Brand Name
Rinvoq
Generic Name
Upadacitinib
View Brand Information FDA approval date: August 16, 2019
Classification: Janus Kinase Inhibitor
Form: Tablet, Solution
What is Rinvoq (Upadacitinib)?
RINVOQ/RINVOQ LQ is a Janus kinase inhibitor. RINVOQ is indicated for the treatment of adults with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to one or more TNF blockers.
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Brand Information
Rinvoq (Upadacitinib)
WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR ADVERSE CARDIOVASCULAR EVENTS, and THROMBOSIS
SERIOUS INFECTIONS
Patients treated with RINVOQ/RINVOQ LQ are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions (5.1), Adverse Reactions (6.1)]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.
If a serious infection develops, interrupt RINVOQ/RINVOQ LQ until the infection is controlled.
Reported infections include:
- Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before RINVOQ/RINVOQ LQ use and during therapy. Treatment for latent infection should be considered prior to RINVOQ/RINVOQ LQ use.
- Invasive fungal infections, including cryptococcosis and pneumocystosis.
- Bacterial, viral, including herpes zoster, and other infections due to opportunistic pathogens.
The risks and benefits of treatment with RINVOQ/RINVOQ LQ should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with RINVOQ/RINVOQ LQ, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy [see Warnings and Precautions (5.1)].
MORTALITY
In a large, randomized, postmarketing safety study in rheumatoid arthritis (RA) patients 50 years of age and older with at least one cardiovascular risk factor comparing another Janus kinase (JAK) inhibitor to tumor necrosis factor (TNF) blockers, a higher rate of all-cause mortality, including sudden cardiovascular death, was observed with the JAK inhibitor [see Warnings and Precautions (5.2)].
MALIGNANCIES
Lymphoma and other malignancies have been observed in patients treated with RINVOQ. In RA patients treated with another JAK inhibitor, a higher rate of malignancies (excluding non-melanoma skin cancer (NMSC)) was observed when compared with TNF blockers. Patients who are current or past smokers are at additional increased risk[see Warnings and Precautions (5.3)].
MAJOR ADVERSE CARDIOVASCULAR EVENTS
In RA patients 50 years of age and older with at least one cardiovascular risk factor treated with another JAK inhibitor, a higher rate of major adverse cardiovascular events (MACE) (defined as cardiovascular death, myocardial infarction, and stroke), was observed when compared with TNF blockers. Patients who are current or past smokers are at additional increased risk. Discontinue RINVOQ/RINVOQ LQ in patients that have experienced a myocardial infarction or stroke [see Warnings and Precautions (5.4)].
THROMBOSIS
Thromboses, including deep venous thrombosis, pulmonary embolism, and arterial thrombosis, have occurred in patients treated for inflammatory conditions with JAK inhibitors, including RINVOQ. Many of these adverse events were serious and some resulted in death. In RA patients 50 years of age and older with at least one cardiovascular risk factor treated with another JAK inhibitor, a higher rate of thrombosis was observed when compared with TNF blockers. Avoid RINVOQ/RINVOQ LQ in patients at risk. Patients with symptoms of thrombosis should discontinue RINVOQ/RINVOQ LQ and be promptly evaluated [see Warnings and Precautions (5.5)].
1DOSAGE FORMS AND STRENGTHS
RINVOQ extended-release tablets:
- 15 mg upadacitinib: purple, biconvex oblong, with dimensions of 14 x 8 mm, and debossed with ‘a15’ on one side.
- 30 mg upadacitinib: red, biconvex oblong, with dimensions of 14 x 8 mm, and debossed with ‘a30’ on one side.
- 45 mg upadacitinib: yellow to mottled yellow, biconvex oblong, with dimensions of 14 x 8 mm, and debossed with ‘a45’ on one side.
RINVOQ LQ oral solution:
- 1 mg/mL upadacitinib; clear, colorless to light yellow solution in bottle of 180 mL.
2CONTRAINDICATIONS
RINVOQ/RINVOQ LQ is contraindicated in patients with known hypersensitivity to upadacitinib or any of its excipients
3ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling:
- Serious Infections
- Mortality
- Malignancy and Lymphoproliferative Disorders
- Major Adverse Cardiovascular Events
- Thrombosis
- Hypersensitivity Reactions
- Gastrointestinal Perforations
- Laboratory Abnormalities
3.1Clinical Trials Experience
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.
Adverse Reactions in Patients with Rheumatoid Arthritis
A total of 3833 adult patients with rheumatoid arthritis were treated with RINVOQ 15 mg or upadacitinib 30 mg tablets once daily in the Phase 3 clinical trials of whom 2806 were exposed for at least one year.
Patients could advance or switch to RINVOQ 15 mg from placebo, or be rescued to RINVOQ from active comparator or placebo from as early as Week 12 depending on the trial design.
A total of 2630 patients received at least 1 dose of RINVOQ 15 mg, of whom 1860 were exposed for at least one year. In trials RA-I, RA-II, RA-III and RA-V, 1213 patients received at least 1 dose of RINVOQ 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.
Other adverse reactions reported in less than 1% of patients in the RINVOQ 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 Trials: Trials RA-III, RA-IV, and RA-V were integrated to represent safety through 12/14 weeks for placebo (n=1042) and RINVOQ 15 mg (n=1035). Trials RA-III and RA-V were integrated to represent safety through 12 weeks for placebo (n=390), RINVOQ 15 mg (n=385), and upadacitinib 30 mg (n=384). Trial RA-IV did not include the 30 mg dose and, therefore, safety data for upadacitinib 30 mg can only be compared with placebo and RINVOQ 15 mg rates from pooling trials RA-III and RA-V.
MTX-controlled Trials: Trials RA-I and RA-II were integrated to represent safety through 12/14 weeks for MTX (n=530), RINVOQ 15 mg (n=534), and upadacitinib 30 mg (n=529).
12-Month Exposure Dataset: Trials RA-I, II, III, and V were integrated to represent the long-term safety of RINVOQ 15 mg (n=1213) and upadacitinib 30 mg (n=1203).
Exposure adjusted incidence rates were adjusted by trial for all the adverse events reported in this section.
Specific Adverse Reactions
Infections
Placebo-controlled Trials: 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 RINVOQ 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 RINVOQ 15 mg, and 126 patients (180.3 per 100 patient-years) treated with upadacitinib 30 mg.
MTX-controlled Trials: 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 RINVOQ 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 RINVOQ 15 mg and 674 patients (99.7 per 100 patient-years) treated with upadacitinib 30 mg.
Serious Infections
Placebo-controlled Trials: 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 RINVOQ 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 RINVOQ 15 mg, and 7 patients (8.2 per 100 patient-years) treated with upadacitinib 30 mg.
MTX-controlled Trials: 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 RINVOQ 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 RINVOQ 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.
Tuberculosis
Placebo-controlled Trials and MTX-controlled Trials: In the placebo-controlled period, there were no active cases of tuberculosis reported in the placebo, RINVOQ 15 mg, and upadacitinib 30 mg groups. In the MTX-controlled period, there were no active cases of tuberculosis reported in the MTX monotherapy, RINVOQ 15 mg monotherapy, and upadacitinib 30 mg monotherapy groups.
12-Month Exposure Dataset: Active tuberculosis was reported for 2 patients treated with RINVOQ 15 mg and 1 patient treated with upadacitinib 30 mg. Cases of extra-pulmonary tuberculosis were reported.
Opportunistic Infections (excluding tuberculosis)
Placebo-controlled Trials: 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 RINVOQ 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 RINVOQ 15 mg, and 6 patients (7.1 per 100 patient-years) treated with upadacitinib 30 mg.
MTX-controlled Trials: Opportunistic infections were reported in 1 patient (0.8 per 100 patient-years) treated with MTX monotherapy, 0 patients treated with RINVOQ 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 RINVOQ 15 mg and 15 patients (1.4 per 100 patient-years) treated with upadacitinib 30 mg.
Malignancies
Placebo-controlled Trials: 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 RINVOQ 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 RINVOQ 15 mg, and 3 patients (3.5 per 100 patient-years) treated with upadacitinib 30 mg.
MTX-controlled Trials: 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 RINVOQ 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 RINVOQ 15 mg and 14 patients (1.3 per 100 patient-years) treated with upadacitinib 30 mg.
Gastrointestinal Perforations
Placebo-controlled Trials: There were no gastrointestinal perforations (based on medical review) reported in patients treated with placebo, RINVOQ 15 mg, and upadacitinib 30 mg.
MTX-controlled Trials: There were no cases of gastrointestinal perforations reported in the MTX and RINVOQ 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 RINVOQ 15 mg and 4 patients treated with upadacitinib 30 mg.
Thrombosis
Placebo-controlled Trials: In RA-IV, venous thrombosis (pulmonary embolism or deep vein thrombosis) was observed in 1 patient treated with placebo and 1 patient treated with RINVOQ 15 mg. In RA-V, venous thrombosis was observed in 1 patient treated with RINVOQ 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 Trials: In RA-II, venous thrombosis was observed in 0 patients treated with MTX monotherapy, 1 patient treated with RINVOQ 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 RINVOQ 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 RINVOQ 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 RINVOQ 15 mg and 2 patients (0.2 per 100 patient-years) treated with upadacitinib 30 mg.
Laboratory Abnormalities
Hepatic Transaminase Elevations
In placebo-controlled trials (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 RINVOQ 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 RINVOQ 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 trials, 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 RINVOQ 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.
Lipid Elevations
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 trials, for up to 12/14 weeks, changes from baseline in lipid parameters in patients treated with RINVOQ 15 mg and upadacitinib 30 mg, respectively, are summarized below:
- Mean LDL cholesterol increased by 14.81 mg/dL and 17.17 mg/dL.
- Mean HDL cholesterol increased by 8.16 mg/dL and 9.01 mg/dL.
- The mean LDL/HDL ratio remained stable.
- Mean triglycerides increased by 13.55 mg/dL and 14.44 mg/dL.
Creatine Phosphokinase Elevations
In placebo-controlled trials (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 RINVOQ 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 RINVOQ 15 mg, and none in patients treated with upadacitinib 30 mg.
Neutropenia
In placebo-controlled trials (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/mm
Lymphopenia
In placebo-controlled trials (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/mm
Anemia
In placebo-controlled trials (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 RINVOQ 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 RINVOQ 15 mg and upadacitinib 30 mg.
Adverse Reactions in Patients with Psoriatic Arthritis
A total of 1827 adult patients with psoriatic arthritis were treated with RINVOQ 15 mg or upadacitinib 30 mg tablets once daily in clinical trials, representing 1639.2 patient-years of exposure, of whom 722 were exposed to upadacitinib for at least one year. In the two Phase 3 trials, 907 patients received at least 1 dose of RINVOQ 15 mg, of whom 359 were exposed for at least one year.
Two placebo-controlled trials were integrated (640 patients on RINVOQ 15 mg once daily and 635 patients on placebo) to evaluate the safety of RINVOQ 15 mg in comparison to placebo for up to 24 weeks after treatment initiation.
Overall, the safety profile observed in patients with active psoriatic arthritis treated with RINVOQ 15 mg was consistent with the safety profile observed in patients with rheumatoid arthritis. During the 24-week placebo-controlled period, the frequencies of herpes zoster and herpes simplex were ≥1% (1.1% and 1.4%, respectively) with RINVOQ 15 mg and 0.8% and 1.3%, respectively with placebo. A higher incidence of acne and bronchitis was also observed in patients treated with RINVOQ 15 mg (1.3% and 3.9%, respectively) compared to placebo (0.3% and 2.7%, respectively).
Adverse Reactions in Patients with Atopic Dermatitis
Three Phase 3 (AD-1, AD-2, and AD-3) and one Phase 2b (AD-4) randomized, double-blind, placebo-controlled, multicenter trials evaluated the safety of RINVOQ in patients with moderate-to-severe atopic dermatitis. The majority of patients were White (68%) and male (57%). The mean age was 34 years (ranged from 12 to 75 years) and 13% of the patients were 12 to less than 18 years. In these 4 trials, 2612 patients were treated with RINVOQ 15 mg tablets or 30 mg tablets orally once daily, with or without concomitant topical corticosteroids (TCS).
In the Phase 3 clinical trials (AD-1, AD-2, and AD-3), a total of 1239 patients received RINVOQ 15 mg, of whom 791 were exposed for at least one year and 1246 patients received RINVOQ 30 mg, of whom 826 were exposed for at least one year.
Trials AD-1, AD-2, and AD-4 compared the safety of RINVOQ monotherapy to placebo through Week 16. Trial AD-3 compared the safety of RINVOQ + TCS to placebo + TCS through Week 16.
Weeks 0 to 16 (Trials AD-1 to AD-4)
In RINVOQ trials with and without TCS (Trials AD-1, 2, 3 and 4) through Week 16, the proportion of patients who discontinued treatment because of adverse reactions in the RINVOQ 15 mg, 30 mg and placebo groups were 2.3%, 2.9% and 3.8%, respectively. Table 5 summarizes the adverse reactions that occurred at a rate of at least 1% in the RINVOQ 15 mg or 30 mg groups during the first 16 weeks of treatment.
Other adverse reactions reported in less than 1% of patients in the RINVOQ 15 mg and/or 30 mg group and at a higher rate than in the placebo group through Week 16 included anemia, oral candidiasis, pneumonia, non-melanoma skin cancer, and the adverse event of retinal detachment.
The safety profile of RINVOQ through Week 52 was generally consistent with the safety profile observed at Week 16.
Overall, the safety profile observed in patients with AD treated with RINVOQ was similar to the safety profile in patients with RA. Other specific adverse reactions that were reported in patients with AD included eczema herpeticum/Kaposi’s varicelliform eruption.
Eczema Herpeticum/Kaposi’s Varicelliform Eruption
Placebo-controlled Period (16 weeks): Eczema herpeticum was reported in 4 patients (1.6 per 100 patient-years) treated with placebo, 6 patients (2.2 per 100 patient-years) treated with RINVOQ 15 mg and 7 patients (2.6 per 100 patient-years) treated with RINVOQ 30 mg.
12-Month Exposure (Weeks 0 to 52): Eczema herpeticum was reported in 18 patients (1.6 per 100 patient-years) treated with RINVOQ 15 mg and 17 patients (1.5 per 100 patient-years) treated with RINVOQ 30 mg.
Adverse Reactions in Patients with Ulcerative Colitis
RINVOQ was studied up to 8 weeks in patients with moderately to severely active ulcerative colitis in two randomized, double-blind, placebo-controlled induction studies (UC-1, UC-2) and a randomized, double-blind, placebo controlled, dose-finding study (UC-4; NCT02819635). Long term safety up to 52-weeks was evaluated in patients who responded to induction therapy in a randomized, double-blind, placebo-controlled maintenance study (UC-3) and a long-term extension study
In the two induction studies (UC-1, UC-2) and a dose finding study (UC-4), 1097 patients were enrolled of whom 719 patients received RINVOQ 45 mg tablets once daily.
In the maintenance study (UC-3), 746 patients were enrolled of whom 250 patients received RINVOQ 15 mg tablets once daily and 251 patients received RINVOQ 30 mg tablets once daily.
Adverse reactions reported in ≥2% of patients in any treatment arm in the induction and maintenance studies are shown in Tables 6 and 7, respectively.
Other adverse reactions reported in less than 2% of patients in the RINVOQ 45 mg group and at a higher rate than in the placebo group through Week 8 included herpes zoster and pneumonia.
The adverse reaction of non-melanoma skin cancer was reported in 1% of patients in the RINVOQ 30 mg group and none of the patients in the RINVOQ 15 mg or placebo group through Week 52.
The safety profile of RINVOQ in the long-term extension study was similar to the safety profile observed in the placebo-controlled induction and maintenance periods.
Overall, the safety profile observed in patients with ulcerative colitis treated with RINVOQ was generally similar to the safety profile in patients with RA and AD.
Specific Adverse Reactions
Serious Infections
Induction Studies: In UC-1, UC-2, and UC-4, serious infections were reported in 5 patients (8.4 per 100 patient-years) treated with placebo and 9 patients (8.4 per 100 patient-years) treated with RINVOQ 45 mg through 8 weeks.
Placebo-controlled Maintenance Study: In UC-3, serious infections were reported in 8 patients (5.9 events per 100 patient-years) treated with placebo, 9 patients (5.0 events per 100 patient-years) treated with RINVOQ 15 mg, and 8 patients (3.7 events per 100 patient-years) treated with RINVOQ 30 mg through 52 weeks.
Laboratory Abnormalities
Hepatic Transaminase Elevations
In studies UC-1, UC-2, and UC-4, elevations of ALT to ≥ 3 x ULN in at least one measurement were observed in 1.5% of patients treated with RINVOQ 45 mg, and 0% of patients treated with placebo for 8 weeks. AST elevations to ≥ 3 x ULN occurred in 1.5% of patients treated with RINVOQ 45 mg, and 0.3% of patients treated with placebo. Elevations of ALT to ≥ 5 x ULN occurred in 0.4% of patients treated with RINVOQ 45 mg and 0% of patients treated with placebo.
In UC-3, elevations of ALT to ≥ 3 x ULN in at least one measurement were observed in 4.4% of patients treated with RINVOQ 30 mg, 2% of patients treated with RINVOQ 15 mg, and 1.2% of patients treated with placebo for 52 weeks. Elevations of AST to ≥ 3 x ULN in at least one measurement were observed in 2% of patients treated with RINVOQ 30 mg, 1.6% of patients treated with RINVOQ 15 mg and 0.4% of patients treated with placebo. Elevations of ALT to ≥ 5 x ULN were observed in 1.2% of patients treated with 30 mg, 0.4% of patients treated with 15 mg, and 0.4% of patients treated with placebo.
Overall, laboratory abnormalities observed in patients with ulcerative colitis treated with RINVOQ were similar to those described in patients with RA.
Adverse Reactions in Patients with Crohn’s Disease
RINVOQ was studied up to 12 weeks in patients with moderately to severely active CD in two randomized, double-blind, placebo-controlled induction studies (CD-1, CD-2). Long term safety up to 52 weeks was evaluated in patients who responded to induction therapy in a randomized, double-blind, placebo-controlled maintenance study (CD-3), with additional data provided from a long-term extension (LTE) period
In the two induction studies (CD-1, CD-2), 1021 patients were enrolled, of whom 674 patients received RINVOQ 45 mg tablets once daily during the placebo-controlled period.
In the maintenance study (CD-3), 673 patients were enrolled, of whom 221 patients received RINVOQ 15 mg tablets once daily and 229 patients received RINVOQ 30 mg tablets once daily during the randomized, placebo-controlled period.
Overall, the safety profile observed in patients with Crohn’s disease treated with RINVOQ was consistent with the known safety profile for RINVOQ in other indications.
Adverse reactions reported in ≥2% of patients treated with RINVOQ and at a higher rate than placebo in the induction and maintenance studies are shown in Tables 8 and 9, respectively.
Adverse reactions reported in less than 2% of patients in the RINVOQ 45 mg group and at a higher rate than in the placebo group through Week 12 included folliculitis, hypercholesterolemia, bronchitis, pneumonia, oral candidiasis, and hyperlipidemia.
Adverse reactions reported in less than 2% of patients in the RINVOQ 15 mg or 30 mg group and at a higher rate than in the placebo group through Week 52 included hyperlipidemia, oral candidiasis, and hypercholesterolemia.
The safety profile of RINVOQ in the long-term extension study was similar to the safety profile observed in the placebo-controlled induction and maintenance periods.
Specific Adverse Reactions
Serious Infections
Induction Studies: In CD-1 and CD-2, serious infections were reported in 6 patients (8 per 100 patient-years) treated with placebo and 13 patients (9 per 100 patient-years) treated with RINVOQ 45 mg through 12 weeks of the placebo-controlled period.
Maintenance Study/LTE: In the long-term placebo-controlled period, serious infections were reported in 10 patients (7 per 100 patient-years) treated with placebo, 7 patients (4 per 100 patient-years) treated with RINVOQ 15 mg, and 13 patients (6 per 100 patient-years) treated with RINVOQ 30 mg.
Gastrointestinal Perforations
Induction Studies: During the induction studies in all patients treated with RINVOQ 45 mg (N=938), gastrointestinal perforation was reported in 4 patients (2 per 100 patient-years). In the placebo-controlled induction period, in CD-1 and CD-2, gastrointestinal perforation was reported in no patients treated with placebo (N=347) and 1 patient (1 per 100 patient-years) treated with RINVOQ 45 mg (N=674) through 12 weeks.
Maintenance Study/LTE: In the long-term placebo-controlled period, gastrointestinal perforation was reported in 1 patient (1 per 100 patient-years) treated with placebo, 1 patient (<1 per 100 patient-years) treated with RINVOQ 15 mg, and 1 patient (<1 per 100 patient-years) treated with RINVOQ 30 mg.
Patients who received placebo or RINVOQ 15 mg for maintenance therapy and lost response were treated with rescue RINVOQ 30 mg (N=336). Among these patients, gastrointestinal perforation was reported in 3 patients (1 per 100 patient-years) through long-term treatment.
Adverse Reactions in Patients with Ankylosing Spondylitis
A total of 596 patients with ankylosing spondylitis were treated with RINVOQ 15 mg tablets in the two clinical trials representing 577.3 patient-years of exposure, of whom 220 were exposed to RINVOQ 15 mg for at least one year.
Overall, the safety profile observed in patients with active ankylosing spondylitis treated with RINVOQ 15 mg was consistent with the safety profile observed in patients with rheumatoid arthritis and psoriatic arthritis. During the 14-week placebo-controlled period in Trial AS-I, the frequency of headache was 5.4% with RINVOQ 15 mg and 2.1% with placebo. During the 14-week placebo-controlled period in Trial AS-II, the frequency of headache was 3.3% with RINVOQ 15 mg and 1.4% with placebo.
Adverse Reactions in Patients with Non-radiographic Axial Spondyloarthritis
A total of 187 patients with non-radiographic axial spondyloarthritis were treated with RINVOQ 15 mg tablets in the clinical trial representing 116.6 patient-years of exposure, of whom 31 were exposed to RINVOQ 15 mg for at least one year.
Overall, the safety profile observed in patients with active non-radiographic axial spondyloarthritis treated with RINVOQ 15 mg was consistent with the safety profile observed in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis.
Adverse Reactions in Patients with Polyarticular Juvenile Idiopathic Arthritis
A total of 83 pediatric patients with juvenile idiopathic arthritis (JIA) with active polyarthritis were treated with RINVOQ/RINVOQ LQ in the clinical trial, representing 123.7 patient-years of exposure, of whom 48 were exposed to RINVOQ/RINVOQ LQ for at least one year.
Overall, the safety profile observed in pediatric patients with JIA with active polyarthritis treated with RINVOQ/RINVOQ LQ was consistent with the known safety profile of RINVOQ.
Adverse Reactions in Patients with Giant Cell Arteritis
In the Phase 3 study, 209 patients with giant cell arteritis received at least 1 dose of RINVOQ 15 mg, of whom 122 were exposed for at least one year during the 52-week placebo-controlled period. The safety profile observed in patients with giant cell arteritis was generally consistent with the known safety profile for RINVOQ.
Specific Adverse Reactions
Opportunistic Infections (excluding tuberculosis and herpes zoster)
In the 52-week placebo-controlled period, opportunistic infections were reported in 1 patient (1.1 per 100 patient-years) treated with placebo and 4 patients (2.3 per 100 patient-years) treated with RINVOQ 15 mg.
Thrombosis
In the 52-week placebo-controlled period, venous thromboembolic events (pulmonary embolism or deep vein thrombosis) were observed in 4 patients (4.3 per 100 patient-years) treated with placebo and 7 patients (3.9 per 100 patient-years) treated with RINVOQ 15 mg. Events of arterial thrombosis were observed in 2 patients (1.1 per 100 patient-years) treated with RINVOQ 15 mg and 0 patients treated with placebo.
4DESCRIPTION
RINVOQ and RINVOQ LQ are formulated with upadacitinib, a JAK inhibitor.
Upadacitinib has the following chemical name: (3
The strength of upadacitinib is based on anhydrous upadacitinib. The solubility of upadacitinib in water is 38 to less than 0.2 mg/mL across a pH range of 2 to 9 at 37
Upadacitinib has a molecular weight of 389.38 g/mol and a molecular formula of C
RINVOQ 15 mg extended-release tablets for oral administration are purple, biconvex oblong, with dimensions of 14 x 8 mm, and debossed with ‘a15’ on one side. Each tablet contains the following inactive ingredients: colloidal silicon dioxide, ferrosoferric oxide, hypromellose, iron oxide red, magnesium stearate, mannitol, microcrystalline cellulose, polyvinyl alcohol, polyethylene glycol, talc, tartaric acid and titanium dioxide.
RINVOQ 30 mg extended-release tablets for oral administration are red, biconvex oblong, with dimensions of 14 x 8 mm, and debossed with ‘a30’ on one side. Each tablet contains the following inactive ingredients: colloidal silicon dioxide, hypromellose, iron oxide red, magnesium stearate, mannitol, microcrystalline cellulose, polyvinyl alcohol, polyethylene glycol, talc, tartaric acid and titanium dioxide.
RINVOQ 45 mg extended-release tablets for oral administration are yellow to mottled yellow, biconvex oblong, with dimensions of 14 x 8 mm, and debossed with ‘a45’ on one side. Each tablet contains the following inactive ingredients: colloidal silicon dioxide, hypromellose, iron oxide yellow, iron oxide red, magnesium stearate, mannitol, microcrystalline cellulose, polyvinyl alcohol, polyethylene glycol, talc, tartaric acid and titanium dioxide.
RINVOQ LQ oral solution for oral administration is a 1 mg/mL clear, colorless to light yellow solution. Each 1 mL RINVOQ LQ contains 1 mg of upadacitinib as free base (equivalent to 1.02 mg upadacitinib hemihydrate) and the following inactive ingredients: citric acid anhydrous, purified water, sodium benzoate, sodium citrate dihydrate, and sucralose.
5HOW SUPPLIED/STORAGE AND HANDLING
How Supplied
RINVOQ extended-release tablets are supplied as:
- 15 mg: purple, biconvex oblong, with dimensions of 14 x 8 mm, and debossed with ‘a15’ on one side.
- 30 mg: red, biconvex oblong, with dimensions of 14 x 8 mm, and debossed with ‘a30’ on one side.
- 45 mg: yellow to mottled yellow, biconvex oblong, with dimensions of 14 x 8 mm, and debossed with ‘a45’ on one side.
RINVOQ LQ oral solution is supplied as:
- A 1 mg/mL oral solution in HDPE bottles with a child-resistant cap. Each bottle contains a labeled volume of 180 mL of clear, colorless to light yellow solution. The bottle is packaged in a carton with one press-in bottle adapter and one 10 mL oral dosing syringe; NDC: 0074-2320-01
Storage and Handling
RINVOQ extended-release tablets
- Store at 2˚C to 25˚C (36˚F to 77˚F).
- Store in the original bottle in order to protect from moisture.
RINVOQ LQ oral solution
- Store between 2°C to 30°C (36°F to 86°F).
- Discard remaining oral solution 60 days after opening the bottle.
6PATIENT COUNSELING INFORMATION
Advise the patient and caregiver to read the FDA-approved patient labeling (
Serious Infections
Inform patients that they may be more likely to develop infections when taking RINVOQ/RINVOQ LQ. Instruct patients to contact their healthcare provider immediately during treatment if they develop any signs or symptoms of an infection
Advise patients that the risk of herpes zoster is increased in patients taking RINVOQ/RINVOQ LQ and in some cases can be serious
Malignancies
Inform patients that RINVOQ/RINVOQ LQ may increase their risk of certain cancers and that periodic skin examinations should be performed while using RINVOQ/RINVOQ LQ.
Advise patients that exposure to sunlight and UV light should be limited by wearing protective clothing and using a broad-spectrum sunscreen
Major Adverse Cardiovascular Events
Inform patients that RINVOQ/RINVOQ LQ may increase their risk of major adverse cardiovascular events (MACE) including myocardial infarction, stroke, and cardiovascular death. Instruct all patients, especially current or past smokers or patients with other cardiovascular risk factors, to be alert for the development of signs and symptoms of cardiovascular events
Thrombosis
Inform patients that events of deep venous thrombosis and pulmonary embolism have been reported in clinical trials with RINVOQ. Instruct patients to seek immediate medical attention if they develop any signs or symptoms of a DVT or PE
Hypersensitivity Reactions
Advise patients to discontinue RINVOQ/RINVOQ LQ and seek immediate medical attention if they develop any signs and symptoms of allergic reactions
Gastrointestinal Perforations
Inform patients that gastrointestinal perforations have been reported in clinical trials with RINVOQ and that risk factors include the use of NSAIDs, corticosteroids, or history of diverticulitis. Instruct patients to seek medical care immediately if they experience new onset of abdominal pain, fever, chills, nausea, or vomiting
Retinal Detachment
Inform patients that retinal detachment has been reported in clinical trials with RINVOQ. Advise patients to immediately inform their healthcare provider if they develop any sudden changes in vision while receiving RINVOQ/RINVOQ LQ
Laboratory Abnormalities
Inform patients that RINVOQ/RINVOQ LQ may affect certain lab tests, and that blood tests are required before and during RINVOQ/RINVOQ LQ treatment
Vaccinations
Advise patients to avoid use of live vaccines with RINVOQ/RINVOQ LQ. Instruct patients to inform their healthcare practitioner that they are taking RINVOQ/RINVOQ LQ prior to a potential vaccination
Embryo-Fetal Toxicity
Advise pregnant women and females of reproductive potential that exposure to RINVOQ/RINVOQ LQ during pregnancy may result in fetal harm. Advise females to inform their healthcare provider of a known or suspected pregnancy
Advise females of reproductive potential that effective contraception should be used during treatment and for 4 weeks following the final dose of RINVOQ/RINVOQ LQ
Advise women exposed to RINVOQ/RINVOQ LQ during pregnancy
Lactation
Advise women not to breastfeed during treatment with RINVOQ/RINVOQ LQ and for 6 days after the last dose
Administration
Advise patients that RINVOQ tablets are not substitutable with RINVOQ LQ
Advise patients not to chew, crush, or split RINVOQ tablets
For RINVOQ LQ, instruct patients and caregivers to read and follow the Instructions for Use for proper preparation, administration, storage, and disposal
Advise patients to avoid food or drink containing grapefruit during treatment with RINVOQ/RINVOQ LQ
Medication Residue in Stool
Instruct patients to notify their healthcare provider if they repeatedly notice medication residue (e.g., intact RINVOQ tablet or fragments) in stool or ostomy output
Manufactured by: AbbVie Inc., North Chicago, IL 60064, USA
7PRINCIPAL DISPLAY PANEL
NDC 0074-2306-30
RINVOQ®
upadacitinib
Extended-Release Tablets
15 mg
RINVOQ and RINVOQ LQ
are NOT substitutable
Dispense in original packaging
FLIP CAP TO CUT FOIL
PEEL BACK FOR INSTRUCTIONS
30 Tablets
Rx only
8PRINCIPAL DISPLAY PANEL
NDC 0074-2310-30
RINVOQ®
upadacitinib
Extended-Release Tablets
30 mg
RINVOQ and RINVOQ LQ
are NOT substitutable
Dispense in original packaging
FLIP CAP TO CUT FOIL
PEEL BACK FOR INSTRUCTIONS
30 Tablets
Rx only
9PRINCIPAL DISPLAY PANEL
NDC 0074-1043-28
RINVOQ®
upadacitinib
Extended-Release Tablets
45 mg
RINVOQ and RINVOQ LQ
are NOT substitutable
Dispense with Medication Guide
FLIP CAP TO CUT FOIL
PEEL BACK FOR INSTRUCTIONS
28 Tablets
Rx only
10PRINCIPAL DISPLAY PANEL
NDC 0074-2320-01
RINVOQ®LQ
Upadacitinib
Oral Solution
Upadacitinib
Oral Solution
1 mg/mL
RINVOQ LQ and RINVOQ
are NOT substitutable.
are NOT substitutable.
Insert bottle adapter
on first use.
on first use.
Do not remove
after insertion.
after insertion.
180 mL per Bottle
Rx Only
abbvie
Rx Only
abbvie
