Chemical formula: C₁₇H₁₉F₃N₆O Molecular mass: 380.375 g/mol
The limited human data on use of upadacitinib in pregnant women are not sufficient to evaluate a drug-associated risk for major birth defects or miscarriage. Based on animal studies, upadacitinib has the potential to adversely affect a developing fetus.
In animal embryo-fetal development studies, oral upadacitinib administration to pregnant rats and rabbits at exposures equal to or greater than approximately 1.6 and 15 times the maximum recommended human dose (MRHD), respectively, resulted in dose-related increases in skeletal malformations (rats only), an increased incidence of cardiovascular malformations (rabbits only), increased post-implantation loss (rabbits only), and decreased fetal body weights in both rats and rabbits. No developmental toxicity was observed in pregnant rats and rabbits treated with oral upadacitinib during organogenesis at approximately 0.3 and 2 times the exposure at the MRHD. In a pre- and post-natal development study in pregnant female rats, oral upadacitinib administration at exposures approximately 3 times the MRHD resulted in no maternal or developmental toxicity [see Animal Data].
The estimated background risks of major birth defects and miscarriage for the indicated population(s) are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages are 2-4% and 15-20%, respectively.
Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with rheumatoid arthritis. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth.
In an oral embryo-fetal development study, pregnant rats received upadacitinib at doses of 5, 25, and 75 mg/kg/day during the period of organogenesis from gestation day 6 to 17. Upadacitinib was teratogenic (skeletal malformations that consisted of misshapen humerus and bent scapula) at exposures equal to or greater than approximately 1.7 times the MRHD (on an AUC basis at maternal oral doses of 5 mg/kg/day and higher). Additional skeletal malformations (bent forelimbs/hindlimbs and rib/vertebral defects) and decreased fetal body weights were observed in the absence of maternal toxicity at an exposure approximately 84 times the MRHD (on an AUC basis at a maternal oral dose of 75 mg/kg/day).
In a second oral embryo-fetal development study, pregnant rats received upadacitinib at doses of 1.5 and 4 mg/kg/day during the period of organogenesis from gestation day 6 to 17. Upadacitinib was teratogenic (skeletal malformations that included bent humerus and scapula) at exposures approximately 1.6 times the MRHD (on an AUC basis at maternal oral doses of 4 mg/kg/day). No developmental toxicity was observed in rats at an exposure approximately 0.3 times the MRHD (on an AUC basis at a maternal oral dose of 1.5 mg/kg/day).
In an oral embryo-fetal developmental study, pregnant rabbits received upadacitinib at doses of 2.5, 10, and 25 mg/kg/day during the period of organogenesis from gestation day 7 to 19. Embryolethality, decreased fetal body weights, and cardiovascular malformations were observed in the presence of maternal toxicity at an exposure approximately 15 times the MRHD (on an AUC basis at a maternal oral dose of 25 mg/kg/day). Embryolethality consisted of increased post-implantation loss that was due to elevated incidences of both total and early resorptions. No developmental toxicity was observed in rabbits at an exposure approximately 2 times the MRHD (on an AUC basis at a maternal oral dose of 10 mg/kg/day).
In an oral pre- and post-natal development study, pregnant female rats received upadacitinib at doses of 2.5, 5, and 10 mg/kg/day from gestation day 6 through lactation day 20. No maternal or developmental toxicity was observed in either mothers or offspring, respectively, at an exposure approximately 3 times the MRHD (on an AUC basis at a maternal oral dose of 10 mg/kg/day).
There are no data on the presence of upadacitinib in human milk, the effects on the breastfed infant, or the effects on milk production. Available pharmacodynamic/toxicological data in animals have shown excretion of upadacitinib in milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because of the potential for serious adverse reactions in the breastfed infant, advise patients that breastfeeding is not recommended during treatment with upadacitinib, and for 6 days (approximately 10 half-lives) after the last dose.
A single oral dose of 10 mg/kg radiolabeled upadacitinib was administered to lactating female Sprague-Dawley rats on post-partum days 7-8. Drug exposure was approximately 30-fold greater in milk than in maternal plasma based on AUC0-t values. Approximately 97% of drug-related material in milk was parent drug.
The carcinogenic potential of upadacitinib was evaluated in Sprague-Dawley rats and Tg.rasH2 mice. No evidence of tumorigenicity was observed in male or female rats that received upadacitinib for up to 101 weeks at oral doses up to 15 or 20 mg/kg/day, respectively (approximately 4 and 10 times the MRHD on an AUC basis, respectively). No evidence of tumorigenicity was observed in male or female Tg.rasH2 mice that received upadacitinib for 26 weeks at oral doses up to 20 mg/kg/day.
Upadacitinib tested negatively in the following genotoxicity assays: the in vitro bacterial mutagenicity assay (Ames assay), in vitro chromosome aberration assay in human peripheral blood lymphocytes, and in vivo rat bone marrow micronucleus assay.
Upadacitinib had no effect on fertility in male or female rats at oral doses up to 50 mg/kg/day in males and 75 mg/kg/day in females (approximately 42 and 84 times the MRHD in males and females, respectively, on an AUC basis). However, maintenance of pregnancy was adversely affected at oral doses of 25 mg/kg/day and 75 mg/kg/day based upon dose-related findings of increased post-implantation losses (increased resorptions) and decreased numbers of mean viable embryos per litter (approximately 22 and 84 times the MRHD on an AUC basis, respectively). The number of viable embryos was unaffected in female rats that received upadacitinib at an oral dose of 5 mg/kg/day and were mated to males that received the same dose (approximately 2 times the MRHD on an AUC basis).
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
A total of 3833 patients with rheumatoid arthritis were treated with upadacitinib in the Phase 3 clinical studies of whom 2806 were exposed for at least one year.
Patients could advance or switch to upadacitinib 15 mg from placebo, or be rescued to upadacitinib from active comparator or placebo from as early as Week 12 depending on the study design.
A total of 2630 patients received at least 1 dose of upadacitinib 15 mg, of whom 1860 were exposed for at least one year. In studies RA-I, RA-II, RA-III and RA-V, 1213 patients received at least 1 dose of upadacitinib 15 mg, of which 986 patients were exposed for at least one year, and 1203 patients received at least 1 dose of upadacitinib 30 mg, of which 946 were exposed for at least one year.
Adverse Reactions Reported in greater than or equal to 1% of Rheumatoid Arthritis Patients Treated with Upadacitinib 15 mg in Placebo-controlled Studies:
| Adverse Reaction | Placebo | Upadacitinib 15 mg |
|---|---|---|
| n=1042 (%) | n=1035 (%) | |
| Upper respiratory tract infection (URTI)* | 9.5 | 13.5 |
| Nausea | 2.2 | 3.5 |
| Cough | 1.0 | 2.2 |
| Pyrexia | 0 | 1.2 |
* URTI includes: acute sinusitis, laryngitis, nasopharyngitis, oropharyngeal pain, pharyngitis, pharyngotonsillitis, rhinitis, sinusitis, tonsillitis, viral upper respiratory tract infection
Other adverse reactions reported in less than 1% of patients in the upadacitinib 15 mg group and at a higher rate than in the placebo group through Week 12 included pneumonia, herpes zoster, herpes simplex (includes oral herpes), and oral candidiasis.
Four integrated datasets are presented in the Specific Adverse Reaction section:
Placebo-controlled Studies: Studies RA-III, RA-IV, and RA-V were integrated to represent safety through 12/14 weeks for placebo (n=1042) and upadacitinib 15 mg (n=1035). Studies RA-III and RA-V were integrated to represent safety through 12 weeks for placebo (n=390), upadacitinib 15 mg (n=385), upadacitinib 30 mg (n=384). Study RA-IV did not include the 30 mg dose and, therefore, safety data for upadacitinib 30 mg can only be compared with placebo and upadacitinib 15 mg rates from pooling studies RA-III and RA-V.
MTX-controlled Studies: Studies RA-I and RA-II were integrated to represent safety through 12/14 weeks for MTX (n=530), upadacitinib 15 mg (n=534), and upadacitinib 30 mg (n=529).
12-Month Exposure Dataset: Studies RA-I, II, III, and V were integrated to represent the long-term safety of upadacitinib 15 mg (n=1213) and upadacitinib 30 mg (n=1203).
Exposure adjusted incidence rates were adjusted by study for all the adverse events reported in this section.
Placebo-controlled Studies: In RA-III, RA-IV, and RA-V, infections were reported in 218 patients (95.7 per 100 patient-years) treated with placebo and 284 patients (127.8 per 100 patient-years) treated with upadacitinib 15 mg. In RA-III and RA-V, infections were reported in 99 patients (136.5 per 100 patient-years) treated with placebo, 118 patients (164.5 per 100 patient-years) treated with upadacitinib 15 mg, and 126 patients (180.3 per 100 patient-years) treated with upadacitinib 30 mg.
MTX-controlled Studies: Infections were reported in 127 patients (119.5 per 100 patient-years) treated with MTX monotherapy, 104 patients (91.8 per 100 patient-years) treated with upadacitinib 15 mg monotherapy, and 128 patients (115.1 per 100 patient-years) treated with upadacitinib 30 mg monotherapy.
12-Month Exposure Dataset: Infections were reported in 615 patients (83.8 per 100 patient-years) treated with upadacitinib 15 mg and 674 patients (99.7 per 100 patient-years) treated with upadacitinib 30 mg.
Placebo-controlled Studies: In RA-III, RA-IV, and RA-V, serious infections were reported in 6 patients (2.3 per 100 patient-years) treated with placebo, and 12 patients (4.6 per 100 patient-years) treated with upadacitinib 15 mg. In RA-III and RA-V, serious infections were reported in 1 patient (1.2 per 100 patient-years) treated with placebo, 2 patients (2.3 per 100 patient-years) treated with upadacitinib 15 mg, and 7 patients (8.2 per 100 patient-years) treated with upadacitinib 30 mg.
MTX-controlled Studies: Serious infections were reported in 2 patients (1.6 per 100 patient-years) treated with MTX monotherapy, 3 patients (2.4 per 100 patient-years) treated with upadacitinib 15 mg monotherapy, and 8 patients (6.4 per 100 patient-years) treated with upadacitinib 30 mg monotherapy.
12-Month Exposure Dataset: Serious infections were reported in 38 patients (3.5 per 100 patient-years) treated with upadacitinib 15 mg and 59 patients (5.6 per 100 patient-years) treated with upadacitinib 30 mg.
The most frequently reported serious infections were pneumonia and cellulitis.
Placebo-controlled Studies and MTX-controlled Studies: In the placebo-controlled period, there were no active cases of tuberculosis reported in the placebo, upadacitinib 15 mg, and upadacitinib 30 mg groups. In the MTX-controlled period, there were no active cases of tuberculosis reported in the MTX monotherapy, upadacitinib 15 mg monotherapy, and upadacitinib 30 mg monotherapy groups.
12-Month Exposure Dataset: Active tuberculosis was reported for 2 patients treated with upadacitinib 15 mg and 1 patient treated with upadacitinib 30 mg. Cases of extra-pulmonary tuberculosis were reported.
Placebo-controlled Studies: In RA-III, RA-IV, and RA-V, opportunistic infections were reported in 3 patients (1.2 per 100 patient-years) treated with placebo, and 5 patients (1.9 per 100 patient-years) treated with upadacitinib 15 mg. In RA-III and RA-V, opportunistic infections were reported in 1 patient (1.2 per 100 patient-years) treated with placebo, 2 patients (2.3 per 100 patient-years) treated with upadacitinib 15 mg, and 6 patients (7.1 per 100 patient-years) treated with upadacitinib 30 mg.
MTX-controlled Studies: Opportunistic infections were reported in 1 patient (0.8 per 100 patient-years) treated with MTX monotherapy, 0 patients treated with upadacitinib 15 mg monotherapy, and 4 patients (3.2 per 100 patient-years) treated with upadacitinib 30 mg monotherapy.
12-Month Exposure Dataset: Opportunistic infections were reported in 7 patients (0.6 per 100 patient-years) treated with upadacitinib 15 mg and 15 patients (1.4 per 100 patient-years) treated with upadacitinib 30 mg.
Placebo-controlled Studies: In RA-III, RA-IV, and RA-V, malignancies excluding NMSC were reported in 1 patient (0.4 per 100 patient-years) treated with placebo, and 1 patient (0.4 per 100 patient-years) treated with upadacitinib 15 mg. In RA-III and RA-V, malignancies excluding NMSC were reported in 0 patients treated with placebo, 1 patient (1.1 per 100 patient-years) treated with upadacitinib 15 mg, and 3 patients (3.5 per 100 patient-years) treated with upadacitinib 30 mg.
MTX-controlled Studies: Malignancies excluding NMSC were reported in 1 patient (0.8 per 100 patient-years) treated with MTX monotherapy, 3 patients (2.4 per 100 patient-years) treated with upadacitinib 15 mg monotherapy, and 0 patients treated with upadacitinib 30 mg monotherapy.
12-Month Exposure Dataset: Malignancies excluding NMSC were reported in 13 patients (1.2 per 100 patient-years) treated with upadacitinib 15 mg and 14 patients (1.3 per 100 patient-years) treated with upadacitinib 30 mg.
Placebo-controlled Studies: There were no gastrointestinal perforations (based on medical review) reported in patients treated with placebo, upadacitinib 15 mg, and upadacitinib 30 mg.
MTX-controlled Studies: There were no cases of gastrointestinal perforations reported in the MTX and upadacitinib 15 mg group through 12/14 weeks. Two cases of gastrointestinal perforations were observed in the upadacitinib 30 mg group.
12-Month Exposure Dataset: Gastrointestinal perforations were reported in 1 patient treated with upadacitinib 15 mg and 4 patients treated with upadacitinib 30 mg.
Placebo-controlled Studies: In RA-IV, venous thrombosis (pulmonary embolism or deep vein thrombosis) was observed in 1 patient treated with placebo and 1 patient treated with upadacitinib 15 mg. In RA-V, venous thrombosis was observed in 1 patient treated with upadacitinib 15 mg. There were no observed cases of venous thrombosis reported in RA-III. No cases of arterial thrombosis were observed through 12/14 weeks.
MTX-controlled Studies: In RA-II, venous thrombosis was observed in 0 patients treated with MTX monotherapy, 1 patient treated with upadacitinib 15 mg monotherapy and 0 patients treated with upadacitinib 30 mg monotherapy through Week 14. In RA-II, no cases of arterial thrombosis were observed through 12/14 weeks. In RA-I, venous thrombosis was observed in 1 patient treated with MTX, 0 patients treated with upadacitinib 15 mg and 1 patient treated with upadacitinib 30 mg through Week 24. In RA-I, arterial thrombosis was observed in 1 patient treated with upadacitinib 30 mg through Week 24.
12-Month Exposure Dataset: Venous thrombosis events were reported in 5 patients (0.5 per 100 patient-years) treated with upadacitinib 15 mg and 4 patients (0.4 per 100 patient-years) treated with upadacitinib 30 mg. Arterial thrombosis events were reported in 0 patients treated with upadacitinib 15 mg and 2 patients (0.2 per 100 patient-years) treated with upadacitinib 30 mg.
In placebo-controlled studies (RA-III, RA-IV, and RA-V) with background DMARDs, for up to 12/14 weeks, alanine transaminase (ALT) and aspartate transaminase (AST) elevations ≥3 x upper limit of normal (ULN) in at least one measurement were observed in 2.1% and 1.5% of patients treated with upadacitinib 15 mg, and in 1.5% and 0.7% of patients treated with placebo, respectively. In RA-III and RA-V, ALT and AST elevations ≥3 x ULN in at least one measurement were observed in 0.8% and 1.0% of patients treated with upadacitinib 15 mg, 1.0% and 0% of patients treated with upadacitinib 30 mg and in 1.3% and 1.0% of patients treated with placebo, respectively.
In MTX-controlled studies, for up to 12/14 weeks, ALT and AST elevations ≥3 x ULN in at least one measurement were observed in 0.8% and 0.4% of patients treated with upadacitinib 15 mg, 1.7% and 1.3% of patients treated with upadacitinib 30 mg and in 1.9% and 0.9% of patients treated with MTX, respectively.
Upadacitinib treatment was associated with dose-related increases in total cholesterol, triglycerides and LDL cholesterol. Upadacitinib was also associated with increases in HDL cholesterol. Elevations in LDL and HDL cholesterol peaked by Week 8 and remained stable thereafter. In controlled studies, for up to 12/14 weeks, changes from baseline in lipid parameters in patients treated with upadacitinib 15 mg and upadacitinib 30 mg, respectively, are summarized below:
In placebo-controlled studies (RA-III, RA-IV, and RA-V) with background DMARDs, for up to 12/14 weeks, dose-related increases in creatine phosphokinase (CPK) values were observed. CPK elevations >5 x ULN were reported in 1.0%, and 0.3% of patients over 12/14 weeks in the upadacitinib 15 mg and placebo groups, respectively. Most elevations >5 x ULN were transient and did not require treatment discontinuation. In RA-III and RA-V, CPK elevations >5 x ULN were observed in 0.3% of patients treated with placebo, 1.6% of patients treated with upadacitinib 15 mg, and none in patients treated with upadacitinib 30 mg.
In placebo-controlled studies (RA-III, RA-IV, and RA-V) with background DMARDs, for up to 12/14 weeks, dose-related decreases in neutrophil counts, below 1000 cells/mm³ in at least one measurement occurred in 1.1% and <0.1% of patients in the upadacitinib 15 mg and placebo groups, respectively. In RA-III and RA-V, decreases in neutrophil counts below 1000 cells/mm³ in at least one measurement occurred in 0.3% of patients treated with placebo, 1.3% of patients treated with upadacitinib 15 mg, and 2.4% of patients treated with upadacitinib 30 mg. In clinical studies, treatment was interrupted in response to ANC less than 1000 cells/mm³.
In placebo-controlled studies (RA-III, RA-IV, and RA-V) with background DMARDs, for up to 12/14 weeks, dose-related decreases in lymphocyte counts below 500 cells/mm³ in at least one measurement occurred in 0.9% and 0.7% of patients in the upadacitinib 15 mg and placebo groups, respectively. In RA-III and RA-V, decreases in lymphocyte counts below 500 cells/mm³ in at least one measurement occurred in 0.5% of patients treated with placebo, 0.5% of patients treated with upadacitinib 15 mg, and 2.4% of patients treated with upadacitinib 30 mg.
In placebo-controlled studies (RA-III, RA-IV, and RA-V) with background DMARDs, for up to 12/14 weeks, hemoglobin decreases below 8 g/dL in at least one measurement occurred in <0.1% of patients in both the upadacitinib 15 mg and placebo groups. In RA-III and RA-V, hemoglobin decreases below 8 g/dL in at least one measurement were observed in 0.3% of patients treated with placebo, and none in patients treated with upadacitinib 15 mg and upadacitinib 30 mg.
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