IMPORTANT SAFETY INFORMATION AND INDICATION

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.

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.

Please see full Prescribing Information, including BOXED WARNING and Medication Guide.

Signs and Symptoms

Head-To-Head Noninferiority Study

POWERFUL EFFICACY, WITH OR WITHOUT MTX, ACROSS A BROAD RANGE OF PATIENT TYPES1-8

Significant reductions of RA signs and symptoms demonstrated across 6 phase 3 studies1-8

Studies were conducted with XELJANZ® (tofacitinib) 5 mg tablets BID dosing.1



ACR20 was a coprimary endpoint in Sync, Standard, Scan, Solo, and Step, and ACR70 was a coprimary endpoint in Start.1


  • XELJANZ XR 11 mg administered once daily is pharmacokinetically equivalent to XELJANZ 5 mg administered twice daily1
  • Recommended dose in patients with moderate and severe renal impairment and moderate hepatic impairment is XELJANZ 5 mg once daily1
  • PK Study Design: A cross-over study including 24 healthy volunteers designed to demonstrate pharmacokinetic equivalence (AUC and Cmax) between XELJANZ XR 11 mg once daily and XELJANZ 5 mg twice daily9

POWERFUL EFFICACY PROVEN IN 2 SEPARATE STUDIES AS A SINGLE AGENT1,2,4,5

XELJANZ delivered rapid response as early as 2 weeks, and powerful efficacy at 3 months, even without MTX1,2,5

ORAL Solo (Study I) in DMARD-IR Patients1,2,5

Studies were conducted with XELJANZ 5 mg tablets BID dosing.1

Data for placebo treatment are not available beyond month 3 due to advancement of placebo patients to treatment with XELJANZ.1

aNonresponder imputation (NRI).2


In ORAL Solo:

  • 209 out of 243 patients received prior MTX in the XELJANZ 5 mg group5
  • 102 out of 122 patients received prior MTX in the placebo group5
  • ACR50 response rate for XELJANZ at month 3 was 31% vs 12% for placebo (P<0.0001)1,2,5
  • ACR70 response rate for XELJANZ at month 3 was 15% vs 6% for placebo (P=0.0026)1,2,5

XELJANZ as a single agent provided powerful reduction in RA signs and symptoms vs MTX4,5,a,b

ORAL Start (Study VI) in MTX-Naïve Patients1,4,5,a

Studies were conducted with XELJANZ 5 mg tablets BID dosing.1

XELJANZ/XELJANZ XR is not indicated in MTX-naïve patients.1

MTX dose started at 10 mg/week, titrated by 5 mg every 4 weeks as tolerated to 20 mg/week by week 8.4

Mean MTX dose at end of titration (month 3)=18.5 mg/week.4


Superior ACR response rates to MTX demonstrated in MTX-naïve patients at month 6, year 1, and year 24,5,b

  • In ORAL Start, ACR20/50 response rates for XELJANZ 5 mg at month 6, year 1, and year 2 were 71%*/47%*, 68%**/50%***, and 64%*/49%* vs MTX 51%/27%, 51%/34%, and 42%/28%, respectively (***P=0.0002 vs MTX)4,5
  • ACR20/50/70 response rates for XELJANZ 5 mg at month 9, month 15, month 18, and month 21 were 72%**/50%/29%*, 69%*/51%*/30%***, 64%*/48%*/32%*, and 65%*/49%*/32%*, respectively (***P=0.0002 vs MTX, P=0.0009 vs MTX)5

More patients overall discontinued MTX (43%) vs XELJANZ (29%) as monotherapy.5,a,c

aStable doses of anti-malarial agents allowed.5

bNonresponder imputation (NRI).4

c43.0% (80/186) of patients discontinued treatment in the MTX group compared with 28.7% (107/373) of patients in the XELJANZ 5 mg BID group at year 2.5


  • XELJANZ XR 11 mg administered once daily is pharmacokinetically equivalent to XELJANZ 5 mg administered twice daily1
  • Recommended dose in patients with moderate and severe renal impairment and moderate hepatic impairment is XELJANZ 5 mg once daily1
  • PK Study Design: A cross-over study including 24 healthy volunteers designed to demonstrate pharmacokinetic equivalence (AUC and Cmax) between XELJANZ XR 11 mg once daily and XELJANZ 5 mg twice daily9

EFFICACY RESULTS AS COMBINATION THERAPY IN 2 SEPARATE STUDIES5,8

ORAL Standard at Month 6
ORAL Standard Video: Clinical Data Review

XELJANZ + MTX demonstrated powerful efficacy in MTX-IR patients compared with placebo + MTX1,5,8

ORAL Standard (Study III) at Month 65,8,a

Studies were conducted with XELJANZ 5 mg tablets BID dosing1: NRI with advancement penalty.b

aORAL Standard was not designed to provide head-to-head comparative efficacy data and should not be interpreted as evidence of superiority or noninferiority to Humira.8


XELJANZ and Humira were independently compared to placebo and not to each other.8


bNRI (nonresponder imputation), with advancement penalty: If patient had any missing ACR component data or did not have a 20% improvement in tender and swollen joint counts by month 3, the treatment was considered to be a failure even if they had a response after month 3.8

  • Significant ACR20/50 responses with XELJANZ 5 mg BID + MTX were observed as early as month 1 (time of first visit) and ACR20/50/70 responses with XELJANZ + MTX observed at month 6 were sustained at year 15
  • In ORAL Standard, ACR20/50 response rates at month 1 were 41%* (80/194) and 15% (29/194) for XELJANZ + MTX and 16% (17/106) and 5% (5/106) for placebo + MTX, respectively5
  • ACR20/50/70 response rates at year 1 were 49%§ (97/196), 37%§ (72/196), and 23%§ (45/196)  for XELJANZ + MTX and 34% (19/56), 21% (12/56), and 11% (6/56) for placebo + MTX, respectively5

*P<0.0001 vs placebo + MTX5

P=0.0018 vs placebo + MTX5

§P<0.0001 compared to baseline within treatment sequence5

A clinical review of the ORAL standard study

A Phase 3 Trial of XELJANZ + MTX vs placebo and Humira + MTX vs placebo in patients with MTX-IR RA.1,5,8





ORAL Standard was not designed to provide head-to-head comparative efficacy data and should not be interpreted as evidence of superiority or noninferiority to Humira.8



ORAL Strategy Noninferiority Study at Month 6
ORAL Strategy Noninferiority Study through Year 1

XELJANZ + MTX noninferior to Humira + MTX as measured by ACR50 at month 65,***

ORAL Strategy noninferiority study in MTX-IR patients at month 65

Studies were conducted with XELJANZ 5 mg tablets BID dosing.5


aP values are for one-sided noninferiority comparisons; must be <0.025 for significance to be declared (98.34% Confidence Interval)5

As measured by ACR50 at month 6:

  • XELJANZ + MTX similar to Humira + MTX based on meeting noninferiority criteria5
  • XELJANZ as a single agent did not meet noninferiority criteria compared to XELJANZ + MTX5,*
  • XELJANZ as a single agent did not meet noninferiority criteria compared to Humira + MTX5,**

Clinically relevant efficacy responses across all 3 treatment arms5

ACR50 results through year 15

ORAL Strategy noninferiority study in MTX-IR patients5

Studies were conducted with XELJANZ 5 mg tablets BID dosing.5



aP values are for one-sided noninferiority comparisons (98.34% confidence interval), and must be <0.025 to declare significance.5

As measured by ACR50 at month 6:

  • XELJANZ + MTX similar to Humira + MTX based on meeting noninferiority criteria5
  • XELJANZ as a single agent did not meet noninferiority criteria compared to XELJANZ + MTX5
  • XELJANZ as a single agent did not meet noninferiority criteria compared to Humira + MTX5

ACR20 response rates for XELJANZ, Humira + MTX, and XELJANZ + MTX were 52%, 53%, and 61% at Week 6, 65%, 71%, and 73% at Month 6, and 62%, 68%, and 70% at Year 1, respectively5

ACR70 response rates for XELJANZ, Humira + MTX, and XELJANZ + MTX were 7%, 8%, and 7% at Week 6, 18%, 21%, and 25% at Month 6, and 21%, 26%, and 29% at Year 1, respectively5

Sustained ACR20/50/70 response rates over time (ACR20 and ACR70 are secondary endpoints)5



MTX=methotrexate; RA=rheumatoid arthritis; BID=twice-daily; DMARD=disease-modifying antirheumatic drug; ACR=American College of Rheumatology; IR=inadequate responder; TNFi=tumor necrosis factor inhibitor; NRI=nonresponder imputation; q 2 wk=every 2 weeks; SE=standard error; NS=nonsignificant; LOCF=last observation carried forward.