New drug
Upadacitinib for rheumatoid arthritis
- First published 6 August 2020
- Aust Prescr 2020;43:178-9
- 1 October 2020
- DOI: 10.18773/austprescr.2020.053
ISSUE 5 OCTOBER
Approved indication: rheumatoid arthritis
Rinvoq (AbbVie)
15 mg modified-release tablets
Upadacitinib is the third Janus kinase (JAK) inhibitor to be approved for rheumatoid arthritis after baricitinib and tofacitinib. These drugs modify immune and inflammatory processes by blocking the cytokine pathway that leads to the activation of lymphocytes.1,2
Upadacitinib is indicated for patients with moderate–severe rheumatoid arthritis who have not adequately responded, or are intolerant, to at least one or more conventional disease-modifying antirheumatic drugs (DMARDs). The drug has been investigated in several phase III randomised clinical trials.3-7 Response to treatment was defined as at least a 20% improvement on the American College of Rheumatology scale (ACR20). At the recommended daily dose of 15 mg, statistically more people responded to upadacitinib, as monotherapy or when added to conventional DMARDs, than to placebo or methotrexate (see Table).
Table - Efficacy of upadacitinib in moderate–severe rheumatoid arthritis
| Trial | Treatment | Efficacy - ACR20* |
| SELECT EARLY3 947 methotrexate-naïve patients randomised to upadacitinib or methotrexate for 12 weeks |
upadacitinib 15 mg/day | 76% |
| upadacitinib 30 mg/day | 77% | |
| methotrexate | 54% | |
| SELECT MONOTHERAPY4 648 patients with inadequate response to methotrexate randomised to switch to upadacitinib monotherapy or continue methotrexate for 14 weeks |
upadacitinib 15 mg/day | 68% |
| upadacitinib 30 mg/day | 71% | |
| methotrexate | 41% | |
| SELECT NEXT5 661 patients with inadequate response to at least one conventional DMARD (methotrexate, sulfazine or leflunomide) randomised to add upadacitinib or placebo for 12 weeks |
upadacitinib 15 mg/day | 64% |
| upadacitinib 30 mg/day | 66% | |
| placebo | 36% | |
| SELECT COMPARE6 1629 patients with inadequate response to methotrexate randomised to add upadacitinib, adalimumab or placebo for 48 weeks (ACR20 measured at 12 weeks) |
upadacitinib 15 mg/day | 71% |
| adalimumab 40 mg every 2 weeks | 63% | |
| placebo | 36% | |
| SELECT BEYOND7 499 patients with inadequate response or intolerance to biological DMARDs and receiving conventional DMARDs randomised to add upadacitinib or placebo for 12 weeks |
upadacitinib 15 mg/day | 65% |
| upadacitinib 30 mg/day | 56% | |
| placebo | 28% |
DMARD disease-modifying antirheumatic drug
* defined as the proportion of patients who had at least a 20% improvement on the American College of Rheumatology
The most common adverse effects with upadacitinib in the trials included urinary and upper respiratory tract infections, altered liver function and nausea. Rare but serious adverse events included malignancy, thrombosis and gastrointestinal perforation.
As with other JAK inhibitors, serious and sometimes fatal infections can occur with upadacitinib – pneumonia and cellulitis were the most commonly reported in the trials. Opportunistic infections such as tuberculosis, multi-dermatomal herpes zoster, oral candidiasis, cryptococcosis and pneumocystosis have also occurred. Upadacitinib should not be used in patients with active infections and caution is urged in those with chronic or recurrent infection or a history of tuberculosis. Care should also be taken in older patients and those with diabetes. Screening for tuberculosis and viral hepatitis is recommended and vaccinations, particularly against herpes zoster, should be up to date before treatment is started.
Upadacitinib can be prescribed as monotherapy or in addition to methotrexate and other conventional DMARDs. It should not be given with other JAK inhibitors, biological DMARDS or potent immunosuppressants like azathioprine or ciclosporin. Upadacitinib should not be started if lymphocytes are less than 0.5 x 109 cells/L or neutrophils are less than 1 x 109 cells/L. Haemoglobin must be at least 80 g/L. Upadacitinib is not recommended in severe hepatic impairment (Child-Pugh C).
Upadacitinib is mainly metabolised by cytochrome P450 (CYP) 3A4, and to a lesser extent by CYP2D6. It has no active metabolites. Steady-state concentrations are reached within four days following once-daily dosing. It has a half-life of 9–14 hours. Two-thirds of the dose is excreted unchanged in the urine (24%) and faeces (38%) and a third is excreted as metabolites.
Giving upadacitinib with a strong CYP3A4 inducer (e.g. rifampicin) may decrease its efficacy, while strong CYP3A4 inhibitors (e.g. clarithromycin) could increase the risk of toxicity. Patients should therefore be closely monitored if they are taking these types of medicines.
Upadacitinib is a category D drug and is not recommended in pregnancy. In animal studies, it caused fetal malformations in early pregnancy. The drug is also not recommended during breastfeeding and was found to be excreted in the milk of lactating rats.
Upadacitinib seems to be effective in moderate–severe rheumatoid arthritis used alone or added to a patient’s conventional DMARD therapy. However, close monitoring is recommended as there is a risk of serious and sometimes fatal adverse effects, particularly infections. To date, there have been no head-to-head trials with other JAK inhibitors.
🅃 manufacturer provided useful information
The Transparency Score is explained in New drugs: transparency, Vol 37 No 1, Aust Prescr 2014;37:27.
At the time the comment was prepared, information about this drug was available on the websites of the Food and Drug Administration in the USA, and the European Medicines Agency and the Therapeutic Goods Administration.
Australian Prescriber welcomes Feedback.
References
- Kubler P. Janus kinase inhibitors: mechanisms of action. Aust Prescr 2014;37:154-7.
- Walker J, Smith M. Janus kinase inhibitors in rheumatoid arthritis: clinical applications. Aust Prescr 2014;37:158-60.
- van Vollenhoven R, Takeuchi T, Pangan AL, Friedman A, Mohamed M, Chen S, et al. A phase 3, randomized, controlled trial comparing upadacitinib monotherapy to MTX monotherapy in MTX-naïve patients with active rheumatoid arthritis [abstract]. Arthritis Rheumatol 2018;70 Suppl 10. [cited 2020 Jul 29]
- Smolen JS, Pangan AL, Emery P, Rigby W, Tanaka Y, Vargas JI, 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;393:2303-11.
- Burmester GR, Kremer JM, Van den Bosch F, Kivitz A, Bessette L, Li Y, et al. Safety and efficacy of upadacitinib in patients with rheumatoid arthritis and inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (SELECT-NEXT): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2018;391:2503-12.
- Fleischmann R, Pangan AL, Song I-H, Mysler E, Bessette L, Peterfy C, et al. Upadacitinib versus placebo or adalimumab in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a phase III, double-blind, randomized controlled trial. Arthitis Rheumatol 2019;71:1788-800.
- Genovese MC, Fleischmann R, Combe B, Hall S, Rubbert-Roth A, Zhang Y, et al. Safety and efficacy of upadacitinib in patients with active rheumatoid arthritis refractory to biologic disease-modifying anti-rheumatic drugs (SELECT-BEYOND): a double-blind, randomised controlled phase 3 trial. Lancet 2018;391:2513-24.
Some of the views expressed on newly approved products should be regarded as preliminary, as there may be limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer’s approved product information, a drug information centre or some other appropriate source.
