RINVOQ is an oral selective and reversible JAK inhibitor indicated for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying anti-rheumatic drugs (DMARDs). RINVOQ may be used as monotherapy or in combination with methotrexate.
SELECT-MONOTHERAPY: Study design
A Phase 3 study investigating the efficacy and safety of RINVOQ monotherapy after switching from MTX compared with cMTX for the treatment of moderate to severe RA in patients who had an inadequate response to MTX2
*For the primary analysis at Week 14, comparisons of RINVOQ 15 mg and upadacitinib 30 mg vs cMTX were done by combining data from the two cMTX groups.
† From Week 14, patients initially randomized to cMTX at baseline were switched to RINVOQ 15 mg or upadacitinib 30 mg per prespecified randomization assignment.
Primary
RINVOQ 15 mg and upadacitinib 30 mg vs cMTX at Week 14 for DAS28 (CRP) <3.2 (EMA) or ACR20 (FDA)
Safety
Adverse events, serious adverse events, adverse events of special interest (e.g., serious infections, opportunistic infections, MACEs, VTEs, malignancies)
- Patients ≥18 years of age were eligible to participate.
- Diagnosis of RA for ≥3 months fulfilling the 2010 ACR/EULAR classification for RA with active disease (at least 6 swollen joints out of 66, at least 6 tender joints out of 68, and more than 3 mg/L hsCRP).
- Patients must have had an inadequate response to MTX.
- No prior exposure to a JAK inhibitor or bDMARD.
The approved dose of RINVOQ is 15 mg once daily. Upadacitinib 30 mg QD is not an approved dose.
ACR: American College of Rheumatology; ACR20: improvement of at least 20% in the American College of Rheumatology core criteria; bDMARD: biological disease-modifying antirheumatic drug; cMTX: continued methotrexate; DAS28 (CRP): disease activity score with 28 joint count (C-reactive protein); EMA: European Medicines Agency; EULAR: European League Against Rheumatism; FDA: Food and Drug Administration; hsCRP: high-sensitivity C-reactive protein; JAK: Janus kinase; MACE: major adverse cardiovascular event; MTX: methotrexate; QD: once daily; VTE: venous thromboembolic event.
RINVOQ monotherapy: Efficacy across endpoints
SELECT-MONOTHERAPY: Low disease activity and remission at Week 14 (NRI)1,2
*P≤0.0001 vs cMTX
cMTX: continued methotrexate; DAS28 (CRP): disease activity score with 28-joint count (C-reactive protein); NRI: nonresponder imputation.
SELECT-MONOTHERAPY: Adverse events through 14 weeks of treatment2
*Serious infection: In the methotrexate group, there was 1 case of urosepsis. In the RINVOQ 15-mg group, there was 1 limb abscess.
†Opportunistic infection: In the methotrexate group, there was 1 case of fungal esophagitis.
‡Hepatic disorder: In the methotrexate group, there were 4 cases of liver enzyme elevations. In the RINVOQ 15-mg group, there were 3 cases of liver enzyme elevations and 1 mild hepatic cyst.
§Malignancies: In the methotrexate group, there was 1 basal cell carcinoma. In the RINVOQ 15-mg group, there was 1 non-Hodgkin lymphoma and 1 breast cancer.
IIVenous thromboembolism: In the RINVOQ 15-mg group, there was 1 pulmonary embolism in a patient on estrogen hormone therapy with a body mass index of 44.9; investigator deemed as unrelated to study drug.
¶Major adverse cardiovascular event (adjudicated): In the RINVOQ 15-mg group, there was 1 hemorrhagic stroke due to ruptured aneurysm (fatal); investigator deemed as unrelated to study drug.
#Death: In the RINVOQ 15-mg group, there was 1 hemorrhagic stroke due to ruptured aneurysm.
Safety Information1
RINVOQ is contraindicated in patients hypersensitive to the active substance or to any of the excipients, in patients with active tuberculosis (TB) or active serious infections, in patients with severe hepatic impairment, and during pregnancy.
Use in combination with other potent immunosuppressants is not recommended.
Serious and sometimes fatal infections have been reported in patients receiving upadacitinib. The most frequent serious infections reported included pneumonia and cellulitis. Cases of bacterial meningitis have been reported. Among opportunistic infections, TB, multidermatomal herpes zoster, oral/esophageal candidiasis, and cryptococcosis have been reported with upadacitinib. Prior to initiating upadacitinib, consider the risks and benefits of treatment in patients with chronic or recurrent infection or with a history of a serious or opportunistic infection, in patients who have been exposed to TB or have resided or traveled in areas of endemic TB or endemic mycoses, and in patients with underlying conditions that may predispose them to infection. Upadacitinib therapy should be interrupted if a patient develops a serious or opportunistic infection. As there is a higher incidence of infections in patients ≥75 years of age, caution should be used when treating this population.
Patients should be screened for TB before starting upadacitinib therapy. Anti-TB therapy should be considered prior to initiation of upadacitinib in patients with previously untreated latent TB or in patients with risk factors for TB infection.
Viral reactivation, including cases of herpes zoster, were reported in clinical studies. Consider interruption of therapy if a patient develops herpes zoster until the episode resolves. Screening for viral hepatitis and monitoring for reactivation should be performed before starting and during therapy with upadacitinib.
The use of live, attenuated vaccines during or immediately prior to therapy is not recommended. It is recommended that patients be brought up to date with all immunizations, including prophylactic zoster vaccinations, prior to initiating upadacitinib, in agreement with current immunization guidelines.
The risk of malignancies, including lymphoma is increased in patients with rheumatoid arthritis (RA). Immunomodulatory medicinal products may increase the risk of malignancies, including lymphoma. The clinical data are currently limited and long-term studies are ongoing. Malignancies, including nonmelanoma skin cancer (NMSC), have been reported in patients treated with upadacitinib. Consider the risks and benefits of upadacitinib treatment prior to initiating therapy in patients with a known malignancy other than a successfully treated NMSC or when considering continuing upadacitinib therapy in patients who develop a malignancy. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.
Absolute neutrophil count <1000 cells/mm3, absolute lymphocyte count <500 cells/mm3, or hemoglobin levels <8 g/dL were reported in ≤1% of patients in clinical trials. Treatment should not be initiated, or should be temporarily interrupted, in patients with these hematological abnormalities observed during routine patient management.
RA patients have an increased risk for cardiovascular disorders. Patients treated with upadacitinib should have risk factors (e.g., hypertension, hyperlipidemia) managed as part of usual standard of care.
Upadacitinib treatment was associated with increases in lipid parameters, including total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined.
Treatment with upadacitinib was associated with an increased incidence of liver enzyme elevation compared to placebo. If increases in ALT or AST are observed during routine patient management and drug-induced liver injury is suspected, upadacitinib therapy should be interrupted until this diagnosis is excluded.
Events of deep vein thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving JAK inhibitors, including upadacitinib. Upadacitinib should be used with caution in patients at high risk for DVT/PE. Risk factors that should be considered in determining the patient’s risk for DVT/PE include older age, obesity, a medical history of DVT/PE, patients undergoing major surgery, and prolonged immobilization. If clinical features of DVT/PE occur, upadacitinib treatment should be discontinued and patients should be evaluated promptly, followed by appropriate treatment.
The most commonly reported adverse drug reactions are upper respiratory tract infections (13.5%), nausea (3.5%), increased blood creatine phosphokinase (2.5%), and cough (2.2%). The most common serious adverse reactions were serious infections.
Please see the RINVOQ Summary of Product Characteristics for complete Prescribing Information.
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References
- RINVOQ [Summary of Product Characteristics]. AbbVie Deutschland GmbH & Co. KG; [MM,YYYY].
- Smolen JS, Pangan AL, Emery P, et al. Upadacitinib as monotherapy in patients with active rheumatoid arthritis and inadequate response to methotrexate (SELECT- MONOTHERAPY): a randomised, placebo-controlled, double-blind phase 3 study. Lancet. 2019;393(10188):2303-2311. doi:10.1016/S0140-6736(19)30419-2