DEMONSTRATED SAFETY PROFILE UP TO 52 WEEKS - RESULTS FROM MEASURE UP 1 AND 22
The safety profile for RINVOQ 15 mg in adolescents was similar to that in adults.**1
Table adapted from Simpson, et al.2
aIncludes all patients in the main study who received at least 1 dose of RINVOQ.
bData from Measure Up 1 and Measure Up 2 studies.
cMyocardial infarction (COVID-19 related) occurred in a patient in their 60s 28 days after the last dose of study medication.
dPrespecified AESIs were based on the known RINVOQ safety profile and previous safety observations for RINVOQ and other JAK inhibitors.
eSearched using a prespecified grouped term.
fFour cases of NMSC were reported in the RINVOQ 15 mg group: 1 Bowen disease (patient in their 50s on day 7), 1 basal cell carcinoma (patient in their 60s on day 22), and 2 cases of squamous cell carcinoma (1 in a patient in their 50s on day 21 and 1 in a patient in their 50s on day 113); 4 NMSCs were reported in the RINVOQ 30 mg group: 1 basal cell carcinoma (patient in their 50s on day 610), 2 cases of squamous cell carcinoma of the skin (1 in a patient in their 60s on day 218 and 1 in a patient in their 60s on day 434), and 1 cutaneous T-cell lymphoma stage I.
gBreast and colon cancer were diagnosed on days 520 and 550 in a patient in their 40s taking RINVOQ 15 mg; 1 case each of endometrial adenocarcinoma (patient in their 60s on day 515), kidney cell carcinoma (patient in their 50s on day 318), anal squamous cell cancer (patient in their 60s on day 64), breast cancer (patient in their 50s on day 21), and gastric cancer (patient in their 70s on day 36) in the RINVOQ 30 mg group.
hA case of cutaneous T-cell lymphoma in a patient in their 50s taking RINVOQ 30 mg on day 194 deemed unrelated to study drug and nonserious by the investigator; after medical review, the patient likely had cutaneous T-cell lymphoma at baseline.
AD, atopic dermatitis; AE, adverse event; CNS, central nervous system; CPK, creatinine phosphokinase; EAER, exposure-adjusted event rate; GI, gastrointestinal; HZ, herpes zoster; MACE, major adverse cardiac event; NMSC, non-melanoma skin cancer; OD, once daily; TB, tuberculosis; TEAE, treatment emergent adverse event; VTE, venous thromboembolism.
- Acne events were nonserious, and treatment discontinuation was rare (1 of 1609 [0.1%]. Most acne events involved the face and consistent primarily of inflammatory papules, pustules, and/or comedones.
- Acne required no intervention in 34 of 84 (40.5%) and 61 of 131 (46.6%) patients in the RINVOQ 15 mg and 30 mg groups, respectively. Most cases of acne were managed with topical therapies. The most common risk factors were history of acne and/or family history of acne.
- Hepatic disorder (mostly transaminase elevations), anaemia, lymphopaenia, and elevations in CPK were reported more frequently in the RINVOQ 30 mg group vs the 15 mg group. These AEs were generally transient, mild to moderate, and asymptomatic.
- Grade 3 to 4 anaemia, lymphopaenia, neutropaenia, and elevated AST, ALT and CPK levels were infrequent across all treatment groups; the frequency of these laboratory abnormalities was higher in the RINVOQ 30 mg group vs the 15 mg group. Changes in laboratory parameters occurred by Weeks 8 to 12 and were stable thereafter. Treatment discontinuations due to laboratory-related toxic effects were infrequent.
- The EAER of malignant neoplasm was 0.6/100 PYs with RINVOQ 15 mg and 0.9/100 PYs with RINVOQ 30 mg.
- NMSC was the most reported malignant neoplasm in both treatment groups. Except for breast cancer in 2 patients, other types of cancers were reported in a single patient.
- Among non-NMSC cancers, 3 of 7 occurred within 3 months of study drug initiation (anal cancer, breast cancer, and gastric cancer). A case of kidney cancer had clinical findings (kidney mass and haematuria) at study entry indicating that the cancer was present at the time of randomisation.
- For the combined studies, the EAER of serious infection was higher with RINVOQ 30 mg compared with RINVOQ 15 mg (3.6/100 PYs vs 2.2/100 PYs), while the EAER of opportunistic infection (excluding tuberculosis and herpes zoster) was similar between treatment groups (1.9/100 PYs with RINVOQ 15 mg and 2.0/100 PYs with RINVOQ 30 mg).
- The most common serious infection was pneumonia in Measure Up 1 and eczema herpeticum in Measure Up 2. All opportunistic infections (excluding tuberculosis and herpes zoster) were cases of eczema herpeticum or Kaposi varicelliform eruption, except for an oesophageal candidiasis in a patient taking RINVOQ 30 mg.
- Across both studies, most events of eczema herpeticum were nonserious; 1 and 2 events reported in the RINVOQ 15 mg and 30 mg groups, respectively, led to treatment discontinuation. The EAERs of herpes zoster were higher with RINVOQ 30 mg compared with RINVOQ 15 mg (5.4/100 PYs vs 3.6/100 PYs, respectively).
- Most herpes zoster events were nonserious, except for 3 in the RINVOQ 30 mg group and 2 in the RINVOQ 15 mg group. One herpes zoster event led to treatment discontinuation. Most herpes zoster (75 of 82 [91.5%]) events involved a single or 2 dermatomes; no central nervous system, ocular, lung, or liver involvement was reported.
- One case of tuberculosis was reported in a patient in their 20s taking RINVOQ 15 mg and another was reported in a patient in their 20s taking RINVOQ 30 mg; both were serious, deemed possibly related to study drug, and led to treatment withdrawal.
- Overall, the incidence of COVID-19 cases was 27 of 809 patients (3.3%) in Measure Up 1 and 29 of 799 patients (3.6%) in Measure Up 2 and similar between treatment groups; most events were nonserious. Serious events of COVID-19 were reported in 5 patients (0.3%); 1 led to treatment discontinuation.
DEMONSTRATED SAFETY PROFILE IN ADULTS UP TO 16 WEEKS - RESULTS FROM HEADS UP STUDY3
Table to show TEAEs through week 16 for all patients receiving 1 dose or more of study drug
Table adapted from Blauvelt A, et al.3
aAs assessed by investigator.
bA 40-year-old woman who had bronchopneumonia associated with influenza A was found deceased at home on study day 70.
cAll opportunistic infections were eczema herpeticum.
dKeratoacanthoma, no reasonable possibility of association with study drug according to the investigator.
eInvasive ductal breast carcinoma, reasonable possibility of association with study drug according to the investigator.
fHepatic disorders: most were elevated transaminase levels.
gMost acne events consisted primarily of inflammatory papules, pustules, and comedones, involving the face. All events were nonserious. None led to treatment discontinuation.
AE, adverse event; CPK, creatinine phosphokinase; NMSC, non-melanoma skin cancer; SAE, serious AE; TB, tuberculosis; TEAE, treatment emergent adverse event
ACNE AND CONJUNCTIVITIS
- All acne events were mild or moderate in severity, primarily involved the face and trunk, and did not result in scarring; none led to study drug discontinuation.3
- All conjunctivitis cases were mild or moderate in severity, and none led to study drug discontinuation.3
AEs OF SPECIAL INTEREST
- Rates of serious infection (4[1.1%] vs 2 [0.6%]), eczema herpeticum (1 [0.3%]vs 0%), and herpes zoster (7 [2.0%] vs 3 [0.9%]) were numerically higher for patients treated with upadacitinib than those treated with dupilumab, all at generally low levels. Each of the serious infections was reported in a single patient. No eczema herpeticum or herpes zoster event was considered to be serious and all herpes zoster events were mild or moderate in severity, and none led to study drug discontinuation.3
- Rates of hepatic disorders was higher among patients treated with upadacitinib than those treated with dupilumab (10 [2.9%] vs 4 [1.2%]). Most were transaminase elevations that were mild or moderate in severity, transient, and reported as singular abnormalities without recurrence; none were serious, and 2 upadacitinib treated patients discontinued study drug owing to transaminase elevation.3
- Rates of anemia (7 [2.0%] vs 1 [0.3%]), neutropenia (6 [1.7%] vs 2 [0.6%]), and creatinine phosphokinase elevations (23 [6.6%] vs 10 [2.9%]) were higher for patients treated with upadacitinib than those treated with dupilumab, respectively. There was a single event of thrombocytopenia (grade 1 in severity) reported in a patient treated with upadacitinib. Most of these laboratory test–related AEs were mild or moderate in severity, transient, and reported as singular abnormalities without recurrence, with only 1 event deemed serious (decreased hemoglobin reported in the dupilumab-treated group); none of these events led to study drug discontinuation. No drug-induced liver injury or rhabdomyolysis events were reported.3
DEMONSTRATED SAFETY PROFILE IN ADULTS UP TO 24 WEEKS - RESULTS FROM HEADS UP STUDY4
Table to show TEAEs through to week 24 for all patients receiving 1 dose or more of study drug
Table adapted from Blauvelt, et al.4
aAs assessed by investigator;
b40 y/o woman found deceased at home on study Day 70 who had bronchopneumonia associated with influenza A
cAll opportunistic infections were eczema herpeticum
einvasive ductal breast carcinoma
fMost acne events consisted primarily of inflammatory papules, pustules and comedones, involving the face. All events were non-serious. None led to treatment discontinuation.
TEAE, Treatment-emergent adverse events; AE, Adverse events; SAE, Serious adverse events; NMSC, Non-melanoma skin cancer; CPK, creatinine phosphokinase
- No new important risks were observed compared to the known safety profile of upadacitinib4
- Rates of serious infection, eczema herpeticum, herpes zoster, and laboratory-related AEs were higher for upadacitinib4
- Each of the serious infections was reported in a single patient; no eczema herpeticum or herpes zoster event was serious; most herpes zoster events involved a single dermatome4
- Most hepatic disorders were asymptomatic transaminase elevations; mild or moderate in severity; none were serious4
- Rates of anemia, neutropenia, and CPK elevation were higher among upadacitinib-treated patients; no events were serious or led to study drug discontinuation4
- No cases of adjudicated venous thromboembolic events or major adverse cardiovascular events, active tuberculosis, or gastrointestinal perforation were reported in either treatment group4
- Most frequently reported AE with upadacitinib was acne; all acne events were mild or moderate in severity, and primarily involved the face and trunk4
- Conjunctivitis was the most commonly-reported AE for dupilumab4
- No acne or conjunctivitis events were serious or led to study drug discontinuation4
The safety profile of RINVOQ with long term treatment was generally similar to the safety profile during the placebo controlled period across indications1
RINVOQ is 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.
RINVOQ is indicated for the treatment of moderate to severe atopic dermatitis in adults and adolescents 12 years and older who are candidates for systemic therapy.
RINVOQ is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response, lost response or were intolerant to either conventional therapy or a biologic agent.
Non-radiographic axial spondyloarthritis
RINVOQ is indicated for the treatment of active non-radiographic axial-spondyloarthritis (nr-axSpA) in adult patients with objective signs of inflammation as indicated by elevated C-reactive protein (CRP) and/or magnetic resonance imaging (MRI), who have responded inadequately to nonsteroidal anti-inflammatory drugs (NSAIDs).
AD, atopic dermatitis; AS, ankylosing spondylitis; NR-AXSPA, non-radiographic; PsA, psoriatic arthritis; RA, rheumatoid arthritis; UC, ulcerative colitis.
Important safety information for RINVOQ
You are also strongly advised to read the prescribing information (PI), which can be found using the link at the top of the page.
Before starting RINVOQ treatment, please note the following:
1. RINVOQ should be initiated and supervised by physicians experienced in the treatment of Atopic Dermatitis.
2. RINVOQ should only be used if no suitable treatment alternatives are available in patients:
a. ≥ 65 years of age
b. With history of atherosclerotic cardiovascular disease or other cardiovascular risk factors (e.g., current or previous long-time smokers)
c. With malignancy risk factors (e.g., current malignancy or history of malignancy)
3. Posology (link to PI above)
The recommended dose of upadacitinib is 15 mg or 30 mg once daily based on individual patient presentation.
- A dose of 15 mg is recommended for patients at higher risk of VTE, MACE and malignancy.
- A dose of 30 mg once daily may be appropriate for patients with high disease burden who are not at higher risk of VTE, MACE and malignancy or patients with an inadequate response to 15 mg once daily.
- The lowest effective dose to maintain response should be used.
For patients ≥65 years of age, the recommended dose is 15 mg once daily.
Adolescents (from 12 to 17 years of age)
The recommended dose of upadacitinib is 15 mg once daily for adolescents weighing ≥30 kg.
Consideration should be given to discontinuing upadacitinib treatment in any patient who shows no evidence of therapeutic benefit after 12 weeks of treatment.
- There is an increased risk of MACE, malignancies, serious infections, and all-cause mortality in patients ≥ 65 years of age
- Only use RINVOQ in patients ≥ 65 years of age and older if no suitable treatment alternatives are available
- There is an increased risk of adverse reactions with RINVOQ 30mg in patients ≥ 65 years of age and older
- In UC maintenance and AD patients ≥ 65 years of age, doses higher than 15mg once daily are not recommended.
Concomitant use with other potent immunosuppressants
- Not recommended, as a risk of additive immunosuppression cannot be excluded
Concomitant use with strong CYP3A4 inhibitors and inducers
- Use with caution (see SmPC for dose adjustments), consider alternatives to strong inhibitors if used long-term and monitor for changes in disease activity if using strong inducers
- Do not use RINVOQ in active, serious infections (including localised infections)
- Consider the risks and benefits in patients with chronic/recurrent infection, those exposed to TB, those that have a history of opportunistic/serious infections, those that have resided or travelled in areas of endemic TB/mycoses or with underlying conditions that predispose them to infection
- Monitor for signs and symptoms of infection during and after treatment. Interrupt treatment if the patient shows signs and symptoms of serious or opportunistic infection. Resume treatment after control of serious infection with careful benefit-risk consideration. Patients who develop new infection require prompt diagnostic testing as appropriate for immunosuppressed patients and appropriate therapy. Monitor closely and interrupt treatment if the patient is not responding to appropriate antimicrobial therapy. Restart RINVOQ when infection is controlled following careful consideration of benefit risk.
- There is a higher rate of serious infections with RINVOQ 30mg compared with RINVOQ 15mg
- There is a higher incidence of infections in the elderly ≥ 65 years of age and in diabetics, caution should be used when treating these populations.
- Screen pre-treatment for TB. Do not start treatment in patients with active TB. Consult with a physician experienced in the treatment of TB and consider anti-TB therapy in those patients with previously untreated latent TB or patients with risk factors for TB infection
- Monitor for the development of signs and symptoms of TB, including those patients that tested negative for latent TB prior to treatment
- Consider interrupting treatment if patient develops herpes zoster until resolution
- Screen pre-treatment for viral hepatitis and monitor for reactivation during therapy. If hepatitis B DNA is detected during treatment consult a liver specialist
- It is not recommended to administer live attenuated vaccines during, or immediately prior to RINVOQ treatment
- It is recommended that patients are brought up-to-date with all immunisations including prophylactic zoster vaccination in agreement with current immunisation guidelines prior to starting RINVOQ
- There is a higher rate of malignancies with RINVOQ 30mg compared to RINVOQ 15mg.
- In patients 65 years of age and older, patients who are current or past long-time smokers, or with other malignancy risk factors (e.g., current malignancy or history of malignancy) upadacitinib should only be used if no suitable treatment alternatives are available.
Non-melanoma skin cancer
- There is a higher rate of NMSC with RINVOQ 30mg compared to RINVOQ 15mg
- Periodically examine skin, particularly patients with risk factors for skin cancer
- Screen pre-treatment for abnormalities
- Do not initiate RINVOQ and consider temporarily interrupting treatment if ANC <1 x 109 cells/L, ALC < 0.5 x 109 cells/L or Hb <8g/dL
Major adverse cardiovascular events
- MACE events have been observed during RINVOQ treatment
- Patients 65 years of age and older, patients who are current or past long-time smokers, and patients with history of atherosclerotic cardiovascular disease or other cardiovascular risk factors, upadacitinib should only be used if no suitable treatment alternatives are available
- Monitor lipid levels at 12 weeks and thereafter according to clinical guidelines for hyperlipidaemia
Hepatic transaminase elevations
- Contraindicated in severe hepatic impairment
- Screen LFTs pre-treatment and monitor throughout therapy. Promptly investigate elevated LFTs to rule out drug induced liver injury. If increases in ALT or AST are observed during routine patient management and drug-induced liver injury is suspected, RINVOQ therapy should be interrupted until this diagnosis is excluded
Severe Renal impairment
- The recommended doses to be used with caution are:
15mg in patients with RA, AS, PsA, nr-axSpA, AD and UC (maintenance dose)
30mg UC (induction dose)
- Use with caution in patients with risk factors for VTE
- Re-evaluate patient periodically to assess change in VTE risk
- Promptly evaluate any signs and symptoms of VTE and discontinue treatment if clinical signs of VTE occur and treat promptly
- Diverticulitis may cause gastrointestinal perforation.
- Use with caution in patients with diverticular disease especially when treated with concomitant medications associated with an increase risk of diverticulitis: NSAIDs, corticosteroids and opioids.
- Promptly evaluate new onset abdominal signs and symptoms for early identification.
- Contraindicated in patients with known hypersensitivity to active substance or to any of its excipients
Pregnancy and lactation
- Contraindicated in pregnancy
- Women of childbearing potential should be advised to use effective contraception during treatment and for 4 weeks following the final dose of RINVOQ
- Should not be used during breastfeeding
Food and drink
- Should not consume food or drink containing grapefruit juice during treatment
- AD patients 12-17 years should weigh at least 30kg
Very common adverse reactions (≥1/10): Upper respiratory tract infections and acne. Common adverse reactions (≥1/100 to <1/10): Bronchitis, herpes zoster, herpes simplex, folliculitis, influenza, urinary tract infection, pneumonia, non-melanoma skin cancer, anaemia, neutropenia, lymphopaenia, hypercholesterolaemia, hyperlipidaemia, cough, abdominal pain, nausea, urticaria, rash, fatigue, pyrexia, increased blood CPK/ALT/AST, increased weight and headache. Serious adverse reactions: The most common serious adverse events were serious infections.
- RINVOQ Summary of Product Characteristics.
- Simpson EL, Papp KA, Blauvelt A, et al. Efficacy and Safety of Upadacitinib in Patients With Moderate to Severe Atopic Dermatitis Analysis of Follow-up Data From the Measure Up 1 and Measure Up 2 Randomized Clinical Trials. JAMA Dermatol. doi:10.1001/jamadermatol.2022.0029. Published online March 9, 2022.
- Blauvelt A, Teixeira H, Simpson E, et al. Efficacy and Safety of Upadacitinib vs Dupilumab in Adults With Moderate-to-Severe Atopic Dermatitis. A Randomized Clinical Trial. JAMA Dermatol. 2021; Published online August 4, 2021. DOI:10.1001/jamadermatol.2021.3023
- Blauvelt A, Teixeira H, Simpson E, et al. Upadacitinib versus dupilumab in adults with moderate-to-severe atopic dermatitis: analysis of the Heads Up Phase 3 trial. Presentation for the 11th Georg Rajka International Symposium on Atopic Dermatitis (ISAD 2021, Hybrid Meeting), April 19–20, 2021
- Reich K, Teixeira HD, Bruin-Weller M, et al. Safety and efficacy of upadacitinib in combination with topical corticosteroids in adolescents and adults with moderate-to-severe atopic dermatitis (AD Up): results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2021;397(10290):2169–2181.
- European Medicines Agency. RINVOQ EPAR: Public Assessment Report. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/rinvoq. Accessed August 2021.
- Rubbert-Roth A, Enejosa J, Pangan AL, et al. Trial of Upadacitinib or Abatacept in Rheumatoid Arthritis. N Engl J Med. 2020;383(16):1511–1521.
- Kameda H, Takeuchi T, Yamaoka K, et al. Efficacy and safety of upadacitinib in Japanese patients with rheumatoid arthritis (SELECT-SUNRISE): a placebo controlled phase IIb/III study. Rheumatology (Oxford). 2020;59(11):3303–3313.
- Xiaofeng Zeng, Dongbao Zhao, Sebastiao Radominski, Efficacy and Safety of Upadacitinib in Patients From China, Brazil, and South Korea With Rheumatoid Arthritis Who Have Had Inadequate Response to Conventional Synthetic Disease-Modifying Antirheumatic Drugs. Abstract presented at the European Congress of Rheumatology, 3–6 June 2020. Abstract SAT0160.
- ClinicalTrials.gov A Study to Evaluate Safety of Upadacitinib in Combination With Topical Corticosteroids in Adolescent and Adult Participants With Moderate to Severe Atopic Dermatitis (Rising Up). Available at: https://clinicaltrials.gov/ct2/show/NCT03661138. Accessed August 2021.
UK-RNQD-230060. Date of preparation: March 2023
Adverse events should be reported. Reporting forms and information can be found at https://yellowcard.mhra.gov.uk or via the MHRA Yellow Card app, available in the Google Play or Apple App Stores.
Adverse events should also be reported to AbbVie on [email protected]