Pfizer Inc. (NYSE: PFE) announced today that the U.S. Food and
Drug Administration (FDA) has extended the action date by three
months for the supplemental New Drug Application (sNDA) for
XELJANZ® (tofacitinib), an oral treatment under investigation for
adult patients with moderately to severely active ulcerative
colitis (UC).
The FDA determined that additional review time was necessary due
to information recently submitted by Pfizer and as such constitutes
a major amendment. The FDA has provided an anticipated Prescription
Drug User Fee Act (PDUFA) date in June 2018.
If approved by the FDA, tofacitinib would be the first oral
Janus kinase (JAK) inhibitor to be a therapeutic option for people
living with moderately to severely active UC.
About Tofacitinib
Tofacitinib citrate is a Janus kinase (JAK) inhibitor.
Applications for tofacitinib for the treatment of moderately to
severely active UC are currently under review by the U.S. FDA and
the European Medicines Agency (EMA). It is not currently approved
for the treatment of UC.
As the developer of tofacitinib, Pfizer is a leader in JAK
science and is committed to enhancing understanding of tofacitinib
through robust clinical development programs in the treatment of
immune-mediated inflammatory conditions.
Please see full Prescribing Information for XELJANZ/XELJANZ XR
available at:
http://labeling.pfizer.com/showlabeling.aspx?id=959
INDICATION
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. It may be used as
monotherapy or in combination with methotrexate or other
nonbiologic disease-modifying antirheumatic drugs (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.
IMPORTANT SAFETY INFORMATION
BOXED WARNING: SERIOUS INFECTIONS AND MALIGNANCY
SERIOUS INFECTIONS
Patients treated with XELJANZ/XELJANZ XR 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/XELJANZ XR
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/XELJANZ XR use and
during therapy. Treatment for latent infection should be initiated
prior to XELJANZ/XELJANZ XR use.
- Invasive fungal infections,
including cryptococcosis and pneumocystosis. Patients with invasive
fungal infections may present with disseminated, rather than
localized, disease.
- Bacterial, viral, and other
infections due to opportunistic pathogens.
The risks and benefits of treatment with XELJANZ/XELJANZ XR
should be carefully considered prior to initiating therapy in
patients with chronic or recurrent infection.
Patients should be closely monitored for the development of
signs and symptoms of infection during and after treatment with
XELJANZ/XELJANZ XR, including the possible development of
tuberculosis in patients who tested negative for latent
tuberculosis infection prior to initiating therapy.
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.
WARNINGS AND PRECAUTIONS
SERIOUS INFECTIONS
The most common serious infections reported with XELJANZ
included pneumonia, cellulitis, herpes zoster, urinary tract
infection, diverticulitis, and appendicitis. Avoid use of
XELJANZ/XELJANZ XR in patients with an active, serious infection,
including localized infections. Consider the risks and benefits of
treatment before initiating XELJANZ/XELJANZ XR in patients:
- with chronic or recurrent
infection;
- who have been exposed to tuberculosis
(TB);
- with a history of a serious or an
opportunistic infection;
- who have lived or traveled in areas of
endemic TB or mycoses; or
- with underlying conditions that may
predispose them to infection.
Patients should be closely monitored for the development of
signs and symptoms of infection during and after treatment with
XELJANZ/XELJANZ XR. XELJANZ/XELJANZ XR should be interrupted if a
patient develops a serious infection, an opportunistic infection,
or sepsis.
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.
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.
Tuberculosis
Evaluate and test patients for latent or active infection prior
to and per applicable guidelines during administration of
XELJANZ/XELJANZ XR. Consider anti-TB therapy prior to
administration of XELJANZ/XELJANZ XR in patients with a past
history of latent or active TB in whom an adequate course of
treatment cannot be confirmed, and for patients with a negative
test for latent TB but who have risk factors for TB infection.
Treat patients with latent TB with standard therapy before
administering XELJANZ/XELJANZ XR.
Viral Reactivation
Viral reactivation, including cases of herpes virus reactivation
(e.g., herpes zoster), was observed in clinical studies with
XELJANZ. Screening for viral hepatitis should be performed in
accordance with clinical guidelines before starting therapy with
XELJANZ/XELJANZ XR. The risk of herpes zoster is increased in
patients treated with XELJANZ/XELJANZ XR and appears to be higher
in patients treated with XELJANZ in Japan and Korea.
MALIGNANCY and LYMPHOPROLIFERATIVE DISORDERS
Consider the risks and benefits of XELJANZ/XELJANZ XR 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/XELJANZ XR in patients who
develop a malignancy.
In the 7 controlled rheumatoid arthritis clinical studies, 11
solid cancers and 1 lymphoma were diagnosed in 3328 patients
receiving XELJANZ with or without DMARD, compared to 0 solid
cancers and 0 lymphomas in 809 patients in the placebo with or
without DMARD group during the first 12 months of exposure.
Lymphomas and solid cancers have also been observed in the
long-term extension studies in rheumatoid arthritis patients
treated with XELJANZ.
In Phase 2B controlled dose-ranging trials in de-novo renal
transplant patients, all of whom received induction therapy with
basiliximab, high-dose corticosteroids, and mycophenolic acid
products, Epstein Barr Virus-associated post-transplant
lymphoproliferative disorder was observed in 5 out of 218 patients
treated with XELJANZ (2.3%) compared to 0 out of 111 patients
treated with cyclosporine.
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.
Non-Melanoma Skin Cancer
Non-melanoma skin cancers (NMSCs) have been reported in patients
treated with XELJANZ. Periodic skin examination is recommended for
patients who are at increased risk for skin cancer.
GASTROINTESTINAL PERFORATIONS
Gastrointestinal perforations have been reported in XELJANZ
rheumatoid arthritis clinical trials, although the role of JAK
inhibition is not known. XELJANZ/XELJANZ XR should be used with
caution in patients who may be at increased risk for
gastrointestinal perforation (e.g., patients with a history of
diverticulitis).
LABORATORY ABNORMALITIES
Lymphocyte Abnormalities
Treatment with XELJANZ was associated with initial lymphocytosis
at 1 month of exposure followed by a gradual decrease in mean
lymphocyte counts of approximately 10% during 12 months of therapy.
Counts less than 500 cells/mm3 were associated with an increased
incidence of treated and serious infections. Avoid initiation of
XELJANZ/XELJANZ XR 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/XELJANZ XR is
not recommended. 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/XELJANZ XR 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/XELJANZ XR 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/XELJANZ XR 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/XELJANZ XR treatment in patients
with a hemoglobin level less than 9 g/dL. Treatment with
XELJANZ/XELJANZ XR 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.
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. If drug-induced liver
injury is suspected, the administration of XELJANZ/XELJANZ XR
should be interrupted until this diagnosis has been excluded.
Lipid Elevations
Treatment with XELJANZ was associated with 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.
Assess lipid parameters approximately 4-8 weeks following
initiation of XELJANZ/XELJANZ XR therapy, and manage patients
according to clinical guidelines for the management of
hyperlipidemia.
VACCINATIONS
Avoid use of live vaccines concurrently with XELJANZ/XELJANZ XR.
The interval between live vaccinations and initiation of
tofacitinib therapy should be in accordance with current
vaccination guidelines regarding immunosuppressive agents. A
varicella virus-naïve patient experienced dissemination of the
vaccine strain of varicella zoster virus 16 days after vaccination
with live attenuated virus vaccine which was 2 days after 5 mg
twice daily treatment with tofacitinib. The patient recovered after
discontinuation of tofacitinib and treatment with antiviral
medication. Update immunizations in agreement with current
immunization guidelines prior to initiating XELJANZ/XELJANZ XR
therapy.
GENERAL
Specific to XELJANZ XR
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/XELJANZ XR in patients with severe hepatic
impairment is not recommended. The recommended dose in patients
with moderate hepatic impairment or with moderate or severe renal
impairment is XELJANZ 5 mg once 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 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 infections (4.5%, 3.3%),
headache (4.3%, 2.1%), diarrhea (4.0%, 2.3%), and nasopharyngitis
(3.8%, 2.8%).
USE IN PREGNANCY
There are no adequate and well-controlled studies in pregnant
women and the estimated background risks of major birth defects and
miscarriage for the indicated population is unknown. Based on
animal studies, tofacitinib has the potential to affect a
developing fetus. Women of reproductive potential should be advised
to use effective contraception.
Pfizer Inc.: Working together for a healthier
world®
At Pfizer, we apply science and our global resources to bring
therapies to people that extend and significantly improve their
lives. We strive to set the standard for quality, safety and value
in the discovery, development and manufacture of health care
products. Our global portfolio includes medicines and vaccines as
well as many of the world's best-known consumer health care
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DISCLOSURE NOTICE: The information contained in this release is
as of December 12, 2017. 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 potential new indication for the treatment of
adult patients with moderately to severely active ulcerative
colitis (the “potential indication”), 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, without limitation, the ability to meet
anticipated trial commencement and completion dates and regulatory
submission dates, as well as the possibility of unfavorable
clinical trial results, including unfavorable new clinical data and
additional analyses of existing clinical data; uncertainties
regarding the commercial success of XELJANZ and XELJANZ XR; the
risk that clinical trial data are subject to differing
interpretations, and, even when we view data as sufficient to
support the safety and/or effectiveness of a product candidate,
regulatory authorities may not share our views and may require
additional data or may deny approval altogether; whether regulatory
authorities will be satisfied with the design of and results from
our clinical studies; whether and when any other applications for
the potential indication or any other potential indications for
XELJANZ or XELJANZ XR may be filed with regulatory authorities in
any jurisdictions; whether and when the FDA and EMA may approve the
applications for XELJANZ for the potential indication and whether
and when regulatory authorities in any jurisdictions may approve
any other applications that may be filed or pending for XELJANZ or
XELJANZ XR, which will depend on the assessment by such regulatory
authorities of the benefit-risk profile suggested by the totality
of the efficacy and safety information submitted; decisions by
regulatory authorities regarding labeling and other matters that
could affect the availability or commercial potential of XELJANZ
and XELJANZ XR, including the potential indication for XELJANZ; 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, 2016 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.
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version on businesswire.com: http://www.businesswire.com/news/home/20171212006393/en/
Pfizer Inc.Media:Neha WadhwaM: +1
212-733-2835Neha.Wadhwa@pfizer.comorInvestors:Chuck TrianoO: +1
212-733-3901Charles.E.Triano@pfizer.com
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