Summary of safety data.
| Tofacitinib All (5 and 10 mg BID ± background DMARD), n = 4102 | Tofacitinib 5 mg BID ± background DMARD, n = 1421 | Tofacitinib 10 mg BID ± background DMARD, n = 2681 | Tofacitinib 5 and 10 mg BID + background DMARD, n = 2742 | Tofacitinib 5 and 10 mg BID monotherapy, n = 1360 | |
|---|---|---|---|---|---|
| Total patient-yrs of exposure* | 5963 | 3215 | 2748 | 3684 | 2279 |
| Events, n (events per 100 patient-yrs) | |||||
| Patients with AE | 3152 (52.9) | 1181 (36.7) | 1971 (71.7) | 2051 (55.7) | 1101 (48.3) |
| Discontinuations due to AE | 437 (7.3) | 211 (6.6) | 226 (8.2) | 284 (7.7) | 153 (6.7) |
| Patients with serious AE | 630 (11.1) | 295 (9.8) | 335 (12.6) | 400 (10.9) | 230 (10.1) |
| Patients with malignancies exc. NMSC | 60 (1.0) | 33 (1.0) | 27 (1.0) | 36 (1.0) | 24 (1.0) |
| Mortality | 31 (0.5) | 21 (0.6) | 10 (0.4) | 22 (0.6) | 9 (0.4) |
| Most frequently reported treatment-emergent (all-causalities) AE by MedDRA preferred term, n (events per 100 patient-yrs) | |||||
| Nasopharyngitis | 521 (8.7) | 303 (9.4) | 218 (7.9) | 296 (8.0) | 225 (9.9) |
| Upper respiratory tract infection | 432 (7.2) | 141 (4.3) | 291 (10.6) | 290 (7.9) | 142 (6.2) |
| Urinary tract infection | 271 (4.5) | 95 (3.0) | 176 (6.4) | 195 (5.3) | 76 (3.3) |
| Bronchitis | 270 (4.5) | 127 (4.0) | 143 (5.2) | 181 (4.9) | 89 (3.9) |
| Herpes zoster | 245 (4.1) | 127 (4.0) | 118 (4.3) | 133 (3.6) | 112 (4.9) |
| Influenza | 162 (2.7) | 92 (2.9) | 70 (2.5) | 104 (2.8) | 58 (2.5) |
| Hypertension | 229 (3.8) | 128 (4.0) | 101 (3.7) | 149 (4.0) | 80 (3.5) |
| Headache | 185 (3.1) | 94 (2.9) | 91 (3.3) | 106 (2.9) | 79 (3.5) |
| Diarrhea | 179 (3.0) | 85 (2.6) | 94 (3.4) | 112 (3.0) | 67 (2.9) |
| Fall | 133 (2.2) | 73 (2.3) | 60 (2.2) | 83 (2.3) | 50 (2.2) |
| Infection events, n (events per 100 patient-yrs; 95% CI) | |||||
| Serious infection events‡ | 184 (3.1; 2.66, 3.55) | 84 (2.6; 2.11, 3.24) | 100 (3.6; 2.96, 4.38) | 111 (3.0; 2.50, 3.62) | 73 (3.2; 2.53, 4.01) |
| Opportunistic infections (including tuberculosis)‡ | 27 (0.4; 0.31, 0.65) | 13 (0.4; 0.23, 0.69) | 14 (0.5; 0.30, 0.85) | 18 (0.5; 0.31, 0.77) | 9 (0.4; 0.20, 0.75) |
| Tuberculosis‡ | 10 (0.2; 0.09, 0.31) | 5 (0.2; 0.06, 0.37) | 5 (0.2; 0.08, 0.43) | NR | NR |
| Herpes zoster‡ | 250 (4.3; 3.83, 4.90) | 128 (4.2; 3.51, 4.97) | 122 (4.5; 3.77, 5.38) | 137 (3.8; 3.23, 4.52) | 113 (5.2; 4.29, 6.20) |
| Adverse cardiovascular events of special interest, n (%) | |||||
| Nonfatal myocardial infarction | 3 (0.05) | 3 (0.1) | 0 | NR | NR |
| Nonfatal cerebrovascular accident | 10 (0.2) | 3 (0.1) | 7 (0.3) | NR | NR |
| Nonfatal congestive heart failure | 5 (0.1) | 2 (0.1) | 3 (0.1) | NR | NR |
| Composite adverse cardiovascular events§ | 16 (0.3) | 8 (0.3) | 8 (0.3) | NR | NR |
| Discontinuations due to AE (all causalities), n (%) | |||||
| Blood and lymphatic system disorders | 14 (0.3) | 7 (0.5) | 7 (0.3) | 11 (0.4) | 3 (0.2) |
| Hepatobiliary disorders | 11 (0.3) | 6 (0.4) | 5 (0.2) | 8 (0.3) | 3 (0.2) |
| Infections and infestations | 156 (3.8) | 69 (4.9) | 87 (3.2) | 89 (3.2) | 67 (4.9) |
| Investigations (e.g., blood, creatinine increased, ALT increased, AST increased) | 66 (1.6) | 31 (2.2) | 35 (1.3) | 50 (1.8) | 16 (1.2) |
| Neoplasms (benign, malignant, and unspecified) | 59 (1.4) | 34 (2.4) | 25 (0.9) | 34 (1.2) | 25 (1.8) |
| Temporary discontinuations / dose reduction of study medication due to AE (all-causalities), n (%) | |||||
| Any AE | 1032 (25.2) | 446 (31.4) | 586 (21.9) | 639 (23.3) | 393 (28.9) |
| Blood and lymphatic system disorders | 29 (0.7) | 9 (0.6) | 20 (0.7) | 20 (0.7) | 9 (0.7) |
| Hepatobiliary disorders | 16 (0.4) | 6 (0.4) | 10 (0.4) | 9 (0.3) | 7 (0.5) |
| Infections and infestations | 590 (14.4) | 264 (18.6) | 326 (12.2) | 358 (13.1) | 232 (17.1) |
| Neoplasms (benign, malignant and unspecified) | 12 (0.3) | 3 (0.2) | 9 (0.3) | 8 (0.3) | 4 (0.3) |
| Laboratory variable observations | |||||
| Decreased hemoglobin, n (%)† | n = 4095 | n = 1419 | n = 2676 | n = 2741 | n = 1354 |
| Decrease ≥ 1 g/dl to ≤ 2 g/dl | 521 (12.7) | 187 (13.2) | 334 (12.5) | 339 (12.4) | 182 (13.4) |
| Decrease > 2 g/dl to < 3 g/dl or hemoglobin > 7 g/dl, but < 8 g/dl | 109 (2.7) | 49 (3.5) | 60 (2.2) | 64 (2.3) | 45 (3.3) |
| Decrease of ≥ 3 g/dl or hemoglobin ≤ 7 g/dl | 41 (1.0) | 24 (1.7) | 17 (< 1.0) | 21 (< 1.0) | 20 (1.5) |
| Neutropenia, n (%)† | n = 4095 | n = 1419 | n = 2676 | n = 2741 | n = 1354 |
| 1500–1999 cells/mm3 | 158 (3.9) | 78 (5.5) | 80 (3.0) | 91 (3.3) | 67 (4.9) |
| 500–1499 cells/mm3 | 30 (< 1.0) | 15 (1.1) | 15 (< 1.0) | 20 (< 1.0) | 10 (< 1.0) |
| < 500 cells/mm3 | 0 | 0 | 0 | 0 | 0 |
| Lymphopenia, n (%)† | n = 4095 | n = 1419 | n = 2676 | n = 2741 | n = 1354 |
| 1500–1999 cells/mm3 | 966 (23.6) | 280 (19.7) | 686 (25.6) | 631 (23.0) | 335 (24.7) |
| 500–1499 cells/mm3 | 2197 (53.7) | 950 (66.9) | 1247 (46.6) | 1495 (54.5) | 702 (51.8) |
| < 500 cells/mm3 | 17 (< 1.0) | 9 (< 1.0) | 8 (< 1.0) | 12 (< 1.0) | 5 (< 1.0) |
| Aminotransferases, n (%) | n = 4054 | n = 1413 | n = 2641 | n = 2721 | n = 1333 |
| AST ≥ 1 × ULN with normal baseline | 1205 (29.7) | 471 (33.3) | 734 (27.8) | 832 (30.6) | 373 (28.0) |
| AST ≥ 2 × ULN with normal baseline | 152 (3.8) | 69 (4.9) | 83 (3.1) | 106 (3.9) | 46 (3.5) |
| AST ≥ 3 × ULN with normal baseline | 50 (1.2) | 25 (1.8) | 25 (1.0) | 37 (1.4) | 13 (1.0) |
| AST ≥ 1 × ULN without regard to baseline abnormality | 1516 (37.4) | 545 (38.6) | 971 (36.8) | 1097 (40.3) | 419 (31.4) |
| AST ≥ 2 × ULN without regard to baseline abnormality | 202 (5.0) | 90 (6.4) | 112 (4.2) | 147 (5.4) | 55 (4.1) |
| AST ≥ 3 × ULN without regard to baseline abnormality | 63 (1.6) | 31 (2.2) | 32 (1.2) | 45 (1.7) | 18 (1.4) |
| ALT ≥1 × ULN with normal baseline | 1134 (28.0) | 451 (31.9) | 683 (25.9) | 774 (28.5) | 360 (27.0) |
| ALT ≥2 × ULN with normal baseline | 244 (6.0) | 109 (7.7) | 135 (5.1) | 173 (6.4) | 71 (5.3) |
| ALT ≥3 × ULN with normal baseline | 90 (2.2) | 43 (3.0) | 47 (1.8) | 61 (2.2) | 29 (2.2) |
| ALT ≥1 × ULN without regard to baseline abnormality | 1513 (37.3) | 553 (39.1) | 960 (36.4) | 1089 (40.0) | 424 (31.8) |
| ALT ≥ 2 × ULN without regard to baseline abnormality | 355 (8.8) | 154 (10.9) | 201 (7.6) | 258 (9.5) | 97 (7.3) |
| ALT ≥ 3 × ULN without regard to baseline abnormality | 133 (3.3) | 64 (4.5) | 69 (2.6) | 95 (3.5) | 38 (2.9) |
| Serum creatinine, n (%)† | n = 4102 | n = 1421 | n = 2681 | n = 2742 | n = 1360 |
| > 50% from baseline | 136 (3.3) | 49 (3.4) | 87 (3.2) | 82 (3.0) | 54 (4.0) |
↵* Total patient-years of exposure are based on the safety population; some individual rates have been calculated using exposures based on specific databases for that variable/group.
↵† Two consecutive values.
↵‡ Some events may have occurred post end of treatment.
↵§ All cardiac deaths, i.e., coronary heart disease, cardiac death [sudden and other]; non-cardiac vascular death, i.e., pulmonary embolism cerebrovascular and other; non-fatal cardiovascular event, i.e., myocardial infarction (MI), procedural MI, cerebrovascular event. AE: adverse event; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BID: twice daily: DMARD: disease-modifying antirheumatic drug; MedDRA: Medical Dictionary for Regulatory Activities; NMSC, non melanoma skin cancer; NR: not reported; ULN: upper limit of normal.