Abstract
BACKGROUND:
On September 9, 2021, the US Food and Drug Administration (FDA) issued a drug safety communication and required revisions to the Boxed Warning for Xeljanz/Xeljanz XR (tofacitinib), Olumiant (baricitinib), and Rinvoq (upadacitinib) to include information about the risk of serious heart-related events, cancer, blood clots, and death. The Boxed Warning was based on a large safety randomized clinical trial of tofacitinib, but neither baricitinib nor upadacitinib has been studied in similar large safety clinical trials.
OBJECTIVE:
To evaluate characteristics of adverse event (AE) reporting of tofacitinib/XR, baricitinib, and upadacitinib to the FDA.
METHODS:
We analyzed the public FDA’s Adverse Event Reporting System data to examine reported AEs that were related to any of the 3 drugs between January 1, 2019, and September 30, 2021. Both brand and generic names of these drugs were used to identify these AEs. Frequencies of AE reports were evaluated by patient demographics (age and sex), type of reporter, reporter region, seriousness, and reactions related to death, cardiovascular, cancer, and blood clots. Chi-square tests were used to compare the proportion of characteristics of AEs between these drugs at P < 0.05.
RESULTS:
We identified 56,833 AE reports of tofacitinib/XR, 2,318 reports of baricitinib, and 5,359 reports of upadacitinib. Higher proportions of patients reporting AEs for tofacitinib/XR were older and female than for baricitinib and upadacitinib. Higher proportions of tofacitinib/XR and baricitinib AEs were reported by health professionals than for upadacitinib. Higher proportions of upadacitinib AEs were in the United States and more serious than those of tofacitinib/XR and baricitinib AEs (all group and paired comparisons at P < 0.05). Regarding reactions, baricitinib AEs had highest proportions of death (7.2%) and cancer-related (4.1%) events, whereas tofacitinib/XR AEs had the highest proportions of cardiovascular-related (14.1%) and blood clot–related (14.8%) events.
CONCLUSIONS:
Although baricitinib and upadacitinib are in the same drug class as tofacitinib/XR, their risk of serious cardiovascular events, cancer, blood clots, and death might not be similar. Findings from this hypothesis-generating study suggest that there may be differential AEs between Janus kinase inhibitors, and therefore, future research for robust comparative safety is warranted.
Plain language summary
The US Food and Drug Administration has sent a drug safety communication and warning for 3 Janus kinase inhibitors regarding the risk of serious heart-related events, cancer, blood clots, and death. Although Olumiant and Rinvoq are in the same drug class as Xeljanz/Xeljanz XR, their risk of these serious adverse events (AEs) might not be similar and should be further studied.
Implications for managed care pharmacy
Based on spontaneously reported AEs to the US Food and Drug Administration, Olumiant AE reports had the highest proportions of death (7.2%) and cancer-related (4.1%) events, whereas Xeljanz/Xeljanz XR AE reports had the highest proportions of cardiovascular-related (14.1%) and blood clot–related (14.8%) events. The heterogeneity in AE reporting profiles (death, cardiovascular, cancer, and blood clots) for these 3 Janus kinase inhibitors in real-world settings should be further evaluated in order to optimize formulary decisions in prescription benefit coverage.
Janus kinase (JAK) inhibitors are the newest class of drugs in rheumatoid arthritis (RA) treatment. JAK inhibitors are small molecule oral treatments and offer a clinically efficacious long-term oral biologic treatment option in RA.1 The first JAK inhibitor tofacitinib was approved by the US Food and Drug Administration (FDA) in November 2012 and marketed under the brand names Xeljanz and Xeljanz XR (extended-release) (Pfizer).2 Olumiant (baricitinib) by Eli Lilly and Rinvoq (upadacitinib) by AbbVie received FDA approval in May 2018 and August 2019, respectively.3,4 These 3 JAK inhibitors currently marketed in the United States to treat arthritis and other inflammatory conditions have different JAK targets: tofacitinib/XR has greater selectivity for JAK1/JAK3, baricitinib is a JAK1/JAK2 inhibitor with moderate activity against TYK2 and minimal activity against JAK3, and upadacitinib solely targets the JAK1 pathway.1 A recently published systematic review and meta-analysis synthesized results from 50 randomized controlled trials including 24,135 adult patients with active RA and provided evidence for the superiority of JAK inhibitors in improving pain and patient-reported outcomes and disease activity indices in RA, compared with placebo, methotrexate, and biological disease-modifying antirheumatic drugs.5 Although this systematic review and meta-analysis focused on efficacy in pain and patient-reported outcomes, it identified no significant difference regarding safety of JAK inhibitors.5
On September 1, 2021, the FDA issued a drug safety communication and required revisions to the Boxed Warning, FDA’s most prominent warning, for tofacitinib/XR, baricitinib, and upadacitinib to include information about the risk of serious heart-related events, cancer, blood clots, and death.6 The FDA’s warning was based on a completed FDA review of a large randomized safety clinical trial comparing tofacitinib with another arthritis treatment—tumor necrosis factor (TNF) blockers—in patients with RA, which found an increased risk of blood clots and death with approved dose of tofacitinib (5 mg twice daily).6 Given the same drug class as tofacitinib/XR, the FDA considered that baricitinib and upadacitinib may have similar risks as seen in the tofacitinib safety trial.6 However, neither baricitinib nor upadacitinib has been studied in similar large safety clinical trials. Their risks of these adverse events (AEs) have not been adequately evaluated. One phase 3 trial (RA-BEAM) reported similar incidence rates for treatment-emergent AEs and infections, including serious events, among patients with RA who switched from a standard TNF blockers treatment to baricitinib and those who continued on baricitinib.7 Another randomized phase 3 trial (SELECT-COMPARE) assessed long-term safety of upadacitinib vs a standard TNF blockers treatment over 3 years among patients with active RA and inadequate response to methotrexate, which found higher incidence rates of herpes zoster, lymphopaenia, and hepatic disorder among patients with upadacitinib compared with the TNF blockers treatment, but not malignancies, major adverse cardiac events, venous thromboembolism, and deaths.8
We analyzed the public FDA’s Adverse Event Reporting System (FAERS) data to examine the characteristics of reported AEs that were related to any of the 3 drugs (tofacitinib/XR, baricitinib, and upadacitinib) between January 1, 2019, and September 30, 2021. Findings from this study could provide exploratory and new evidence in type and severity of reported AEs of these 3 JAK inhibitors currently marketed in the United States. Understanding the differences in characteristics of reported AEs could help researchers and policymakers to develop rigorous, controlled studies to evaluate risk of serious heart-related events, cancer, blood clots, and death for these JAK inhibitors.
Methods
DATA SOURCE
This analysis used the FAERS Public Dashboard data, which is a highly interactive web-based tool that allows for the querying of FAERS data in a user-friendly fashion.9 The FAERS is a database that contains AE reports, medication error reports, and product quality complaints resulting in AEs that were submitted to the FDA.10 The FAERS is designed to support the FDA’s postmarketing safety surveillance program for drug and therapeutic biologic products. Health care professionals (voluntary), consumers (voluntary), and manufacturers (mandatory) may all submit AE reports to FAERS.10 However, the FDA does not require that a causal relationship between a product and an AE be proven, and not all AEs or medication errors that occur with a product are reported to FAERS.10 FAERS has been used to detect potential drug safety signals in postmarketing surveillance studies (eg, remdesivir with serious renal and cardiac AEs among patients with coronavirus disease 2019 [COVID-19]11) as well as regulatory sciences. Title IX, Section 921 of the FDA Amendments Act of 2007 requires the FDA to conduct regular, biweekly screening of FAERS and post quarterly reports to identify potential signals of serious risks/new safety information.12 One study evaluated a total of 555 potential signals of serious risk or new safety information posted by the FDA since the beginning of the FDA Amendments Act Section 921 posting requirement, and found 47% (n = 262) of these posts resulting in decisions requiring updated product labeling and 39% (n = 218) indicating that the FDA was evaluating the need for regulatory action.13
MEASUREMENTS AND STATISTICAL APPROACH
Both brand and generic names of tofacitinib/XR, baricitinib, and upadacitinib were manually searched using the search function in the FAERS Public Dashboard. All AEs related to these 3 drugs were identified and downloaded, and we limited our analysis to identified AE reports between January 1, 2019, and September 30, 2021. Frequencies of AE reports were evaluated by patient demographics (age and sex), type of reporter (health care professionals, consumers, not specified/other), reporter region (United States and non-United States), seriousness (serious and nonserious), and reactions related to death, cardiovascular events, cancer, and blood clots. Serious AEs have been predefined by the FDA and categorized as death, hospitalization, life-threatening, disability, congenital anomaly, and/or other serious outcome.10 A clinician investigator screened the reported reactions of AE reports of these 3 JAK inhibitors to identify and categorize reactions related to cardiovascular events, cancer, and blood clots (Supplementary Table 1 (96.4KB, pdf) , available in online article) in corresponding to the FDA’s Boxed Warning, then verified by a second investigator (discrepancies were resolved by group consensus). Death cases were reported as an outcome of each FAERS AE report. Given that tofacitinib/XR and baricitinib were tested in clinical trials for treating severe acute respiratory syndrome coronavirus 2 pneumonia shortly after the declaration of the COVID-19 pandemic in the United States on March 13, 2020,14-16 we also conducted a sensitivity analysis limiting to tofacitinib/XR and baricitinib AE reports between January 1, 2019, and March 13, 2020. Chi-square tests were used to compare the proportion of characteristics of AEs between all of these 3 drugs and each pair of the drugs at P < 0.05. All analyses were conducted using SAS (version 9.4; SAS Institute).
Results
We identified 56,833 AE reports of tofacitinib/XR, 2,318 reports of baricitinib, and 5,359 reports of upadacitinib between January 1, 2019, and September 30, 2021 (Table 1). Higher proportions of patients reporting AEs for tofacitinib/XR were older and female compared with baricitinib and upadacitinib (significantly different between all groups and paired comparisons at P < 0.05). Specifically, 76.5% of AE reports for tofacitinib/XR were related to female patients (vs 19.7% related to male patients), whereas 70.9% of AE reports for baricitinib (vs 22.6% related to males) and 75.1% AE reports for upadacitinib (vs 20.5% related to males) were related to female patients. Higher proportions of tofacitinib/XR (57.3%) and baricitinib (54.5%) AEs were reported by health professionals than for upadacitinib (16.1%), and the proportions of reporter type were significantly different between all groups and paired comparisons (all P < 0.001). Higher proportions of upadacitinib AE reports were in the United States (79.4%) and serious (79.6%) than those of tofacitinib/XR (77.3% and 45.2%, respectively) and baricitinib (45.9% and 65.3%, respectively) AE reports (all groups and paired comparisons at P < 0.05).
TABLE 1.
Characteristics and Comparisons of Adverse Event Reports for Rinvoq, Xeljanz/Xeljanz XR, and Olumiant in the FAERS Between January 1, 2019, and September 30, 2021
| Characteristics | Rinvoq | Xeljanz/Xeljanz XR | Olumiant | P valuea | P valueb | P valuec | P valued |
|---|---|---|---|---|---|---|---|
| Total number of reports | 5,359 | 56,833 | 2,318 | ||||
| Patient age, n (%) | |||||||
| ≤ 18 years | 12 (0.2) | 283 (0.5) | 7 (0.3) | < 0.0001 | < 0.0001 | < 0.0001 | < 0.0001 |
| 19-64 years | 1,871 (34.9) | 30,170 (53.1) | 843 (36.4) | ||||
| 65-84 years | 1,058 (19.7) | 18,433 (32.4) | 750 (32.4) | ||||
| ≥ 85 years | 55 (1.0) | 847 (1.5) | 51 (2.2) | ||||
| Not specified | 2,363 (44.1) | 7,100 (12.5) | 667 (28.8) | ||||
| Patient sex, n (%) | |||||||
| Female | 4,023 (75.1) | 43,471 (76.5) | 1,643 (70.9) | < 0.0001 | 0.0250 | < 0.0001 | < 0.0001 |
| Male | 1,101 (20.5) | 11,203 (19.7) | 523 (22.6) | ||||
| Not specified | 235 (4.4) | 2,159 (3.8) | 152 (6.6) | ||||
| Type of reporter, n (%) | |||||||
| Health care professional | 862 (16.1) | 32,547 (57.3) | 1,264 (54.5) | < 0.0001 | < 0.0001 | < 0.0001 | < 0.0001 |
| Consumer | 3,984 (74.3) | 22,999 (40.5) | 807 (34.8) | ||||
| Not specified/other | 513 (9.6) | 1,287 (2.3) | 247 (10.7) | ||||
| Location of adverse event, n (%) | |||||||
| United States | 4,257 (79.4) | 43,909 (77.3) | 1,063 (45.9) | < 0.0001 | 0.0003 | < 0.0001 | < 0.0001 |
| Non–United States | 1,102 (20.6) | 12,924 (22.7) | 1,255 (54.1) | ||||
| Severity of adverse events, n (%) | |||||||
| Serious | 4,267 (79.6) | 25,658 (45.2) | 1,514 (65.3) | < 0.0001 | < 0.0001 | < 0.0001 | < 0.0001 |
| Nonserious | 1,092 (20.4) | 31,175 (54.9) | 804 (34.7) | ||||
| Reactions, n (%) | |||||||
| Death | 203 (3.8) | 1,597 (2.8) | 167 (7.2) | < 0.0001 | < 0.0001 | < 0.0001 | < 0.0001 |
| Cardiovascular-related events | 243 (4.5) | 8,017 (14.1) | 237 (10.2) | < 0.0001 | < 0.0001 | < 0.0001 | < 0.0001 |
| Cancer-related events | 190 (3.6) | 1,601 (2.8) | 94 (4.1) | < 0.0001 | 0.0020 | 0.2770 | 0.0005 |
| Blood clot–related events | 230 (4.3) | 8,416 (14.8) | 318 (13.7) | < 0.0001 | < 0.0001 | < 0.0001 | 0.1470 |
a P value: Chi-square test comparing all 3 drugs.
b P value: Rinvoq vs Xeljanz/Xeljanz XR.
c P value: Rinvoq vs Olumiant.
d P value: Xeljanz/Xeljanz XR; vs Olumiant.
FAERS = US Food and Drug Administration’s Adverse Event Reporting System.
Regarding reactions, tofacitinib/XR AE reports had the highest proportions of cardiovascular-related (14.1%) and blood clot–related (14.8%) events, followed by baricitinib (cardiovascular-related [10.2%] and blood clot–related [13.7%] events) and upadacitinib (cardiovascular-related [4.5%] and blood clot–related [4.3%] events). Baricitinib AE reports had the highest proportions of cancer-related events (4.1%) and death (7.2%), followed by upadacitinib (cancer-related events [3.6%] and death [3.8%]) and tofacitinib/XR (cancer related-events [2.8%] and death [2.8%]). All 3 drug comparisons and paired drug comparisons on the proportions of these adverse reactions were statistically significantly different at P < 0.05, except for proportion of cancer-related events between baricitinib and upadacitinib and proportion of blood clot–related events between tofacitinib/XR and baricitinib (Table 1).
FINDINGS FROM SENSITIVITY ANALYSIS
A total number of 22,586 AE reports of tofacitinib/XR and 1,153 reports of baricitinib were identified between January 1, 2019, and March 13, 2020 (Table 2). Similar to results from the main analysis, higher proportions of patients reporting AEs for tofacitinib/XR were older and female than for baricitinib and upadacitinib. Higher proportions of tofacitinib/XR (52.3%) and baricitinib (73.1%) AEs were reported by health professionals than for upadacitinib (16.1%). Much higher proportions of AE reports of tofacitinib/XR (80.5%) and upadacitinib (79.4%) were in the United States than baricitinib (48.6%) (all group and paired comparisons were statistically significant at P < 0.05; Table 2). Upadacitinib AE reports (79.6%) still had the highest proportion of serious AEs compared with tofacitinib/XR (41.5%) and baricitinib (56.9%). Tofacitinib/XR AE reports still had the highest proportions of cardiovascular-related (11.8%) and blood clot–related (13.5%) events, and baricitinib AE reports still had highest proportions of death (6.0%) and cancer-related (4.2%) events.
TABLE 2.
Characteristics and Comparisons of Adverse Event Reports for Rinvoq, Xeljanz/Xeljanz XR, and Olumiant in the FAERS Between January 1, 2019, and March 13, 2020 (Sensitivity Analysis)
| Characteristics | Rinvoq | Xeljanz/Xeljanz XR | Olumiant | P valuea | P valueb | P valuec | P valued |
|---|---|---|---|---|---|---|---|
| Total number of reports | 5,359 | 22,586 | 1,153 | ||||
| Patient age, n (%) | |||||||
| ≤ 18 years | 12 (0.2) | 100 (0.4) | 2 (0.2) | < 0.0001 | < 0.0001 | < 0.0001 | < 0.0001 |
| 19-64 years | 1,871 (34.9) | 11,525 (51.0) | 410 (35.6) | ||||
| 65-84 years | 1,058 (19.7) | 7,443 (33.0) | 372 (32.3) | ||||
| ≥ 85 years | 55 (1.0) | 351 (1.6) | 25 (2.2) | ||||
| Not specified | 2,363 (44.1) | 3,167 (14.0) | 344 (29.8) | ||||
| Patient sex, n (%) | |||||||
| Female | 4,023 (75.1) | 17,299 (76.6) | 857 (74.3) | 0.0040 | 0.0170 | 0.3420 | 0.0110 |
| Male | 1,101 (20.5) | 4,451 (19.7) | 234 (20.3) | ||||
| Not specified | 235 (4.4) | 836 (3.7) | 62 (5.4) | ||||
| Type of reporter, n (%) | |||||||
| Health care professional | 862 (16.1) | 11,821 (52.3) | 843 (73.1) | < 0.0001 | < 0.0001 | < 0.0001 | < 0.0001 |
| Consumer | 3,984 (74.3) | 10,093 (44.7) | 165 (14.3) | ||||
| Not specified/other | 513 (9.6) | 672 (3.0) | 145 (12.6) | ||||
| Location of adverse event, n (%) | |||||||
| United States | 4,257 (79.4) | 18,177 (80.5) | 560 (48.6) | < 0.0001 | 0.0850 | < 0.0001 | < 0.0001 |
| Non–United States | 1,102 (20.6) | 4,409 (19.5) | 593 (51.4) | ||||
| Severity of adverse events, n (%) | |||||||
| Serious | 4,267 (79.6) | 9,378 (41.5) | 656 (56.9) | < 0.0001 | < 0.0001 | < 0.0001 | < 0.0001 |
| Nonserious | 1,092 (20.4) | 13,208 (58.5) | 497 (43.1) | ||||
| Reactions, n (%) | |||||||
| Death | 203 (3.8) | 707 (3.1) | 69 (6.0) | < 0.0001 | 0.0150 | 0.0007 | < 0.0001 |
| Cardiovascular-related events | 243 (4.5) | 2,671 (11.8) | 117 (10.2) | < 0.0001 | < 0.0001 | < 0.0001 | 0.0840 |
| Cancer-related events | 190 (3.6) | 599 (2.7) | 48 (4.2) | < 0.0001 | 0.0004 | 0.3110 | 0.0020 |
| Blood clot–related events | 230 (4.3) | 3,050 (13.5) | 149 (12.9) | < 0.0001 | < 0.0001 | < 0.0001 | 0.5730 |
Rinvoq reports included between January 1, 2019, and September 30, 2021; Xeljanz/Xeljanz XR and Olumiant reports included between January 1, 2019, and March 13, 2020.
a P value: Chi-square test comparing all 3 drugs.
b P value 2: Rinvoq vs Xeljanz/Xeljanz XR.
c P value: Rinvoq vs Olumiant.
d P value: Xeljanz/Xeljanz XR vs Olumiant.
FAERS = US Food and Drug Administration’s Adverse Event Reporting System.
Discussion
This exploratory analysis assessed and compared characteristics of AE reports of tofacitinib/XR, baricitinib, and upadacitinib with the FDA. We found significant differences in proportions of AEs across these 3 drugs by patient demographics (age and sex), type of reporter, region, seriousness, and reactions related to death, cardiovascular events, cancer, and blood clots. During the study period, although a higher proportion of upadacitinib AE reports were serious events than those of tofacitinib/XR and baricitinib, baricitinib AE reports had the highest proportions of death and cancer-related events, and tofacitinib/XR AE reports had the highest proportions of cardiovascular-related and blood clot–related events.
The FDA Boxed Warning on JAK inhibitors regarding increased risk of serious heart-related events such as heart attack or stroke, cancer, blood clots, and death was based on a completed review of a large randomized safety clinical trial comparing tofacitinib with TNF blockers in patients with RA.17 The trial’s final results showed an increased risk of blood clots and death with approved dose of tofacitinib.17 However, at the time of the FDA’s Boxed Warning, baricitinib and upadacitinib have not been studied in trials similar to the large safety clinical trial with tofacitinib, so their risks have not been adequately evaluated.6 Therefore, it is critical to conduct a postmarketing analysis to monitor potential safety events of these drugs. One recent analysis using the FAERS (2013-2020) included 23,720 AEs related to tofacitinib/XR, baricitinib, and upadacitinib and identified reporting risk signals for infections and vascular disorders for all 3 drugs.18 However, 91.5% of AE reports included in this analysis were reports on tofacitinib/XR.18 Our analysis focused on the difference in distributions of characteristics of AE reports across the 3 JAK inhibitors, and we found heterogeneity in patient characteristics and AE reactions related to death, cardiovascular events, cancer, and blood clots. We found the highest proportion of death and cancer-related events for baricitinib AE reports among the 3 assessed JAK inhibitors, which is consistent with Song et al.18 We found the highest proportion of cardiovascular-related and blood clot–related events for tofacitinib/XR AE reports, which also supports the FDA Boxed Warning on such AEs.17 However, the heterogeneity in AE profiles for these 3 JAK inhibitors found in our study highlight the necessity in monitoring routine clinical practice for each individual drugs. Future research using longitudinal, real-world databases is warranted to test the hypotheses of individual JAK inhibitor exposures and these AE outcomes.
LIMITATIONS
Study limitations included the embedded limitations with the FAERS data. Given that it is a spontaneous reporting system, AE reports received by the FDA are likely prone to underreporting bias because the FDA does not receive reports for every AE or medication error that occurs with a product.10 In addition, there were missing data in patient demographics such as age and sex, as well as type of reporter in the FAERS, which may lead to imprecise estimates of distributions of AE reporting characteristics for the study drugs. Third, the AE reporting for tofacitinib/XR and baricitinib might have been impacted by COVID-19 cases because these 2 drugs were tested in clinical trials for treating severe acute respiratory syndrome coronavirus 2 pneumonia during the study period. Therefore, we conducted a sensitivity analysis limiting to AE reports of these 2 drugs prior to the declaration of the COVID-19 pandemic in the United States. Most importantly, the nature of the spontaneous reporting database such as FAERS provides no certainty that the reported event (AE or medication error) was due to the product.10 Therefore, our findings could not establish the causal relationship between serious and/or certain type of AEs and the studied JAK inhibitors. However, our findings provided new evidence in the heterogeneity in AE profiles (death, cardiovascular events, cancer, and blood clots) for these 3 JAK inhibitors in real-world settings.
Conclusions
Although baricitinib and upadacitinib are in the same drug class as tofacitinib/XR, their risk of serious cardiovascular events, cancer, blood clots, and death might not be similar and should be further evaluated. Findings from this hypothesis-generating study suggest that there may be differential AEs between JAK inhibitors. Given the limitation of FAERS data, future research using longitudinal, real-world databases is warranted to test the hypotheses of individual JAK inhibitor exposures and these AE outcomes.
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