Market Overview

XELJANZ® (tofacitinib citrate) Receives Marketing Authorization in the European Union for Moderately to Severely Active Ulcerative Colitis

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Pfizer Inc. (NYSE:PFE) announced today that the European Commission (EC)
has approved XELJANZ® (tofacitinib citrate) 10 mg twice-daily
(BID) for at least eight weeks, followed by XELJANZ 5 mg BID or 10 mg
BID, for the treatment of adult patients 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.1 XELJANZ is the first and only oral therapy
and Janus kinase (JAK) inhibitor to be approved for this patient
population.

In approving XELJANZ for UC, the European Medicines Agency's (EMA)
Committee for Human Medicinal Products (CHMP) has, as part of its
assessment, determined XELJANZ to be of significant clinical benefit for
patients with UC in comparison with existing therapies.

"Ulcerative colitis is a chronic disease that can develop at any age, be
difficult to manage and affect multiple aspects of daily life," said
Angela Lukin, regional president, Inflammation and Immunology, Pfizer.
"The EC approval of XELJANZ provides an additional treatment option that
can help improve the care of adults in Europe living with this
debilitating inflammatory bowel disease."

XELJANZ is now approved for three indications in the EU. In 2017,
XELJANZ, in combination with methotrexate (MTX), was first approved by
the EC for the treatment of moderate to severe active rheumatoid
arthritis (RA) in adult patients who have responded inadequately to, or
who are intolerant to one or more disease-modifying antirheumatic drugs
(DMARDs), and as monotherapy in case of intolerance to MTX or when
treatment with MTX is inappropriate.2 In June 2018, XELJANZ,
in combination with MTX, was approved by the EC for the treatment of
active psoriatic arthritis (PsA) in adult patients who have had an
inadequate response or who have been intolerant to a prior DMARD therapy.2

"Until now, people living with moderately to severely active ulcerative
colitis have not had an oral treatment available that can both induce
and maintain steroid-free remission," said Silvio Danese, head of IBD
Center, Department of Gastroenterology Humanitas Research Hospital,
Milan, Italy, President of the European Crohn's and Colitis Organisation
(ECCO) Governing Board. "This approval of XELJANZ, the first JAK
inhibitor to be approved for this condition, offers the ulcerative
colitis community an additional treatment option."

The EC approval follows the review of the application for marketing
authorization which included data from three pivotal Phase 3 studies
from the Oral Clinical
Trials for tofAcitinib
in ulceratiVE colitis global
clinical development program (OCTAVE Induction 1, OCTAVE Induction 2 and
OCTAVE Sustain), and OCTAVE Open, an ongoing open label long-term
extension study.3,4

About Ulcerative Colitis

UC is a chronic and often debilitating inflammatory bowel disease that
affects approximately 2.1 million people in Europe.5,6,7 Symptoms
of UC can include chronic diarrhea with blood and mucus, abdominal pain
and cramping, and weight loss.8,9 UC can have a significant
effect on work, family and social activities.9

About XELJANZ® (tofacitinib citrate)

XELJANZ® (tofacitinib citrate) is the first and only Janus
kinase (JAK) inhibitor approved by the FDA for three indications in
adults: moderately to severely active rheumatoid arthritis (RA), active
psoriatic arthritis (PsA) and moderately to severely active ulcerative
colitis (UC). XELJANZ is now approved in more than 80 countries for the
treatment of adult patients with moderate to severe RA, with additional
applications pending globally for all three respective indications.
XELJANZ is also approved for the treatment of adult patients with
moderately to severely active UC in the U.S., Japan, Peru and Russia.

As the developer of XELJANZ, Pfizer is committed to advancing JAK
science and enhancing understanding of XELJANZ through robust clinical
development programs in the treatment of immune-mediated inflammatory
conditions.

INDICATIONS AND IMPORTANT XELJANZ® (tofacitinib)
SAFETY INFORMATION FROM THE U.S. PRESCRIBING INFORMATION

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.

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
    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.

Ulcerative Colitis

  • XELJANZ (tofacitinib) is indicated for the treatment of adult patients
    with moderately to severely active ulcerative colitis (UC).
  • Limitations of Use: Use of XELJANZ in combination with biologic
    therapies for UC or with potent immunosuppressants such as
    azathioprine and cyclosporine is not recommended.

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, 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/XELJANZ XR 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/XELJANZ XR 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. 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/XELJANZ
XR, 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.

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/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.

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. NMSC
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.

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/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 or taking NSAIDs).

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/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. 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/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. If drug-induced liver injury is
suspected, the administration of XELJANZ/XELJANZ XR 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/XELJANZ XR
therapy.

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. Update immunizations in agreement with current
immunization guidelines prior to initiating XELJANZ/XELJANZ XR 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/XELJANZ XR 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 rheumatoid arthritis (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 psoriatic arthritis 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 ulcerative colitis 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/XELJANZ XR 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.

Please see full U.S. Prescribing Information, including BOXED WARNING
for XELJANZ/XELJANZ XR available at: http://labeling.pfizer.com/showlabeling.aspx?id=959

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
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DISCLOSURE NOTICE: The information contained in this release is as of
August 1, 2018.
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 and a
new indication in the EU for the treatment of adult patients 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, 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, uncertainties regarding the commercial success of XELJANZ and
XELJANZ XR, including for the new indication for XELJANZ; the
uncertainties inherent in research and development, including the
ability to meet anticipated clinical 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; 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
applications for the new indication or any other potential indications
for XELJANZ or XELJANZ XR may be filed with regulatory authorities in
any additional jurisdictions; whether and when regulatory authorities in
any other jurisdictions may approve any applications that may be pending
or filed for the new indication or for any other indications 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 and, if approved, whether they
will be commercially successful; decisions by regulatory authorities
regarding labeling and other matters that could affect the availability
or commercial potential of XELJANZ and XELJANZ XR, including the new
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, 2017 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 Pfizer. Data on File. European Commission Approval Letter.

2 XELJANZ Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/product/2500/smpc.
Accessed August 1, 2018.

3 Sandborn WJ, Su C, Sands B, et al. Tofacitinib as induction
and maintenance therapy for ulcerative colitis. N Engl J Med.
2017;376(18):1723-1736.

4 Long-Term Study Of CP-690,550 In Subjects With Ulcerative
Colitis (OCTAVE). https://clinicaltrials.gov/ct2/show/NCT01470612?term=octave+open&rank=1.
Accessed August 1, 2018.

5 Crohn's and Colitis Foundation. What is Ulcerative Colitis.
Available at: http://www.crohnscolitisfoundation.org/what-are-crohns-and-colitis/what-is-ulcerative-colitis.
Accessed August 1, 2018.

6 Burisch J, et al. The burden of inflammatory bowel disease
in Europe. Journal of Crohn's and Colitis. 2013;7(4):322-337.

7 NHS Choices. Ulcerative colitis: Living with. Available at: https://www.nhs.uk/conditions/ulcerative-colitis/living-with/.
Accessed August 1, 2018.

8 Hanauer SB. Inflammatory bowel disease. N Engl J Med. 1996;334(13):841-8.

9 Irvine EJ. Quality of Life of Patients with Ulcerative
Colitis: Past, Present, and Future. Inflammatory Bowel Diseases.
2008;14(4):554-563.

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