XELJANZ / XELJANZ XR 8 Adverse Reactions

tofacitinib

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8.1 Adverse Reaction Overview

Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis

The most common serious adverse reactions (SAEs) in rheumatoid arthritis clinical trials were osteoarthritis and serious infections, including pneumonia, cellulitis, herpes zoster, and urinary tract infection.

The most commonly reported adverse reactions during the first 3 months in controlled clinical trials in rheumatoid arthritis clinical trials (occurring in ≥2% of patients treated with XELJANZ monotherapy or in combination with DMARDs) were upper respiratory tract infections, headache, nasopharyngitis, and diarrhea. Additionally, bronchitis, urinary tract infection, herpes zoster, RA, back pain and hypertension were also reported in the 5 mg BID XELJANZ group in the long-term extension trial.

The most common adverse reactions in rheumatoid arthritis clinical trials that resulted in discontinuation of XELJANZ were infections. Pneumonia was the most common adverse reactions leading to discontinuation of therapy, followed by blood creatinine increased and herpes zoster.

Asian patients had higher rates of herpes zoster, opportunistic infections, elevated transaminases (ALT, AST) and decreased WBCs. Asian patients with RA also have an increased risk of ILD (see 7.1.5 Asian Patients). Therefore, XELJANZ/XELJANZ XR should be used with caution in Asian patients.

Ulcerative Colitis

In the induction studies, the most common categories of serious adverse events were gastrointestinal disorders and infections. The most common serious adverse events (excluding events reported as UC) were abdominal pain, anal abscess, and drug hypersensitivity. The most common adverse events (≥5%) were headache and nasopharyngitis.

In the maintenance study, the most common categories of serious adverse events were gastrointestinal disorders, infections, injuries, and nervous system disorders. All serious adverse events were single reports (excluding events reported as UC). The most common adverse events (≥5%) (excluding events reported as UC) in patients treated with 5 mg BID were nasopharyngitis, arthralgia, headache, and upper respiratory tract infection. In patients treated with 10 mg BID, the most common adverse events were nasopharyngitis, arthralgia, blood creatine phosphokinase increased, upper respiratory tract infection, rash, hypercholesterolemia, and herpes zoster.

In induction studies, adverse events were reported in 515 subjects (54.9%) treated with 10 mg BID and 155 subjects (55.0%) treated with placebo. In the maintenance study, adverse events were reported in 143 subjects (72.2%) treated with 5 mg BID, 156 subjects (79.6%) treated with 10 mg BID, and 149 subjects (75.3%) treated with placebo.

In induction and maintenance studies, the most frequent reason for study discontinuation was worsening of UC. Excluding discontinuations due to worsening of UC, the proportion of patients who discontinued due to adverse reactions was less than 5% in any of the XELJANZ or placebo treatment groups in these studies.

Four cases of pulmonary embolism were reported in patients taking XELJANZ 10 mg BID.

Overall, the safety profile observed in UC patients treated with XELJANZ was consistent with the safety profile of XELJANZ across indications. Dose-dependent risks seen in patients treated with XELJANZ 10 mg BID in comparison with 5 mg BID include the following: herpes zoster infections, serious infections, and NMSC.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions.  The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

Rheumatoid Arthritis

During controlled clinical trials, 8.0% (11.0 events/100 patient-years) of patients in the 5 mg BID in the XELJANZ group were hospitalized due to serious adverse reactions compared to 7.8% (9.1 events/100 patient-years) and 3.8% (13.0 events/100 patient-years) of patients in the adalimumab and placebo group, respectively.

During the first 3 months of Phase 3 studies, serious infections (those requiring parenteral antibiotics or hospitalization) were reported in 0.7% (2.8 events/100 patient-years) and 0.2% (0.6 events/100 patient-years) of patients treated with XELJANZ or placebo, respectively. From 0-12 months, serious infections were reported in 2.4% (3.2 events/100 patient-years) of XELJANZ treated patients (see 7 WARNINGS AND PRECAUTIONS). In a post-authorization safety study, the frequency of pulmonary embolism was increased in patients treated with 10 mg BID XELJANZ (1.65%) compared to the TNF inhibitor (0.21%) and 5 mg BID XELJANZ (0.62%).

Deaths occurred in 0.4% (0.6 events/100 patient-years) of patients in the 5 mg BID XELJANZ group, compared to 0.5% (0.6 events/100 patient-years) and 0.2% (0.5 events/100 patient-years) of patients in the adalimumab and placebo groups, respectively. In a post-authorization safety study, all cause mortality was increased in patients treated with 10 mg BID XELJANZ (2.7%) compared to the TNF inhibitor (1.2%) and 5 mg BID XELJANZ treatment arms (1.8%).

The proportion of patients who discontinued treatment due to any adverse reactions during the first 3 months in double-blind placebo-controlled studies was 7.8% for patients taking 5 mg BID of XELJANZ and 3.7% for placebo-treated patients. In the long-term extension trial, the proportion of patients who discontinued treatment due to any adverse reaction was 24.8% (6.78 events/100 patient-years) for all patients, 27.9% (6.67 events/100 patient-years) for patients taking 5 mg BID of XELJANZ, and 23.8% (6.83 events/100 patient-years) for patients taking 10 mg BID of tofacitinib.

Following completion of the Phase 2/3, open-label, uncontrolled, long-term extension follow-up trial (up to 114 months) from the Phase 2 studies and Phase 3 clinical program, there were 4040 subjects with 16113 patient-years of exposure to tofacitinib. 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. Tofacitinib 10 mg BID is not recommended in RA patients. Overall, the safety profile of XELJANZ 5 mg BID in the long-term extension study was comparable to what was seen in the controlled clinical trials.

Table 5 below lists the adverse events (regardless of causality) occurring in ≥1% of patients treated with XELJANZ during the double-blind, placebo-controlled portion of the phase 3 RA studies. 

Table 5: Summary of Adverse Events Reported by ≥1% of RA Patients Treated with XELJANZ (All Causalities) - All Phase 3 Studies (up to 3 months)

Body

System/Adverse Event

XELJANZ 5mg BID

N=1216 (%)

Placebo

N=681 (%)

Adalimumab

40 mg SC q2w

N=204 (%)

Blood and lymphatic system disorders

Anemia

15 (1.2)

8 (1.2)

0

Gastrointestinal disorders

Diarrhoea

45 (3.7)

16 (2.3)

2 (1.0)

Nausea

32 (2.6)

18 (2.6)

3 (1.5)

Dyspepsia

19 (1.6)

11 (1.6)

3 (1.5)

Abdominal pain upper

23 (1.9)

5 (0.7)

3 (1.5)

Vomiting

21 (1.7)

10 (1.5)

0

Constipation

16 (1.3)

6 (0.9)

2 (1.0)

Gastritis

12 (1.0)

7 (1.0)

0

Gastroenteritis

12 (1.0)

5 (0.7)

0

General disorders and administration site conditions

Oedema peripheral

17 (1.4)

16 (2.3)

3 (1.5)

Pyrexia

13 (1.1)

5 (0.7)

1 (0.5)

Infections and infestations

Upper respiratory tract infection

53 (4.4)

23 (3.4)

7 (3.4)

Nasopharyngitis

48 (3.9)

19 (2.8)

7 (3.4)

Urinary tract infection

25 (2.1)

12 (1.8)

7 (3.4)

Bronchitis

14 (1.2)

10 (1.5)

4 (2.0)

Investigations

Alanine aminotransferase increased

14 (1.2)

7 (1.0)

1 (0.5)

Metabolism and nutrition disorders

Hypercholesterolaemia

12 (1.0)

3 (0.4)

1 (0.5)

Musculoskeletal and connective tissue disorders

Rheumatoid arthritis

17 (1.4)

17 (2.5)

1 (0.5)

Back pain

18 (1.5)

5 (0.7)

1 (0.5)

Arthralgia

13 (1.1)

16 (2.3)

4 (2.0)

Nervous system disorders

Headache

54 (4.4)

15 (2.2)

5 (2.5)

Dizziness

13 (1.1)

8 (1.2)

3 (1.5)

Vascular disorders

Hypertension

20 (1.6)

7 (1.0)

0

Overall Infections

In the five controlled trials, during 0 to 3 months exposure, the overall frequency of infections was 20% in the 5 mg BID XELJANZ group, and 18% in the placebo group.

In the long-term extension trial, overall frequency of infections was 67.7% (39.63 events/100 patient-years) in all XELJANZ group; 65.5% of patients (33.22 events/100 patient-years) and 68.4% of patients (42.24 events/100 patient-years) in the 5 mg and 10 BID of tofacitinib, respectively.

Infections were also reported in a post-authorization safety study in RA patients who were 50 years or older with at least one additional cardiovascular risk factor.

The most commonly reported infections were upper respiratory tract infections, nasopharyngitis, bronchitis, herpes zoster, and urinary tract infections.

Serious Infections

In the five controlled trials, during the 0 to 3 months exposure, serious infections were reported in 1 patient (0.6 events/100 patient-years) who received placebo and 8 patients (2.8 events/100 patient-years) who received 5 mg BID of XELJANZ.

During 0 to 12 months exposure, the overall frequencies of serious infections were 2.4% (3.2 events/100 patient-years) for the 5 mg BID XELJANZ group.

In the long-term extension trial, the most common serious infections reported with XELJANZ included pneumonia, cellulitis, appendicitis, diverticulitis, gastroenteritis, urinary tract infection, and herpes zoster (see 7 WARNINGS AND PRECAUTIONS).

Serious infections were more frequently reported in subjects taking XELJANZ compared to TNF inhibitors (TNFi), and in patients treated with XELJANZ 10 mg BID compared to those treated with XELJANZ 5 mg BID in a post-authorization safety study (Study RA-VI), as shown in Table 6.

Table 6. Serious Infections in Study RA-VI

XELJANZ 5 mg BID

N = 1455

XELJANZ 10 mg BID*

N = 1456

All XELJANZ

N= 2911

TNFi

N = 1451

n (%)

141 (9.69)

169 (11.61)

310 (10.65)

119 (8.20)

IR per 100 PY (95% CI)

2.86 (2.41, 3.37)

3.64 (3.11, 4.23)

3.24 (2.89, 3.62)

2.44 (2.02, 2.92)

XELJANZ vs TNFi HR (95% CI)

1.17 (0.92, 1.50)

1.48 (1.17, 1.87)

1.32 (1.07, 1.63)

--

*
The XELJANZ 10 mg BID treatment group consists of data from patients that were switched from XELJANZ 10 mg BID to XELJANZ 5 mg BID during the trial as a result of a study modification following a recommendation by the Data and Safety Monitoring Board in February 2019.
 
Abbreviations: IR=incidence rate, CI=confidence interval, PY=patient years, HR=hazard ratio

Tuberculosis

Cases of tuberculosis have been reported with treatment with XELJANZ.

In the five controlled Phase 3 trials, during 0 to 3 months exposure, no cases of tuberculosis were reported in patients who received placebo or 5 mg BID of XELJANZ.

During 0 to 12 months of exposure, tuberculosis was reported in 0 patients who received 5 mg BID of XELJANZ. 

In the long-term extension trial, adjudicated tuberculosis events were reported in 0.6% patients (0.15 events/100 patient-years) who received XELJANZ; 0.4% of patients (0.10 events/100 patient-years) and 0.6% of patients (0.17 events/100 patient-years) in the 5 mg and 10 mg BID of tofacitinib, respectively.   

Cases of disseminated tuberculosis were also reported. The median XELJANZ exposure prior to diagnosis of tuberculosis was 10 months (range from 152 to 960 days) (see 7 WARNINGS AND PRECAUTIONS.

Opportunistic Infections (excluding tuberculosis)

In the five controlled Phase 3 trials, during 0 to 3 months exposure, opportunistic infections were reported in 0 patients who received placebo and 2 (0.2%) patients (0.7 events/100 patient-years) who received 5 mg BID of XELJANZ.

During 0 to 12 months of exposure, opportunistic infections were reported in 3 (0.3%) patients (0.3 events/100 patient-years) who received 5 mg BID of XELJANZ.

The median XELJANZ exposure prior to diagnosis of an opportunistic infection was 8 months (range from 41 to 698 days).

The similar frequency of opportunistic infections was observed in the long-term extension trial with XELJANZ treatment up to 114 months.

Malignancy (excluding non-melanoma skin cancer)

In the five Phase 3 controlled trials, during 0 to 3 months exposure, malignancies (excluding non-melanoma skin cancer) were reported in 0 patients who received placebo and 2 (0.2%) patients (0.7 events/100 patient-years) who received 5 mg BID of XELJANZ.

During 0 to 12 months of exposure, malignancies (excluding non-melanoma skin cancer) were reported in 5 (0.4%) patients (0.6 events/100 patient-years) who received 5 mg BID of XELJANZ.

In the long-term extension trial, overall frequency of malignancies (excluding non-melanoma skin cancer) was 3.1% (0.83 events/100 patient-years) in all XELJANZ-treated patients; 3.4% of patients (0.8 events/100 patient-years) and 3% of patients (0.84 events/100 patient-years) in the 5 mg and 10 mg BID of XELJANZ, respectively.

The most common types of malignancy (excluding non-melanoma skin cancer), including malignancies observed during the long-term extension, were lung and breast cancer, followed by gastric, colorectal, renal cell, prostate cancer, lymphoma and malignant melanoma (see 7 WARNINGS AND PRECAUTIONS).

In a post-authorization safety study (Study RA-VI), malignancies (excluding NMSC) were observed more frequently in patients taking XELJANZ compared with patients taking TNFi (Table 7). Frequency of lung cancer was higher in patients taking XELJANZ 10 mg BID compared with patients taking XELJANZ 5 mg BID. Thyroid cancer was observed in 5, 2, and 0 subjects taking XELJANZ 5 mg BID, taking XELJANZ 10 mg BID, and TNFi, respectively.

Table 7: Malignancies (Excluding NMSC), Lymphoma, and Lung Cancer in Study RA-VI

XELJANZ 5 mg BID

N = 1455

XELJANZ 10 mg BID*

N = 1456

All XELJANZ

N=2911

TNFi

N = 1451

Malignancies excluding NMSC

   n (%)

62 (4.26)

60 (4.12)

122 (4.19)

42 (2.89)

   IR (95% CI) per 100 PY

1.13 (0.87, 1.45)

1.13 (0.86, 1.45)

1.13 (0.94, 1.35)

0.77 (0.55, 1.04)

   XELJANZ vs TNFi HR (95% CI)

1.47 (1.00, 2.18)

1.48 (1.00, 2.19)

1.48 (1.04, 2.09)ǂ

--

Lymphoma

   n (%)

4 (0.27)

6 (0.41)

10 (0.34)

1 (0.07)

   IR (95% CI) per 100 PY

0.07 (0.02, 0.18)

0.11 (0.04, 0.24)

0.09 (0.04, 0.17)

0.02 (0.00, 0.10)

   XELJANZ vs TNFi HR (95% CI)

3.99 (0.45, 35.70)

6.24 (0.75, 51.86)

5.09 (0.65, 39.78)

--

Lung Cancer

   n (%)

13 (0.89)

17 (1.17)

30 (1.03)

7 (0.48)

   IR (95% CI) per 100 PY

0.23 (0.12, 0.40)

0.32 (0.18, 0.51)

0.28 (0.19, 0.39)

0.13 (0.05, 0.26)

   XELJANZ vs TNFi HR (95% CI)

1.84 (0.74, 4.62)

2.50 (1.04, 6.02)

2.17 (0.95, 4.93)

--

*
The XELJANZ 10 mg BID treatment group consists of data from patients that were switched from XELJANZ 10 mg BID to XELJANZ 5 mg BID during the trial as a result of a study modification following a recommendation by the Data and Safety Monitoring Board in February 2019.
ǂ
The non-inferiority criterion was not met for the primary comparison of the combined tofacitinib doses to TNFi since the upper limit of the 95% CI exceeded the pre-specified non-inferiority criterion of 1.8.
 
Abbreviations: IR=incidence rate, CI=confidence interval, PY=patient years, HR=hazard ratio

Non-Melanoma Skin Cancer

NMSC is a dose related adverse reaction, with a greater risk in patients treated with 10 mg BID of XELJANZ than in patients treated with 5 mg BID.

In the five Phase 3 controlled trials, during the 0 to 3 months exposure, NMSC was reported in 1 (0.2%) patient (0.6 events/100 patient-years) who received placebo and 2 (0.2%) patients (0.7 events/100 patient-years) who received 5 mg BID of XELJANZ.

During 0 to 12 months exposure, NMSC was reported in 3 (0.3%) patients (0.3 events/100 patient-years) who received 5 mg BID of XELJANZ.

In the long-term extension trial, overall frequency of NMSC was 2.6% (0.71 events/100 patient-years) in all XELJANZ-treated patients; 2.5% of patients (0.6 events/100 patient-years) and 2.6% of patients (0.75 events/100 patient-years) in the 5 mg and 10 mg BID of tofacitinib, respectively.

In a post-authorization safety study (Study RA-VI), NMSC, including cutaneous squamous cell carcinoma, was more frequently observed in patients taking XELJANZ compared with patients taking TNFi (Table 8).

Table 8: NMSC in Study RA-VI

XELJANZ 5 mg BID

N = 1455

XELJANZ 10 mg BID*

N = 1456

All XELJANZ

N=2911

TNFi

N = 1451

Non-melanoma Skin Cancer (NMSC)

   n (%)

31 (2.13)

33 (2.27)

64 (2.20)

16 (1.10)

   IR (95% CI) per 100 PY

0.61 (0.41, 0.86)

0.69 (0.47, 0.96)

0.64 (0.50, 0.82)

0.32 (0.18, 0.52)

   XELJANZ vs TNFi HR (95% CI)

1.90 (1.04, 3.47)

2.16 (1.19, 3.92)

2.02 (1.17, 3.50)

--

Basal Cell Carcinoma

   n (%)

19 (1.31)

16 (1.10)

35 (1.20)

13 (0.90)

   IR (95% CI) per 100 PY

0.37 (0.22, 0.58)

0.33 (0.19, 0.54)

0.35 (0.24, 0.49)

0.26 (0.14, 0.44)

   XELJANZ vs TNFi HR (95% CI)

1.43 (0.71, 2.90)

1.28 (0.61, 2.66)

1.36 (0.72, 2.56)

--

Cutaneous Squamous Cell Carcinoma

   n (%)

15 (1.03)

22 (1.51)

37 (1.27)

8 (0.55)

   IR (95% CI) per 100 PY

0.29 (0.16, 0.48)

0.45 (0.29, 0.69)

0.37 (0.26, 0.51)

0.16 (0.07, 0.31)

   XELJANZ vs TNFi HR (95% CI)

1.82 (0.77, 4.30)

2.86 (1.27, 6.43)

2.32 (1.08, 4.99)

--

*
The XELJANZ 10 mg BID treatment group consists of data from patients that were switched from XELJANZ 10 mg BID to XELJANZ 5 mg BID during the trial as a result of a study modification following a recommendation by the Data and Safety Monitoring Board in February 2019.  Abbreviations: IR=incidence rate, CI=confidence interval, PY=patient years, HR=hazard ratio

Mortality

In a post-authorization safety study (Study RA-VI), all-cause mortality was observed more frequently for patients taking XELJANZ (n=65/2911; 2.2%) compared with patients taking TNFi (n=17/1451; 1.2%). Related study data is presented in Table 9.

Table 9. Mortality in Study RA-VI
Parameter

Tofacitinib 5mg BID

N=1455

Tofacitinib 10mg BID*

N=1456

All Tofa

N=2911

TNFi

N=1451

Deaths - Total

   n (%)

26 (1.79)

39 (2.68)

65 (2.23)

17 (1.17)

   IR (95% CI) per 100 PY

0.50 (0.33, 0.74)

0.80 (0.57, 1.09)

0.65 (0.50, 0.82)

0.34 (0.20, 0.54)

   XELJANZ vs TNFi HR (95% CI)

1.49 (0.81, 2.74)

2.37 (1.34, 4.18)

1.91 (1.12, 3.27)

 

Deaths - Infections  

   n (%)

4 (0.27)

9 (0.62)

13 (0.45)

3 (0.21)

   IR (95% CI) per 100 PY

0.08 (0.02, 0.20)

0.18 (0.08, 0.35)

0.13 (0.0, 0.22)

0.06 (0.01, 0.17)

   XELJANZ vs TNFi HR (95% CI)

1.30 (0.29, 5.79)

3.10 (0.84, 11.45)

2.17 (0.62, 7.62)

 

Deaths - Cardiovascular Events

   n (%)

13 (0.89)

20 (1.37)

33 (1.13)

10 (0.69)

   IR (95% CI) per 100 PY

0.25 (0.13, 0.43)

0.41 (0.25, 0.63)

0.33 (0.23, 0.46)

0.20 (0.10, 0.36)

   XELJANZ vs TNFi HR (95% CI)

1.26 (0.55, 2.88)

2.05 (0.96, 4.39)

1.65 (0.81, 3.34)

 

Deaths - Malignancies

   n (%)

5 (0.34)

0

5 (0.17)

1 (0.07)

   IR (95% CI) per 100 PY

0.10 (0.03, 0.23)

0.00 (0.00, 0.08)

0.05 (0.02, 0.12)

0.02 (0.00, 0.11)

   XELJANZ vs TNFi HR (95% CI)

4.88 (0.57, 41.74)

0 (0.00, Inf)

2.53 (0.30, 21.64)

 

Deaths - Other Causes

   n (%)

4 (0.27)

10 (0.69)

14 (0.48)

3 (0.21)

   IR (95% CI) per 100 PY

0.08 (0.02, 0.20)

0.21 (0.10, 0.38)

0.14 (0.08, 0.23)

0.06 (0.01, 0.17)

   XELJANZ vs TNFi HR (95% CI)

1.30 (0.29, 5.81)

3.45 (0.95, 12.54)

2.34 (0.67, 8.16)

 

*
The XELJANZ 10 mg BID treatment group consists of data from patients that were switched from XELJANZ 10 mg BID to XELJANZ 5 mg BID during the trial as a result of a study modification following a recommendation by the Data and Safety Monitoring Board in February 2019.

Thromboembolism

Venous thromboembolism, including pulmonary embolism, were observed more frequently in a post-authorization safety study (Study RA-VI), as shown in Table 10. Pulmonary embolism was observed more frequently with XELJANZ 10 mg BID than XELJANZ 5 mg BID. Deep vein thrombosis, and arterial thromboembolism were also observed in the study.

Table 10: Thromboembolism Adverse Reactions in Study RA-VI

XELJANZ 5 mg BID

N = 1455

XELJANZ 10 mg BID*

N = 1456

All XELJANZ

N=2911

TNFi

N = 1451

Venous Thromboembolism**

   n(%)

17 (1.17)

34 (2.34)

51 (1.75)

10 (0.69)

   IR (95% CI) per 100 PY

0.33 (0.19, 0.53)

0.70 (0.49, 0.99)

0.51 (0.38, 0.67)

0.20 (0.10, 0.37)

   XELJANZ vs TNFi HR (95% CI)

1.66 (0.76, 3.63)

3.52 (1.74, 7.12)

2.56 (1.30, 5.05)

--

Pulmonary Embolism

   n (%)

9 (0.62)

24 (1.65)

33 (1.13)

3 (0.21)

   IR (95% CI) per 100 PY

0.17 (0.08, 0.33)

0.50 (0.32, 0.74)

0.33 (0.23, 0.46)

0.06 (0.01, 0.17)

   XELJANZ vs TNFi HR (95% CI)

2.93 (0.79, 10.83)

8.26 (2.49, 27.43)

5.53 (1.70, 18.02)

--

Deep Vein Thrombosis

   n(%)

11 (0.76)

15 (1.03)

26 (0.89)

7 (0.48)

   IR (95% CI) per 100 PY

0.21 (0.11, 0.38)

0.31 (0.17, 0.51)

0.26 (0.17, 0.38)

0.14 (0.06, 0.29)

   XELJANZ vs TNFi HR (95% CI)

1.54 (0.60, 3.97)

2.21 (0.90, 5.43)

1.87 (0.81, 4.30)

--

Arterial Thromboembolism

   n(%)

47 (3.23)

45 (3.09)

92 (3.16)

41 (2.83)

   IR (95% CI) per 100 PY

0.92 (0.68, 1.22)

0.94 (0.68, 1.25)

0.93 (0.75, 1.14)

0.82 (0.59, 1.12)

   XELJANZ vs TNFi HR (95% CI)

1.12 (0.74, 1.70)

1.14 (0.75, 1.74)

1.13 (0.78, 1.63)

--

*
The XELJANZ 10 mg BID treatment group consists of data from patients that were switched from XELJANZ 10 mg BID to XELJANZ 5 mg BID during the trial as a result of a study modification following a recommendation by the Data and Safety Monitoring Board in February 2019. Abbreviations: IR=incidence rate, CI=confidence interval, PY=patient years, HR=hazard ratio
**
Venous thromboembolism (e.g., pulmonary embolism, deep vein thrombosis, retinal venous thrombosis).

Major Adverse Cardiovascular Events (MACE), Including Myocardial Infarction

In a post-authorization study (Study RA-VI) the risk of MACE, including non-fatal myocardial infarction, was higher in patients treated with XELJANZ, compared to patients treated with TNFi (Table 11).  In the XELJANZ 5 mg BID, XELJANZ 10 mg BID, All XELJANZ, and TNFi treatment arms, there were a total of 19, 19, 38, and 11 patients with MI events, respectively. Of these totals, the number of patients with fatal MI events was 0, 3, 3, and 3, respectively, whereas the number of patients with non-fatal MI events was 19, 16, 35, and 8, respectively.

Table 11: MACE (Including Myocardial Infarction) in Study RA-VI

XELJANZ 5 mg BID

N = 1455

XELJANZ 10 mg BID*

N = 1456

All XELJANZ

N=2911

TNFi

N = 1451

Major Adverse Cardiovascular Events (MACE)α

   n (%)

47 (3.23)

51 (3.50)

98 (3.37)

37 (2.55)

   IR (95% CI) per 100 PY

0.91 (0.67, 1.21)

1.05 (0.78, 1.38)

0.98 (0.79, 1.19)

0.73 (0.52, 1.01)

   XELJANZ vs TNFi HR (95% CI)

1.24 (0.81, 1.91)

1.43 (0.94, 2.18)

1.33 (0.91, 1.94)ǂ

--

Non-fatal Myocardial Infarction

   n (%)

19 (1.31)

16 (1.10)

35 (1.20)

8 (0.55)

   IR (95% CI) per 100 PY

0.37 (0.22, 0.57)

0.33 (0.19, 0.53)

0.35 (0.24, 0.48)

0.16 (0.07, 0.31)

   XELJANZ vs TNFi HR (95% CI)

2.32 (1.02, 5.30)

2.08 (0.89, 4.86)

2.20 (1.02, 4.75)

--

*
The XELJANZ 10 mg BID treatment group consists of data from patients that were switched from XELJANZ 10 mg BID to XELJANZ 5 mg BID during the trial as a result of a study modification following a recommendation by the Data and Safety Monitoring Board in February 2019.
ǂ
The non-inferiority criterion was not met for the primary comparison of the combined tofacitinib doses to TNFi since the upper limit of the 95% CI exceeded the pre-specified non-inferiority criterion of 1.8.
α
MACE includes nonfatal myocardial infarction, nonfatal stroke, and cardiovascular deaths excluding pulmonary embolism.
 
Abbreviations: IR=incidence rate, CI=confidence interval, PY=patient years, HR=hazard ratio

Gastrointestinal Perforations

In a post-authorization study (Study RA-VI), gastrointestinal perforations were observed in subjects treated with XELJANZ 5 mg BID, XELJANZ 10 mg BID, and TNF inhibitors (Table 12).

Table 12: Gastrointestinal Perforations in Study RA-VI

XELJANZ 5 mg BID

N = 1455

XELJANZ 10 mg BID*

N = 1456

All XELJANZ

N=2911

TNFi

N = 1451

n(%)

9 (0.62)

5 (0.34)

14 (0.48)

4 (0.28)

IR (95% CI) per 100 PY

0.17 (0.08, 0.33)

0.10 (0.03, 0.24)

0.14 (0.08, 0.23)

0.08 (0.02, 0.20)

XELJANZ vs TNFi HR (95% CI)

2.20 (0.68, 7.15)

1.29 (0.35, 4.80)

1.76 (0.58, 5.34)

--

*
The XELJANZ 10 mg BID treatment group consists of data from patients that were switched from XELJANZ 10 mg BID to XELJANZ 5 mg BID during the trial as a result of a study modification following a recommendation by the Data and Safety Monitoring Board in February 2019. Abbreviations: IR=incidence rate, CI=confidence interval, PY=patient years, HR=hazard ratio

Fractures

In a post-authorization study (Study RA-VI) the incidence rate (IR) (95% CI) for fractures was 2.79 (95%CI: 2.34-3.30) for XELJANZ 5 mg BID, and 2.87 (95% CI: 2.40-3.40) for XELJANZ 10 mg BID, compared to 2.27 (95% CI: 1.87-2.74) for TNF inhibitors.

Psoriatic Arthritis

A total of 783 patients were treated with any dose of XELJANZ in PsA clinical studies resulting in 1238 patient-years of exposure. Of these, 635 patients were exposed to XELJANZ for at least one year.

The most common serious adverse reactions were serious infections. The most commonly reported adverse reactions (≥2%) in patients treated with XELJANZ 5 mg BID during the first 3 months in placebo‑controlled clinical studies were bronchitis, diarrhea, dyspepsia, headache, nasopharyingitis, nausea.

The proportion of patients who discontinued treatment due to any adverse reactions during the first 3‑months of the double-blind placebo‑controlled studies was 3.2% for XELJANZ‑treated patients and 2.5% for placebo-treated patients.

Overall, the safety profile observed in patients with active PsA treated with XELJANZ was consistent with the safety profile observed in patients with RA treated with XELJANZ. Incidence rates and types of adverse drug reactions, overall infections, serious infections, opportunistic infections in the two controlled Phase 3 PsA clinical studies were generally similar to those reported in RA Phase 3 clinical studies. The incidence rates of tuberculosis, malignancies (excluding NMSC), and NMSC in the two controlled Phase 3 PsA clinical studies were generally similar to those reported in RA Phase 3 clinical studies. 

Ankylosing Spondylitis

In the safety population of the combined Phase 2 and the Phase 3 clinical trials, a total of 420 patients were treated with study-specified dose XELJANZ corresponding to 233 patient-years of experience. Of these, 108 patients received XELJANZ 5 mg twice daily for 12 months or longer. Concomitant treatment with stable doses of cDMARDs, NSAIDs, or corticosteroids (≤10 mg/day) was permitted. The study population treated with XELJANZ included 13 (3.1%) patients aged 65 years or older and 18 (4.3%) patients with diabetes at baseline.

The safety profile observed in patients with AS treated with XELJANZ was consistent with the safety profile observed in RA and PsA patients. The incidence rates and types of adverse drug reactions, overall infections, and serious infections reported in the controlled Phase 3 AS clinical study were similar to those reported in RA Phase 3 clinical studies. During the 16-week placebo-controlled period in study AS-I, the frequency of increased transaminases was 4.3% with XELJANZ 5 mg and 1.07% with placebo.

Ulcerative Colitis

Table 13 below lists adverse drug reactions reported by ≥1% of patients treated with XELJANZ – UC Phase 2 and Phase 3 Induction Studies

Table 13: Summary of Adverse Drug Reactions (adverse events for which there is evidence of causality) Reported by ≥1% of Patients Treated with XELJANZ – UC Phase 2 and Phase 3 Induction Studies (up to 8 weeks)

Body

System±/Adverse

Drug Reaction

XELJANZ 10 mg BID

N=938 (%)

Placebo

N=282 (%)

Subjects with one or more ADR

494 (52.7)

130 (46.1)

Blood and lymphatic system disorders

26 (2.8)

10 (3.5)

Anemia

22 (2.3)

9 (3.2)

Gastrointestinal disorders

82 (8.7)

26 (9.2)

Nausea

28 (3.0)

11 (3.9)

Abdominal pain 

25 (2.7)

11 (3.9)

Vomiting

9 (1.0)

3 (1.1)

Dyspepsia

12 (1.3)

1(0.4)

General disorders and administration site conditions

48 (5.1)

13 (4.6)

Fatigue

17 (1.8)

5 (1.8)

Pyrexia

24 (2.6)

4 (1.4)

Infections and infestations

111 (11.8)

24 (8.5)

Nasopharyngitis

56 (6.0)

14 (5.0)

Influenza

9 (1.0)

3 (1.1)

Urinary tract infection

11 (1.2)

1 (0.4)

Pharyngitis 

10 (1.1)

1 (0.4)

Investigations

65 (6.9)

4 (1.4)

Blood creatine phosphokinase increased

25 (2.7)

3 (1.1)

Elevated cholesterol levels*

 31 (3.3)

0

Musculoskeletal and connective tissue disorders

33 (3.5)

12 (4.3)

Arthralgia

 27 (2.9)

12 (4.3)

Nervous system disorders

77 (8.2)

20 (7.1)

Headache

73 (7.8)

19 (6.7)

Respiratory

14 (1.5)

8 (2.8)

Cough

 13 (1.4)

7 (2.5)

Skin and Subcutaneous Tissue Disorders

18 (1.9)

9 (3.2)

Rash

12 (1.3)

  2 (0.7)

Vascular disorders

9 (1.0)

1 (0.4)

Hypertension

9 (1.0)

1 (0.4)

*
includes: hypercholesterolemia, hyperlipidemia, blood cholesterol increased, dyslipidemia, blood triglycerides increased, low density lipoprotein increased, low density lipoprotein abnormal, or lipids increased.
±
the total number of subjects with adverse reactions and the total number of subjects with adverse reactions for each body system include all adverse drug reactions (those reported by ≥1% of subjects treated with XELJANZ and those reported by
Table 14: Summary of Adverse Drug Reactions (adverse events for which there is evidence of causality) Reported by ≥1% of Patients Treated with XELJANZ – UC Phase 3 Maintenance Study (up to 12 months)

Body

System±/Adverse Drug Reaction

XELJANZ 5mg BID

N=198 (%)

XELJANZ 10mg BID

N=196 (%)

Placebo

N=198 (%)

 Subjects with one or more ADR (%)

 

166 (83.8)

 

207 (100)

 

153 (77.3)

Blood and lymphatic system disorders

9 (4.5)

5 (2.6)

3 (1.5)

Anemia

8(4.0)

4 (2.0)

3 (1.5)

Gastrointestinal disorders

16 (8.1)

32 (16.3)

26 (13.1)

Diarrhea

3 (1.5)

 9 (4.6)

5 (2.5)

Nausea

1 (0.5)

8 (4.1)

5 (2.5)

Abdominal pain 

5 (2.5)

7 (3.6)

11 (5.6)

Vomiting

3 (1.5)

6 (3.1)

2 (1.0)

Dyspepsia

4 (2.0)

1 (0.5)

 2 (1.0)

General disorders and administration site conditions

12 (6.1)

11 (5.6)

17 (8.6)

Fatigue

8 (4.0)

4 (2.0)

11 (5.6)

Pyrexia

3 (1.5)

6 (3.1)

5 (2.5)

Infections and infestations

51 (25.8)

65 (33.2)

37 (18.7)

Nasopharyngitis

19 (9.6)

27 (13. 8)

11 (5.6)

Herpes zoster

3 (1.5)

 10 (5.1)

 1 (0.5)

Influenza

4 (2.0)

7 (3.6)

7 (3.5)

Urinary tract infection

 5 (2.5)

6 (3.1)

4 (2.0)

Bronchitis

 5 (2.5)

6 (3.1)

3 (1.5)

Sinusitis

6 (3.0)

2 (1.0)

2 (1.0)

Pharyngitis 

6 (3.0)

1 (0.5)

3 (1.5)

Gastroenteritis viral

0

3 (1.5)

2 (1.0)

Viral infection

2 (1.0)

1 (0.5)

1 (0.5)

Injury, poisoning and procedural complications

2 (1.0)

2 (1.0)

0

Ligament sprain

1 (0.5)

2 (1.0)

0

Investigations

19 (9.6)

38 (19.4)  

7 (3.5) 

Elevated cholesterol levels*

9 (4.5)

18 (9.2)

3 (1.5)

Blood creatine phosphokinase increased

6 (3.0)

13 (6.6)

4 (2.0)

Weight increased

3 (1.5)

4 (2.0)

0

Gamma glutamyltransferase increased,

1 (0.5)

3 (1.5)

0

Musculoskeletal and connective tissue disorders

19 (9.6)

19 (9.7)

25 (12.6)

Arthralgia

17 (8.6)

17 (8.7)

19 (9.6)

Musculoskeletal pain

1 (0.5)

2 (1.0)

5 (2.5)

Neoplasms benign, malignant and unspecified (including cysts and polyps)

0

2 (1.0)

1 (0.5)

Non-melanoma skin cancers

0

2 (1.0)

1 (0.5)

Nervous system disorders 

18 (9.1)

7 (3.6)

12 (6.1)

Headache

 17 (8.6)

6 (3.1)

12 (6.1)

Psychiatric 

3 (1.5) 

1 (0.5)

1 (0.5)

Insomnia

3 (1.5)

1 (0.5)

1 (0.5)

Respiratory

6 (3.0)

8 (4.1)

6 (3.0)

Cough

6 (3.0)

5 (2.6)

5 (2.5)

Dyspnea

0

2 (1.0)

1 (0.5)

Skin and Subcutaneous Tissue Disorders 

7 (3.5)

12 (6.1) 

17 (8.6)

Rash

6 (3.0)

11 (5.6)

8 (4.0)

Vascular disorders

4 (2.0) 

4 (2.0)

1 (0.5)

Hypertension

4 (2.0)

4 (2.0)

1 (0.5)

*
includes: hypercholesterolemia, hyperlipidemia, blood cholesterol increased, dyslipidemia, blood triglycerides increased, low density lipoprotein increased, low density lipoprotein abnormal, or lipids increased.
±
The total number of subjects with adverse reactions and the total number of subjects with adverse reactions for each body system include all adverse drug reactions (those reported by ≥1% of subjects treated with XELJANZ and those reported by

Overall Infections

In the randomised 8-week Phase 2/3 induction studies, the proportions of patients with infections were 21.1% (198 patients) in the XELJANZ 10 mg BID group compared to 15.2% (43 patients) in the placebo group. In the randomised 52-week Phase 3 maintenance study, the proportion of patients with infections were 35.9% (71 patients) in the 5 mg BID and 39.8% (78 patients) in the 10 mg BID XELJANZ groups, compared to 24.2% (48 patients) in the placebo group.

In the maintenance study, results suggested that the risk of opportunistic infection was possibly dose related: XELJANZ 10 mg BID (2.0%), XELJANZ 5 mg BID (1.0%), and placebo (0.5%). All opportunistic infections were herpes zoster infections. Herpes zoster was reported more frequently with XELJANZ 10 mg BID (5.1%), as compared to XELJANZ 5 mg BID (1.5%), or placebo (0.5%), indicating that the risk of herpes zoster is dose related.

In the entire treatment experience with XELJANZ, the most commonly reported infection was nasopharyngitis, occurring in 18.2% of patients (211 patients). 

Serious Infections

The incidence rates and types of serious infections in the UC clinical trials were generally similar to those reported in RA Phase 3 clinical trials with XELJANZ.

Patients treated with XELJANZ 10 mg BID had a higher rate of serious infections compared to those treated with 5 mg BID. 

Opportunistic infections (excluding tuberculosis)

In the maintenance study, herpes zoster was reported more frequently with XELJANZ 10 mg BID (5.1%), as compared to XELJANZ 5 mg BID (1.5%), or placebo (0.5%), indicating that the risk of herpes zoster is dose related.

Also, opportunistic herpes zoster infections (including serious cases, such as, disseminated, meningoencephalitis, ophthalmologic) were reported in patients treated with XELJANZ 10 mg BID. 

Malignancies (excluding NMSC)

In the controlled clinical studies (up to 52-week treatment), no malignancies (excluding NMSC) were reported with XELJANZ.

In the long-term extension open-label study, malignancies (excluding NMSC) have been observed in patients treated with XELJANZ 10 mg BID, including solid cancers and lymphoma. 

8.3 Less Common Clinical Trial Adverse Reactions

Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis

Blood and Lymphatic System Disorders: leukopenia, lymphopenia, neutropenia

Cardiovascular: congestive heart failure, myocardial infarction

Gastrointestinal Disorders: abdominal pain, appendicitis, gastrointestinal perforation

General Disorders and Administration Site Conditions: influenza

Hepatobiliary Disorders: hepatic steatosis

Infections and Infestations:  atypical mycobacterial infection, arthritis bacterial, bacteraemia, cellulitis, cytomegalovirus infection, disseminated tuberculosis, diverticulitis, encephalitis, gastroenteritis viral, herpes simplex, herpes zoster, meningitis cryptococcal, mycobacterium avium complex infection, necrotising fasciitis, pneumonia bacterial, pneumonia pneumococcal, pneumocystis jiroveci pneumonia, pyelonephritis, sepsis, staphylococcal bacteraemia, tuberculosis, tuberculosis of central nervous system, urosepsis, viral infection.

Injury, Poisoning and Procedural Complications: muscle strain, fall

Investigations: blood cholesterol increased, blood creatinine increased, blood creatine phosphokinase increased, gamma glutamyltransferase increased, hepatic enzyme increased, liver function test abnormal, low density lipoprotein increased, transaminases increased, weight increased,

Metabolism and Nutrition Disorders: dehydration, dyslipidemia, hyperlipidemia

Musculoskeletal and Connective Tissue Disorders: joint swelling, ligament sprain, musculoskeletal pain, tendonitis,

Neoplasm Benign, Malignant and Unspecified (Including Cysts and Polyps): lymphoma, non-melanoma skin cancers, solid tumours  

Nervous System Disorders: paraesthesia

Psychiatric Disorders: insomnia

Respiratory, Thoracic and Mediastinal Disorders: cough, dyspnoea, sinus congestion,  

Skin and Subcutaneous Tissue Disorders: erythema, pruritus

Vascular disorders: arterial thrombosis, deep vein thrombosis, pulmonary embolism. 

 

Ulcerative Colitis

Blood and Lymphatic System Disorders: neutropenia, lymphopenia, leukopenia

Gastrointestinal Disorders: gastritis

General Disorders and Administration Site Conditions: oedema peripheral

Hepatobiliary Disorders: hepatic steatosis

Infections and Infestations: pneumonia, pyelonephritis, cellulitis, herpes simplex, tuberculosis, arthritis bacterial, cytomegalovirus infection, diverticulitis

Injury, Poisoning and Procedural Complications: muscle strain

Investigations: hepatic enzyme increased, transaminases increased, blood creatinine increased, liver function test abnormal, low density lipoprotein increased

Metabolism and Nutrition Disorders: dehydration

Musculoskeletal and Connective Tissue Disorders: tendonitis, joint swelling

Neoplasm Benign, Malignant and Unspecified (Including Cysts and Polyps): non-melanoma skin cancers, solid cancers, lymphomas  

Nervous System Disorders: paraesthesia

Respiratory, Thoracic and Mediastinal Disorders: sinus congestion

Skin and Subcutaneous Tissue Disorders: erythema, pruritus

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Clinical Trial Findings

Laboratory Tests – Rheumatoid Arthritis and Ulcerative Colitis

Creatine Kinase

Treatment with XELJANZ was associated with increases in creatine kinase (CK). Maximum effects were generally observed within 6 months. Rhabdomyolysis was reported in one patient treated with XELJANZ.

CK levels should be checked in patients with symptoms of muscle weakness and/or muscle pain to evaluate for evidence of rhabdomyolysis (see 7 WARNINGS AND PRECAUTIONS)

ECG Findings

In placebo-controlled Phase 2 clinical trials, steady-state treatment with 5-10 mg BID XELJANZ was associated with statistically significant 4-7 bpm decreases in heart rate and 4-10 ms increases in the PR interval compared with placebo (see 7WARNINGS AND PRECAUTIONS and 9 DRUG INTERACTIONS).

Lipids

Treatment with XELJANZ was associated with dose related increases in lipid parameters.

Elevations in lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) generally reached maximal effects at 6 weeks following initiation of XELJANZ in the controlled RA double-blind clinical trials. Changes in lipid parameters from baseline through the end of the study (6-12 months) in the controlled clinical studies in RA are summarized below:

  • Mean LDL cholesterol increased by 14% in the XELJANZ 5 mg BID arm.
  • Mean HDL cholesterol increased by 16% in the XELJANZ 5 mg BID arm.
  • Mean LDL/HDL ratios were essentially unchanged in XELJANZ-treated patients.

In the five controlled RA clinical trials, 4.4% of patients treated with 5 mg BID, initiated lipid-lowering medication while on study.  

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

Increases of total cholesterol, LDL cholesterol, and HDL cholesterol were also reported in a post-authorization safety (Study RA-VI; Table 15). 

Table 15: Mean percent increase of cholesterol (Study RA-VI)
XELJANZ 5 mg BID XELJANZ 10 mg BID* TNFi

LDL, mean percent increase

12 months

13.80

17.04

5.50

24 months

12.71

18.14

3.64

HDL, mean percent increase

12 months

11.71

13.63

2.82

24 months

11.58

13.54

1.42

*
The XELJANZ 10 mg BID treatment group consists of data from patients that were switched from XELJANZ 10 mg BID to XELJANZ 5 mg BID during the trial as a result of a study modification following a recommendation by the Data and Safety Monitoring Board in February 2019.

Liver Enzyme Tests

Confirmed increases in liver enzymes >3x upper limit of normal (ULN) were uncommonly observed. In those 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 dose, resulted in decrease or normalization of liver enzymes.

In the controlled portion of the RA Phase 3 monotherapy study (0-3 months), ALT elevations >3x ULN were observed in 1.65% and 0.41% of patients receiving placebo and 5 mg BID, respectively. In this study, AST elevations >3x ULN were observed in 1.65%, and 0.41% of patients receiving placebo and 5 mg BID, respectively.

In the controlled portion of the RA Phase 3 studies on background DMARDs (0-3 months), ALT elevations >3x ULN were observed in 0.9% and 1.24% of patients receiving placebo and 5 mg BID, respectively. In these studies, AST elevations >3x ULN were observed in 0.72% and 0.52% of patients receiving placebo and 5 mg BID, respectively.

In the RA long-term extension trial, ALT and AST elevations greater than 3x ULN were observed in 2.2% and 1.1% of all XELJANZ-treated patients, respectively. Overall, total bilirubin elevations greater than 2x ULN were observed in 3 (0.1%) patients. Increases to ≥5x and ≥10x ULN were observed for both ALT (0.5% and 0.2% of patients, respectively) and AST (0.3% and 0.1% of patients, respectively) in all patients treated with XELJANZ.

In RA patients taking 5 mg BID of XELJANZ, the ALT and AST elevations greater than 3x ULN were observed in 2.4% and 1.3% of patients, respectively. There was no subject who had the total bilirubin elevations greater than 2x ULN. Increases to ≥5 and ≥10x ULN were observed for both ALT (0.4% and 0.1% of patients, respectively) and AST (0.2% and 0% of patients, respectively).

In RA patients taking 10 mg BID of tofacitinib, the ALT and AST elevations greater than 3x ULN were observed in 2.1% and 1.1% of patients, respectively. The total bilirubin elevations greater than 2x ULN were observed in 3 (0.1%) patients. Increases to ≥5 and ≥10x ULN were observed for both ALT (0.5% and 0.2% of patients, respectively) and AST (0.3% and 0.1% of patients, respectively).

Two patients treated with 10 mg BID of tofacitinib in the RA long-term extension trial were assessed as probable DILI by the adjudication committee. One of the two patients had other possible causes of alcohol intake and methotrexate.

Elevations of ALT and AST were reported more frequently in patients taking XELJANZ compared with patients taking TNFi in a post-authorization safety study (Study RA-VI; Table 16).

Table 16: Percentage of patients with at least one post-baseline elevation of liver enzymes (Study RA-VI)
XELJANZ 5 mg BID XELJANZ 10 mg BID*

All XELJANZ

TNFi

ALT elevation, percentage of patients

> 1 x ULN

52.83

54.46

53.64

43.33

> 3 x ULN

6.01

6.51

6.27

3.77

> 5 x ULN

1.68

1.97

1.82

1.12

AST elevation, percentage of patients

> 1 x ULN

45.84

51.58

48.70

37.18

> 3 x ULN

3.21

4.57

3.89

2.38

> 5 x ULN

0.98

1.62

1.30

0.70

*
The XELJANZ 10 mg BID treatment group consists of data from patients that were switched from XELJANZ 10 mg BID to XELJANZ 5 mg BID during the trial as a result of a study modification following a recommendation by the Data and Safety Monitoring Board in February 2019.

In the clinical studies in UC, changes in liver enzyme tests observed with XELJANZ 5 mg BID treatment were similar to the changes observed in clinical studies in RA.

In UC patients, XELJANZ treatment with 5 and 10 mg BID was also associated with an increased incidence of liver enzyme elevation compared to placebo, with a trend for higher incidence with the 10 mg BID as compared to the 5 mg BID dose.

One patient with XELJANZ 10 mg BID in the maintenance UC study experienced an increase in liver enzymes which decreased upon discontinuation of treatment. The case was adjudicated as possible DILI, while noting ultrasound findings of fatty liver. 

Lymphocytes

In the five controlled RA clinical trials, confirmed decreases in absolute lymphocyte counts below 0.5 x109 cells/L occurred in 0.2% of patients for the 5 mg BID XELJANZ group during 12 months of exposure.

Confirmed lymphocyte counts less than 0.5 x109 cells/L were associated with an increased incidence of treated and serious infections (see 7 WARNINGS AND PRECAUTIONS).

In the RA long-term extension trial, cases of lymphopenia have been reported in 181 (4.0%) patients (1.11 events/100 patient-years) treated with XELJANZ; 4.5% of patients (1.07 events/100 patient-years) and 3.9% of patients (1.12 events/100 patient-years) in the 5 mg and 10 mg BID of tofacitinib, respectively. Confirmed decreased in absolute lymphocyte counts below 0.5 x109 cells/L occurred in 1.3% of all XELJANZ-treated patients; 1.1% of patients for the 5 mg BID XELJANZ group, and 1.4% of patients for the 10 mg BID tofacitinib group.

In a post-authorization safety study (Study RA-VI) the median decrease in lymphocyte counts were greater in patients taking XELJANZ (-0.21) compared with patients taking TNFi (0.37).

In the 52-week maintenance study in UC, a single absolute lymphocyte count below 0.5 x109 cells/L was reported in 2.6% (n=5) of patients treated with 10 mg BID, and was not reported in patients treated with 5 mg BID or placebo. No patients in any treatment group had confirmation of a lymphocyte count below 0.5 x109 cells/L based on two sequential tests.

Neutrophils

In the controlled RA clinical studies, confirmed decreases in ANC below 1x109 cells/L occurred in 0.08% of patients in the 5 mg BID XELJANZ group during 12 months of exposure. There were no confirmed decreases in ANC below 0.5 x109 cells/L observed in any treatment group.

There was no clear relationship between neutropenia and the occurrence of serious infections.

In the long-term extension trial, cases of neutropenia have been reported in 86 (1.9%) patients (0.52 events/100 patient-years) treated with XELJANZ; 4.0% of patients (0.97 events/100 patient-years) and 1.2% of patients (0.35 events/100 patient-years) in the 5 mg and 10 mg BID of tofacitinib, respectively. Confirmed decreased in ANC below 1x109 cells/L occurred in 0.2% in all XELJANZ-treated patients; 0.4% of patients for the 5 mg BID XELJANZ group, and 0.1% of patients for the 10 mg BID tofacitinib group. 

In the clinical studies in UC, changes in neutrophils observed with XELJANZ treatment were similar to the changes observed in clinical studies in RA.

Serum Creatinine

In the controlled RA clinical trials, dose-related elevations in serum creatinine were observed with XELJANZ treatment. The mean increase in serum creatinine was

In the UC studies, an increase of more than 50% in serum creatinine was reported in 1.6% of patients predominantly treated with XELJANZ 5 mg BID, and 3.4% of those predominantly treated with XELJANZ 10 mg BID.  

Laboratory Tests – Psoriatic Arthritis

In the controlled clinical trials in PsA, changes in hematologic and clinical chemistry findings observed with XELJANZ treatment were similar to the changes observed in Phase 3 clinical trials in RA. 

Laboratory Tests - Ankylosing Spondylitis

In the controlled clinical trials in AS, changes in hematologic and clinical chemistry findings observed with XELJANZ treatment were similar to the changes observed in Phase 3 clinical trials in RA.

8.5 Post-Market Adverse Reactions

Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune system disorders: drug hypersensitivity reactions including angioedema and urticaria (see 2 CONTRAINDICATIONS and 7 WARNINGS AND PRECAUTIONS)

Serious infections: viral reactivation (hepatitis B reactivation) (see 7 WARNINGS AND PRECAUTIONS)

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8 Adverse Reactions

8.1 Adverse Reaction Overview

Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis

The most common serious adverse reactions (SAEs) in rheumatoid arthritis clinical trials were osteoarthritis and serious infections, including pneumonia, cellulitis, herpes zoster, and urinary tract infection.

The most commonly reported adverse reactions during the first 3 months in controlled clinical trials in rheumatoid arthritis clinical trials (occurring in ≥2% of patients treated with XELJANZ monotherapy or in combination with DMARDs) were upper respiratory tract infections, headache, nasopharyngitis, and diarrhea. Additionally, bronchitis, urinary tract infection, herpes zoster, RA, back pain and hypertension were also reported in the 5 mg BID XELJANZ group in the long-term extension trial.

The most common adverse reactions in rheumatoid arthritis clinical trials that resulted in discontinuation of XELJANZ were infections. Pneumonia was the most common adverse reactions leading to discontinuation of therapy, followed by blood creatinine increased and herpes zoster.

Asian patients had higher rates of herpes zoster, opportunistic infections, elevated transaminases (ALT, AST) and decreased WBCs. Asian patients with RA also have an increased risk of ILD (see 7.1.5 Asian Patients). Therefore, XELJANZ/XELJANZ XR should be used with caution in Asian patients.

Ulcerative Colitis

In the induction studies, the most common categories of serious adverse events were gastrointestinal disorders and infections. The most common serious adverse events (excluding events reported as UC) were abdominal pain, anal abscess, and drug hypersensitivity. The most common adverse events (≥5%) were headache and nasopharyngitis.

In the maintenance study, the most common categories of serious adverse events were gastrointestinal disorders, infections, injuries, and nervous system disorders. All serious adverse events were single reports (excluding events reported as UC). The most common adverse events (≥5%) (excluding events reported as UC) in patients treated with 5 mg BID were nasopharyngitis, arthralgia, headache, and upper respiratory tract infection. In patients treated with 10 mg BID, the most common adverse events were nasopharyngitis, arthralgia, blood creatine phosphokinase increased, upper respiratory tract infection, rash, hypercholesterolemia, and herpes zoster.

In induction studies, adverse events were reported in 515 subjects (54.9%) treated with 10 mg BID and 155 subjects (55.0%) treated with placebo. In the maintenance study, adverse events were reported in 143 subjects (72.2%) treated with 5 mg BID, 156 subjects (79.6%) treated with 10 mg BID, and 149 subjects (75.3%) treated with placebo.

In induction and maintenance studies, the most frequent reason for study discontinuation was worsening of UC. Excluding discontinuations due to worsening of UC, the proportion of patients who discontinued due to adverse reactions was less than 5% in any of the XELJANZ or placebo treatment groups in these studies.

Four cases of pulmonary embolism were reported in patients taking XELJANZ 10 mg BID.

Overall, the safety profile observed in UC patients treated with XELJANZ was consistent with the safety profile of XELJANZ across indications. Dose-dependent risks seen in patients treated with XELJANZ 10 mg BID in comparison with 5 mg BID include the following: herpes zoster infections, serious infections, and NMSC.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions.  The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

Rheumatoid Arthritis

During controlled clinical trials, 8.0% (11.0 events/100 patient-years) of patients in the 5 mg BID in the XELJANZ group were hospitalized due to serious adverse reactions compared to 7.8% (9.1 events/100 patient-years) and 3.8% (13.0 events/100 patient-years) of patients in the adalimumab and placebo group, respectively.

During the first 3 months of Phase 3 studies, serious infections (those requiring parenteral antibiotics or hospitalization) were reported in 0.7% (2.8 events/100 patient-years) and 0.2% (0.6 events/100 patient-years) of patients treated with XELJANZ or placebo, respectively. From 0-12 months, serious infections were reported in 2.4% (3.2 events/100 patient-years) of XELJANZ treated patients (see 7 WARNINGS AND PRECAUTIONS). In a post-authorization safety study, the frequency of pulmonary embolism was increased in patients treated with 10 mg BID XELJANZ (1.65%) compared to the TNF inhibitor (0.21%) and 5 mg BID XELJANZ (0.62%).

Deaths occurred in 0.4% (0.6 events/100 patient-years) of patients in the 5 mg BID XELJANZ group, compared to 0.5% (0.6 events/100 patient-years) and 0.2% (0.5 events/100 patient-years) of patients in the adalimumab and placebo groups, respectively. In a post-authorization safety study, all cause mortality was increased in patients treated with 10 mg BID XELJANZ (2.7%) compared to the TNF inhibitor (1.2%) and 5 mg BID XELJANZ treatment arms (1.8%).

The proportion of patients who discontinued treatment due to any adverse reactions during the first 3 months in double-blind placebo-controlled studies was 7.8% for patients taking 5 mg BID of XELJANZ and 3.7% for placebo-treated patients. In the long-term extension trial, the proportion of patients who discontinued treatment due to any adverse reaction was 24.8% (6.78 events/100 patient-years) for all patients, 27.9% (6.67 events/100 patient-years) for patients taking 5 mg BID of XELJANZ, and 23.8% (6.83 events/100 patient-years) for patients taking 10 mg BID of tofacitinib.

Following completion of the Phase 2/3, open-label, uncontrolled, long-term extension follow-up trial (up to 114 months) from the Phase 2 studies and Phase 3 clinical program, there were 4040 subjects with 16113 patient-years of exposure to tofacitinib. 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. Tofacitinib 10 mg BID is not recommended in RA patients. Overall, the safety profile of XELJANZ 5 mg BID in the long-term extension study was comparable to what was seen in the controlled clinical trials.

Table 5 below lists the adverse events (regardless of causality) occurring in ≥1% of patients treated with XELJANZ during the double-blind, placebo-controlled portion of the phase 3 RA studies. 

Table 5: Summary of Adverse Events Reported by ≥1% of RA Patients Treated with XELJANZ (All Causalities) - All Phase 3 Studies (up to 3 months)

Body

System/Adverse Event

XELJANZ 5mg BID

N=1216 (%)

Placebo

N=681 (%)

Adalimumab

40 mg SC q2w

N=204 (%)

Blood and lymphatic system disorders

Anemia

15 (1.2)

8 (1.2)

0

Gastrointestinal disorders

Diarrhoea

45 (3.7)

16 (2.3)

2 (1.0)

Nausea

32 (2.6)

18 (2.6)

3 (1.5)

Dyspepsia

19 (1.6)

11 (1.6)

3 (1.5)

Abdominal pain upper

23 (1.9)

5 (0.7)

3 (1.5)

Vomiting

21 (1.7)

10 (1.5)

0

Constipation

16 (1.3)

6 (0.9)

2 (1.0)

Gastritis

12 (1.0)

7 (1.0)

0

Gastroenteritis

12 (1.0)

5 (0.7)

0

General disorders and administration site conditions

Oedema peripheral

17 (1.4)

16 (2.3)

3 (1.5)

Pyrexia

13 (1.1)

5 (0.7)

1 (0.5)

Infections and infestations

Upper respiratory tract infection

53 (4.4)

23 (3.4)

7 (3.4)

Nasopharyngitis

48 (3.9)

19 (2.8)

7 (3.4)

Urinary tract infection

25 (2.1)

12 (1.8)

7 (3.4)

Bronchitis

14 (1.2)

10 (1.5)

4 (2.0)

Investigations

Alanine aminotransferase increased

14 (1.2)

7 (1.0)

1 (0.5)

Metabolism and nutrition disorders

Hypercholesterolaemia

12 (1.0)

3 (0.4)

1 (0.5)

Musculoskeletal and connective tissue disorders

Rheumatoid arthritis

17 (1.4)

17 (2.5)

1 (0.5)

Back pain

18 (1.5)

5 (0.7)

1 (0.5)

Arthralgia

13 (1.1)

16 (2.3)

4 (2.0)

Nervous system disorders

Headache

54 (4.4)

15 (2.2)

5 (2.5)

Dizziness

13 (1.1)

8 (1.2)

3 (1.5)

Vascular disorders

Hypertension

20 (1.6)

7 (1.0)

0

Overall Infections

In the five controlled trials, during 0 to 3 months exposure, the overall frequency of infections was 20% in the 5 mg BID XELJANZ group, and 18% in the placebo group.

In the long-term extension trial, overall frequency of infections was 67.7% (39.63 events/100 patient-years) in all XELJANZ group; 65.5% of patients (33.22 events/100 patient-years) and 68.4% of patients (42.24 events/100 patient-years) in the 5 mg and 10 BID of tofacitinib, respectively.

Infections were also reported in a post-authorization safety study in RA patients who were 50 years or older with at least one additional cardiovascular risk factor.

The most commonly reported infections were upper respiratory tract infections, nasopharyngitis, bronchitis, herpes zoster, and urinary tract infections.

Serious Infections

In the five controlled trials, during the 0 to 3 months exposure, serious infections were reported in 1 patient (0.6 events/100 patient-years) who received placebo and 8 patients (2.8 events/100 patient-years) who received 5 mg BID of XELJANZ.

During 0 to 12 months exposure, the overall frequencies of serious infections were 2.4% (3.2 events/100 patient-years) for the 5 mg BID XELJANZ group.

In the long-term extension trial, the most common serious infections reported with XELJANZ included pneumonia, cellulitis, appendicitis, diverticulitis, gastroenteritis, urinary tract infection, and herpes zoster (see 7 WARNINGS AND PRECAUTIONS).

Serious infections were more frequently reported in subjects taking XELJANZ compared to TNF inhibitors (TNFi), and in patients treated with XELJANZ 10 mg BID compared to those treated with XELJANZ 5 mg BID in a post-authorization safety study (Study RA-VI), as shown in Table 6.

Table 6. Serious Infections in Study RA-VI

XELJANZ 5 mg BID

N = 1455

XELJANZ 10 mg BID*

N = 1456

All XELJANZ

N= 2911

TNFi

N = 1451

n (%)

141 (9.69)

169 (11.61)

310 (10.65)

119 (8.20)

IR per 100 PY (95% CI)

2.86 (2.41, 3.37)

3.64 (3.11, 4.23)

3.24 (2.89, 3.62)

2.44 (2.02, 2.92)

XELJANZ vs TNFi HR (95% CI)

1.17 (0.92, 1.50)

1.48 (1.17, 1.87)

1.32 (1.07, 1.63)

--

*
The XELJANZ 10 mg BID treatment group consists of data from patients that were switched from XELJANZ 10 mg BID to XELJANZ 5 mg BID during the trial as a result of a study modification following a recommendation by the Data and Safety Monitoring Board in February 2019.
 
Abbreviations: IR=incidence rate, CI=confidence interval, PY=patient years, HR=hazard ratio

Tuberculosis

Cases of tuberculosis have been reported with treatment with XELJANZ.

In the five controlled Phase 3 trials, during 0 to 3 months exposure, no cases of tuberculosis were reported in patients who received placebo or 5 mg BID of XELJANZ.

During 0 to 12 months of exposure, tuberculosis was reported in 0 patients who received 5 mg BID of XELJANZ. 

In the long-term extension trial, adjudicated tuberculosis events were reported in 0.6% patients (0.15 events/100 patient-years) who received XELJANZ; 0.4% of patients (0.10 events/100 patient-years) and 0.6% of patients (0.17 events/100 patient-years) in the 5 mg and 10 mg BID of tofacitinib, respectively.   

Cases of disseminated tuberculosis were also reported. The median XELJANZ exposure prior to diagnosis of tuberculosis was 10 months (range from 152 to 960 days) (see 7 WARNINGS AND PRECAUTIONS.

Opportunistic Infections (excluding tuberculosis)

In the five controlled Phase 3 trials, during 0 to 3 months exposure, opportunistic infections were reported in 0 patients who received placebo and 2 (0.2%) patients (0.7 events/100 patient-years) who received 5 mg BID of XELJANZ.

During 0 to 12 months of exposure, opportunistic infections were reported in 3 (0.3%) patients (0.3 events/100 patient-years) who received 5 mg BID of XELJANZ.

The median XELJANZ exposure prior to diagnosis of an opportunistic infection was 8 months (range from 41 to 698 days).

The similar frequency of opportunistic infections was observed in the long-term extension trial with XELJANZ treatment up to 114 months.

Malignancy (excluding non-melanoma skin cancer)

In the five Phase 3 controlled trials, during 0 to 3 months exposure, malignancies (excluding non-melanoma skin cancer) were reported in 0 patients who received placebo and 2 (0.2%) patients (0.7 events/100 patient-years) who received 5 mg BID of XELJANZ.

During 0 to 12 months of exposure, malignancies (excluding non-melanoma skin cancer) were reported in 5 (0.4%) patients (0.6 events/100 patient-years) who received 5 mg BID of XELJANZ.

In the long-term extension trial, overall frequency of malignancies (excluding non-melanoma skin cancer) was 3.1% (0.83 events/100 patient-years) in all XELJANZ-treated patients; 3.4% of patients (0.8 events/100 patient-years) and 3% of patients (0.84 events/100 patient-years) in the 5 mg and 10 mg BID of XELJANZ, respectively.

The most common types of malignancy (excluding non-melanoma skin cancer), including malignancies observed during the long-term extension, were lung and breast cancer, followed by gastric, colorectal, renal cell, prostate cancer, lymphoma and malignant melanoma (see 7 WARNINGS AND PRECAUTIONS).

In a post-authorization safety study (Study RA-VI), malignancies (excluding NMSC) were observed more frequently in patients taking XELJANZ compared with patients taking TNFi (Table 7). Frequency of lung cancer was higher in patients taking XELJANZ 10 mg BID compared with patients taking XELJANZ 5 mg BID. Thyroid cancer was observed in 5, 2, and 0 subjects taking XELJANZ 5 mg BID, taking XELJANZ 10 mg BID, and TNFi, respectively.

Table 7: Malignancies (Excluding NMSC), Lymphoma, and Lung Cancer in Study RA-VI

XELJANZ 5 mg BID

N = 1455

XELJANZ 10 mg BID*

N = 1456

All XELJANZ

N=2911

TNFi

N = 1451

Malignancies excluding NMSC

   n (%)

62 (4.26)

60 (4.12)

122 (4.19)

42 (2.89)

   IR (95% CI) per 100 PY

1.13 (0.87, 1.45)

1.13 (0.86, 1.45)

1.13 (0.94, 1.35)

0.77 (0.55, 1.04)

   XELJANZ vs TNFi HR (95% CI)

1.47 (1.00, 2.18)

1.48 (1.00, 2.19)

1.48 (1.04, 2.09)ǂ

--

Lymphoma

   n (%)

4 (0.27)

6 (0.41)

10 (0.34)

1 (0.07)

   IR (95% CI) per 100 PY

0.07 (0.02, 0.18)

0.11 (0.04, 0.24)

0.09 (0.04, 0.17)

0.02 (0.00, 0.10)

   XELJANZ vs TNFi HR (95% CI)

3.99 (0.45, 35.70)

6.24 (0.75, 51.86)

5.09 (0.65, 39.78)

--

Lung Cancer

   n (%)

13 (0.89)

17 (1.17)

30 (1.03)

7 (0.48)

   IR (95% CI) per 100 PY

0.23 (0.12, 0.40)

0.32 (0.18, 0.51)

0.28 (0.19, 0.39)

0.13 (0.05, 0.26)

   XELJANZ vs TNFi HR (95% CI)

1.84 (0.74, 4.62)

2.50 (1.04, 6.02)

2.17 (0.95, 4.93)

--

*
The XELJANZ 10 mg BID treatment group consists of data from patients that were switched from XELJANZ 10 mg BID to XELJANZ 5 mg BID during the trial as a result of a study modification following a recommendation by the Data and Safety Monitoring Board in February 2019.
ǂ
The non-inferiority criterion was not met for the primary comparison of the combined tofacitinib doses to TNFi since the upper limit of the 95% CI exceeded the pre-specified non-inferiority criterion of 1.8.
 
Abbreviations: IR=incidence rate, CI=confidence interval, PY=patient years, HR=hazard ratio

Non-Melanoma Skin Cancer

NMSC is a dose related adverse reaction, with a greater risk in patients treated with 10 mg BID of XELJANZ than in patients treated with 5 mg BID.

In the five Phase 3 controlled trials, during the 0 to 3 months exposure, NMSC was reported in 1 (0.2%) patient (0.6 events/100 patient-years) who received placebo and 2 (0.2%) patients (0.7 events/100 patient-years) who received 5 mg BID of XELJANZ.

During 0 to 12 months exposure, NMSC was reported in 3 (0.3%) patients (0.3 events/100 patient-years) who received 5 mg BID of XELJANZ.

In the long-term extension trial, overall frequency of NMSC was 2.6% (0.71 events/100 patient-years) in all XELJANZ-treated patients; 2.5% of patients (0.6 events/100 patient-years) and 2.6% of patients (0.75 events/100 patient-years) in the 5 mg and 10 mg BID of tofacitinib, respectively.

In a post-authorization safety study (Study RA-VI), NMSC, including cutaneous squamous cell carcinoma, was more frequently observed in patients taking XELJANZ compared with patients taking TNFi (Table 8).

Table 8: NMSC in Study RA-VI

XELJANZ 5 mg BID

N = 1455

XELJANZ 10 mg BID*

N = 1456

All XELJANZ

N=2911

TNFi

N = 1451

Non-melanoma Skin Cancer (NMSC)

   n (%)

31 (2.13)

33 (2.27)

64 (2.20)

16 (1.10)

   IR (95% CI) per 100 PY

0.61 (0.41, 0.86)

0.69 (0.47, 0.96)

0.64 (0.50, 0.82)

0.32 (0.18, 0.52)

   XELJANZ vs TNFi HR (95% CI)

1.90 (1.04, 3.47)

2.16 (1.19, 3.92)

2.02 (1.17, 3.50)

--

Basal Cell Carcinoma

   n (%)

19 (1.31)

16 (1.10)

35 (1.20)

13 (0.90)

   IR (95% CI) per 100 PY

0.37 (0.22, 0.58)

0.33 (0.19, 0.54)

0.35 (0.24, 0.49)

0.26 (0.14, 0.44)

   XELJANZ vs TNFi HR (95% CI)

1.43 (0.71, 2.90)

1.28 (0.61, 2.66)

1.36 (0.72, 2.56)

--

Cutaneous Squamous Cell Carcinoma

   n (%)

15 (1.03)

22 (1.51)

37 (1.27)

8 (0.55)

   IR (95% CI) per 100 PY

0.29 (0.16, 0.48)

0.45 (0.29, 0.69)

0.37 (0.26, 0.51)

0.16 (0.07, 0.31)

   XELJANZ vs TNFi HR (95% CI)

1.82 (0.77, 4.30)

2.86 (1.27, 6.43)

2.32 (1.08, 4.99)

--

*
The XELJANZ 10 mg BID treatment group consists of data from patients that were switched from XELJANZ 10 mg BID to XELJANZ 5 mg BID during the trial as a result of a study modification following a recommendation by the Data and Safety Monitoring Board in February 2019.  Abbreviations: IR=incidence rate, CI=confidence interval, PY=patient years, HR=hazard ratio

Mortality

In a post-authorization safety study (Study RA-VI), all-cause mortality was observed more frequently for patients taking XELJANZ (n=65/2911; 2.2%) compared with patients taking TNFi (n=17/1451; 1.2%). Related study data is presented in Table 9.

Table 9. Mortality in Study RA-VI
Parameter

Tofacitinib 5mg BID

N=1455

Tofacitinib 10mg BID*

N=1456

All Tofa

N=2911

TNFi

N=1451

Deaths - Total

   n (%)

26 (1.79)

39 (2.68)

65 (2.23)

17 (1.17)

   IR (95% CI) per 100 PY

0.50 (0.33, 0.74)

0.80 (0.57, 1.09)

0.65 (0.50, 0.82)

0.34 (0.20, 0.54)

   XELJANZ vs TNFi HR (95% CI)

1.49 (0.81, 2.74)

2.37 (1.34, 4.18)

1.91 (1.12, 3.27)

 

Deaths - Infections  

   n (%)

4 (0.27)

9 (0.62)

13 (0.45)

3 (0.21)

   IR (95% CI) per 100 PY

0.08 (0.02, 0.20)

0.18 (0.08, 0.35)

0.13 (0.0, 0.22)

0.06 (0.01, 0.17)

   XELJANZ vs TNFi HR (95% CI)

1.30 (0.29, 5.79)

3.10 (0.84, 11.45)

2.17 (0.62, 7.62)

 

Deaths - Cardiovascular Events

   n (%)

13 (0.89)

20 (1.37)

33 (1.13)

10 (0.69)

   IR (95% CI) per 100 PY

0.25 (0.13, 0.43)

0.41 (0.25, 0.63)

0.33 (0.23, 0.46)

0.20 (0.10, 0.36)

   XELJANZ vs TNFi HR (95% CI)

1.26 (0.55, 2.88)

2.05 (0.96, 4.39)

1.65 (0.81, 3.34)

 

Deaths - Malignancies

   n (%)

5 (0.34)

0

5 (0.17)

1 (0.07)

   IR (95% CI) per 100 PY

0.10 (0.03, 0.23)

0.00 (0.00, 0.08)

0.05 (0.02, 0.12)

0.02 (0.00, 0.11)

   XELJANZ vs TNFi HR (95% CI)

4.88 (0.57, 41.74)

0 (0.00, Inf)

2.53 (0.30, 21.64)

 

Deaths - Other Causes

   n (%)

4 (0.27)

10 (0.69)

14 (0.48)

3 (0.21)

   IR (95% CI) per 100 PY

0.08 (0.02, 0.20)

0.21 (0.10, 0.38)

0.14 (0.08, 0.23)

0.06 (0.01, 0.17)

   XELJANZ vs TNFi HR (95% CI)

1.30 (0.29, 5.81)

3.45 (0.95, 12.54)

2.34 (0.67, 8.16)

 

*
The XELJANZ 10 mg BID treatment group consists of data from patients that were switched from XELJANZ 10 mg BID to XELJANZ 5 mg BID during the trial as a result of a study modification following a recommendation by the Data and Safety Monitoring Board in February 2019.

Thromboembolism

Venous thromboembolism, including pulmonary embolism, were observed more frequently in a post-authorization safety study (Study RA-VI), as shown in Table 10. Pulmonary embolism was observed more frequently with XELJANZ 10 mg BID than XELJANZ 5 mg BID. Deep vein thrombosis, and arterial thromboembolism were also observed in the study.

Table 10: Thromboembolism Adverse Reactions in Study RA-VI

XELJANZ 5 mg BID

N = 1455

XELJANZ 10 mg BID*

N = 1456

All XELJANZ

N=2911

TNFi

N = 1451

Venous Thromboembolism**

   n(%)

17 (1.17)

34 (2.34)

51 (1.75)

10 (0.69)

   IR (95% CI) per 100 PY

0.33 (0.19, 0.53)

0.70 (0.49, 0.99)

0.51 (0.38, 0.67)

0.20 (0.10, 0.37)

   XELJANZ vs TNFi HR (95% CI)

1.66 (0.76, 3.63)

3.52 (1.74, 7.12)

2.56 (1.30, 5.05)

--

Pulmonary Embolism

   n (%)

9 (0.62)

24 (1.65)

33 (1.13)

3 (0.21)

   IR (95% CI) per 100 PY

0.17 (0.08, 0.33)

0.50 (0.32, 0.74)

0.33 (0.23, 0.46)

0.06 (0.01, 0.17)

   XELJANZ vs TNFi HR (95% CI)

2.93 (0.79, 10.83)

8.26 (2.49, 27.43)

5.53 (1.70, 18.02)

--

Deep Vein Thrombosis

   n(%)

11 (0.76)

15 (1.03)

26 (0.89)

7 (0.48)

   IR (95% CI) per 100 PY

0.21 (0.11, 0.38)

0.31 (0.17, 0.51)

0.26 (0.17, 0.38)

0.14 (0.06, 0.29)

   XELJANZ vs TNFi HR (95% CI)

1.54 (0.60, 3.97)

2.21 (0.90, 5.43)

1.87 (0.81, 4.30)

--

Arterial Thromboembolism

   n(%)

47 (3.23)

45 (3.09)

92 (3.16)

41 (2.83)

   IR (95% CI) per 100 PY

0.92 (0.68, 1.22)

0.94 (0.68, 1.25)

0.93 (0.75, 1.14)

0.82 (0.59, 1.12)

   XELJANZ vs TNFi HR (95% CI)

1.12 (0.74, 1.70)

1.14 (0.75, 1.74)

1.13 (0.78, 1.63)

--

*
The XELJANZ 10 mg BID treatment group consists of data from patients that were switched from XELJANZ 10 mg BID to XELJANZ 5 mg BID during the trial as a result of a study modification following a recommendation by the Data and Safety Monitoring Board in February 2019. Abbreviations: IR=incidence rate, CI=confidence interval, PY=patient years, HR=hazard ratio
**
Venous thromboembolism (e.g., pulmonary embolism, deep vein thrombosis, retinal venous thrombosis).

Major Adverse Cardiovascular Events (MACE), Including Myocardial Infarction

In a post-authorization study (Study RA-VI) the risk of MACE, including non-fatal myocardial infarction, was higher in patients treated with XELJANZ, compared to patients treated with TNFi (Table 11).  In the XELJANZ 5 mg BID, XELJANZ 10 mg BID, All XELJANZ, and TNFi treatment arms, there were a total of 19, 19, 38, and 11 patients with MI events, respectively. Of these totals, the number of patients with fatal MI events was 0, 3, 3, and 3, respectively, whereas the number of patients with non-fatal MI events was 19, 16, 35, and 8, respectively.

Table 11: MACE (Including Myocardial Infarction) in Study RA-VI

XELJANZ 5 mg BID

N = 1455

XELJANZ 10 mg BID*

N = 1456

All XELJANZ

N=2911

TNFi

N = 1451

Major Adverse Cardiovascular Events (MACE)α

   n (%)

47 (3.23)

51 (3.50)

98 (3.37)

37 (2.55)

   IR (95% CI) per 100 PY

0.91 (0.67, 1.21)

1.05 (0.78, 1.38)

0.98 (0.79, 1.19)

0.73 (0.52, 1.01)

   XELJANZ vs TNFi HR (95% CI)

1.24 (0.81, 1.91)

1.43 (0.94, 2.18)

1.33 (0.91, 1.94)ǂ

--

Non-fatal Myocardial Infarction

   n (%)

19 (1.31)

16 (1.10)

35 (1.20)

8 (0.55)

   IR (95% CI) per 100 PY

0.37 (0.22, 0.57)

0.33 (0.19, 0.53)

0.35 (0.24, 0.48)

0.16 (0.07, 0.31)

   XELJANZ vs TNFi HR (95% CI)

2.32 (1.02, 5.30)

2.08 (0.89, 4.86)

2.20 (1.02, 4.75)

--

*
The XELJANZ 10 mg BID treatment group consists of data from patients that were switched from XELJANZ 10 mg BID to XELJANZ 5 mg BID during the trial as a result of a study modification following a recommendation by the Data and Safety Monitoring Board in February 2019.
ǂ
The non-inferiority criterion was not met for the primary comparison of the combined tofacitinib doses to TNFi since the upper limit of the 95% CI exceeded the pre-specified non-inferiority criterion of 1.8.
α
MACE includes nonfatal myocardial infarction, nonfatal stroke, and cardiovascular deaths excluding pulmonary embolism.
 
Abbreviations: IR=incidence rate, CI=confidence interval, PY=patient years, HR=hazard ratio

Gastrointestinal Perforations

In a post-authorization study (Study RA-VI), gastrointestinal perforations were observed in subjects treated with XELJANZ 5 mg BID, XELJANZ 10 mg BID, and TNF inhibitors (Table 12).

Table 12: Gastrointestinal Perforations in Study RA-VI

XELJANZ 5 mg BID

N = 1455

XELJANZ 10 mg BID*

N = 1456

All XELJANZ

N=2911

TNFi

N = 1451

n(%)

9 (0.62)

5 (0.34)

14 (0.48)

4 (0.28)

IR (95% CI) per 100 PY

0.17 (0.08, 0.33)

0.10 (0.03, 0.24)

0.14 (0.08, 0.23)

0.08 (0.02, 0.20)

XELJANZ vs TNFi HR (95% CI)

2.20 (0.68, 7.15)

1.29 (0.35, 4.80)

1.76 (0.58, 5.34)

--

*
The XELJANZ 10 mg BID treatment group consists of data from patients that were switched from XELJANZ 10 mg BID to XELJANZ 5 mg BID during the trial as a result of a study modification following a recommendation by the Data and Safety Monitoring Board in February 2019. Abbreviations: IR=incidence rate, CI=confidence interval, PY=patient years, HR=hazard ratio

Fractures

In a post-authorization study (Study RA-VI) the incidence rate (IR) (95% CI) for fractures was 2.79 (95%CI: 2.34-3.30) for XELJANZ 5 mg BID, and 2.87 (95% CI: 2.40-3.40) for XELJANZ 10 mg BID, compared to 2.27 (95% CI: 1.87-2.74) for TNF inhibitors.

Psoriatic Arthritis

A total of 783 patients were treated with any dose of XELJANZ in PsA clinical studies resulting in 1238 patient-years of exposure. Of these, 635 patients were exposed to XELJANZ for at least one year.

The most common serious adverse reactions were serious infections. The most commonly reported adverse reactions (≥2%) in patients treated with XELJANZ 5 mg BID during the first 3 months in placebo‑controlled clinical studies were bronchitis, diarrhea, dyspepsia, headache, nasopharyingitis, nausea.

The proportion of patients who discontinued treatment due to any adverse reactions during the first 3‑months of the double-blind placebo‑controlled studies was 3.2% for XELJANZ‑treated patients and 2.5% for placebo-treated patients.

Overall, the safety profile observed in patients with active PsA treated with XELJANZ was consistent with the safety profile observed in patients with RA treated with XELJANZ. Incidence rates and types of adverse drug reactions, overall infections, serious infections, opportunistic infections in the two controlled Phase 3 PsA clinical studies were generally similar to those reported in RA Phase 3 clinical studies. The incidence rates of tuberculosis, malignancies (excluding NMSC), and NMSC in the two controlled Phase 3 PsA clinical studies were generally similar to those reported in RA Phase 3 clinical studies. 

Ankylosing Spondylitis

In the safety population of the combined Phase 2 and the Phase 3 clinical trials, a total of 420 patients were treated with study-specified dose XELJANZ corresponding to 233 patient-years of experience. Of these, 108 patients received XELJANZ 5 mg twice daily for 12 months or longer. Concomitant treatment with stable doses of cDMARDs, NSAIDs, or corticosteroids (≤10 mg/day) was permitted. The study population treated with XELJANZ included 13 (3.1%) patients aged 65 years or older and 18 (4.3%) patients with diabetes at baseline.

The safety profile observed in patients with AS treated with XELJANZ was consistent with the safety profile observed in RA and PsA patients. The incidence rates and types of adverse drug reactions, overall infections, and serious infections reported in the controlled Phase 3 AS clinical study were similar to those reported in RA Phase 3 clinical studies. During the 16-week placebo-controlled period in study AS-I, the frequency of increased transaminases was 4.3% with XELJANZ 5 mg and 1.07% with placebo.

Ulcerative Colitis

Table 13 below lists adverse drug reactions reported by ≥1% of patients treated with XELJANZ – UC Phase 2 and Phase 3 Induction Studies

Table 13: Summary of Adverse Drug Reactions (adverse events for which there is evidence of causality) Reported by ≥1% of Patients Treated with XELJANZ – UC Phase 2 and Phase 3 Induction Studies (up to 8 weeks)

Body

System±/Adverse

Drug Reaction

XELJANZ 10 mg BID

N=938 (%)

Placebo

N=282 (%)

Subjects with one or more ADR

494 (52.7)

130 (46.1)

Blood and lymphatic system disorders

26 (2.8)

10 (3.5)

Anemia

22 (2.3)

9 (3.2)

Gastrointestinal disorders

82 (8.7)

26 (9.2)

Nausea

28 (3.0)

11 (3.9)

Abdominal pain 

25 (2.7)

11 (3.9)

Vomiting

9 (1.0)

3 (1.1)

Dyspepsia

12 (1.3)

1(0.4)

General disorders and administration site conditions

48 (5.1)

13 (4.6)

Fatigue

17 (1.8)

5 (1.8)

Pyrexia

24 (2.6)

4 (1.4)

Infections and infestations

111 (11.8)

24 (8.5)

Nasopharyngitis

56 (6.0)

14 (5.0)

Influenza

9 (1.0)

3 (1.1)

Urinary tract infection

11 (1.2)

1 (0.4)

Pharyngitis 

10 (1.1)

1 (0.4)

Investigations

65 (6.9)

4 (1.4)

Blood creatine phosphokinase increased

25 (2.7)

3 (1.1)

Elevated cholesterol levels*

 31 (3.3)

0

Musculoskeletal and connective tissue disorders

33 (3.5)

12 (4.3)

Arthralgia

 27 (2.9)

12 (4.3)

Nervous system disorders

77 (8.2)

20 (7.1)

Headache

73 (7.8)

19 (6.7)

Respiratory

14 (1.5)

8 (2.8)

Cough

 13 (1.4)

7 (2.5)

Skin and Subcutaneous Tissue Disorders

18 (1.9)

9 (3.2)

Rash

12 (1.3)

  2 (0.7)

Vascular disorders

9 (1.0)

1 (0.4)

Hypertension

9 (1.0)

1 (0.4)

*
includes: hypercholesterolemia, hyperlipidemia, blood cholesterol increased, dyslipidemia, blood triglycerides increased, low density lipoprotein increased, low density lipoprotein abnormal, or lipids increased.
±
the total number of subjects with adverse reactions and the total number of subjects with adverse reactions for each body system include all adverse drug reactions (those reported by ≥1% of subjects treated with XELJANZ and those reported by
Table 14: Summary of Adverse Drug Reactions (adverse events for which there is evidence of causality) Reported by ≥1% of Patients Treated with XELJANZ – UC Phase 3 Maintenance Study (up to 12 months)

Body

System±/Adverse Drug Reaction

XELJANZ 5mg BID

N=198 (%)

XELJANZ 10mg BID

N=196 (%)

Placebo

N=198 (%)

 Subjects with one or more ADR (%)

 

166 (83.8)

 

207 (100)

 

153 (77.3)

Blood and lymphatic system disorders

9 (4.5)

5 (2.6)

3 (1.5)

Anemia

8(4.0)

4 (2.0)

3 (1.5)

Gastrointestinal disorders

16 (8.1)

32 (16.3)

26 (13.1)

Diarrhea

3 (1.5)

 9 (4.6)

5 (2.5)

Nausea

1 (0.5)

8 (4.1)

5 (2.5)

Abdominal pain 

5 (2.5)

7 (3.6)

11 (5.6)

Vomiting

3 (1.5)

6 (3.1)

2 (1.0)

Dyspepsia

4 (2.0)

1 (0.5)

 2 (1.0)

General disorders and administration site conditions

12 (6.1)

11 (5.6)

17 (8.6)

Fatigue

8 (4.0)

4 (2.0)

11 (5.6)

Pyrexia

3 (1.5)

6 (3.1)

5 (2.5)

Infections and infestations

51 (25.8)

65 (33.2)

37 (18.7)

Nasopharyngitis

19 (9.6)

27 (13. 8)

11 (5.6)

Herpes zoster

3 (1.5)

 10 (5.1)

 1 (0.5)

Influenza

4 (2.0)

7 (3.6)

7 (3.5)

Urinary tract infection

 5 (2.5)

6 (3.1)

4 (2.0)

Bronchitis

 5 (2.5)

6 (3.1)

3 (1.5)

Sinusitis

6 (3.0)

2 (1.0)

2 (1.0)

Pharyngitis 

6 (3.0)

1 (0.5)

3 (1.5)

Gastroenteritis viral

0

3 (1.5)

2 (1.0)

Viral infection

2 (1.0)

1 (0.5)

1 (0.5)

Injury, poisoning and procedural complications

2 (1.0)

2 (1.0)

0

Ligament sprain

1 (0.5)

2 (1.0)

0

Investigations

19 (9.6)

38 (19.4)  

7 (3.5) 

Elevated cholesterol levels*

9 (4.5)

18 (9.2)

3 (1.5)

Blood creatine phosphokinase increased

6 (3.0)

13 (6.6)

4 (2.0)

Weight increased

3 (1.5)

4 (2.0)

0

Gamma glutamyltransferase increased,

1 (0.5)

3 (1.5)

0

Musculoskeletal and connective tissue disorders

19 (9.6)

19 (9.7)

25 (12.6)

Arthralgia

17 (8.6)

17 (8.7)

19 (9.6)

Musculoskeletal pain

1 (0.5)

2 (1.0)

5 (2.5)

Neoplasms benign, malignant and unspecified (including cysts and polyps)

0

2 (1.0)

1 (0.5)

Non-melanoma skin cancers

0

2 (1.0)

1 (0.5)

Nervous system disorders 

18 (9.1)

7 (3.6)

12 (6.1)

Headache

 17 (8.6)

6 (3.1)

12 (6.1)

Psychiatric 

3 (1.5) 

1 (0.5)

1 (0.5)

Insomnia

3 (1.5)

1 (0.5)

1 (0.5)

Respiratory

6 (3.0)

8 (4.1)

6 (3.0)

Cough

6 (3.0)

5 (2.6)

5 (2.5)

Dyspnea

0

2 (1.0)

1 (0.5)

Skin and Subcutaneous Tissue Disorders 

7 (3.5)

12 (6.1) 

17 (8.6)

Rash

6 (3.0)

11 (5.6)

8 (4.0)

Vascular disorders

4 (2.0) 

4 (2.0)

1 (0.5)

Hypertension

4 (2.0)

4 (2.0)

1 (0.5)

*
includes: hypercholesterolemia, hyperlipidemia, blood cholesterol increased, dyslipidemia, blood triglycerides increased, low density lipoprotein increased, low density lipoprotein abnormal, or lipids increased.
±
The total number of subjects with adverse reactions and the total number of subjects with adverse reactions for each body system include all adverse drug reactions (those reported by ≥1% of subjects treated with XELJANZ and those reported by

Overall Infections

In the randomised 8-week Phase 2/3 induction studies, the proportions of patients with infections were 21.1% (198 patients) in the XELJANZ 10 mg BID group compared to 15.2% (43 patients) in the placebo group. In the randomised 52-week Phase 3 maintenance study, the proportion of patients with infections were 35.9% (71 patients) in the 5 mg BID and 39.8% (78 patients) in the 10 mg BID XELJANZ groups, compared to 24.2% (48 patients) in the placebo group.

In the maintenance study, results suggested that the risk of opportunistic infection was possibly dose related: XELJANZ 10 mg BID (2.0%), XELJANZ 5 mg BID (1.0%), and placebo (0.5%). All opportunistic infections were herpes zoster infections. Herpes zoster was reported more frequently with XELJANZ 10 mg BID (5.1%), as compared to XELJANZ 5 mg BID (1.5%), or placebo (0.5%), indicating that the risk of herpes zoster is dose related.

In the entire treatment experience with XELJANZ, the most commonly reported infection was nasopharyngitis, occurring in 18.2% of patients (211 patients). 

Serious Infections

The incidence rates and types of serious infections in the UC clinical trials were generally similar to those reported in RA Phase 3 clinical trials with XELJANZ.

Patients treated with XELJANZ 10 mg BID had a higher rate of serious infections compared to those treated with 5 mg BID. 

Opportunistic infections (excluding tuberculosis)

In the maintenance study, herpes zoster was reported more frequently with XELJANZ 10 mg BID (5.1%), as compared to XELJANZ 5 mg BID (1.5%), or placebo (0.5%), indicating that the risk of herpes zoster is dose related.

Also, opportunistic herpes zoster infections (including serious cases, such as, disseminated, meningoencephalitis, ophthalmologic) were reported in patients treated with XELJANZ 10 mg BID. 

Malignancies (excluding NMSC)

In the controlled clinical studies (up to 52-week treatment), no malignancies (excluding NMSC) were reported with XELJANZ.

In the long-term extension open-label study, malignancies (excluding NMSC) have been observed in patients treated with XELJANZ 10 mg BID, including solid cancers and lymphoma. 

8.3 Less Common Clinical Trial Adverse Reactions

Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis

Blood and Lymphatic System Disorders: leukopenia, lymphopenia, neutropenia

Cardiovascular: congestive heart failure, myocardial infarction

Gastrointestinal Disorders: abdominal pain, appendicitis, gastrointestinal perforation

General Disorders and Administration Site Conditions: influenza

Hepatobiliary Disorders: hepatic steatosis

Infections and Infestations:  atypical mycobacterial infection, arthritis bacterial, bacteraemia, cellulitis, cytomegalovirus infection, disseminated tuberculosis, diverticulitis, encephalitis, gastroenteritis viral, herpes simplex, herpes zoster, meningitis cryptococcal, mycobacterium avium complex infection, necrotising fasciitis, pneumonia bacterial, pneumonia pneumococcal, pneumocystis jiroveci pneumonia, pyelonephritis, sepsis, staphylococcal bacteraemia, tuberculosis, tuberculosis of central nervous system, urosepsis, viral infection.

Injury, Poisoning and Procedural Complications: muscle strain, fall

Investigations: blood cholesterol increased, blood creatinine increased, blood creatine phosphokinase increased, gamma glutamyltransferase increased, hepatic enzyme increased, liver function test abnormal, low density lipoprotein increased, transaminases increased, weight increased,

Metabolism and Nutrition Disorders: dehydration, dyslipidemia, hyperlipidemia

Musculoskeletal and Connective Tissue Disorders: joint swelling, ligament sprain, musculoskeletal pain, tendonitis,

Neoplasm Benign, Malignant and Unspecified (Including Cysts and Polyps): lymphoma, non-melanoma skin cancers, solid tumours  

Nervous System Disorders: paraesthesia

Psychiatric Disorders: insomnia

Respiratory, Thoracic and Mediastinal Disorders: cough, dyspnoea, sinus congestion,  

Skin and Subcutaneous Tissue Disorders: erythema, pruritus

Vascular disorders: arterial thrombosis, deep vein thrombosis, pulmonary embolism. 

 

Ulcerative Colitis

Blood and Lymphatic System Disorders: neutropenia, lymphopenia, leukopenia

Gastrointestinal Disorders: gastritis

General Disorders and Administration Site Conditions: oedema peripheral

Hepatobiliary Disorders: hepatic steatosis

Infections and Infestations: pneumonia, pyelonephritis, cellulitis, herpes simplex, tuberculosis, arthritis bacterial, cytomegalovirus infection, diverticulitis

Injury, Poisoning and Procedural Complications: muscle strain

Investigations: hepatic enzyme increased, transaminases increased, blood creatinine increased, liver function test abnormal, low density lipoprotein increased

Metabolism and Nutrition Disorders: dehydration

Musculoskeletal and Connective Tissue Disorders: tendonitis, joint swelling

Neoplasm Benign, Malignant and Unspecified (Including Cysts and Polyps): non-melanoma skin cancers, solid cancers, lymphomas  

Nervous System Disorders: paraesthesia

Respiratory, Thoracic and Mediastinal Disorders: sinus congestion

Skin and Subcutaneous Tissue Disorders: erythema, pruritus

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Clinical Trial Findings

Laboratory Tests – Rheumatoid Arthritis and Ulcerative Colitis

Creatine Kinase

Treatment with XELJANZ was associated with increases in creatine kinase (CK). Maximum effects were generally observed within 6 months. Rhabdomyolysis was reported in one patient treated with XELJANZ.

CK levels should be checked in patients with symptoms of muscle weakness and/or muscle pain to evaluate for evidence of rhabdomyolysis (see 7 WARNINGS AND PRECAUTIONS)

ECG Findings

In placebo-controlled Phase 2 clinical trials, steady-state treatment with 5-10 mg BID XELJANZ was associated with statistically significant 4-7 bpm decreases in heart rate and 4-10 ms increases in the PR interval compared with placebo (see 7WARNINGS AND PRECAUTIONS and 9 DRUG INTERACTIONS).

Lipids

Treatment with XELJANZ was associated with dose related increases in lipid parameters.

Elevations in lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) generally reached maximal effects at 6 weeks following initiation of XELJANZ in the controlled RA double-blind clinical trials. Changes in lipid parameters from baseline through the end of the study (6-12 months) in the controlled clinical studies in RA are summarized below:

  • Mean LDL cholesterol increased by 14% in the XELJANZ 5 mg BID arm.
  • Mean HDL cholesterol increased by 16% in the XELJANZ 5 mg BID arm.
  • Mean LDL/HDL ratios were essentially unchanged in XELJANZ-treated patients.

In the five controlled RA clinical trials, 4.4% of patients treated with 5 mg BID, initiated lipid-lowering medication while on study.  

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

Increases of total cholesterol, LDL cholesterol, and HDL cholesterol were also reported in a post-authorization safety (Study RA-VI; Table 15). 

Table 15: Mean percent increase of cholesterol (Study RA-VI)
XELJANZ 5 mg BID XELJANZ 10 mg BID* TNFi

LDL, mean percent increase

12 months

13.80

17.04

5.50

24 months

12.71

18.14

3.64

HDL, mean percent increase

12 months

11.71

13.63

2.82

24 months

11.58

13.54

1.42

*
The XELJANZ 10 mg BID treatment group consists of data from patients that were switched from XELJANZ 10 mg BID to XELJANZ 5 mg BID during the trial as a result of a study modification following a recommendation by the Data and Safety Monitoring Board in February 2019.

Liver Enzyme Tests

Confirmed increases in liver enzymes >3x upper limit of normal (ULN) were uncommonly observed. In those 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 dose, resulted in decrease or normalization of liver enzymes.

In the controlled portion of the RA Phase 3 monotherapy study (0-3 months), ALT elevations >3x ULN were observed in 1.65% and 0.41% of patients receiving placebo and 5 mg BID, respectively. In this study, AST elevations >3x ULN were observed in 1.65%, and 0.41% of patients receiving placebo and 5 mg BID, respectively.

In the controlled portion of the RA Phase 3 studies on background DMARDs (0-3 months), ALT elevations >3x ULN were observed in 0.9% and 1.24% of patients receiving placebo and 5 mg BID, respectively. In these studies, AST elevations >3x ULN were observed in 0.72% and 0.52% of patients receiving placebo and 5 mg BID, respectively.

In the RA long-term extension trial, ALT and AST elevations greater than 3x ULN were observed in 2.2% and 1.1% of all XELJANZ-treated patients, respectively. Overall, total bilirubin elevations greater than 2x ULN were observed in 3 (0.1%) patients. Increases to ≥5x and ≥10x ULN were observed for both ALT (0.5% and 0.2% of patients, respectively) and AST (0.3% and 0.1% of patients, respectively) in all patients treated with XELJANZ.

In RA patients taking 5 mg BID of XELJANZ, the ALT and AST elevations greater than 3x ULN were observed in 2.4% and 1.3% of patients, respectively. There was no subject who had the total bilirubin elevations greater than 2x ULN. Increases to ≥5 and ≥10x ULN were observed for both ALT (0.4% and 0.1% of patients, respectively) and AST (0.2% and 0% of patients, respectively).

In RA patients taking 10 mg BID of tofacitinib, the ALT and AST elevations greater than 3x ULN were observed in 2.1% and 1.1% of patients, respectively. The total bilirubin elevations greater than 2x ULN were observed in 3 (0.1%) patients. Increases to ≥5 and ≥10x ULN were observed for both ALT (0.5% and 0.2% of patients, respectively) and AST (0.3% and 0.1% of patients, respectively).

Two patients treated with 10 mg BID of tofacitinib in the RA long-term extension trial were assessed as probable DILI by the adjudication committee. One of the two patients had other possible causes of alcohol intake and methotrexate.

Elevations of ALT and AST were reported more frequently in patients taking XELJANZ compared with patients taking TNFi in a post-authorization safety study (Study RA-VI; Table 16).

Table 16: Percentage of patients with at least one post-baseline elevation of liver enzymes (Study RA-VI)
XELJANZ 5 mg BID XELJANZ 10 mg BID*

All XELJANZ

TNFi

ALT elevation, percentage of patients

> 1 x ULN

52.83

54.46

53.64

43.33

> 3 x ULN

6.01

6.51

6.27

3.77

> 5 x ULN

1.68

1.97

1.82

1.12

AST elevation, percentage of patients

> 1 x ULN

45.84

51.58

48.70

37.18

> 3 x ULN

3.21

4.57

3.89

2.38

> 5 x ULN

0.98

1.62

1.30

0.70

*
The XELJANZ 10 mg BID treatment group consists of data from patients that were switched from XELJANZ 10 mg BID to XELJANZ 5 mg BID during the trial as a result of a study modification following a recommendation by the Data and Safety Monitoring Board in February 2019.

In the clinical studies in UC, changes in liver enzyme tests observed with XELJANZ 5 mg BID treatment were similar to the changes observed in clinical studies in RA.

In UC patients, XELJANZ treatment with 5 and 10 mg BID was also associated with an increased incidence of liver enzyme elevation compared to placebo, with a trend for higher incidence with the 10 mg BID as compared to the 5 mg BID dose.

One patient with XELJANZ 10 mg BID in the maintenance UC study experienced an increase in liver enzymes which decreased upon discontinuation of treatment. The case was adjudicated as possible DILI, while noting ultrasound findings of fatty liver. 

Lymphocytes

In the five controlled RA clinical trials, confirmed decreases in absolute lymphocyte counts below 0.5 x109 cells/L occurred in 0.2% of patients for the 5 mg BID XELJANZ group during 12 months of exposure.

Confirmed lymphocyte counts less than 0.5 x109 cells/L were associated with an increased incidence of treated and serious infections (see 7 WARNINGS AND PRECAUTIONS).

In the RA long-term extension trial, cases of lymphopenia have been reported in 181 (4.0%) patients (1.11 events/100 patient-years) treated with XELJANZ; 4.5% of patients (1.07 events/100 patient-years) and 3.9% of patients (1.12 events/100 patient-years) in the 5 mg and 10 mg BID of tofacitinib, respectively. Confirmed decreased in absolute lymphocyte counts below 0.5 x109 cells/L occurred in 1.3% of all XELJANZ-treated patients; 1.1% of patients for the 5 mg BID XELJANZ group, and 1.4% of patients for the 10 mg BID tofacitinib group.

In a post-authorization safety study (Study RA-VI) the median decrease in lymphocyte counts were greater in patients taking XELJANZ (-0.21) compared with patients taking TNFi (0.37).

In the 52-week maintenance study in UC, a single absolute lymphocyte count below 0.5 x109 cells/L was reported in 2.6% (n=5) of patients treated with 10 mg BID, and was not reported in patients treated with 5 mg BID or placebo. No patients in any treatment group had confirmation of a lymphocyte count below 0.5 x109 cells/L based on two sequential tests.

Neutrophils

In the controlled RA clinical studies, confirmed decreases in ANC below 1x109 cells/L occurred in 0.08% of patients in the 5 mg BID XELJANZ group during 12 months of exposure. There were no confirmed decreases in ANC below 0.5 x109 cells/L observed in any treatment group.

There was no clear relationship between neutropenia and the occurrence of serious infections.

In the long-term extension trial, cases of neutropenia have been reported in 86 (1.9%) patients (0.52 events/100 patient-years) treated with XELJANZ; 4.0% of patients (0.97 events/100 patient-years) and 1.2% of patients (0.35 events/100 patient-years) in the 5 mg and 10 mg BID of tofacitinib, respectively. Confirmed decreased in ANC below 1x109 cells/L occurred in 0.2% in all XELJANZ-treated patients; 0.4% of patients for the 5 mg BID XELJANZ group, and 0.1% of patients for the 10 mg BID tofacitinib group. 

In the clinical studies in UC, changes in neutrophils observed with XELJANZ treatment were similar to the changes observed in clinical studies in RA.

Serum Creatinine

In the controlled RA clinical trials, dose-related elevations in serum creatinine were observed with XELJANZ treatment. The mean increase in serum creatinine was

In the UC studies, an increase of more than 50% in serum creatinine was reported in 1.6% of patients predominantly treated with XELJANZ 5 mg BID, and 3.4% of those predominantly treated with XELJANZ 10 mg BID.  

Laboratory Tests – Psoriatic Arthritis

In the controlled clinical trials in PsA, changes in hematologic and clinical chemistry findings observed with XELJANZ treatment were similar to the changes observed in Phase 3 clinical trials in RA. 

Laboratory Tests - Ankylosing Spondylitis

In the controlled clinical trials in AS, changes in hematologic and clinical chemistry findings observed with XELJANZ treatment were similar to the changes observed in Phase 3 clinical trials in RA.

8.5 Post-Market Adverse Reactions

Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune system disorders: drug hypersensitivity reactions including angioedema and urticaria (see 2 CONTRAINDICATIONS and 7 WARNINGS AND PRECAUTIONS)

Serious infections: viral reactivation (hepatitis B reactivation) (see 7 WARNINGS AND PRECAUTIONS)

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