Pfizer Inc. (NYSE: PFE) announced today that the European
Commission has approved XELJANZ® (tofacitinib) 5 mg twice daily for
the treatment of adults with active ankylosing spondylitis (AS) who
have responded inadequately to conventional therapy.
XELJANZ is the first and only oral Janus kinase (JAK) inhibitor
approved for five indications in the European Union (EU), including
in adults with moderate to severe active rheumatoid arthritis (RA),
adults with active psoriatic arthritis (PsA), adults with
moderately to severely active ulcerative colitis (UC), and patients
2 years of age or older with active polyarticular juvenile
idiopathic arthritis (pcJIA) and juvenile psoriatic arthritis
(PsA).
“Ankylosing spondylitis is a debilitating and chronic
immuno-inflammatory disease that affects the lives of more than one
million people in the EU who are in need of additional treatment
options,” 1 said Ana Paula Carvalho, International Developed
Markets Regional President, Inflammation & Immunology at
Pfizer. “We are proud to make XELJANZ, a medicine that does not
require an injection or an infusion, available to patients and
their healthcare providers to help address this unmet medical
need.”
The approval of XELJANZ for AS is based on data from a Phase 3,
multicenter, randomized, double-blind, placebo-controlled study
that evaluated the efficacy and safety of tofacitinib 5 mg twice
daily versus placebo in 269 adult patients living with active AS.
The study met its primary endpoint showing that at week 16, the
percentage of patients achieving an Assessment in SpondyloArthritis
International Society (ASAS) 20 response was significantly greater
with tofacitinib (56.4%) versus placebo (29.4%) (p<0.0001). In
addition, the percentage of ASAS40 response was significantly
greater with tofacitinib (40.6%) versus placebo (12.5%)
(p<0.0001), a key secondary endpoint of the study.2 ASAS20/40
are used for defining improvement or response to treatment.3 In
general, the types of adverse drug reactions in patients with
ankylosing spondylitis were consistent with the known safety
profile of XELJANZ.
XELJANZ has been studied in more than 50 clinical trials
worldwide, including more than 20 trials in RA patients, and
prescribed to over 300,000 adult patients (the majority of whom
were RA patients) since 2012.4,5,6
About XELJANZ® (tofacitinib)
XELJANZ (film-coated immediate release tablet, twice daily
dosing) is the first and only oral JAK inhibitor approved in the
European Union in five indications: adults with active ankylosing
spondylitis (AS) who have responded inadequately to conventional
therapy, adults with moderately to severely active rheumatoid
arthritis (RA) after disease modifying antirheumatic drug (DMARD)
failure or intolerance, adults with active PsA after DMARD failure
or intolerance, adults with moderately to severely active
ulcerative colitis (UC) who have had an inadequate response, lost
response, or were intolerant to either conventional therapy or a
biologic agent, and active polyarticular juvenile idiopathic
arthritis (JIA) and juvenile psoriatic arthritis (PsA) in patients
two years of age and older who have responded inadequately to
previous therapy with DMARDs.
XELJANZ has been studied in more than 50 clinical trials
worldwide, including more than 20 trials in RA patients, and
prescribed to over 300,000 adult patients (the majority of whom
were RA patients) worldwide since 2012.4,5,6 As the developer of
tofacitinib, Pfizer is committed to advancing the science of JAK
inhibition and enhancing understanding of tofacitinib through
robust clinical development programs in the treatment of
immune-mediated inflammatory conditions.
In June 2021, the Committee for Medicinal Products for Human
(CHMP) Use of the European Medicines Agency adopted a
recommendation from the Pharmacovigilance Risk Assessment Committee
(PRAC) following the PRAC review of the co-primary endpoints data
from ORAL Surveillance, which states that in patients over 65 years
of age, patients who are current or past smokers, patients with
other cardiovascular (CV) risk factors, and patients with other
malignancy risk factors, XELJANZ should only be used if no suitable
treatment alternatives are available. The updated summary of
product characteristics reflecting the CHMP-endorsed PRAC
recommendation is now effective and is applicable to all EU member
states. PRAC’s review of the complete ORAL Surveillance data is
ongoing.
In September 2021, the U.S. Food and Drug Administration (FDA)
issued a Drug Safety Communication (DSC) related to XELJANZ/XELJANZ
XR and two other arthritis medicines in the same drug class, based
on its complete review of the ORAL Surveillance trial. More
information is available on the DSC here. Pfizer is continuing to
work with the FDA, EMA, and other regulatory agencies to update
XELJANZ labeling across the world, in light of the ORAL
Surveillance data.
About Ankylosing Spondylitis (AS)
AS is a chronic, inflammatory disease that affects men and women
in early adulthood. The first symptoms usually occur before the age
of 30 and seldom occur after the age of 45. Symptoms of AS include
chronic pain and stiffness in the back and hips for those living
with the disease and can negatively impact health-related quality
of life.7 Over time, some patients may experience fusion of the
vertebrae in the spinal column.8 According to studies,
approximately more than one million people in the European Union
live with AS.1
U.S. FDA-APPROVED INDICATIONS
Rheumatoid Arthritis
- XELJANZ/XELJANZ XR (tofacitinib) is indicated for the treatment
of adult patients with moderately to severely active rheumatoid
arthritis who have had an inadequate response or intolerance to
methotrexate.
- Limitations of Use: Use of XELJANZ/XELJANZ XR in combination
with biologic DMARDs or with potent immunosuppressants such as
azathioprine and cyclosporine is not recommended.
Psoriatic Arthritis
- XELJANZ/XELJANZ XR (tofacitinib) is indicated for the treatment
of adult patients with active psoriatic arthritis who have had an
inadequate response or intolerance to methotrexate or other
DMARDs.
- Limitations of Use: Use of XELJANZ/XELJANZ XR in combination
with biologic DMARDs or with potent immunosuppressants such as
azathioprine and cyclosporine is not recommended.
Ulcerative Colitis
- XELJANZ/XELJANZ XR (tofacitinib) is indicated for the treatment
of adult patients with moderately to severely active ulcerative
colitis (UC), who have had an inadequate response or who are
intolerant to TNF blockers.
- Limitations of Use: Use of XELJANZ/XELJANZ XR in combination
with biological therapies for UC or with potent immunosuppressants
such as azathioprine and cyclosporine is not recommended.
Polyarticular Course Juvenile Idiopathic Arthritis
- XELJANZ/XELJANZ Oral Solution is indicated for the treatment of
active polyarticular course juvenile idiopathic arthritis (pcJIA)
in patients 2 years of age and older.
- Limitations of Use: Use of XELJANZ/XELJANZ Oral Solution in
combination with biologic DMARDs or potent immunosuppressants such
as azathioprine and cyclosporine is not recommended.
U.S. IMPORTANT SAFETY INFORMATION
SERIOUS INFECTIONS
Patients treated with XELJANZ* are at increased risk for
developing serious infections that may lead to hospitalization or
death. Most patients who developed these infections were taking
concomitant immunosuppressants, such as methotrexate or
corticosteroids.
If a serious infection develops, interrupt XELJANZ until the
infection is controlled.
Reported infections include:
- Active tuberculosis, which may present with pulmonary or
extrapulmonary disease. Patients should be tested for latent
tuberculosis before XELJANZ use and during therapy. Treatment for
latent infection should be initiated prior to XELJANZ use.
- Invasive fungal infections, including cryptococcosis and
pneumocystosis. Patients with invasive fungal infections may
present with disseminated, rather than localized, disease.
- Bacterial, viral, including herpes zoster, and other
infections due to opportunistic pathogens.
The most common serious infections reported with XELJANZ
included pneumonia, cellulitis, herpes zoster, urinary tract
infection, diverticulitis, and appendicitis. Avoid use of XELJANZ
in patients with an active, serious infection, including localized
infections, or with chronic or recurrent infection.
In the UC population, XELJANZ 10 mg twice daily was associated
with greater risk of serious infections compared to 5 mg twice
daily. Opportunistic herpes zoster infections (including
meningoencephalitis, ophthalmologic, and disseminated cutaneous)
were seen in patients who were treated with XELJANZ 10 mg twice
daily.
The risks and benefits of treatment with XELJANZ should be
carefully considered prior to initiating therapy in patients with
chronic or recurrent infection, or those who have lived or
traveled in areas of endemic TB or mycoses. Viral reactivation
including herpes virus and hepatitis B reactivation have been
reported. Screening for viral hepatitis should be performed in
accordance with clinical guidelines before starting therapy.
Patients should be closely monitored for the development of
signs and symptoms of infection during and after treatment with
XELJANZ, including the possible development of tuberculosis in
patients who tested negative for latent tuberculosis infection
prior to initiating therapy.
Caution is also recommended in patients with a history of
chronic lung disease, or in those who develop interstitial lung
disease, as they may be more prone to infection.
MORTALITY
Rheumatoid arthritis (RA) patients 50 years of age and older
with at least one additional cardiovascular (CV) risk factor
treated with XELJANZ 10 mg twice a day had a higher rate of
all-cause mortality, including sudden CV death, compared to those
treated with XELJANZ 5 mg given twice daily or TNF blockers in a
large postmarketing safety study. XELJANZ 10 mg twice daily or
XELJANZ XR 22 mg once daily is not recommended for the treatment of
RA or PsA.
For UC, use XELJANZ at the lowest effective dose and for the
shortest duration needed to achieve/maintain therapeutic
response.
MALIGNANCIES
Lymphoma and other malignancies have been observed in
patients treated with XELJANZ. Epstein Barr Virus-associated
post-transplant lymphoproliferative disorder has been observed at
an increased rate in renal transplant patients treated with XELJANZ
and concomitant immunosuppressive medications.
Consider the risks and benefits of XELJANZ treatment prior to
initiating therapy in patients with a known malignancy other than a
successfully treated non-melanoma skin cancer (NMSC) or when
considering continuing XELJANZ in patients who develop a
malignancy.
Malignancies (including solid cancers and lymphomas) were
observed more often in patients treated with XELJANZ 10 mg twice
daily dosing in the UC long-term extension study.
Other malignancies were observed in clinical studies and the
post-marketing setting including, but not limited to, lung cancer,
breast cancer, melanoma, prostate cancer, and pancreatic cancer.
NMSCs have been reported in patients treated with XELJANZ. In the
UC population, treatment with XELJANZ 10 mg twice daily was
associated with greater risk of NMSC. Periodic skin examination is
recommended for patients who are at increased risk for skin
cancer.
THROMBOSIS
Thrombosis, including pulmonary embolism, deep venous
thrombosis, and arterial thrombosis, have occurred in patients
treated with XELJANZ and other Janus kinase inhibitors used to
treat inflammatory conditions. RA patients who were 50 years of age
and older with at least one additional CV risk factor treated with
XELJANZ 10 mg twice daily compared to XELJANZ 5 mg twice daily or
TNF blockers in a large, postmarketing safety study had an observed
increase in incidence of these events. Many of these events were
serious and some resulted in death. Avoid XELJANZ in patients at
risk. Discontinue XELJANZ and promptly evaluate patients with
symptoms of thrombosis. For patients with UC, use XELJANZ at the
lowest effective dose and for the shortest duration needed to
achieve/maintain therapeutic response. XELJANZ 10 mg twice
daily or XELJANZ XR 22 mg once daily is not recommended for the
treatment of RA or PsA. In a long-term extension study in UC, four
cases of pulmonary embolism were reported in patients taking
XELJANZ 10 mg twice daily, including one death in a patient with
advanced cancer.
GASTROINTESTINAL PERFORATIONS
Gastrointestinal perforations have been reported in XELJANZ
clinical trials, although the role of JAK inhibition is not known.
In these studies, many patients with rheumatoid arthritis were
receiving background therapy with Nonsteroidal Anti-Inflammatory
Drugs (NSAIDs). There was no discernable difference in frequency of
gastrointestinal perforation between the placebo and the XELJANZ
arms in clinical trials of patients with UC, and many of them were
receiving background corticosteroids. XELJANZ should be used with
caution in patients who may be at increased risk for
gastrointestinal perforation (e.g., patients with a history of
diverticulitis or taking NSAIDs).
HYPERSENSITIVITY
Angioedema and urticaria that may reflect drug hypersensitivity
have been observed in patients receiving XELJANZ and some events
were serious. If a serious hypersensitivity reaction occurs,
promptly discontinue tofacitinib while evaluating the potential
cause or causes of the reaction.
LABORATORY ABNORMALITIES
Lymphocyte Abnormalities: Treatment with XELJANZ was
associated with initial lymphocytosis at one month of exposure
followed by a gradual decrease in mean lymphocyte counts. Avoid
initiation of XELJANZ treatment in patients with a count less than
500 cells/mm3. In patients who develop a confirmed absolute
lymphocyte count less than 500 cells/mm3, treatment with XELJANZ is
not recommended. Risk of infection may be higher with increasing
degrees of lymphopenia and consideration should be given to
lymphocyte counts when assessing individual patient risk of
infection. Monitor lymphocyte counts at baseline and every 3 months
thereafter.
Neutropenia: Treatment with XELJANZ was associated with
an increased incidence of neutropenia (less than 2000 cells/mm3)
compared to placebo. Avoid initiation of XELJANZ treatment in
patients with an ANC less than 1000 cells/mm3. For patients who
develop a persistent ANC of 500-1000 cells/mm3, interrupt XELJANZ
dosing until ANC is greater than or equal to 1000 cells/mm3. In
patients who develop an ANC less than 500 cells/mm3, treatment with
XELJANZ is not recommended. Monitor neutrophil counts at baseline
and after 4-8 weeks of treatment and every 3 months thereafter.
Anemia: Avoid initiation of XELJANZ treatment in patients
with a hemoglobin level less than 9 g/dL. Treatment with XELJANZ
should be interrupted in patients who develop hemoglobin levels
less than 8 g/dL or whose hemoglobin level drops greater than 2
g/dL on treatment. Monitor hemoglobin at baseline and after 4-8
weeks of treatment and every 3 months thereafter.
Liver Enzyme Elevations: Treatment with XELJANZ was
associated with an increased incidence of liver enzyme elevation
compared to placebo. Most of these abnormalities occurred in
studies with background DMARD (primarily methotrexate) therapy. If
drug-induced liver injury is suspected, the administration of
XELJANZ should be interrupted until this diagnosis has been
excluded. Routine monitoring of liver tests and prompt
investigation of the causes of liver enzyme elevations is
recommended to identify potential cases of drug-induced liver
injury.
Lipid Elevations: Treatment with XELJANZ was associated
with dose-dependent increases in lipid parameters, including total
cholesterol, low-density lipoprotein (LDL) cholesterol, and
high-density lipoprotein (HDL) cholesterol. Maximum effects were
generally observed within 6 weeks. There were no clinically
relevant changes in LDL/HDL cholesterol ratios. Manage patients
with hyperlipidemia according to clinical guidelines. Assessment of
lipid parameters should be performed approximately 4-8 weeks
following initiation of XELJANZ therapy.
VACCINATIONS
Avoid use of live vaccines concurrently with XELJANZ. The
interval between live vaccinations and initiation of tofacitinib
therapy should be in accordance with current vaccination guidelines
regarding immunosuppressive agents. Update immunizations in
agreement with current immunization guidelines prior to initiating
XELJANZ therapy.
PATIENTS WITH GASTROINTESTINAL NARROWING
Caution should be used when administering XELJANZ XR to patients
with pre-existing severe gastrointestinal narrowing. There have
been rare reports of obstructive symptoms in patients with known
strictures in association with the ingestion of other drugs
utilizing a non-deformable extended release formulation.
HEPATIC and RENAL IMPAIRMENT
Use of XELJANZ in patients with severe hepatic impairment is not
recommended.
For patients with moderate hepatic impairment or with moderate
or severe renal impairment taking XELJANZ 5 mg twice daily, reduce
to XELJANZ 5 mg once daily.
For UC patients with moderate hepatic impairment or with
moderate or severe renal impairment taking XELJANZ 10 mg twice
daily, reduce to XELJANZ 5 mg twice daily.
ADVERSE REACTIONS
The most common serious adverse reactions were serious
infections. The most commonly reported adverse reactions during the
first 3 months in controlled clinical trials in patients with RA
with XELJANZ 5 mg twice daily and placebo, respectively, (occurring
in greater than or equal to 2% of patients treated with XELJANZ
with or without DMARDs) were upper respiratory tract infection,
nasopharyngitis, diarrhea, headache, and hypertension. The safety
profile observed in patients with active PsA treated with XELJANZ
was consistent with the safety profile observed in RA patients.
Adverse reactions reported in ≥5% of patients treated with
either 5 mg or 10 mg twice daily of XELJANZ and ≥1% greater than
reported in patients receiving placebo in either the induction or
maintenance clinical trials for UC were: nasopharyngitis, elevated
cholesterol levels, headache, upper respiratory tract infection,
increased blood creatine phosphokinase, rash, diarrhea, and herpes
zoster.
USE IN PREGNANCY
Available data with XELJANZ use in pregnant women are
insufficient to establish a drug associated risk of major birth
defects, miscarriage or adverse maternal or fetal outcomes. There
are risks to the mother and the fetus associated with rheumatoid
arthritis and UC in pregnancy. In animal studies, tofacitinib at
6.3 times the maximum recommended dose of 10 mg twice daily
demonstrated adverse embryo-fetal findings. The relevance of these
findings to women of childbearing potential is uncertain. Consider
pregnancy planning and prevention for females of reproductive
potential.
* Unless otherwise stated, “XELJANZ” in the Important Safety
Information refers to XELJANZ, XELJANZ XR, and XELJANZ Oral
Solution.
Please see full Prescribing Information, including BOXED WARNING
for XELJANZ available at: www.xeljanzpi.com.
About Pfizer Inflammation & Immunology
At Pfizer Inflammation & Immunology, we strive to deliver
breakthroughs that enable freedom from day-to-day suffering for
people living with autoimmune and chronic inflammatory diseases,
which can be debilitating, disfiguring and distressing,
dramatically affecting what they can do. With a focus on
Rheumatology, Gastroenterology and Medical Dermatology, our current
portfolio of approved medicines and investigational molecules spans
multiple action and delivery mechanisms, from topicals to small
molecules, biologics and biosimilars. Our differentiated R&D
approach resulted in one of the broadest pipelines in the industry,
where we purposefully match molecules to diseases where we believe
they can make the biggest difference. Building on our decades-long
commitment and pioneering science, we continue to advance the
standard of care for patients with these debilitating diseases and
are working hand-in-hand with patients, caregivers and the broader
healthcare community on healthcare solutions for the many
challenges of managing chronic inflammatory diseases, allowing
patients to live their best lives. To learn more, visit
www.pfizer.com/science/immunology-inflammation.
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DISCLOSURE NOTICE: The information contained in this release is
as of November 18, 2021. Pfizer assumes no obligation to update
forward-looking statements contained in this release as the result
of new information or future events or developments.
This release contains forward-looking information about XELJANZ
(tofacitinib) and a new indication in the European Union for the
treatment of adults with active ankylosing spondylitis (AS) who
have responded inadequately to conventional therapy, including
their potential benefits, that involves substantial risks and
uncertainties that could cause actual results to differ materially
from those expressed or implied by such statements. Risks and
uncertainties include, among other things, the uncertainties
inherent in research and development, including the ability to meet
anticipated clinical endpoints, commencement and/or completion
dates for our clinical trials, regulatory submission dates,
regulatory approval dates and/or launch dates, as well as the
possibility of unfavorable new clinical data and further analyses
of existing clinical data; the risk that clinical trial data are
subject to differing interpretations and assessments by regulatory
authorities; whether regulatory authorities will be satisfied with
the design of and results from our clinical studies; uncertainties
regarding the commercial success of XELJANZ, XELJANZ XR and XELJANZ
Oral Solution; whether and when applications for XELJANZ, XELJANZ
XR or XELJANZ Oral Solution for AS or any other indications may be
filed in any jurisdictions; whether and when any applications that
may be pending or filed for any potential indications for XELJANZ,
XELJANZ XR or XELJANZ Oral Solution in any jurisdictions may be
approved by regulatory authorities, which will depend on myriad
factors, including making a determination as to whether the
product’s benefits outweigh its known risks and determination of
the product’s efficacy, and, if approved, whether they will be
commercially successful; uncertainties regarding the commercial or
other impact of the results of clinical trial A3921133 (ORAL
Surveillance) or any other Janus kinase (JAK) inhibitor studies and
data, the FDA’s drug safety communication, the CHMP-endorsed PRAC
recommendation and any potential actions by regulatory authorities
based on analysis of such studies and data, including on other JAK
inhibitors in our portfolio, which will depend, in part, on
benefit-risk assessments and labeling determinations; decisions by
regulatory authorities impacting labeling, manufacturing processes,
safety and/or other matters that could affect the availability or
commercial potential of XELJANZ, XELJANZ XR and XELJANZ Oral
Solution; uncertainties regarding the impact of COVID-19 on our
business, operations and financial results; and competitive
developments.
A further description of risks and uncertainties can be found in
Pfizer’s Annual Report on Form 10-K for the fiscal year ended
December 31, 2020 and in its subsequent reports on Form 10-Q,
including in the sections thereof captioned “Risk Factors” and
“Forward-Looking Information and Factors That May Affect Future
Results”, as well as in its subsequent reports on Form 8-K, all of
which are filed with the U.S. Securities and Exchange Commission
and available at www.sec.gov and
www.pfizer.com.
______________________________________ 1 Dean LE, Jones GT,
MacDonald AG, Downham C, Sturrock RD, Macfarlane GJ. Global
prevalence of ankylosing spondylitis. Rheumatology (Oxford). 2014
Apr;53(4):650-7. doi: 10.1093/rheumatology/ket387. Epub 2013 Dec 9.
PMID: 24324212.
https://academic.oup.com/rheumatology/article/53/4/650/1841972 2
Deodhar A, Sliwinska-Stanczyk P, Xu H, Baraliakos X, Gensler LS,
Fleishaker D, Wang L, Wu J, Menon S, Wang C, Dina O, Fallon L,
Kanik KS, van der Heijde D. Tofacitinib for the treatment of
ankylosing spondylitis: a phase III, randomised, double-blind,
placebo-controlled study. Ann Rheum Dis. 2021 Apr 27;80(8):1004–13.
doi: 10.1136/annrheumdis-2020-219601. Epub ahead of print. PMID:
33906853; PMCID: PMC8292568. 3 Landewé R, van Tubergen A. Clinical
Tools to Assess and Monitor Spondyloarthritis. Curr Rheumatol Rep.
2015;17(7):47. doi:10.1007/s11926-015-0522-3 4 Pfizer Data on File.
XELJANZ Worldwide Registration Status. 5 ClinicalTrials.gov.
Tofacitinib RA Studies. Accessed June 25, 2020. 6 Pfizer. Data on
File. Tofa Counts. April 2019 7 University of Maryland Medical
Center. A Patient’s Guide to AS. Accessed August 2021. Available
at:
https://www.umms.org/ummc/health-services/orthopedics/services/spine/patient-guides/ankylosing-spondylitis
8 Exarchou S, Lindstr�m U, Askling J, et al. The prevalence of
clinically diagnosed ankylosing spondylitis and its clinical
manifestations: a nationwide register study. Arthritis Res Ther.
2015;17(1):118. Published 2015 May 9. doi:10.1186/s13075-015-0627-0
https://pubmed.ncbi.nlm.nih.gov/25956915/
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