UK Clinical Pharmacy Association

Upadacitinib

Under Review

This monograph is pending review by the Periscope clinical trial team from University of York

Issues for surgery 

Risk of perioperative flare in disease activity (potentially leading to an increase in glucocorticoid use), if omitted. 

Risk of post-operative infection if continued. 

Risk of venous thromboembolism (VTE), particularly if continued - see Further information

Advice in the perioperative period 

Elective surgery  

Establish indication and dose (see Further information). 

Check liver function test (LFTs) pre-operatively if not recently checked. 

The Surgical Team and patient’s Rheumatologist / Dermatologist / Gastroenterologist along with the patient should be involved in the planning for elective surgery to balance the potential benefit of preventing post-operative infection by stopping upadacitinib against the risk of developing severe or unstable disease. 

Modifiable risk factors for perioperative infection, such as glycaemic control and smoking should ideally be addressed prior to surgery.  

Glucocorticoid use is associated with increased perioperative infection in a dose dependent manner. Where possible consider delaying elective surgery until patients taking upadacitinib can be managed on less than 15mg prednisolone (or equivalent).  

Minor procedures 

Consider continuing upadacitinib before low-risk surgery (i.e. surgery without a break in sterile technique, during which the respiratory, gastrointestinal, and genitourinary tracts are not entered) e.g. endoscopy, bronchoscopy, hysteroscopy, cystoscopy, breast biopsy, dermatologic or ophthalmological procedures. 

Ensure adequate thromboprophylaxis if continued (see Further information). 

All other procedures 

Surgery should be scheduled to enable the patient to miss THREE days of upadacitinib (i.e., scheduling surgery for 4 days after last dose of upadacitinib).  

EXCEPT:

If the Surgical Team deem the procedure to be of especially high infection risk, consider stopping 7 days before surgery. However, a flare in disease activity may occur, which may result in glucocorticoids being administered, further increasing the infection risk. 

Emergency surgery  

Consider withholding any doses due in the immediate post-operative period to reduce risk of VTE and infection. Monitor closely for infection and postoperative VTE.  

Ensure adequate thromboprophylaxis (see Further information).  

Patients presenting with new onset abdominal signs and symptoms 

Patients presenting with new onset abdominal signs and symptoms should be evaluated promptly for early identification of diverticulitis or gastrointestinal perforation. If diagnosed stop upadacitinib and discuss with Specialist – see Further information

Perioperative considerations 

Control of body temperature and avoidance of blood transfusion may minimise the risk of infection.   

Post-operative advice 

If stopped, recommence post-operatively once wound healing stable – discuss with Surgical Team. To prevent relapse consideration should be given to restarting upadacitinib 3 - 5 days after surgery, if no concerns. Ideally treatment interruption should not exceed 14 days (see Further information). 

If post-operative bloods indicate haemoglobin, neutrophils, or lymphocytes below normal range or liver function tests elevated, consult product literature as treatment interruption may be required – discuss with Specialist. 

If post-operative VTE, or infection, develops discontinue upadacitinib and discuss with Specialist. 

Interactions with common anaesthetic agents 

None. 

Interactions with other common medicines used in the perioperative period 

Clarithromycin is predicted to increase exposure to upadacitinib (via CYP3A4 inhibition). For some indications the manufacturer advises dose reduction with this combination and for other indications concurrent use is not recommended; however, they also advise interruption of upadacitinib in patients who develop serious infections until the infection is controlled. 

Further information  

Indications and dosing frequency 

Upadacitinib is used for rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, atopic eczema, ulcerative colitis, and Crohn’s disease. This is an oral formulation, and doses are administered once daily.  

Venous thromboembolism (VTE) risk 

Ensure patients receive adequate thromboprophylaxis when undergoing surgery as serious VTE events have been observed in patients taking upadacitinib. In a randomised post authorisation safety study in patients with rheumatoid arthritis who were 50 years of age or older with at least one additional cardiovascular risk factor, a dose-dependent increased risk for VTE was observed with tofacitinib compared to tumour necrosis factor (TNF) inhibitors. Following a European safety review this increased risk of VTE is regarded as a JAK inhibitors class effect.  It is not known if pre-operative cessation of upadacitinib reduces the VTE risk back to baseline. 

Diverticulitis 

Diverticulitis and gastrointestinal perforations have been reported in clinical trials and post-marketing use with upadacitinib. Upadacitinib should be used with caution in patients with diverticular disease or a history of diverticulitis, or who are taking non-steroidal anti-inflammatory drugs, corticosteroids, or opioids due to the risk for gastrointestinal perforation. 

Rationale for recommendations - risk of infection versus risk of disease  

Inflammatory arthritis 

Upadacitinib is known to increase the risk of serious infections, particularly in the elderly, hence use is not recommended in patients over 65 years old unless there is no suitable alternative. Upadacitinib has a short half-life; approximately between 9 and 14 hours. However, concerns that the duration of pharmacodynamic activity of JAK inhibitors is longer than the half-life initially led to the American College of Rheumatology / American Association of Hip and Knee Surgeons (ACR / AAHKS) recommending to stop 7 days pre-operatively, however, they have since revised their guidance and recommend stopping 3 days prior to arthroplasty (with the caveat that a longer cessation period may be considered if history of infections or previous prosthetic joint infection). This aligns with the recommendations from the German Society for Rheumatology. The change in advice is attributed to a sub-study which showed a rapid increase in disease activity after discontinuing tofacitinib with patients experiencing flares within 2 weeks, sooner than with TNF inhibitors.  These findings are expected to extrapolate to upadacitinib. 

Psoriasis and eczema 

Whilst there are currently no recommendations from dermatology societies regarding the perioperative management of JAK inhibitors it seems reasonable to extrapolate the recommendations from rheumatology societies. 

Inflammatory bowel disease 

Currently there is very limited data on the perioperative safety of JAK inhibitors in patients with IBD; the single study available reported an increase in the number of venous thromboembolic events in patients taking tofacitinib and recommended prolonged use of thromboprophylaxis. Cohen et al recommend stopping JAK inhibitors three days prior to surgery which aligns with the recommendations by rheumatology societies. Their recommendations for restarting JAK inhibitors vary from 3 days to 14 days post-operatively depending on the clinical situation. Figure 2 and 3 in Cohen et al may be useful tools when weighing this decision.   

References 

Albrecht, K. Poddubnyy, D. Leipe, J. et al. Perioperative management of patients with inflammatory rheumatic diseases: Updated recommendations of the German Society for Rheumatology. Zeitschrift fur Rheumatologie. 2022, 82:1-11 doi:10.1007/s00393-021-01150-9 

Baxter K, Preston CL (eds), Stockley’s Drug Interactions (online) London: Pharmaceutical Press. http://www.medicinescomplete.com [Accessed 21st May 2024] 

Cohen, BL. Lincango, E. & Holubar, S. How to manage targeted immune suppressants (biologics and oral small-molecule drugs) perioperatively for inflammatory bowel disease and non-inflammatory bowel disease surgery. Clinical Gastroenterology and Hepatology. 2023; 21:1148-1151 doi:10.1016/j.cgh.2023.01.042.  

Goodman, SM. Springer, BD. Chen AF. American College of Rheumatology and American Association of Hip and Knee Surgeons (AAHKS) 2022 American College of Rheumatology / American Association of Hip and Knee Surgeons Guideline for the Perioperative Management of Antirheumatic Medication in Patients with Rheumatic Diseases Undergoing Elective Total Hip or Total Knee Arthroplasty. 2022; 74(9):1399-1408 doi:10.1002/acr.24893 

Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press http://www.medicinescomplete.com [Accessed 21st May 2024] 

Kaine, J. Tesser, J. Takiya, L. Re-establishment of efficacy of tofacitinib, an oral JAK inhibitor, after temporary discontinuation in patients with rheumatoid arthritis. Clin Rheumatol. 2020;39(7):2127-2137 doi:10.1007/s10067-020-04956-1 

Moreira P, Correia A, Cerquerira M, Gil M. Perioperative management of disease-modifying antirheumatic drugs and other immunomodulators. ARP Rheumatol. 2022; 3: 218-224.  

Sebastian, S. Segal, JP. Hedin, C. et al. ECCO Topical Review: Roadmap to Optimal Peri-Operative Care in IBD. Journal of Crohn’s and Colitis. 2023, 17:153-169 doi:10.1093/ecco-jcc/jjac129  

Summary of Product Characteristics – RINVOQ (upadacitinib) 15 mg prolonged-release tablets. AbbVie Ltd. Accessed via www.medicines.org.uk 21/05/24 [date of revision of the text December 2023] 

Upadacitinib. In: Brayfield A (Ed), Martindale: The Complete Drug Reference. London: The Royal Pharmaceutical Society of Great Britain. Electronic version. Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com [Accessed 24th May 2024]