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      The safety profile of RINVOQ in AS was consistent with previously reported results in Rheumatoid Arthritis1,2

       

      SELECT-AXIS 1: Adverse events through Week 14 and Week 641-3

      ANKYLOSING SPONDYLITIS

      The most common adverse event with RINVOQ through Week 14 was increased creatine phosphokinase.2

      No serious infections, active tuberculosis, venous thromboembolic events, gastrointestinal perforation, major adverse cardiovascular events, renal dysfunction, or deaths were reported. 

      *Cardiovascular disorder, reported as mild circulation dysregulation.
      Spinal osteoarthritis, reported as moderate worsening of cervical spondylosis 4/5.
      Dyspepsia (n=1), blood creatine phosphokinase increased (n=1), and atlantoaxial instability (n=1).
      §Otitis media (n=1) and myalgia (n=1).
      Esophageal candidiasis in patient with gastro-esophageal reflux disease; study drug continued after treatment with fluconazole.
      ¥Including non-melanoma skin cancer, malignancy other than non-melanoma skin cancer, and lymphoma.
      #All seven hepatic disorders were based on asymptomatic alanine aminotransferase or aspartate aminotransferase increases, and none led to premature discontinuation of study drug.
      **All asymptomatic except for one patient in the placebo group.
      ††Two non-serious events of esophageal candidiasis in the same patient.
      ‡‡Five events in four patients; all non-serious and limited to one dermatome.
      ##Majority based on asymptomatic alanine aminotransferase/aspartate aminotransferase elevations; all were non-serious and none led to study drug discontinuation.
      §§All events were non-serious and none led to study drug discontinuation.
      ¥¥Squamous cell carcinoma of tongue in 61-year old former smoker; no reasonable possibility to be study drug related per investigator.
      PYs, patient years; QD, once daily; TEAE, treatment-emergent adverse event.

       

      Summary of the RINVOQ safety profile

      The most commonly reported adverse reactions with RINVOQ 15 mg were upper respiratory tract infections, blood creatinine phosphokinase (CPK) increased, alanine transaminase increased, bronchitis, nausea, cough, aspertate transaminase increased, and hypercholesterolaemia. The most common serious adverse reactions were serious infections (see RINVOQ Summary of Product Characteristics for more details).1

      Adverse drug reactions

      The following table of adverse reactions is based on experience from clinical studies.1

      The frequency of adverse reactions is defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.1

      For full safety information, please refer to the RINVOQ SmPC. 

      *Presented as grouped term. 

      In atopic dermatitis trials, the frequency of bronchitis, hypercholesterolaemia, ALT increased, and AST increased was uncommon.

      In rheumatologic disease trials, the frequency was common for acne and uncommon for urticaria.

      Screening your patients

      Like many other AS treatments, RINVOQ is associated with an increased rate of infections compared to placebo. The benefits and risks of treatment with RINVOQ should be considered prior to initiating therapy in patients with active, chronic, or recurrent infections.1

      • Serious infections: RINVOQ should not be initiated in patients with an active, serious infection, including localised infections. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with RINVOQ.
      • Tuberculosis: Patients should be screened for tuberculosis (TB) before starting treatment with RINVOQ. Treatment should not be initiated in patients with active TB. Anti-TB therapy should be considered prior to treatment initiation of RINVOQ in patients with previously untreated TB or in patients with risk factors for TB infection. Consultation with a physician with expertise in the treatment of TB is recommended to aid in the decision about whether initiating anti-TB therapy is appropriate for an individial patient.
      • Viral reactivation: Screening for viral hepatitis and monitoring for reactivation should be performed before starting and during treatment with RINVOQ. Patients who were positive for hepatitis C antibody and hepatitis C virus RNA were excluded from clinical studies. Patients who were positive for hepatitis B surface antigen or hepatitis B virus DNA were excluded from clinical studies. If hepatitis B virus DNA is detected while receiving RINVOQ, a liver specialist should be consulted. If a patient develops herpes zoster, consider interruption of RINVOQ therapy until the episode resolves.
      • Non-melanoma skin cancer: Periodic skin examination is recommended for patients who are at increased risk for skin cancer.
      • Vaccinations: Use of live, attenuated vaccines during, or immediately prior to, RINVOQ treatment is not recommended. Prior to initiating RINVOQ, it is recommended that patients be brought up to date with all immunizations, including prophylactic zoster vaccinations, in agreement with current immunization guidelines.
      • Venous thromboembolism: RINVOQ should be used with caution in patients at high rish for deep venous thrombosis (DVT)/pulmonary embolism (PE). If clinical features of DVT/PE occur, RINVOQ treatment should be discontinued and patients should be evaluated promptly, followed by appropriate treatment.
      • Diverticulitis: RINVOQ should be used with caution in patients with diverticular disease and especially in patients chronically treated with concomitant medications associated with an increased risk of diverticulitis: nonsteroidal anti-inflammatory drugs, corticosteroids, and opioids. Patients presenting with new onset abdominal signs and symptoms should be evaluated promptly for early identification of diverticulitis to prevent gastrointestinal perforation.

      Contraindications

      • Hypersensitivity to the active substance or to any of the excipients listed (RINVOQ SmPC section 6.1)
      • Active TB or active serious infections (RINVOQ SmPC section 4.4)
      • Severe hepatic impairment
      • Pregnancy

      Monitoring requirements

      Treatment with RINVOQ should not be initiated, or should be interrupted if:1

      • Absolute neutrophil count <1 x 109 cells/L*
      • Absolute lymphocyte count <0.5 x 109 cells/L*
      • Haemoglobin <8 g/dL
      • Drug-induced liver injury is suspected
      • Patient develops a serious infection
      • A patient with an infection is not responding to antimicrobial therapy

      Laboratory measures and monitoring guidance1

      Renal impairment

      No dose adjustment is required in patients with mild or moderate renal impairment. There are limited data on the use of RINVOQ in subjects with severe renal impairment. RINVOQ should be used with caution in patients with severe renal impairment.1

      Hepatic impairment

      No dose adjustment is required in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment. RINVOQ should not be used in patients with severe hepatic impairment.1

      *Treatment may be initiated or restarted after levels return above specified values.

      Lab abnormalities1

      Hepatic transaminase elevations

      In RA population: In placebo-controlled studies with background DMARDs, for up to 12/14 weeks, alanine transaminase (ALT) and aspartate transaminase (AST) elevations ≥3x upper limit of normal (ULN) in at least one measurement were observed in 2.1% and 1.5% of patients treated with RINVOQ, compared to 1.5% and 0.7%, respectively, of patients treated with placebo. Most cases of hepatic transaminase elevations were asymptomatic and transient.

      In MTX-controlled studies, for up to 12/14 weeks, ALT and AST elevations ≥3x ULN in at least one measurement were observed in 0.8% and 0.4% of patients treated with RINVOQ, compared to 1.9% and 0.9%, respectively, of patients treated with MTX.

      The pattern and incidence of elevation in ALT/AST remained stable over time including in long-term extension studies.

      In PsA populations: Hepatic transaminase elevations (ALT elevations Grade 3 and higher rates 1.4% and 0.4% respectively) were observed in patients treated with monotherapy. 

      In AS population: Overall, the safety profile observed in patients with active AS treated with Rinvoq was consistent with the safety profile observed in patients with RA 

      Lipid elevations

      RINVOQ treatment was associated with dose-dependent increases in lipid parameters, including total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. There was no change in the LDL/HDL ratio. Elevations were observed at 2 to 4 weeks of treatment and remained stable with longer-term treatment.

      Creatine phosphokinase (CPK)

      In placebo-controlled studies with background DMARDs, for up to 12/14 weeks, increases in CPK were observed. CPK elevations >5x upper limit of normal (ULN) were reported in 1.0%, and 0.3% of patients over 12/14 weeks in the RINVOQ and placebo groups, respectively. Most elevations >5x ULN were transient and did not require treatment discontinuation. Mean CPK values increased by 4 weeks with a mean increase of 60 U/L at 12 weeks and then remained stable at an increased value thereafter, including with extended therapy.

      Neutropenia

      In placebo-controlled studies with background DMARDs, for up to 12/14 weeks, decreases in neutrophil counts below 1 x 109 cells/L in at least one measurement occurred in 1.1% and <0.1% of patients in the RINVOQ and placebo groups, respectively. In clinical studies, treatment was interrupted in response to ANC <1 x 109 cells/L. Mean neutrophil counts decreased over 4 to 8 weeks. The decreases in neutrophil counts remained stable at a lower value than baseline over time, including with extended therapy.

      Safety Information1

      Important safety information for RINVOQ

      Before starting RINVOQ treatment, please note the following:

      1. RINVOQ should be initiated and supervised by physicians experienced in the treatment of ankylosing spondylitis.
      2. Treatment should not be initiated in patients with an absolute lymphocyte count (ALC) <0.5 x 109 cells/L, absolute neutrophil count (ANC) <1 x 109 cells/L or Hb <8 g/dL.

       

      Concomitant use with other potent immunosuppressants

      • Not recommended, as a risk of additive immunosuppression cannot be excluded

       

      Infections

      • Do not use RINVOQ in active, serious and 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. 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 controlled
      • There is a higher incidence of infections in the elderly ≥65 years of age, caution should be used when treating this population, doses higher than 15 mg once daily are not recommended in patients aged 65 years and older. 

       

      Tuberculosis

      • 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

       

      Viral reactivation

      • 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 is detected during treatment consult a liver specialist

       

      Vaccination

      • 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

       

      Malignancy

      • Immunological medicinal products may increase the risk of malignancies in RA patients, consider the risk benefit prior to initiating RINVOQ

       

      Haematologic abnormalities

      • 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

       

      Lipids

      • 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, upadacitinib therapy should be interrupted until this diagnosis is excluded

       

      Renal impairment

      • Use with caution in patients with severe renal impairment

       

      VTE

      • Use with caution in patient at high risk of DVT/PE and discontinue treatment if clinical signs of DVT/PE occur and treat promptly

       

      Diverticulitis 

      • 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. 

       

      Cardiovascular

      • Manage patients with known cardiovascular risk factors e.g. hypertension, hyperlipidaemia as part of usual standard of care

       

      Allergic reaction                        

      • 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

       

      Adverse reactions

      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, anaemia, neutropenia, hypercholesterolaemia, cough, abdominal pain, nausea, urticaria, fatigue, pyrexia, increased blood CPK/ALT/AST, increased weight and headache. Serious adverse reactions:  The most common serious adverse events were serious infections. 

       

      Please refer to Summary of Product Characteristics for complete product information.

       

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      References

      1. RINVOQ (upadacitinib) SmPC.
      2. van der Heijde D, Song IH, Pangan AI, et al. Efficacy and safety of upadacitinib in patients with active ankylosing spondylitis (SELECT-AXIS 1): A multicenter, randomised, double-blind, placebo-controlled, phase 2/3 trial. Lancet. 2019 doi:https://doi.org/10.1016/S0140-6736(19)32534-6.
      3. Deodhar A et al. Efficacy and Safety of Upadacitinib in Patients With Active Ankylosing Spondylitis: 1-Year Results From a Randomized, Double-Blind, Placebo-Controlled Study With Open-Label Extension. 1-year SELECT AXIS 1 Abstract. American College of Rheumatology Convergence, November 2020.

      UK-UPAD-220079. Date of preparation: March 2022.

      Adverse events should be reported. Reporting forms and information can be found at yellowcard.mhra.gov.uk.
      Adverse events should also be reported to AbbVie on GBPV@abbvie.com