XELJANZ (tofacitinib) | Sikkerhetsprofil

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Rask respons (ACR20)

Effekt PsA

Effekt AS

ASAS20/40 effektdata

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Effekt UC

8-ukers effektdata

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52-ukers effektdata

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Effekt JIA

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Kontraindikasjoner

Overfølsomhet overfor virkestoff/hjelpestoff
aktiv tuberkulose (TB)
alvorlige infeksjoner som sepsis eller opportunistiske infeksjoner
alvorlig nedsatt leverfunksjon
graviditet eller amming.

Forsiktighetsregler

Xeljanz bør bare brukes hvis ingen egnede behandlingsalternativer er tilgjengelige hos:
- pasienter som er 65 år og eldre
- pasienter med tidligere aterosklerotisk kardiovaskulær sykdom eller som har andre risikofaktorer for kardiovaskulær sykdom (f.eks. er røykere eller som tidligere har vært røykere over lengre tid)
- pasienter med risikofaktorer for malignitet (f.eks. eksisterende malignitet eller tidligere malignitet)
10 mg BID; anbefales ikke som vedlikjeholdsbehandling hos UC-pasienter som har kjente risikofaktorer for VTE, MACE og malignitet med mindre det ikke er noen egnet alternativ behandling tilgjengelig.
Kombinasjon med biologiske og visse andre immundempende legemidler; mulig risiko for økt immunsuppresjon og økt infeksjonsfare.
Andre: Alvorlige infeksjoner, retinal venetrombose, TB, reaktivering av virus, maligniteter og lymfoproliferativ sykdom, interstitiell lungesykdom, gastrointestinale perforasjoner, frakturer, forhøyede leverensymer, lymfopeni, nøytropeni, anemi, hyperlipidemi, hypoglykemi hos pasienter som før behandling mot diabetes. Det er ikke anbefalt å gi levende vaksiner samtidig med Xeljanz.

Bivirkninger

RA: De vanligste alvorlige bivirkningene var alvorlige infeksjoner (pneumoni, herpes zoster, urinveisinfeksjon, cellulitt, divertikulitt og appendisitt).
UC: De vanligste alvorlige bivirkninger som er rapportert er gastrointestinale sykdommer, infeksjoner og forverring av UC.
JIA: Bivirkningene hos JIA-pasienter i det kliniske utviklingsprogrammet var samsvarende i type og frekvens med de som ble sett hos voksne RA-pasienter, med unntak av noen infeksjoner (influensa, faryngitt, sinusitt, virusinfeksjon) og gastrointestinale eller generelle lidelser (abdominale smerter, kvalme, oppkast, feber, hodepine, hoste), som var mer vanlige i den pediatriske JIA-populasjonen.
UC, PsA og AS: Observert sikkerhetsprofil var generelt i samsvar med sikkerhetsprofilen som ble observert hos RA-pasienter

Sikkehetsprofilen over er oppdatert i henhold til SPC og EMA sin gjennomgang av fem ulike JAK-hemmere.^2,3

Data fra ORAL Suveillance var en av flere kilder for EMA sin gjennomgang. Studien ORAL Surveillance (som er beskrevet i mer detalj under) var en stor (N=4362), randomisert, aktivt kontrollert sikkerhetsovervåkningsstudie etter godkjenning som inkluderte pasienter med revmatoid artritt over 50 år med minst én ytterligere kardiovaskulær risikofaktor (kardiovaskulære risikofaktorer er definert som: nåværende røyker, diagnostisert hypertensjon, diabetes mellitus, familiehistorikk med prematur koronarsykdom, historikk med koronararteriesykdom inkludert historikk med revaskulariserende inngrep, koronar bypass-operasjon, hjerteinfarkt, hjertestans, ustabil angina, akutt koronarsyndrom, samt tilstedeværelse av ekstraartikulær sykdom forbundet med RA, f.eks. noduli, Sjögrens syndrom, anemi pga. kronisk sykdom, lungemanifestasjoner).

Sikkerhet ved RA, inkludert data fra ORAL Surveillance etter markedsføring

ORAL Surveillance study description¹

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Design	Phase IIIb/IV randomized, open-label, non-inferiority, postauthorization safety endpoint-driven study
Primary objective	Evaluate the safety of tofacitinib at 2 doses (5 mg BID and 10 mg BID) compared with a TNFi in patients with RA who were 50 years of age or older and had at least 1 additional CV risk factor
Coprimary endpoints	Adjudicated MACE^a and adjudicated malignancies (excluding NMSC)
Statistical plan	Determine whether the upper limit of the 95% CI for the primary comparison of the combined tofacitinib doses compared to TNFi exceeded the pre-specified non-inferiority criterion of 1.8
Regulatory update	Pfizer continues to work with the EMA and other regulatory agencies to update XELJANZ labeling in their respective markets based on their ongoing review of the complete ORAL Surveillance results

The approved dose of tofacitinib for RA is 5 mg BID.²

MACE defined as cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke.

Patients who were treated with tofacitinib 10 mg BID were switched to tofacitinib 5 mg BID.

Patients randomized to TNFi in North America, including United States, Puerto Rico, and Canada received adalimumab 40 mg q2w; in the rest of the world, those randomized to TNFi received etanercept 50 mg qw.

Based on Cox proportional hazard model.

NNH over a period of 5 years was the number of patients who would need to be treated for that duration with tofacitinib rather than a TNFi to result in one additional adverse event; calculations were performed post hoc.

ORAL Surveillance: Baseline Characteristics¹

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	Treated patients (N=4362)
Female, n (%)	3410 (78.2)
Median age, years (range)	60.0 (50.0-88.0)
Mean disease duration, years (SD)	10.4 (9.1)
Mean BMI, kg/m² (SD)	29.8 (6.5)
Current/ex-smokers, n (%)	2103 (48.2)
Selected comorbidities, n (%)
History of CHD	497 (11.4)
History of diabetes mellitus	759 (17.4)
History of hypertension	2878 (66.0)
History of extra-articular disease	1605 (36.8)

ORAL Surveillance: Coprimary Endpoint Results for Adjudicated MACE and Adjudicated Malignancies (Excluding NMSC)¹

For adjudicated MACE and adjudicated malignancies (excluding NMSC), the prespecified noninferiority criterion was not met for the primary comparison of the combined tofacitinib doses to TNFi^a

Adjudicated MACE

The primary analyses included 135 patients with MACE
The most frequently reported MACE for tofacitinib was non-fatal myocardial infarction
A 60-day on-treatment time analysisb was used to assess the MACE coprimary endpoint

Adjudicated malignancies (excluding NMSC)

The primary analyses included 164 patients with malignancies (excluding NMSC)
The most frequently reported malignancy with tofacitinib was lung cancer
A total time analysis^c was used to assess the malignancy coprimary endpoint

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	Tofacitinib 5 mg BID	Tofacitinib 10 mg BID (includes patients switched to 5 mg BID dose per Feb 2019 protocol amendment)	Tofacitinib Doses Combined	TNFi
Adjudicated MACE
No. of pts with first event/total no. (%)	47/1455 (3.2)	51/1456 (3.5)	98/2911 (3.4)	37/1451 (2.5)
No. of patient-years	5166.32	4871.96	10,038.28	5045.27
Incidence rate per 100 patient-year (95% CI)	0.91 (0.67, 1.21)	1.05 (0.78, 1.38)	0.98 (0.79, 1.19)	0.73 (0.52, 1.01)
Hazard ratio for tofacitinib vs TNFi (95% CI)^d	1.24 (0.81, 1.91)	1.43 (0.94, 2.18)	1.33 (0.91, 1.94)^a
Noninferiority margin for primary comparison (criterion not met; 1.94>1.8)
NNH (over 5-year period) vs TNFi^e	113	64

Adjudicated malignancies (excluding NMSC)
No. of pts with first event/total no. (%)	62/1455 (4.3)	60/1456 (4.1)	122/2911 (4.2)	42/1451 (2.9)
No. of patient-years	5491.48	5311.71	10,803.19	5482.30
Incidence rate per 100 patient-year (95% CI)	1.13 (0.87, 1.45)	1.13 (0.86, 1.45)	1.13 (0.94, 1.35)	0.77 (0.55, 1.04)
Hazard ratio for tofacitinib vs TNFi (95% CI)^d	1.47 (1.00, 2.18)	1.48 (1.00, 2.19)	1.48 (1.04, 2.09)^a
Noninferiority margin for primary comparison (criterion not met; 2.09>1.8)
NNH (over 5-year period) vs TNFi^e	55	55

The approved dose of tofacitinib for RA is 5 mg BID.² Pfizer continues to work with the EMA and other regulatory agencies to update XELJANZ labeling in their respective markets based on their ongoing review of the complete ORAL Surveillance results.

The noninferiority criterion was not met for the primary comparison of the combined tofacitinib doses to TNFi since the upper limit of the 95% CI exceeded the pre-specified noninferiority criterion of 1.8. (ie, for MACE: 1.94>1.8, for malignancy: 2.09>1.8).

Defined as the time from the first dose of a trial drug until the end of the risk period (ie, last contact date or last trial dose plus 60 days, whichever was earliest).

Defined as the time from the first dose of a trial drug until the last contact date. The last contact date was the latest of the following: the start date of an AE, the end date of an AE, the date of the last trial visit, the withdrawal date, the telephone contact date, or the date of death.

Based on Cox proportional hazard model.

ORAL Surveillance: Adverse Events of Special Interest¹

A 28-day on-treatment period analysis was used to assess AEs ^a

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	Tofacitinib 5 mg BID	Tofacitinib 10 mg BID (N=1456) (includes patients switched to 5 mg BID per Feb 2019 protocol amendment)	TNFi (N=1451)
Serious AE, n (%)	351 (24.1)	306 (21.1)	306 (21.1)
AEs of special interest, n (%) Hazard ratio for tofacitinib vs TNFi (95% CI)^b
Serious infection	141 (9.7) 1.17 (0.92, 1.50)	169 (11.6) 1.48 (1.17, 1.87)	119 (8.2) —
Adjudicated opportunistic infection^c	39 (2.7) 1.82 (1.07, 3.09)	44 (3.0) 2.17 (1.29, 3.66)	21 (1.4) —
All herpes zoster^d (non-serious/serious)	180 (12.4) 3.28 (2.44, 4.41)	178 (12.2) 3.39 (2.52, 4.55)	58 (4.0) —
Adjudicated hepatic event	46 (3.2) 1.29 (0.83, 2.00)	72 (4.9) 2.14 (1.43, 3.21)	35 (2.4) —
Adjudicated NMSC	31 (2.1) 1.90 (1.04, 3.47)	33 (2.3) 2.16 (1.19, 3.92)	16 (1.1) —
Adjudicated pulmonary embolism	9 (0.6) 2.93 (0.79, 10.83)	24 (1.6) 8.26 (2.49, 27.43)	3 (0.2) —
Adjudicated deep vein thrombosis	11 (0.8) 1.54 (0.60, 3.97)	15 (1.0) 2.21 (0.90, 5.43)	7 (0.5) —
Adjudicated venous thromboembolism	17 (1.2) 1.66 (0.76, 3.63)	34 (2.3) 3.52 (1.74, 7.12)	10 (0.7) —
Adjudicated death from any cause	26 (1.8) 1.49 (0.81, 2.74)	39 (2.7) 2.37 (1.34, 4.18)	17 (1.2) —

Defined as the minimum of the date of last contact or the date of the last dose of a trial treatment plus 28 days.

Based on Cox proportional hazard model.

Also included are opportunistic herpes zoster and tuberculosis events.

Included are herpes zoster adjudicated as an opportunistic infection and nonadjudicated herpes zoster events.

Safety profile from the RA clinical trial programs^4-5

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Most common adverse reactions in the first 3 months of 2 phase 2 and 5 phase 3 clinical trials^3,a
	XELJANZ® 5 mg BID (n=1336)	Placebo (n=809)
Upper respiratory tract infection	4%	3%
Headache	4%	2%
Diarrhea	4%	2%
Nasopharyngitis	4%	3%

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Adverse events (AEs)[all-cause] and serious adverse events (SAEs) in patients receiving XELJANZ over more than 9 years⁴
	All XELJANZb (n=4481) 16,291 pt-yrs	XELJANZ 5 mg BID (n=1123) 4683 pt-yrs
Patients with AEs (any cause), n (%)	4036 (90.1)	1015 (90.4)
Discontinuation due to AEs, n (%)	1120 (25.0)	315 (28.0)
SAEs, patients with events/100 pt-yrs (95% CI)	9.0 (8.6, 9.5)	8.2 (7.3, 9.1)

Limitations of pooled and long-term extension (LTE) data

Pooled, post hoc analysis of studies from the RA clinical trial program are subject to certain limitations. First, unlike ORAL Surveillance, the patient population is not limited to a high-risk population but includes all enrolled patients. Second, endpoints of interest (such as MACE and malignancy for ORAL Surveillance) were not all specifically defined or adjudicated. Additionally, ORAL Surveillance was a long-term safety study (vs RCT phase 3 which are short term and designed to test efficacy). Resultant incidence rates in ORAL Surveillance differed from rates seen from pooled study data, suggesting the pooled data may be obscuring information about predictors of events given adverse rates may differ from one patient population to another and may change over time
LTE studies may provide useful data, however, conduct of open-label LTE studies where both treatment and dose are known to both investigator and patient is subject to certain biases and limitations. Most participants were known to have responded to, and tolerated, XELJANZ® (all had completed a qualifying study), hence our findings might not be generalizable to patients new to XELJANZ
Biases include, but are not limited to, patient selection (patient willingness or ineligibility to enroll, which may be due to a prior serious AE), prior treatment, volunteer, observer, initial dose or study drug, investigator/patient expectation and study duration. Limitations include, but are not limited to, AE frequencies and incidence rates subject to change over time due to patient entry/exit, dose changes influenced by both investigator and patient, dose restrictions in certain countries, the number of patients and exposure for a specific safety event possibly differing depending on the timing of censored events, and the number of observed patients with longer exposure times becoming lower

Integrated safety summary (ISS): baseline characteristics and demographics⁵

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Characteristics	RA \| All XELJANZ® Doses^a,b (N=7964)
Mean age, years	52.6
≥65 at baseline, n (%)	1270 (15.9)
Female, n (%)	6522 (81.9)
BMI (kg/m2), mean	27.1
Disease duration (years), mean (range)	8.1 (0.00-65.7)
CRP (mg/L). median (Q1-Q3)	9.2 (3.8-22.8)
Current/ past smokers, n (%)	2754 (34.6)
Prior therapy. n (%)
Methotrexate	6657 (83.6)
Non-bDMARD(non-methotrexate)	3739 (46.9)
TNFi	1245 (15.6)
Non-TNFi bDMARD	414 (5.2)
Concomitant corticosteroids, n (%)	4254 (53.4)

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Incidence rates, patients with events/100 pt-yrs (95% CI) for safety events of interest^5,6,c
	RA \| All XELJANZ® Doses^b,c (N=7964) 23,497 pt-yrs
Serious infections	2.5 (2.3, 2.7)
HZ (nonserious and serious)	3.6 (3.3, 3.8)
TB^f	0.2 (0.1, 0.2)
Opportunistic infections (excluding TB)^f	0.4 (0.3, 05)
Malignancies (excluding NMSC)^f	0.7 (06, 0.9)
NMSC^f	0.6 (0.5, 0.7)
Lymphoma/lymphoproliferative disorders^f	0.1 (0.0, 0.1)
MACE^f,g	0.4 (0.3, 0.5)
VTE	0.25 (0.19, 0.33)
DVT	0.2 (0.1, 0.2)
PE	0.1 (0.1, 0.2)
ATE	0.35 (0.28, 0.44)
Gastrointestinal perforation^f	0.1 (0.1, 0.2)

The ISS and analysis of adverse events of special interest includes pooled data from patients exposed to ≥1 dose of XELJANZ in phase 1, 2, 3, or 3b/4 clinical trials, and LTE studies in RA⁵
In LTE studies, dose adjustments for XELJANZ or concomitant medications were allowed at the investigator’s discretion for efficacy or safety reasons⁵

Adverse reactions occurring in ≥2% of patients receiving XELJANZ 5 mg BID and ≥1% greater than that observed in patients on placebo (XELJANZ 5 mg BID and placebo ± csDMARDs).³

Includes XELJANZ 5 mg BID and 10 mg BID treatment arms ± csDMARDs2; XELJANZ 5 mg BID is the recommended dose in most countries.⁴

Final data for the RA cohorts are from April 18, 2019.⁵

All doses in RA included XELJANZ 1 mg, 3 mg, 5 mg, 10 mg, 15 mg, 30 mg BID; 10 mg or 20 mg QD; or 11 mg MR QD.⁷

XELJANZ 5 mg BID or 11 mg prolonged release QD are the only approved dosages for the treatment of RA, which should not be exceeded. 10 mg BID is not licensed for RA.²

Adjudicated events.⁵

Composite MACE defined as any myocardial infarction, stroke, or cardiovascular death.⁵

NB! XELJANZ 10 mg BID daglig er kun godkjent for pasienter med UC. Se SPC.

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Se utvalgte bivirkninger

ACR=American College of Rheumatology; ATE=arterial thromboembolism; BID=twice daily; csDMARD=conventional synthetic disease-modifying antirheumatic drug; CV=cardiovascular; DSMB=Data Safety Monitoring Board; DVT=deep vein thrombosis; EMA=European Medicines Agency; HZ=herpes zoster; IR=inadequate response; JAKi=Janus kinase inhibitor; MACE=major adverse cardiovascular event; MR=modified release; MTX=methotrexate; NMSC=nonmelanoma skin cancer; PsA=psoriatic arthritis; pt-yr=patient year; QD=once daily; qw=once a week; q 2 wk=every 2 weeks; RA=rheumatoid arthritis; TB=tuberculosis; TNF=tumor necrosis factor; UC=ulcerative colitis; VTE=venous thromboembolism.

References:

Ytterberg SR, Deepak L Bhatt DL, Mikuls T, et al. Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis. N Engl J Med. 2022;386:316-26.

XELJANZ SPC

https://www.ema.europa.eu/en/medicines/human/referrals/janus-kinase-inhibitors-jaki (Lest 19.04.2023)

Wollenhaupt J, Lee E-B, Curtis JR, et al. Safety and efficacy of tofacitinib for up to 9.5 years in the treatment of rheumatoid arthritis: final results of a global, open-label, long-term extension study. Arthritis Res Ther. 2019;21(1):89. doi:10.1186/s13075-019-1866-2

Burmester GR, Nash P, Sands BE, et al. Adverse events of special interest in clinical trials of rheumatoid arthritis, psoriatic arthritis, ulcerative colitis and psoriasis with 37 066 patient-years of tofacitinib exposure. RMD Open. 2021;7:e001595. doi:10.1136/rmdopen-2021-001595

Mease P, Charles-Schoeman C, Cohen S, et al. Incidence of venous and arterial thromboembolic events reported in the tofacitinib rheumatoid arthritis, psoriasis and psoriatic arthritis development programmes and from real-world data. Ann Rheum Dis. 2020;79(11):1400-1413.

Burmester GR, Nash P, Sands BE, et al. Adverse events of special interest in clinical trials of rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, and psoriasis with 37 066 patient-years of tofacitinib exposure. [supplementary appendix]. RMD Open. 2021;7(2):1-36.

Preparatomtale

PP-XEL-NOR-0335 Mai 2023

Sikkerhet

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ERFARINGER

Finn ut mer om erfaringer ved bruk av XELJANZ innen RA, PsA, AS, UC og JIA

XELJANZ Erfaringer

Pfizer AS, Org.nr 915 213 596

Postadresse: Postboks 3, 1324 Lysaker
Besøksadresse: Drammensveien 288, 0283 Oslo

Tlf.: +47 67 52 61 00

PP-BCP-NOR-0001 juni 2023

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