excluded, and caution is recommended when substrates with a narrow therapeutic index (e.g., digoxin) are co-administered with filgotinib.

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.

Filgotinib has not been studied in patients with severe hepatic impairment (Child-Pugh C) and is therefore not recommended for use in these patients.

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.

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.

In animal studies, decreased fertility, impaired spermatogenesis, and histopathological effects on male reproductive organs were observed. 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.

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

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.

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.

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

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.

Fertility

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

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). 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).

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 × 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

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.