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XELJANZ / XELJANZ XR (tofacitinib) Adverse Reactions

Adverse Reactions

Adverse Drug Reaction Overview

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.

The most common serious adverse reactions (SAEs) were osteoarthritis and serious infections, including pneumonia, cellulitis, herpes zoster, and urinary tract infection. During the first 3 months, 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 WARNINGS AND PRECAUTIONS).

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.

The most commonly reported adverse reactions during the first 3 months in controlled 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, rheumatoid arthritis, back pain and hypertension were also reported in the 5 mg BID XELJANZ group in the long-term extension trial.

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. The most common adverse reactions 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.

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.

Asian Patients: 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 interstitial lung disease. Therefore, XELJANZ/ XELJANZ XR should be used with caution in Asian patients.

Psoriatic Arthritis

The safety data includes 2 double‑blind, controlled, multicenter studies: study PsA-I (A3921091) with a 12‑month duration and study PsA-II (A3921125) with a 6‑month duration; both included a 3‑month placebo‑controlled period. All patients in the clinical studies were required to receive treatment with a stable dose of a csDMARD. An additional long‑term, open‑label clinical study was conducted and included patients with PsA who originally participated in either of the 2 double‑blind, controlled clinical studies.

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 5mg 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.

Ulcerative Colitis

Four randomized, double-blind, placebo-controlled studies and one open-label study were conducted in patients with moderately to severely active UC: two similar 8-week pivotal Phase 3 induction studies (OCTAVE Induction 1 and 2), one 52-week pivotal Phase 3 maintenance study (OCTAVE Sustain), and one dose-ranging Phase 2 induction study (A3921063). A long-term open-label uncontrolled extensions study was also conducted (see CLINICAL TRIALS). In the 52-week OCTAVE Sustain study, 99 patients were treated with 5 mg BID, and 113 patients with 10 mg BID for 52 weeks.

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 ulcerative colitis) 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 ulcerative colitis). The most common adverse events (≥ 5%) (excluding events reported as ulcerative colitis) 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 ulcerative colitis. Excluding discontinuations due to worsening of ulcerative colitis, 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 twice daily.

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.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Rheumatoid Arthritis

Table 1 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 RA studies.

Table 1: 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)

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)

Blood and lymphatic system disorders

Anemia

15 (1.2)

8 (1.2)

0

Metabolism and nutrition disorders

Hypercholesterolaemia

12 (1.0)

3 (0.4)

1 (0.5)

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

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

Hepatobiliary Disorders

Alanine aminotransferase increased

14 (1.2)

7 (1.0)

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)

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)

Psoriatic Arthritis

The incidence rates and types of adverse drug reactions reported in the two controlled Phase 3 PsA clinical studies were generally similar to those reported in RA clinical studies.

Ulcerative Colitis

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

Table 2: 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)
*
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 < 1% of subjects treated with XELJANZ); the total also includes some subjects who reported more than one adverse drug reaction (which inflates the percentage)

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)

Table 3: 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)
*
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 < 1% of subjects treated with XELJANZ); the total also includes some subjects who reported more than one adverse drug reaction (which inflates the percentage)

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)

Overall Infections

Rheumatoid Arthritis

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.

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

Psoriatic Arthritis

The incidence rates and types of overall infections in the two controlled Phase 3 PsA clinical studies were generally similar to those reported in RA clinical studies.

Ulcerative Colitis

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

Rheumatoid Arthritis

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 the 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 WARNINGS AND PRECAUTIONS).

Psoriatic arthritis

The incidence rates and types of serious infections in the two controlled Phase 3 PsA clinical studies were generally similar to those reported in RA clinical studies.

Ulcerative Colitis

The incidence rates and types of serious infections in the UC clinical trials were generally similar to those reported in RA 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 twice daily.

Tuberculosis

Cases of tuberculosis have been reported with treatment with XELJANZ

Rheumatoid Arthritis

In the five controlled 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 the 0 to 12 months 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-year) who received XELJANZ: 0.4% of patients (0.10 events/100 patient-year) and 0.6% of patients (0.17 events/100 patient-years) in the 5mg and 10mg 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 WARNINGS AND PRECAUTIONS).

Psoriatic Arthritis

The incidence rates of tuberculosis in the two controlled Phase 3 PsA clinical studies were generally similar to those reported in RA clinical studies.

Opportunistic Infections (excluding tuberculosis)

Rheumatoid Arthritis

In the five controlled 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 the 0 to 12 months 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.

Psoriatic Arthritis

The incidence rates and types of opportunistic infections in the two controlled Phase 3 PsA clinical studies were generally similar to those reported in RA clinical studies.

Ulcerative Colitis

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 twice daily.

Malignancy (excluding non-melanoma skin cancer)

Rheumatoid Arthritis

In the five controlled trials, during the 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 the 0 to 12 months 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 tofacitinib, 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 WARNINGS AND PRECAUTIONS).

Psoriatic Arthritis

The incidence rates of malignancies (excluding NMSC) in the two controlled Phase 3 PsA clinical studies were generally similar to those reported in RA clinical studies.

Ulcerative Colitis

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.

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.

Rheumatoid Arthritis

In the five 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 the 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.

Psoriatic Arthritis

The incidence rates of NMSC in the two controlled Phase 3 PsA clinical studies were generally similar to those reported in RA clinical studies.

Less Common Clinical Trial Adverse Drug Reactions (<1%)

Rheumatoid Arthritis

Blood and Lymphatic System Disorders: neutropenia

Cardiovascular: congestive heart failure, myocardial infarction

Gastrointestinal Disorders: abdominal pain

General Disorders and Administration site conditions: Influenza

Hepatobiliary Disorders: hepatic steatosis

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

Injury, Poisoning and Procedural Complications: muscle strain, fall

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

Metabolism and Nutrition Disorders: dehydration, dyslipidemia, hyperlipidemia

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

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

Nervous System Disorders: paraesthesia

Psychiatric Disorders: insomnia

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

Skin and Subcutaneous Tissue Disorders: erythema, pruritus

Psoriatic Arthritis ÷

The incidence rates of less common clinical trial adverse drug reactions (<1%) in the two controlled Phase 3 PsA clinical studies were generally similar to those reported in RA clinical studies.

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 MediastinalDisorders: sinus congestion

Skin and Subcutaneous Tissue Disorders: erythema, pruritus

Abnormal Hematologic and Clinical Chemistry 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 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 WARNINGS AND PRECAUTIONS and 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.

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 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 twice daily 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.

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 500 cells/mm3 occurred in 0.2% of patients for the 5 mg BID XELJANZ group during 12 months of exposure.

Confirmed lymphocyte counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections (see WARNINGS AND PRECAUTIONS).

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 500 cells/mm3 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 the 52-week maintenance study in UC, a single absolute lymphocyte count below 500 cells/mm3 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 500 cells/mm3 based on two sequential tests.

Neutrophils
In the controlled RA clinical studies, confirmed decreases in ANC below 1000/mm3 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 500/mm3 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 1000 cells/mm3 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 <0.1 mg/dL in the 12-month pooled safety analysis; however, with increasing duration of exposure in the long-term extension trial, up to 6.9% of patients were discontinued from XELJANZ treatment due to the protocol-specified discontinuation criterion of an increase in creatinine by more than 50% of baseline. The clinical significance of the observed serum creatinine elevations is unknown.

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 clinical trials in RA.

Post-Marketing Adverse Drug 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 CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS)

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

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