RINVOQ PRESCRIBING INFORMATION

ADALIMUMAB PRESCRIBING INFORMATION

The safety profile of RINVOQ in AS was consistent with previously reported results in Rheumatoid Arthritis^1,2

SELECT-AXIS 1: Adverse events through Week 14 and Week 64^1-3

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

SYSTEM ORGAN CLASS	VERY COMMON (≥1/10)	COMMON (≥1/100 to <1/10)	UNCOMMON (≥1/1000 to <1/100)
Infections and infestations	Upper respiratory tract infections (URTI)^a	Bronchitis^a,b, Herpes zoster^a, Herpes simplex^a, Folliculitis, Influenza, Urinary tract infection	Pneumonia, Oral candidiasis, Diverticulitis, Sepsis
Neoplasms benign, malignant and unspecified (including cysts and polyps)		Non-melanoma skin cancer^f
Blood and lymphatic system disorders		Anaemia^a, Neutropaenia^a, Lymphopaenia
Metabolism and nutrition disorders		Hypercholesterolaemia^a,b, Hyperlipidaemia^a,b	Hypertriglyceridaemia
Respiratory, thoracic, and mediastinal disorders		Cough
Gastrointestinal disorders		Abdominal pain^a,d, Nausea
Skin and subcutaneous tissue disorders	Acne^a,c,d	Rash^a
General disorders and administration site conditions		Fatigue, Pyrexia
Investigations		Blood CPK increased, ALT increased^b AST increased^b, Weight increased
Nervous system disorders		Headache^a
Immune system disorders		Urticaria^c	Serious hypersensitivity reactions^a,e

SYSTEM ORGAN CLASS	VERY COMMON (≥1/10)	COMMON (≥1/100 to <1/10)	UNCOMMON (≥1/1000 to <1/100)
Infections and infestations	Upper respiratory tract infections (URTI)^a	Bronchitis^a,b, Herpes zoster^a, Herpes simplex^a, Folliculitis, Influenza, Urinary tract infection	Pneumonia, Oral candidiasis, Diverticulitis, Sepsis
Neoplasms benign, malignant and unspecified (including cysts and polyps)		Non-melanoma skin cancer^f
Blood and lymphatic system disorders		Anaemia^a, Neutropaenia^a, Lymphopaenia
Metabolism and nutrition disorders		Hypercholesterolaemia^a,b, Hyperlipidaemia^a,b	Hypertriglyceridaemia
Respiratory, thoracic, and mediastinal disorders		Cough
Gastrointestinal disorders		Abdominal pain^a,d, Nausea
Skin and subcutaneous tissue disorders	Acne^a,c,d	Rash^a
General disorders and administration site conditions		Fatigue, Pyrexia
Investigations		Blood CPK increased, ALT increased^b AST increased^b, Weight increased
Nervous system disorders		Headache^a
Immune system disorders		Urticaria^c	Serious hypersensitivity reactions^a,e

^aPresented as grouped term.

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

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

^dIn ulcerative colitis trials, the frequency was common for acne; abdominal pain was less frequent for upadacitinib than for placebo.

^eSerious hypersensitivity reactions including anaphylactic reaction and angioedema.

^fMost events reported as basal cell carcinoma and squamous cell carcinoma of skin.

For more detailed safety information, please see the RINVOQ Prescribing Information link at the top of the page, or for complete product information, the RINVOQ Summary of Product Characteristics.

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 all patients, particularly those with risk factors 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 immunisations, including prophylactic zoster vaccinations, in agreement with current immunisations guidelines.
Venous thromboembolism: Rinvoq should be used with caution in patients with known VTE risk factors. Patients should be re-evaluated periodically during Rinvoq treatment to assess for changes in VTE risk. Promptly evaluate patients with signs and symptoms of VTE and discontinue Rinvoq in patients with suspected VTE.
Gastrointestinal perforations: Rinvoq should be used with caution in patients who may be at risk for gastrointestinal perforation (e.g., patients with diverticular disease, a history of diverticulitis, or who are taking NSAIDs, corticosteroids, or opioids). Patients presenting with new onset abdominal signs and symptoms should be evaluated promptly for early identification of diverticulitis or 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 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

You are also strongly advised to read the prescribing information (PI) which can be found at the top of this page

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. 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

Rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis

The recommended dose of upadacitinib is 15 mg once daily.

Consideration should be given to discontinuing treatment in patients with axial spondyloarthritis who have shown no clinical response after 16 weeks of treatment. Some patients with initial partial response may subsequently improve with continued treatment beyond 16 weeks.

Elderly

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 30 mg in patients ≥65 years of age and older
The licensed dose in AS is 15mg once daily

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

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. 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 incidence of infections in the elderly ≥ 65 years of age and in diabetics, caution should be used when treating these populations.

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

There is a higher rate of malignancies with RINVOQ 30 mg compared to RINVOQ 15 mg
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 30 mg compared to RINVOQ 15 mg
Periodically examine skin, particularly patients with risk factors for skin cancer

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

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

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

The recommended dose to be used with caution is:

15 mg in patients with RA, AS, PsA, nr-axSpA

Venous thromboembolism

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

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

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, urinary tract infection, non-melanoma skin cancer, 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.

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Risk Management Plan Documents

References

RINVOQ SmPC.
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.
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.
RINVOQ Product Safety Message.