XELJANZ / XELJANZ XR® (tofacitinib) 6 ADVERSE REACTIONS

(tofacitinib)

Prescribing Information

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

•: Serious Infections [see Warnings and Precautions (5.1)]
•: Increased Risk of Mortality [see Warnings and Precautions (5.2)]
•: Malignancy and Lymphoproliferative Disorders [see Warnings and Precautions (5.3)]
•: Major Adverse Cardiovascular Events [see Warnings and Precautions (5.4)]
•: Thrombosis [see Warnings and Precautions (5.5)]
•: Gastrointestinal Perforations [see Warnings and Precautions (5.6)]
•: Hypersensitivity Reactions [see Warnings and Precautions (5.7)]
•: Laboratory Abnormalities [see Warnings and Precautions (5.8)]

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice.

The clinical studies described in this subsection were conducted using XELJANZ tablets (referred to as “XELJANZ” in this subsection of labeling) and/or XELJANZ oral solution.

Adverse Reactions in Adults with Rheumatoid Arthritis

In RA Safety Study 1, 1,455 adults were treated with XELJANZ 5 mg twice daily, 1,456 adults were treated with 10 mg twice daily, and 1,451 adults were treated with a TNF blocker for a median of 4 years [see Clinical Studies (14.6)]. A dosage of XELJANZ 10 mg twice daily is not recommended for the treatment of RA because of increased risks [see Dosage and Administration (2.3) and Warnings and Precautions (5)]. For the treatment of adults with moderately to severely active RA [see Indications and Usage (1.1)], the recommended dosage of XELJANZ is 5 mg twice daily and the recommended dosage for XELJANZ XR is 11 mg once daily.

The safety of XELJANZ was also evaluated in two Phase 2 and five Phase 3 double-blind, placebo-controlled, multicenter trials in patients with RA. In these trials, adults were randomized to receive:

•: XELJANZ (monotherapy) 5 mg twice daily (292 patients) or 10 mg twice daily (306 patients),
•: In combination with DMARDs (including methotrexate), XELJANZ 5 mg twice daily (1044 patients) or 10 mg twice daily (1043 patients and
•: Placebo (809 patients).

All seven trials included provisions for patients taking placebo to receive treatment with XELJANZ at Month 3 or Month 6 either by patient response (based on uncontrolled disease activity) or by design, so that adverse events cannot always be unambiguously attributed to a given treatment. Therefore, some analyses that follow include patients who changed treatment by design or by patient response from placebo to XELJANZ in both the placebo and XELJANZ group of a given interval. Comparisons between placebo and XELJANZ groups were based on the first 3 months of exposure, and comparisons between XELJANZ 5 mg twice daily and XELJANZ 10 mg twice daily were based on the first 12 months of exposure.

The long-term safety population includes all adults with RA who participated in a double-blind, placebo-controlled trial (including earlier development phase studies) and then participated in one of two long-term safety studies. The design of the long-term safety studies allowed for modification of XELJANZ doses according to clinical judgment. This limits the interpretation of the long-term safety data with respect to dose.

The most common serious adverse reactions were serious infections [see Warnings and Precautions (5.1)].

The proportion of patients who discontinued treatment due to any adverse reaction during the 0 to 3 months exposure in the double-blind, placebo-controlled trials was 4% for XELJANZ-treated patients and 3% for placebo-treated patients.

Overall Infections

In the seven placebo-controlled trials in patients with RA, during the 0 to 3 months exposure, the overall frequency of infections was 20% and 22% in the XELJANZ 5 mg twice daily and XELJANZ 10 mg twice daily groups, respectively, and 18% in the placebo group.

The most commonly reported infections with XELJANZ were upper respiratory tract infections, nasopharyngitis, and urinary tract infections (4%, 3%, and 2% of patients, respectively).

Serious Infections: In the seven placebo-controlled trials in patients with RA, during the 0 to 3 months exposure, serious infections were reported in 1 patient (0.5 events per 100 patient-years) who received placebo and 11 patients (1.7 events per 100 patient-years) who received XELJANZ 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 1.1 (-0.4, 2.5) events per 100 patient-years for the combined XELJANZ 5 mg twice daily and 10 mg twice daily group minus placebo.

In the seven placebo-controlled trials, during the 0 to 12 months exposure, serious infections were reported in 34 patients (2.7 events per 100 patient-years) who received XELJANZ 5 mg twice daily and 33 patients (2.7 events per 100 patient-years) who received XELJANZ 10 mg twice daily. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was -0.1 (-1.3, 1.2) events per 100 patient-years for XELJANZ 10 mg twice daily minus XELJANZ 5 mg twice daily.

The most common serious infections included pneumonia, cellulitis, herpes zoster, and urinary tract infection [see Warnings and Precautions (5.1)].

Tuberculosis: In the seven placebo-controlled trials in patients with RA, during the 0 to 3 months exposure, tuberculosis (TB) was not reported in patients who received placebo, XELJANZ 5 mg twice daily, or XELJANZ 10 mg twice daily.

In the seven placebo-controlled trials, during the 0 to 12 months exposure, TB was reported in 0 patients who received XELJANZ 5 mg twice daily and 6 patients (0.5 events per 100 patient-years) who received XELJANZ 10 mg twice daily. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0.5 (0.1, 0.9) events per 100 patient-years for XELJANZ 10 mg twice daily minus XELJANZ 5 mg twice daily.

Cases of disseminated TB were also reported. The median XELJANZ exposure prior to diagnosis of TB was 10 months (range from 152 to 960 days) [see Warnings and Precautions (5.1)].

Opportunistic Infections (excluding tuberculosis): In the seven placebo-controlled trials in patients with RA, during the 0 to 3 months exposure, opportunistic infections were not reported in patients who received placebo, XELJANZ 5 mg twice daily, or XELJANZ 10 mg twice daily.

In the seven placebo-controlled trials, during the 0 to 12 months exposure, opportunistic infections were reported in 4 patients (0.3 events per 100 patient-years) who received XELJANZ 5 mg twice daily and 4 patients (0.3 events per 100 patient-years) who received XELJANZ 10 mg twice daily. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0 (-0.5, 0.5) events per 100 patient-years for XELJANZ 10 mg twice daily minus XELJANZ 5 mg twice daily.

The median XELJANZ exposure prior to diagnosis of an opportunistic infection was 8 months (range from 41 to 698 days) [see Warnings and Precautions (5.1)].

Malignancies

In the seven placebo-controlled trials in patients with RA, during the 0 to 3 months exposure, malignancies excluding NMSC were reported in 0 patients who received placebo and 2 patients (0.3 events per 100 patient-years) who received either XELJANZ 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 0.3 (-0.1, 0.7) events per 100 patient-years for the combined XELJANZ 5 mg and 10 mg twice daily group minus placebo.

In the seven placebo-controlled trials, during the 0 to 12 months exposure, malignancies excluding NMSC were reported in 5 patients (0.4 events per 100 patient-years) who received XELJANZ 5 mg twice daily and 7 patients (0.6 events per 100 patient-years) who received XELJANZ 10 mg twice daily. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0.2 (-0.4, 0.7) events per 100 patient-years for XELJANZ 10 mg twice daily minus XELJANZ 5 mg twice daily. One of these malignancies was a case of lymphoma that occurred during the 0-to-12-month period in a patient treated with XELJANZ 10 mg twice daily.

The most common types of malignancy, including malignancies observed during the long-term extension in XELJANZ-treated patients, were lung and breast cancer, followed by gastric, colorectal, renal cell, prostate cancer, lymphoma, and malignant melanoma [see Warnings and Precautions (5.3)].

Laboratory Abnormalities

Lymphopenia: In the placebo-controlled clinical trials in patients with RA, confirmed decreases in absolute lymphocyte counts below 500 cells/mm3 occurred in 0.04% of patients for the XELJANZ 5 mg twice daily and 10 mg twice daily groups combined during the first 3 months of exposure.

Confirmed lymphocyte counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections [see Warnings and Precautions (5.8)].

Neutropenia: In the placebo-controlled clinical trials in patients with RA, confirmed decreases in ANC below 1,000 cells/mm3 occurred in 0.07% of patients for the XELJANZ 5 mg twice daily and 10 mg twice daily groups combined during the first 3 months of exposure.

There were no confirmed decreases in ANC below 500 cells/mm3 observed in any treatment group. There was no clear relationship between neutropenia and the occurrence of serious infections.

In the long-term safety population, the pattern and incidence of confirmed decreases in ANC remained consistent with what was seen in the placebo-controlled clinical trials [see Warnings and Precautions (5.8)].

Liver Enzyme Elevations: Confirmed increases in liver enzymes greater than 3 times the upper limit of normal (3× ULN) were observed in patients with RA treated with XELJANZ. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of XELJANZ, or reduction in XELJANZ dosage, resulted in decrease or normalization of liver enzymes.

In the placebo-controlled monotherapy trials (0–3 months), no differences in the incidence of ALT or AST elevations were observed between the placebo, and XELJANZ 5 mg, and 10 mg twice daily groups.

In the placebo-controlled background DMARD trials (0–3 months), ALT elevations greater than 3× ULN were observed in 1.0%, 1.3% and 1.2% of patients who received placebo, XELJANZ 5 mg, and 10 mg twice daily, respectively. In these trials, AST elevations greater than 3× ULN were observed in 0.6%, 0.5% and 0.4% of patients who received placebo, XELJANZ 5 mg, and 10 mg twice daily, respectively.

One case of drug-induced liver injury was reported in a patient treated with XELJANZ 10 mg twice daily for approximately 2.5 months. The patient developed symptomatic elevations of AST and ALT greater than 3× ULN and bilirubin elevations greater than 2× ULN, which required hospitalizations and a liver biopsy.

Lipid Elevations: In the placebo-controlled clinical trials in patients with RA, dose-related elevations in lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) were observed at one month of exposure and remained stable thereafter. Changes in lipid parameters during the first 3 months of exposure in the placebo-controlled clinical trials are summarized below:

•: Mean LDL cholesterol increased by 15% in the XELJANZ 5 mg twice daily arm and 19% in the XELJANZ 10 mg twice daily arm.
•: Mean HDL cholesterol increased by 10% in the XELJANZ 5 mg twice daily arm and 12% in the XELJANZ 10 mg twice daily arm.
•: Mean LDL/HDL ratios were essentially unchanged in XELJANZ-treated patients.

In a placebo-controlled clinical trial, elevations in LDL cholesterol and ApoB decreased to pretreatment levels in response to statin therapy.

In the long-term safety population, elevations in lipid parameters remained consistent with what was seen in the placebo-controlled clinical trials.

Serum Creatinine Elevations: In the placebo-controlled clinical trials in patients with RA, dose-related elevations in serum creatinine were observed with XELJANZ treatment. The mean increase in serum creatinine was <0.1 mg/dL in the 12-month pooled safety analysis; however, with increasing duration of exposure in the long-term extensions, up to 2% of patients were discontinued from XELJANZ treatment due to the protocol-specified discontinuation criterion of an increase in creatinine by more than 50% of baseline. The clinical significance of the observed serum creatinine elevations is unknown.

Common Adverse Reactions

Table 5 displays adverse reactions that occurred in 2% or more of patients on XELJANZ 5 mg or 10 mg twice daily and at least 1% greater than in XELJANZ-treated patients that observed in placebo-treated patients with or without DMARD in the RA trials.

Table 5: Common Adverse Reactions* in Clinical Trials of XELJANZ for the Treatment of Rheumatoid Arthritis in Adults With or Without Concomitant DMARDs (0–3 Months)
Preferred Term	Placebo	XELJANZ 5 mg Twice Daily	XELJANZ 10 mg Twice Daily†
Preferred Term	N = 809 (%)	N = 1336 (%)	N = 1349 (%)
N reflects randomized and treated patients from the seven placebo-controlled clinical trials.
* reported in ≥2% of patients treated with either dose of XELJANZ and ≥1% greater than that reported for placebo. † The recommended dose of XELJANZ for the treatment of RA is 5 mg twice daily [see Dosage and Administration (2)].
Upper respiratory tract infection	3	4	4
Nasopharyngitis	3	4	3
Diarrhea	2	4	3
Headache	2	4	3
Hypertension	1	2	2

Other adverse reactions that occurred in placebo-controlled and open-label extension studies in patients with RA included:

Blood and lymphatic system disorders: Anemia

Infections and infestations: Diverticulitis

Metabolism and nutrition disorders: Dehydration

Psychiatric disorders: Insomnia

Nervous system disorders: Paresthesia

Respiratory, thoracic and mediastinal disorders: Dyspnea, cough, sinus congestion, interstitial lung disease (cases were limited to patients with RA and some were fatal)

Gastrointestinal disorders: Abdominal pain, dyspepsia, vomiting, gastritis, nausea

Hepatobiliary disorders: Hepatic steatosis

Skin and subcutaneous tissue disorders: Rash, erythema, pruritus

Musculoskeletal, connective tissue and bone disorders: Musculoskeletal pain, arthralgia, tendonitis, joint swelling

Neoplasms benign, malignant and unspecified (including cysts and polyps): Non-melanoma skin cancers

General disorders and administration site conditions: Pyrexia, fatigue, peripheral edema

Clinical Experience in Methotrexate-Naïve Patients

Study RA-VI was an active-controlled clinical trial in methotrexate-naïve patients [see Clinical Studies (14)]. The safety experience in these patients was consistent with Studies RA-I through V.

Adverse Reactions in Adults with Psoriatic Arthritis

The safety of XELJANZ was evaluated in 2 double-blind Phase 3 clinical trials in adults with active psoriatic arthritis (PsA):

•: Study PsA-I (NCT01877668) had a duration of 12 months and enrolled adults who had an inadequate response to a nonbiologic DMARD and who were naïve to treatment with a TNF blocker. Study PsA-I included a 3-month placebo-controlled period and also included adalimumab 40 mg subcutaneously once every 2 weeks for 12 months.
•: Study PsA-II (NCT01882439) had a duration of 6 months and enrolled adults who had an inadequate response to at least one approved TNF blocker. This clinical trial included a 3-month placebo-controlled period.

In these combined Phase 3 clinical trials, 238 patients were randomized and treated with XELJANZ 5 mg twice daily and 236 patients were randomized and treated with XELJANZ 10 mg twice daily. A dosage of XELJANZ 10 mg twice daily is not recommended for the treatment of PsA. For the treatment of adults with active PsA [see Indications and Usage (1.2)], the recommended dosage of XELJANZ is 5 mg twice daily and the recommended dosage for XELJANZ XR is 11 mg once daily [see Dosage and Administration (2.3)].

All patients in the clinical trials in patients with PsA were required to receive treatment with a stable dose of a nonbiologic DMARD [the majority (79%) received methotrexate]. The study population randomized and treated with XELJANZ (474 patients) included 45 (10%) patients aged 65 years or older and 66 (14%) patients with diabetes at baseline.

During the 2 PsA controlled clinical trials, there were:

•: 3 malignancies (excluding NMSC) in 474 patients who received XELJANZ plus non-biologic DMARD (6 to 12 months exposure)
•: 0 malignancies in 236 patients who received placebo plus non-biologic DMARD group (3 months exposure) and
•: 0 malignancies in 106 patients in patients who received adalimumab plus non-biologic DMARD group (12 months exposure).

No lymphomas were reported. Malignancies have also been observed in the long-term extension study in patients with PsA treated with XELJANZ.

The safety profile observed in adults with active PsA treated with XELJANZ was consistent with the safety profile observed in adults with RA.

Adverse Reactions in Adults with Ankylosing Spondylitis

The safety of XELJANZ was evaluated in adults with active ankylosing spondylitis (AS) in a double-blind placebo-controlled Phase 3 clinical trial (Study AS-I) and in a dose-ranging Phase 2 clinical trial (Study AS-II).

•: Study AS-I (NCT03502616) had a duration of 48 weeks and enrolled adults who had an inadequate response to at least 2 NSAIDs. Study AS-I included a 16-week double-blind period in which patients received XELJANZ 5 mg or placebo twice daily and a 32-week open-label treatment period in which all patients received XELJANZ 5 mg twice daily.
•: Study AS-II (NCT01786668) had a duration of 16 weeks and enrolled adults who had an inadequate response to at least 2 NSAIDs. This clinical trial included a 12-week treatment period in which patients received either XELJANZ 2 mg (40% of the recommended dose), 5 mg, 10 mg, or placebo twice daily. A dosage of XELJANZ 10 mg twice daily is not recommended for the treatment of AS. For the treatment of adults with active AS [see Indications and Usage (1.3)], the recommended dosage of XELJANZ is 5 mg twice daily and the recommended dosage for XELJANZ XR is 11 mg once daily [see Dosage and Administration (2.3)].

In the combined Phase 2 and Phase 3 clinical trials, a total of 420 patients were treated with either XELJANZ 2 mg, 5 mg, or 10 mg twice daily. Of these, 316 patients were treated with XELJANZ 5 mg twice daily for up to 48 weeks. In the combined double-blind period, 185 patients were randomized to and treated with XELJANZ 5 mg twice daily and 187 to placebo for up to 16 weeks. Concomitant treatment with stable doses of nonbiologic DMARDs, NSAIDs, or corticosteroids (≤10 mg/day) was permitted. The study population randomized and treated with XELJANZ included 13 (3%) patients aged 65 years or older and 18 (4%) patients with diabetes at baseline.

The safety profile observed in adults with AS treated with XELJANZ was consistent with the safety profile observed in adults with RA and PsA.

Adverse Reactions in Pediatric Patients 2 Years of Age and Older with Polyarticular Course Juvenile Idiopathic Arthritis

XELJANZ tablets and XELJANZ oral solution 5 mg twice daily or weight-based equivalent twice daily was studied in 225 pediatric patients from 2 years to 17 years of age in Study pcJIA-I [see Clinical Studies (14.4)] and one open-label extension study (Study A3921145). The total patient exposure (defined as patients who received at least one dose of XELJANZ tablets or XELJANZ oral solution) was 105.6 patient-years in Study pcJIA-I and 777.5 patient-years in Study A3921145.

In general, the types of adverse reactions in pediatric patients 2 years of age and older with pcJIA, were consistent with those seen in adults with RA and PsA (see Adverse Reactions in Adults with Rheumatoid Arthritis and Adverse Reactions in Adults with Psoriatic Arthritis).

Adverse Reactions in Adults with Ulcerative Colitis

The safety of XELJANZ has been evaluated in adults with moderately to severely active UC in 4 randomized, double-blind, placebo-controlled trials (UC-I, UC-II, UC-III, and dose-ranging UC-V) and an open-label long-term extension study (UC-IV) [see Clinical Studies (14.5)].

Adverse reactions reported in ≥5% of patients treated with either XELJANZ 5 mg or 10 mg twice daily and ≥1% greater than reported in patients receiving placebo in either the induction or maintenance clinical trials of patients with UC were: nasopharyngitis, elevated cholesterol levels, headache, upper respiratory tract infection, increased blood creatine phosphokinase, rash, diarrhea, and herpes zoster.

Induction Trials in Adults with UC

Common adverse reactions reported in ≥2% of patients treated with XELJANZ 10 mg twice daily and ≥1% greater in XELJANZ-treated patients than placebo-treated patients in the 3 induction trials of patients with UC (Studies UC-I, UC-II, and UC-V) were: headache, nasopharyngitis, elevated cholesterol levels, acne, increased blood creatine phosphokinase, and pyrexia.

Maintenance Trial in Adults with UC

Common adverse reactions reported in ≥4% of patients treated with either dosage of XELJANZ and ≥1% greater than reported in patients treated with placebo in the maintenance trial of patients with UC (Study UC-III) are shown in Table 6.

Table 6: Common Adverse Reactions* in Adults with UC During the 52-Week Maintenance Trial (Study UC-III)
* Reported in ≥4% of patients treated with either XELJANZ dosage and ≥1% greater in XELJANZ-treated patients than placebo-treated patients. † Includes hypercholesterolemia, hyperlipidemia, blood cholesterol increased, dyslipidemia, blood triglycerides increased, low-density lipoprotein increased, low-density lipoprotein abnormal, or lipids increased.
Preferred Term	Placebo	XELJANZ 5 mg Twice Daily	XELJANZ 10 mg Twice Daily
Preferred Term	N = 198 (%)	N = 198 (%)	N = 196 (%)
Nasopharyngitis	6	10	14
Elevated cholesterol levels†	1	5	9
Headache	6	9	3
Upper respiratory tract infection	4	7	6
Increased blood creatine phosphokinase	2	3	7
Rash	4	3	6
Diarrhea	3	2	5
Herpes zoster	1	1	5
Gastroenteritis	3	3	4
Anemia	2	4	2
Nausea	3	1	4

Dose-dependent adverse reactions seen in patients treated with XELJANZ 10 mg twice daily, in comparison to 5 mg twice daily, include the following: herpes zoster infections, serious infections, and NMSC [see Warnings and Precautions (5.1, 5.3)].

During the UC controlled clinical studies (8-week induction and 52-week maintenance studies), which included 1,220 patients, 0 cases of solid cancer or lymphoma were observed in XELJANZ-treated patients.

In the long-term extension study, malignancies (including solid cancers, lymphomas and NMSC) were observed in patients treated with XELJANZ 5 mg and 10 mg twice daily [see Warnings and Precautions (5.3)]. Five cases of pulmonary embolism were reported in patients taking XELJANZ 10 mg twice daily, including one fatality in a patient with advanced cancer [see Warnings and Precautions (5.5)].

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of XELJANZ (tablets and oral solution) and XELJANZ XR (extended-release tablets). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune system disorders: Drug hypersensitivity (events such as angioedema and urticaria have been observed)

Skin and subcutaneous tissue disorders: Acne

Medication Guide

MEDICATION GUIDE

MEDICATION GUIDE
XELJANZ (ZEL' JANS') (tofacitinib) tablets, for oral use			XELJANZ XR (ZEL' JANS' EKS-AHR) (tofacitinib) extended-release tablets for oral use		XELJANZ (ZEL' JANS') (tofacitinib) oral solution
What is the most important information I should know about XELJANZ/XELJANZ XR/XELJANZ oral solution? XELJANZ/XELJANZ XR/XELJANZ oral solution may cause serious side effects including:
1.		Serious infections. XELJANZ/XELJANZ XR/XELJANZ oral solution are medicines that affect your immune system. XELJANZ/XELJANZ XR/XELJANZ oral solution can lower the ability of your immune system to fight infections. Some people can have serious infections while taking XELJANZ/XELJANZ XR/XELJANZ oral solution, including tuberculosis (TB), and infections caused by bacteria, fungi, or viruses that can spread throughout the body. Some people have died from these infections. • Your healthcare provider should test you for TB before starting XELJANZ/XELJANZ XR/XELJANZ oral solution and during treatment. • Your healthcare provider should monitor you closely for signs and symptoms of TB infection during treatment with XELJANZ/XELJANZ XR/XELJANZ oral solution. You should not start taking XELJANZ/XELJANZ XR/XELJANZ oral solution if you have any kind of infection unless your healthcare provider tells you it is okay. You may be at a higher risk of developing shingles (herpes zoster). People with ulcerative colitis taking the higher dose of XELJANZ (10 mg twice daily) or XELJANZ XR (22 mg one time each day) have a higher risk of serious infections and shingles. Before starting XELJANZ/XELJANZ XR/XELJANZ oral solution, tell your healthcare provider if you: • think you have an infection or have symptoms of an infection such as:
		o fever, sweating, or chills o cough o blood in phlegm o warm, red, or painful skin or sores on your body o burning when you urinate or urinating more often than normal		o muscle aches o shortness of breath o weight loss o diarrhea or stomach pain o feeling very tired
		• are being treated for an infection. • get a lot of infections or have infections that keep coming back. • have diabetes, chronic lung disease, HIV, or a weak immune system. People with these conditions have a higher chance for infections. • have TB, or have been in close contact with someone with TB. • live or have lived, or have traveled to certain parts of the country (such as the Ohio and Mississippi River valleys and the Southwest) where there is an increased chance for getting certain kinds of fungal infections (histoplasmosis, coccidioidomycosis, or blastomycosis). These infections may happen or become more severe if you take XELJANZ/XELJANZ XR/XELJANZ oral solution. Ask your healthcare provider if you do not know if you have lived in an area where these infections are common. • have or have had hepatitis B or C. After starting XELJANZ/XELJANZ XR/XELJANZ oral solution, call your healthcare provider right away if you have any symptoms of an infection. XELJANZ/XELJANZ XR/XELJANZ oral solution can make you more likely to get infections or make worse any infection that you have.
2.		Increased risk of death in people 50 years of age and older who have at least 1 heart disease (cardiovascular) risk factor and are taking XELJANZ 5 mg or 10 mg twice daily.
3.		Cancer and immune system problems. XELJANZ/XELJANZ XR/XELJANZ oral solution may increase your risk of certain cancers by changing the way your immune system works. • Lymphoma and other cancers including skin cancers can happen in people taking XELJANZ/XELJANZ XR/XELJANZ oral solution. People taking XELJANZ 5 mg twice daily or XELJANZ 10 mg twice daily have a higher risk of certain cancers including lymphoma and lung cancer, especially if you are a current or past smoker. People with ulcerative colitis taking the higher dose of XELJANZ (10 mg twice daily) or XELJANZ XR (22 mg one time each day) have a higher risk of skin cancers. Tell your healthcare provider if you have ever had any type of cancer.
4.		Increased risk of major cardiovascular events such as heart attack, stroke or death in people 50 years of age and older who have at least 1 heart disease (cardiovascular) risk factor and are taking XELJANZ 5 mg or 10 mg twice daily, especially if you are a current or past smoker. Get emergency help right away if you have any symptoms of a heart attack or stroke while taking XELJANZ/XELJANZ XR/XELJANZ oral solution, including: • discomfort in the center of your chest that lasts for more than a few minutes, or that goes away and comes back • severe tightness, pain, pressure, or heaviness in your chest, throat, neck, or jaw • pain or discomfort in your arms, back, neck, jaw, or stomach • shortness of breath with or without chest discomfort • breaking out in a cold sweat • nausea or vomiting • feeling lightheaded • weakness in one part or on one side of your body • slurred speech
5.		Blood clots in the lungs, veins of the legs or arms, and arteries. Blood clots in the lungs (pulmonary embolism, PE), veins of the legs (deep vein thrombosis, DVT) and arteries (arterial thrombosis) have happened more often in people who are 50 years of age and older and with at least 1 heart disease (cardiovascular) risk factor taking XELJANZ 5 mg or 10 mg twice daily. Blood clots in the lungs have also happened in people with ulcerative colitis. Some people have died from these blood clots. • Stop taking XELJANZ/XELJANZ XR/XELJANZ oral solution and tell your healthcare provider right away if you develop signs and symptoms of a blood clot, such as sudden shortness of breath or difficulty breathing, chest pain, swelling of the leg or arm, leg pain or tenderness, or redness or discoloration in the leg or arm.
6.		Tears (perforation) in the stomach or intestines. • Tell your healthcare provider if you have had diverticulitis (inflammation in parts of the large intestine) or ulcers in your stomach or intestines. Some people taking XELJANZ/XELJANZ XR/XELJANZ oral solution can get tears in their stomach or intestines. This happens most often in people who also take nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or methotrexate. Tell your healthcare provider right away if you have fever and stomach-area pain that does not go away, and a change in your bowel habits.
7.		Allergic reactions. • Symptoms such as swelling of your lips, tongue, or throat, or hives (raised, red patches of skin that are often very itchy) that may mean you are having an allergic reaction have been seen in people taking XELJANZ/XELJANZ XR. Some of these reactions were serious. If any of these symptoms occur while you are taking XELJANZ/XELJANZ XR/XELJANZ oral solution, stop XELJANZ/XELJANZ XR/XELJANZ oral solution and call your healthcare provider right away.
8.		Changes in certain laboratory test results. Your healthcare provider should do blood tests before you start taking XELJANZ/XELJANZ XR/XELJANZ oral solution and while you take XELJANZ/XELJANZ XR/XELJANZ oral solution to check for the following side effects: • changes in lymphocyte counts. Lymphocytes are white blood cells that help the body fight off infections. • low neutrophil counts. Neutrophils are white blood cells that help the body fight off infections. • low red blood cell count. This may mean that you have anemia, which may make you feel weak and tired. Your healthcare provider should routinely check certain liver tests. You should not take XELJANZ/XELJANZ XR/XELJANZ oral solution if your lymphocyte count, neutrophil count, or red blood cell count is too low or your liver tests are too high. Your healthcare provider may stop your XELJANZ/XELJANZ XR/XELJANZ oral solution treatment for a period of time if needed because of changes in these blood test results. You may also have changes in other laboratory tests, such as your blood cholesterol levels. Your healthcare provider should do blood tests to check your cholesterol levels 4 to 8 weeks after you start taking XELJANZ/XELJANZ XR/XELJANZ oral solution, and as needed after that. Normal cholesterol levels are important to good heart health.
See "What are the possible side effects of XELJANZ/XELJANZ XR/XELJANZ oral solution?" for more information about side effects.
What is XELJANZ/XELJANZ XR/XELJANZ oral solution? • XELJANZ/XELJANZ XR/XELJANZ oral solution is a prescription medicine called a Janus kinase (JAK) inhibitor. XELJANZ/XELJANZ XR is used to treat adults with moderately to severely active rheumatoid arthritis when 1 or more medicines called tumor necrosis factor (TNF) blockers have been used and did not work well or cannot be tolerated. • XELJANZ/XELJANZ XR is used to treat adults and XELJANZ/XELJANZ oral solution is used to treat children 2 years of age and older with active psoriatic arthritis when 1 or more TNF blocker medicines have been used, and did not work well or cannot be tolerated. • XELJANZ/XELJANZ XR is used to treat adults with active ankylosing spondylitis when 1 or more TNF blocker medicines have been used and did not work well or cannot be tolerated. • XELJANZ/XELJANZ XR is used to treat adults with moderately to severely active ulcerative colitis when 1 or more TNF blocker medicines have been used, and did not work well or cannot be tolerated. • XELJANZ/XELJANZ oral solution is used to treat children 2 years of age and older with active polyarticular course juvenile arthritis when 1 or more TNF blocker medicines have been used, and did not work well or cannot be tolerated. It is not known if XELJANZ/XELJANZ XR/XELJANZ oral solution is safe and effective in people with Hepatitis B or C. XELJANZ/XELJANZ XR/XELJANZ oral solution is not recommended for people with severe liver problems. It is not known if XELJANZ/XELJANZ oral solution is safe and effective in children for treatment other than active polyarticular course juvenile arthritis and psoriatic arthritis. It is not known if XELJANZ XR is safe and effective in children.
What should I tell my healthcare provider before taking XELJANZ/XELJANZ XR/XELJANZ oral solution? Before taking XELJANZ/XELJANZ XR/XELJANZ oral solution, tell your healthcare provider about all of your medical conditions, including if you: • have an infection. See "What is the most important information I should know about XELJANZ/XELJANZ XR/XELJANZ oral solution?" • are a current or past smoker. • have had any type of cancer. • have had a heart attack, other heart problems or stroke. • have had blood clots in the veins of your legs, arms, or lungs, or clots in the arteries in the past. • have liver problems. • have kidney problems. • have any stomach-area (abdominal) pain or been diagnosed with diverticulitis or ulcers in your stomach or intestines. • have had a reaction to tofacitinib or any of the ingredients in XELJANZ/XELJANZ XR/XELJANZ oral solution. • have recently received or are scheduled to receive a vaccine. People who take XELJANZ/XELJANZ XR/XELJANZ oral solution should not receive live vaccines. People taking XELJANZ/XELJANZ XR/XELJANZ oral solution can receive non-live vaccines. • plan to become pregnant or are pregnant. XELJANZ/XELJANZ XR/XELJANZ oral solution may affect the ability of females to get pregnant. It is not known if this will change after stopping XELJANZ/XELJANZ XR/XELJANZ oral solution. It is not known if XELJANZ/XELJANZ XR/XELJANZ oral solution will harm an unborn baby. • plan to breastfeed or are breastfeeding. You and your healthcare provider should decide if you will take XELJANZ/XELJANZ XR/XELJANZ oral solution or breastfeed. You should not do both. After you stop your treatment with XELJANZ/XELJANZ XR/XELJANZ oral solution do not start breastfeeding again until: o 18 hours after your last dose of XELJANZ/XELJANZ oral solution or o 36 hours after your last dose of XELJANZ XR Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. XELJANZ/XELJANZ XR/XELJANZ oral solution and other medicines may affect each other causing side effects. Especially tell your healthcare provider if you take: • any other medicines to treat your rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, or polyarticular course juvenile arthritis. You should not take tocilizumab (Actemra), etanercept (Enbrel), adalimumab (Humira), infliximab (Remicade), rituximab (Rituxan), abatacept (Orencia), anakinra (Kineret), certolizumab (Cimzia), golimumab (Simponi), ustekinumab (Stelara), secukinumab (Cosentyx), vedolizumab (Entyvio), ixekizumab (Taltz), azathioprine, cyclosporine, or other immunosuppressive drugs while you are taking XELJANZ/XELJANZ XR/XELJANZ oral solution. Taking XELJANZ/XELJANZ XR/XELJANZ oral solution with these medicines may increase your risk of infection. • medicines that affect the way certain liver enzymes work. Ask your healthcare provider if you are not sure if your medicine is one of these. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
How should I take XELJANZ/XELJANZ XR/XELJANZ oral solution? Take XELJANZ/XELJANZ XR/XELJANZ oral solution exactly as your healthcare provider tells you to take it. • Take XELJANZ/XELJANZ oral solution 2 times a day with or without food. • Take XELJANZ XR 1 time a day with or without food. • Swallow XELJANZ XR tablets whole and intact. Do not crush, split, or chew. • When you take XELJANZ XR, you may see something in your stool that looks like a tablet. This is the empty shell from the tablet after the medicine has been absorbed by your body. • If you take too much XELJANZ/XELJANZ XR/XELJANZ oral solution, call your healthcare provider or go to the nearest hospital emergency room right away. • For the treatment of psoriatic arthritis, take XELJANZ/XELJANZ XR/XELJANZ oral solution in combination with methotrexate, sulfasalazine or leflunomide as instructed by your healthcare provider. • XELJANZ XR should not be used instead of XELJANZ oral solution.
What are the possible side effects of XELJANZ/XELJANZ XR/XELJANZ oral solution? XELJANZ/XELJANZ XR/XELJANZ oral solution may cause serious side effects, including: • See "What is the most important information I should know about XELJANZ/XELJANZ XR/XELJANZ oral solution?" • Hepatitis B or C activation infection in people who carry the virus in their blood. If you are a carrier of the hepatitis B or C virus (viruses that affect the liver), the virus may become active while you use XELJANZ/XELJANZ XR/XELJANZ oral solution. Your healthcare provider may do blood tests before you start treatment with XELJANZ/XELJANZ XR/XELJANZ oral solution and while you are taking XELJANZ/XELJANZ XR/XELJANZ oral solution. Tell your healthcare provider if you have any of the following symptoms of a possible hepatitis B or C infection:
	o feel very tired o little or no appetite o clay-colored bowel movements o chills o muscle aches o skin rash			o skin or eyes look yellow o vomiting o fevers o stomach discomfort o dark urine
Common side effects of XELJANZ/XELJANZ XR/XELJANZ oral solution in people with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis include: • upper respiratory tract infections (common cold, sinus infections) • headache • diarrhea • nasal congestion, sore throat, and runny nose (nasopharyngitis) • high blood pressure (hypertension) • acne Common side effects of XELJANZ/XELJANZ XR in people with ulcerative colitis include: • nasal congestion, sore throat, and runny nose (nasopharyngitis) • increased cholesterol levels • headache • upper respiratory tract infections (common cold, sinus infections) • increased muscle enzyme levels • rash • acne • diarrhea • shingles (herpes zoster) Common side effects of XELJANZ/XELJANZ oral solution in children with polyarticular course juvenile arthritis and psoriatic arthritis include: • upper respiratory tract infections (common cold, sinus infections) • nasal congestion, sore throat, and runny nose (nasopharyngitis) • headache • fever • nausea • vomiting • acne Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of XELJANZ/XELJANZ XR/XELJANZ oral solution. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Pfizer at 1-800-438-1985.
How should I store XELJANZ/XELJANZ XR/XELJANZ oral solution? • Store XELJANZ/XELJANZ XR at room temperature between 68°F to 77°F (20°C to 25°C). • Store XELJANZ oral solution at room temperature between 68°F to 77°F (20°C to 25°C) in the original bottle and carton to protect from light. • Safely throw away XELJANZ oral solution that is out of date or no longer needed. Use XELJANZ oral solution within 60 days of opening the bottle. Throw away (discard) remaining oral solution after 60 days. Keep XELJANZ/XELJANZ XR/XELJANZ oral solution and all medicines out of the reach of children.
General information about the safe and effective use of XELJANZ/XELJANZ XR/XELJANZ oral solution. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use XELJANZ/XELJANZ XR/XELJANZ oral solution for a condition for which it was not prescribed. Do not give XELJANZ/XELJANZ XR/XELJANZ oral solution to other people, even if they have the same symptoms you have. It may harm them. This Medication Guide summarizes the most important information about XELJANZ/XELJANZ XR/XELJANZ oral solution. If you would like more information, talk to your healthcare provider. You can ask your pharmacist or healthcare provider for information about XELJANZ/XELJANZ XR/XELJANZ oral solution that is written for health professionals.
What are the ingredients in XELJANZ 5 mg? Active ingredient: tofacitinib citrate Inactive ingredients: croscarmellose sodium, HPMC 2910/Hypromellose 6cP, lactose monohydrate, macrogol/PEG3350, magnesium stearate, microcrystalline cellulose, titanium dioxide, and triacetin. What are the ingredients in XELJANZ 10 mg? Active ingredient: tofacitinib citrate Inactive ingredients: croscarmellose sodium, FD&C Blue #1/Brilliant Blue FCF Aluminum Lake, FD&C Blue #2/Indigo Carmine Aluminum Lake, HPMC 2910/Hypromellose 6cP, lactose monohydrate, macrogol/PEG3350, magnesium stearate, microcrystalline cellulose, titanium dioxide, and triacetin. What are the ingredients in XELJANZ XR 11 mg? Active ingredient: tofacitinib citrate Inactive ingredients: cellulose acetate, copovidone, hydroxyethyl cellulose, hydroxypropyl cellulose, HPMC 2910/Hypromellose, magnesium stearate, red iron oxide, sorbitol, titanium dioxide, and triacetin. Printing ink contains ammonium hydroxide, ferrosoferric oxide/black iron, propylene glycol, and shellac glaze. What are the ingredients in XELJANZ XR 22 mg? Active ingredient: tofacitinib citrate Inactive ingredients: cellulose acetate, copovidone, FD&C Blue #2 Aluminum Lake, hydroxyethyl cellulose, hydroxypropyl cellulose, HPMC 2910/Hypromellose, magnesium stearate, red iron oxide, sorbitol, titanium dioxide, triacetin, and yellow iron oxide. Printing ink contains ammonium hydroxide, ferrosoferric oxide/black iron oxide, propylene glycol, and shellac glaze. What are the ingredients in XELJANZ oral solution? Active ingredient: tofacitinib citrate Inactive ingredients: grape flavor (natural), hydrochloric acid, lactic acid, purified water, sodium benzoate, sucralose, and xylitol. This Medication Guide may have been updated. For the most recent Medication Guide, please visit www.pfizer.com. LAB-0535-16.0

This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: October 2025

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