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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; OD, 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, neutropaenia, 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.

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 or opportunistic 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

Lipid elevations

Creatine phosphokinase (CPK)

Neutropaenia

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.

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.

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.

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.

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

Safety Information4

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 is controlled following careful consideration of benefit risk
  • There is a higher incidence of infections in the elderly ≥65 years of age, caution should be used when treating this population

 

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 DNA 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 the risk of malignancies, including lymphoma is increased. 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, RINVOQ therapy should be interrupted until this diagnosis is excluded

 

Severe renal impairment

  • Use 15mg 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 (across all RINVOQ indications)

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, anaemia, neutropaenia, 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

 

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

 

References

  1. RINVOQ 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.
  4. RINVOQ Product Safety Message.

UK-UPAD-220205. Date of preparation: August 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