In February 2024, the US Food and Drug Administration (FDA) approved Xolair (omalizumab; Genentech, Inc), an anti-immunoglobulin E (IgE) antibody, for the treatment of IgE-mediated food allergies in patients aged 1 year and older for the reduction of type 1 allergic reactions, including anaphylaxis, that may occur with accidental exposure to 1 or more foods. The treatment should be used in conjunction with food allergen avoidance.

Xolair should not be used for the treatment of emergency allergic reactions, including anaphylaxis. 

Omalizumab works by inhibiting the binding of IgE to the high-affinity IgE receptor (FcεRI) on mast cell, basophil, and dendritic cell surfaces. This results in FcεRI down-regulation on these cells. 

Additional indications for Xolair include treatment of asthma, chronic rhinosinusitis with nasal polyps, and chronic spontaneous urticaria.

Clinical Trials

The approval of Xolair for food allergies was based on results obtained from the food allergy (FA) trial (ClinicalTrials.gov identifier: NCT03881696). The multicenter study was a randomized, double-blind, and placebo-controlled clinical trial that included patients allergic to peanut and at least 2 other foods (milk, egg, wheat, cashew, hazelnut, or walnut).

A total of 168 adult and pediatric patients aged 1 to less than 56 years were enrolled in the trial. During the screening double-blind, placebo-controlled food challenge (DBPCFC), eligible participants experienced dose-limiting symptoms to a single dose of ≤100 mg of peanut protein and ≤300 mg protein for each of the other 2 foods. Dose-limiting symptoms included moderate to severe skin reactions, respiratory symptoms, or gastrointestinal symptoms. Patients were excluded from the study if they had a history of severe anaphylaxis, defined as neurological compromise or requiring intubation. 

Study participants were randomly assigned  (2:1) to receive either Xolair subcutaneously or placebo for 16 to 20 weeks. The dose of Xolair was calculated based on the patient’s body weight and baseline serum total IgE level (IU/mL). Following the 16- to 20-week study period, each patient underwent a DBPCFC consisting of placebo and each of their 3 studied foods. After the DBPCFC, the first 60 patients (59 pediatric patients, 1 adult patient) continued to receive Xolair in a 24- to 28-week open-label extension study. 

The efficacy analyses included 165 pediatric patients (Figure 1). 

The primary efficacy outcome was the percentage of patients able to consume 1 dose of ≥600 mg of peanut protein without experiencing dose-limiting symptoms during DBPCFC. Secondary outcomes of the study included the percentage of patients able to consume 1 dose of ≥1000 mg of cashew, milk, or egg protein without experiencing dose-limiting symptoms during DBPCFC.

Findings revealed treatment with Xolair resulted in statistically higher response rates for the primary and secondary endpoints compared with placebo (Figure 2). 

Findings also revealed that 17% of patients receiving Xolair were not able to have >100 mg of peanut protein without experiencing moderate to severe dose-limiting symptoms. Additionally, 18%, 22%, and 41% of patients treated with Xolair were not able to consume >300 mg of milk, egg, and cashew protein, respectively, without dose-limiting symptoms. 

Secondary analyses also assessed the percentage of patients able to consume at least 2 or all 3 foods during DBPCFC. When analyzing 2 foods, 71% of Xolair-treated patients were able to consume a single dose of ≥600 mg compared with 5% of patients who received placebo. This analysis also showed 67% of patients in the Xolair group were able to consume a single dose of ≥1000 mg of 2 foods vs 4% of patients in the placebo group. 

Findings also showed that 48% and 39% of Xolair patients were able to consume ≥600 mg and ≥1000 mg of 3 foods without symptoms, respectively, compared with 4% and 0% of placebo patients. 

Xolair effectiveness is supported for adult patients by the results obtained through adequate trials completed in pediatric patients and the similarities of the disease and pharmacokinetic profiles between these populations. 

For the 38 pediatric patients who continued to receive Xolair for the 24- to 28-week open-label extension study, findings showed that the percentage of patients able to tolerate ≥600 mg of peanut protein and ≥1000 mg egg, milk, and/or cashew protein was maintained without dose-limiting symptoms.

Dosage and Administration

Xolair is supplied as a prefilled syringe, an autoinjector, and as a lyophilized powder for single-use. Both the prefilled syringe and the autoinjector come in the following strengths: 75 mg/0.5 mL, 150 mg/mL, and 300 mg/2 mL. The lyophilized powder is dispensed as 150 mg for injection in a single-dose vial for reconstitution. 

The recommended dosage of Xolair for the treatment of IgE-mediated FA is 75 mg to 600 mg by subcutaneous injection every 4 weeks (Table 1) or every 2 weeks (Table 2) based on a patient’s serum total IgE level (IU/mL) at the start of treatment and body weight (kg). The dose of Xolair must be adjusted if  significant changes in body weight occur during treatment. As the appropriate duration of therapy for IgE-mediated FA has not been evaluated, periodic reassessment is recommended to see if continued therapy is needed.

Do not retest IgE levels during treatment with Xolair as a guide for determining a patient’s dose. IgE levels will be elevated during treatment with Xolair as well as for up to 1 year following discontinuation of the medication. For interruptions in therapy lasting less than a year, base the dose on the serum IgE level obtained at the initial dose determination. For interruptions lasting 1 year or more, retest serum IgE levels to determine a patient’s dose of Xolair. 

At the beginning of treatment, the prefilled syringe and autoinjector forms of Xolair must be given under the supervision of a healthcare provider. Once safety has been established, Xolair can be self-administered by the patient or a caregiver at home. The Xolair lyophilized powder formulation must be prepared and administered by a healthcare provider only. 

When selecting patients for self-administration of Xolair, certain factors should be considered (Table 3).

Intructions For Prefilled Syringe and Autoinjector Use

• Xolair prefilled syringes should not be handled by patients and caregivers with latex allergies. 
• Determine the number of prefilled syringes or autoinjectors required for a patient’s dose.
• Subcutaneously administer Xolair into the thigh or abdomen.
  • Avoid the 2-inch area directly around the navel.
  • Outer area of the upper arms may be used only if Xolair is being given by a caregiver or healthcare provider.
  • If more than 1 injection is required to complete a full dose, administer each injection at least 1 inch apart from other injection sites.

Instructions For Xolair Lyophilized Powder

• Determine the number of vials required for a patient’s dose.
• Inject 1.4 mL of Sterile Water for Injection (SWFI) USP into the lyophilized powder vial and swirl for approximately 1 minute.
  • Continue to swirl for 5 to 10 seconds every 5 minutes to dissolve the product.
  • It should take 15 to 20 minutes for the product to completely dissolve.
  • Use the Xolair solution within 8 hours after reconstitution when stored in the vial between 36°F and 46°F or within 4 hours of reconstitution when stored at room temperature.  
• Withdraw all of the product using a 3 mL syringe equipped with a 1-inch, 18-gauge needle.
  • Replace 18-gauge needle with a 25-gauge needle for subcutaneous injection.
• Administer 1.2 mL of solution (corresponding to a 150-mg Xolair dose) or 0.6 mL of solution (corresponding to a 75-mg dose).
  • Do not inject more than 150 mg (1 vial) per injection site; divide doses >150 mg between 2 or more injection sites at least 1 inch apart.

Contraindications, Warnings, Precautions, and Adverse Reactions

Xolair is contraindicated in patients with a hypersensitivity to Xolair or any of its components.

Anaphylaxis

Cases of anaphylaxis, including life-threatening events, have occurred in patients receiving Xolair. Signs and symptoms of anaphylaxis include bronchospasm, hypotension, syncope, urticaria, and/or angioedema of the tongue or throat.

During premarketing clinical trials, anaphylaxis was reported in 0.1% (3/3507) of patients with asthma. Of these 3 patients, 2 experienced anaphylaxis with their first dose of Xolair and 1 experienced it with their fourth dose. In 2 patients, the onset of anaphylaxis was reported to be 90 minutes following administration while 1 patient experienced anaphylaxis 2 hours after receiving Xolair.

A case-control study revealed that compared with patients with no prior anaphylaxis history, patients with a history of anaphylaxis to foods, medications, or other agents had an increased risk of anaphylaxis associated with Xolair use.

Postmarketing spontaneous reports estimated the frequency of anaphylaxis associated with Xolair use to be at least 0.2% of patients based on an estimated exposure of 57,300 patients between June 2003 and December 2006. It was also reported that anaphylaxis occurred between the first dose of treatment through 1 year after receiving Xolair regularly. It is estimated that about 60% to 70% of cases of anaphylaxis occur within the first 3 doses of Xolair. 

Xolair should only be initiated in a healthcare setting equipped to manage anaphylaxis. Patients should be monitored for an appropriate time period following Xolair administration. Patients should also be counseled on the signs and symptoms of anaphylaxis and should be informed to seek medical care immediately if they experience any signs or symptoms of this life-threatening condition. 

Select patients may be qualified for self-administration of the Xolair prefilled syringe or autoinjector outside of a healthcare setting once Xolair therapy has been established. Xolair should be discontinued in patients who experience a severe hypersensitivity reaction.

Malignancy

In clinical studies including adults and adolescents ≥12 years of age who have asthma and other allergic disorders, malignant neoplasms were reported in 0.5% (20/4127) of patients. A variety of types of malignancies were observed in varying frequencies: breast, nonmelanoma skin, prostate, melanoma, and parotid occurred at least once; 5 other types occurred 1 time each. Most patients were observed for less than 1 year. It is unknown whether longer Xolair exposure or a higher risk of malignancy impacts the risk of malignancy in these patients. 

In a subsequent observational study, the incidence rates of primary malignancies were found to be similar among Xolair-treated and non-Xolair-treated patients. However,  malignancy risk with Xolair could not be ruled out as the study had several limitations.

Fever, Arthralgia, and Rash

A constellation of signs and symptoms, including arthritis/arthralgia, rash, fever, and lymphadenopathy, may occur with Xolair use. The onset of these symptoms typically occurs 1 to 5 days following Xolair administration. These signs and symptoms may recur following subsequent Xolair injections and are similar to those observed in patients with serum sickness. Xolair should be discontinued in patients who develop these signs and symptoms. 

Parasitic (Helminth) Infection

Patients at high risk for geohelminth infection should be monitored while receiving Xolair therapy. There are insufficient data on the exact length of monitoring required for geohelminth infections following Xolair discontinuation. 

A 1-year clinical study conducted in Brazil revealed that 53% (36/68) of Xolair-treated patients who were considered high risk for geohelminthic infections were diagnosed with an infection compared with 42% (29/69) of placebo patients.  The point estimate of the odds ratio for infection was reported to be 1.96 (95% CI, 0.88-4.36). This indicates that a patient with an infection was between 0.88 and 4.36 times as likely to have received Xolair vs a patient who did not have an infection. No difference was observed between treatment groups when analyzing response to appropriate anti-geohelminth therapy for infection, which is measured by stool egg counts. 

Laboratory Tests

Due to the formation of Xolair:IgE complexes, an increase in serum total IgE levels will be observed following Xolair administration. This elevation may persist for up to 1 year after Xolair discontinuation. Since these levels are not reflective of steady-state free IgE levels, serum total IgE levels obtained less than 1 year after Xolair discontinuation should not be used to reassess the dosing regimen for Xolair.

Potential Medication Error Related to Emergency Treatment of Anaphylaxis

Xolair is not indicated for emergency treatment of allergic reactions, including anaphylaxis. According to studies simulating use, a number of patients and caregivers did not understand that Xolair should not be used to treat allergic reactions. The safety and effectiveness of Xolair have not been established to treat emergency allergic reactions. It is important to counsel patients and caregivers that Xolair is intended to be used as maintenance treatment to reduce allergic reaction to food allergens.

Adverse Reactions

The safety of Xolair was assessed in the FA trial, including 168 patients (165 pediatric and 3 adult patients) with type 1 IgE-mediated allergic reactions to peanuts and at least 2 other foods. 

During the study, patients randomly received Xolair or placebo subcutaneously every 2 or 4 weeks for 16 to 20 weeks. A patient’s dose was dependent on their baseline total IgE level (IU/mL) and body weight (kg).

Safety findings obtained from the primary analysis population (pediatric patients aged 1 to 17 years old) revealed that 15.5% (17/110) of Xolair-treated patients experienced injection-site reactions and 6.4% (7/110) experienced pyrexia. Comparatively, 10.9% (6/55) and 3.6% (2/55) of placebo patients experienced injection-site reactions and pyrexia, respectively.

Drug Interactions

No drug interaction studies for Xolair have been conducted at this time. Concomitant use of Xolair with allergen immunotherapy has also not been evaluated at this time.

Considerations for Specific Populations

No increase in major birth defects or miscarriage was observed in a registry study including 250 pregnant women with asthma, 246 of whom were exposed to Xolair during pregnancy. An increased risk of low birth weight was seen in registry infants (13.7%) compared with those in other cohorts (9.8%), regardless of average gestational age at birth. It was noted, however, that it was difficult to determine if this low birth weight was caused by Xolair or disease severity since women taking Xolair during pregnancy had more severe asthma. Poorly or moderately controlled asthma during pregnancy is known to cause problems after pregnancy. 

Xolair may be transmitted to the developing fetus from the mother since human IgG antibodies are known to cross the placental barrier. 

No data currently exist on the presence of Xolair in breast milk or its effect on milk production. It is known, however,  that IgG is present in breast milk. 

Based on data obtained from the registry exposure study, infants exposed to Xolair did not have a significantly increased risk for “infections and infestations” events compared with infants not breastfed or exposed to Xolair. During the study, 80.9% (186/230) of infants were breastfed. The benefits of breastfeeding, a mother’s clinical need for Xolair, and the potential adverse effects of Xolair on the breastfed child should be considered.

The efficacy and safety of Xolair have been established in pediatric patients aged 1 year and older who have an IgE-mediated FA. This study included 165 pediatric patients, including 61 patients aged 1 to less than 6 years of age and 104 patients aged 6 to less than 18 years of age. Study findings revealed that a significantly greater percentage of patients treated with Xolair were able to consume a single dose of food without dose-limiting symptoms compared with patients who received placebo. The safety and effectiveness of Xolair have not been established in pediatric patients less than 1 year of age. 

The FA study did not include patients aged 65 years or older; therefore, it is unclear if these patients would respond differently from younger patients. 

Reference

Xolair^®. Prescribing information. Genentech, Inc; 2024. Accessed February 26, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/103976s5245lbl.pdf.

Posted by Haymarket’s Clinical Content Hub. The editorial staff of MPR had no role in this content’s preparation.

Reviewed March 2024

In May 2023, Veozah (fezolinetant; Astellas Pharma US, Inc) became the first medication within its class to be approved by the US Food and Drug Administration (FDA) for the treatment of moderate to severe vasomotor symptoms due to menopause. These symptoms are also colloquially known as hot flashes. 

Veozah acts as a neurokinin 3 (NK3) receptor antagonist, which inhibits the binding of neurokinin B to kisspeptin/neurokinin B/dynorphin neurons in the thermoregulatory center of the hypothalamus. Veozah is highly selective for the NK3 receptor compared with the NK1 and NK2 receptors. It does not appear to affect sex hormones (follicle-stimulating hormone, testosterone, estrogen, and dehydroepiandrosterone sulfate) in menopausal women other than causing a transient decrease in luteinizing hormone levels.

Clinical Trials

Veozah gained FDA approval for the treatment of moderate to severe vasomotor symptoms due to menopause by demonstrating efficacy and safety across two phase 3 trials, along with long-term safety in a third phase 3 trial.

Efficacy and safety were first evaluated in postmenopausal women enrolled into 2 multicenter, randomized, double-blind, placebo-controlled phase 3 studies (SKYLIGHT 1 [ClinicalTrials.gov identifier: NCT04003155] and SKYLIGHT 2 [ClinicalTrials.gov identifier: NCT04003142]). Study participants were randomly assigned to once-daily treatment with Veozah 45 mg, fezolinetant 30 mg, or placebo; randomization was stratified by self-reported smoking status. These 2 identically designed studies were split into 2 phases measuring exposure over 52 weeks: a 12-week initial treatment period and a 40-week extension where participants in the placebo arm were re-randomized to once-daily Veozah.

More than 1000 postmenopausal women were included in the trials (SKYLIGHT 1: N=522; SKYLIGHT 2: N=500). Study participants experienced, on average, at least 7 moderate to severe vasomotor symptoms per day. 

The coprimary endpoints measured during the initial 12-week treatment phase were the mean change from baseline in frequency and severity of vasomotor symptoms at weeks 4 and 12. A clinically meaningful reduction in the frequency of moderate to severe vasomotor symptoms was defined as at least 2 fewer hot flashes over 24 hours. 

Results from SKYLIGHT 1 showed that treatment with Veozah 45 mg reduced the frequency of moderate to severe vasomotor symptoms compared with placebo at week 4 (difference vs placebo, -2.1 [95% CI, -2.9, -1.3; P <.001]) and at week 12 (difference vs placebo, -2.6 [95% CI, -3.4, -1.7; P <.001]). Similar results were observed in SKYLIGHT 2 at week 4 (difference vs placebo, -2.6 [95% CI, -3.5, -1.6; P <.001]) and week 12 (difference vs placebo, -2.5 [95% CI, -3.6, -1.5; P <.001]).

The 45 mg dosage strength was also associated with a statistically significant reduction from baseline in the severity of moderate to severe vasomotor symptoms (over 24 hours) compared with placebo at week 4 (SKYLIGHT 1: difference vs placebo, -0.2 [95% CI, -0.3, -0.1; P =.002]; SKYLIGHT 2: difference vs placebo, -0.3 [95% CI, -0.4, -0.2; P <.001]) and week 12 (SKYLIGHT 1: difference vs placebo, -0.2 [95% CI, -0.4, -0.1; P =.007]; SKYLIGHT 2: difference vs placebo, -0.3 [95% CI, -0.5, -0.1; P <.001]).

The safety profile of Veozah was determined by pooling the 52-week results from the initial two phase 3 trials (SKYLIGHT 1 and 2) and a third phase 3 trial (SKYLIGHT 4 [ClinicalTrials.gov identifier: NCT04003389]). 

Findings from SKYLIGHT 4, which included 609 patients who received Veozah 45 mg once daily, showed that the most common adverse reactions (≥2% of participants and more frequently than placebo) were abdominal pain, including lower abdominal pain and upper abdominal pain (4.3% vs 2.1%); diarrhea (3.9% vs 2.6%); insomnia (3.9% vs 1.8%); back pain (3% vs 2.1%); hot flush (2.5% vs 1.6%); and hepatic transaminase elevation, including abnormal alanine aminotransferase (ALT), increased ALT, abnormal aspartate aminotransferase (AST), and increased AST (2.3% vs 0.8%).

The pooled phase 3 data across the 3 trials included a total of 1100 women who received Veozah 45 mg. Elevation of hepatic transaminases greater than 3 times the upper limit of normal (ULN) occurred in 2.3% of women (2.7 exposure adjusted incidence rate [EAIR]) on Veozah 45 mg compared with 0.9% (1.5 EAIR) of the 952 women who received placebo.

The effects of Veozah 45 mg on the endometrium were also investigated across the 3 trials. Endometrial biopsy assessments revealed 1 case of endometrial simple hyperplasia without atypia and 1 case of endometrial adenocarcinoma among 350 patients treated with Veozah 45 mg. No cases were reported among patients in the placebo group (n=186). 

Disordered proliferative endometrium was reported in 5 women receiving Veozah 45 mg compared with 4 women receiving placebo. The EAIR was reported to be 1.4 per 100 person-years vs 2 per 100 person-years for Veozah 45mg and placebo, respectively.

Dosage and Administration

Veozah is manufactured as a 45-mg film-coated tablet stored at room temperature. This film coating should remain intact during administration, and thus Veozah should be swallowed whole with liquids. The recommended dose of Veozah is a single 45-mg tablet taken orally once daily with or without food. 

Veozah is intended to be administered at approximately the same time each day, and missed doses should be taken as soon as possible unless there is less than 12 hours until the next scheduled dose. If that is the case, then the patient should resume the regular dosing schedule the following day.

Before starting patients on Veozah, it is recommended that baseline bloodwork be performed to evaluate for hepatic function and injury.

Contraindications, Warnings, Precautions, and Adverse Reactions

Known Cirrhosis

Veozah is contraindicated in patients with known cirrhosis, as the drug is primarily metabolized by the liver. Compared with women with normal hepatic function, those with Child-Pugh class A or B hepatic impairment experienced an increase in exposure to Veozah. Clinical trials did not include patients with Child-Pugh class C hepatic impairment.

Severe Renal Impairment or End-Stage Renal Disease

Veozah is contraindicated in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] 15 to <30 mL/min/1.73 m²)  or end-stage renal disease (eGFR <15 mL/min/1.73 m²). Following administration, over 75% of the drug is excreted in the urine. Patients with severe renal impairment experienced a 380% increase in AUC of the major metabolite of fezolinetant following a single 30-mg dose. Veozah was not studied in patients with end-stage renal disease. 

Concomitant Use With CYP1A2 Inhibitors

Veozah is contraindicated in patients being treated concomitantly with medications that inhibit the CYP1A2 enzyme because the patient will experience increased exposure to Veozah. The drug is primarily metabolized by CYP1A2 and only 1.2% of the dose is excreted unchanged. Inhibition of the CYP1A2 enzymes will inhibit the metabolism of Veozah and thus increase the risk of adverse events. Weak (cimetidine), moderate (mexiletine), and strong (fluvoxamine) CYP1A2 inhibitors increased the maximum serum concentration of Veozah by 30%, 40%, and 80%, respectively, and the AUC by 100%, 360%, and 840%, respectively.

Hepatic Transaminase Elevation

Clinical safety data gathered across 3 pivotal trials have provided evidence that baseline bloodwork should be performed and assessed for serum concentration elevations of ALT, AST, and total bilirubin (see Dosage and Administration). Women treated with Veozah experienced elevations of ALT and/or AST greater than 3 times the ULN at a rate of 2.3% (EAIR of 2.7 per 100 patient-years) compared with 0.9% (EAIR of 1.5 per 100 patient-years) of those treated with placebo. There were no reports of total bilirubin serum concentration exceeding 2 times the ULN in these trials. 

Most women with ALT or AST elevations remained asymptomatic, and serum concentrations returned to or close to baseline without additional signs or symptoms while the patients were on treatment, upon interrupting treatment, or once treatment was discontinued. It should be noted that women with cirrhosis were not included in the clinical trials.

Drug Interactions

Veozah is contraindicated in patients using CYP1A2 inhibitors because the drug is primarily metabolized by the CYP1A2 enzyme. Concomitant use with weak, moderate, or strong CYP1A2 inhibitors increases Veozah exposure. In vitro studies show that Veozah is a substrate of CYP1A2 and does not inhibit or induce CYP1A2.  

Considerations for Specific Populations

Veozah is indicated for the treatment of moderate to severe vasomotor symptoms due to menopause and was only studied in menopausal women. No data currently exist evaluating the safety of Veozah in pregnant women.

The absence of data extends into safety assessments regarding the drug’s presence in human milk, its effects on breastfed children, and its effects on milk production.

Efficacy and safety data in women aged over 65 years are insufficient to determine differences from younger women due to the small sample size of geriatric participants in the clinical trials. The safety and efficacy of Veozah have not been established in patients aged younger than 18 years.

Veozah is contraindicated in patients with severe renal impairment (eGFR 15 to <30 mL/min/1.73 m²) or end-stage renal disease (eGFR <15 mL/min/1.73 m²). No dose adjustments are recommended in the presence of mild (eGFR 60 to <90 mL/min/1.73 m²) or moderate (eGFR 30 to <60 mL/min/1.73 m²) renal impairment. 

Veozah is also contraindicated in patients with cirrhosis and has not been studied in patients with Child-Pugh class C hepatic impairment. Patients with Child-Pugh class A or B hepatic impairment will experience increased exposure to Veozah.

Reference

Veozah. Prescribing information. Astellas Pharma US, Inc; 2023. Accessed June 1, 2023. https://www.astellas.com/us/system/files/veozah_uspi.pdf.

Posted by Haymarket’s Clinical Content Hub. The editorial staff of MPR had no role in this content’s preparation.

Reviewed June 2023

In December 2021, the US Food and Drug Administration (FDA) approved upadacitinib (Rinvoq^® [AbbVie, Inc.]), a Janus kinase (JAK) inhibitor, for the treatment of adults with active psoriatic arthritis with an inadequate response or who demonstrate intolerance to at least 1 tumor necrosis factor (TNF) blocker. 

Upadacitinib acts by inhibiting intracellular JAK enzymes, which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, phosphorylation of JAKs promotes the activation of signal transducers and activators of transcription (STATs), which influence intracellular activity, including gene expression. By preventing the phosphorylation of JAKs, upadacitinib inhibits the activation of STATs and modulates the signaling pathway. 

Additional indications for Rinvoq include the treatment of adults with moderately to severely active rheumatoid arthritis with an inadequate response or who demonstrate intolerance to at least 1 TNF blocker and the treatment of patients at least 12 years of age with refractory, moderate to severe atopic dermatitis that is not adequately controlled with other systemic drug products, including biologics, or when use of those therapies is inadvisable. 

Coadministration of Rinvoq with other JAK inhibitors, biologic disease-modifying antirheumatic drugs (DMARDs), or other potent immunosuppressants is not recommended.

Radiographic response was also assessed in SELECT-PsA 1 at week 24. This was expressed as the change from baseline in modified Total Sharp Score (mTSS) and its components, the erosion score, and the joint space narrowing score. At week 24, structural joint damage progression was found to be inhibited in patients who received treatment with upadacitinib 15 mg, with the estimated difference in mTSS between treatment vs placebo reported to be -0.25 (95% CI, -0.41 to -0.09). Consistent results were observed when analyzing erosion and joint space narrowing scores. Additionally, at week 24, no radiographic progression (mTSS change ≤0) occurred in 93% of patients who received therapy with upadacitinib compared with 89% of those who received placebo. 

In both clinical trials, the 36-Item Short Form Health Survey Physical Component Summary (SF-36) was used to assess health-related quality of life outcomes. Findings obtained from both studies showed a significantly greater improvement in the Physical Component Summary score from baseline in patients who received upadacitinib 15 mg compared with placebo at week 12. Improvement in the Mental Component Summary score, as well as in all domains of SF-36, in patients treated with upadacitinib was also observed compared with placebo. Additionally, both studies showed a greater improvement in fatigue from baseline, as measured by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) score, among patients who received upadacitinib 15 mg compared with those who received placebo at week 12. 

The safety population included 1827 patients with psoriatic arthritis who received upadacitinib during the clinical studies. This population represented 1639.2 patient-years of exposure, and 722 patients were exposed to upadacitinib for at least 1 year. A total of 907 patients received at least 1 dose of upadacitinib 15 mg during the clinical studies; 359 of these patients were exposed to the drug for at least 1 year. 

To evaluate the safety of Rinvoq, the 2 clinical studies were integrated and included 640 patients who received upadacitinib 15 mg once daily and 635 patients who received placebo. Safety findings revealed the frequencies of herpes zoster and herpes simplex were 1.1% and 1.4%, respectively, in patients who received upadacitinib compared with 0.8% and 1.3%, respectively, in those who received placebo during the 24-week period. Treatment with upadacitinib was also found to be associated with a higher incidence of acne and bronchitis (1.3% and 3.9%, respectively) compared with placebo (0.3% and 2.7%, respectively). 

Treatment with Rinvoq should be interrupted in patients who develop a serious infection until the infection is controlled. 

Rinvoq dosing should be interrupted in patients presenting with any of the following laboratory abnormalities: absolute neutrophil count (ANC) <1000 cells/mm³, absolute lymphocyte count (ALC) <500 cells/mm³, or hemoglobin (Hb) level <8 g/dL. Treatment can resume once the values are in the normal range. 

If drug-induced liver injury is suspected due to abnormal levels of hepatic transaminases, Rinvoq should be interrupted until this diagnosis is excluded. 

Serious Infections

The prescribing information for Rinvoq includes a Boxed Warning regarding the risk of serious and sometimes fatal infections. The most frequent serious infections reported with Rinvoq use were pneumonia and cellulitis. Opportunistic infections have also been reported with Rinvoq use. These include tuberculosis (TB), multidermatomal herpes zoster, oral/esophageal candidiasis, and cryptococcosis. 

Rinvoq should be avoided in patients with active serious infections, including localized infections. Prior to initiation, the risks and benefits of treatment with Rinvoq must be considered in patients with chronic or recurrent infections, underlying conditions that predispose them to infection, a past exposure to tuberculosis, or history of a serious or an opportunistic infection. 

Additionally, treatment risks and benefits should be considered in patients who have resided in or traveled to areas of endemic tuberculosis or mycoses.

Patients should be monitored for signs and symptoms of an infection during and after treatment with Rinvoq. Development of a serious or opportunistic infection requires the interruption of Rinvoq. 

In patients who develop a new infection while being treated with Rinvoq, immediate and complete diagnostic testing that is appropriate for an immunocompromised patient should be completed. Antimicrobial therapy should be initiated, and Rinvoq should be interrupted if the patient is not responding appropriately. Once the infection is controlled, Rinvoq may be resumed. 

Prior to initiation of Rinvoq, patients should be evaluated and tested for both latent as well as active TB infection. Rinvoq should be avoided in patients with active TB, and treatment initiation should be delayed in patients with latent TB until standard antimycobacterial therapy is complete. Prior to initiating Rinvoq, anti-TB therapy should be considered in patients with previously untreated latent or active TB in whom an adequate course of treatment cannot be confirmed and in those with a negative test for latent TB but who are at risk for  infection. A physician specializing in TB treatment should be consulted to determine whether anti-TB therapy is appropriate. Patients should be monitored for signs and symptoms of TB during treatment with Rinvoq. 

During clinical trials, Rinvoq was found to cause viral reactivation, including herpes virus reactivation as well as hepatitis B reactivation. Rinvoq should be temporarily discontinued in patients who develop herpes zoster until the episode resolves. Prior to initiation of and during therapy with Rinvoq, viral hepatitis screenings and monitoring for reactivation should be completed according to clinical guidelines. 

Clinical trials excluded patients who were positive for hepatitis C antibody, hepatitis C virus RNA, hepatitis B surface antigen, and hepatitis B virus DNA. Cases of hepatitis B reactivation were still reported in clinical trials assessing Rinvoq. A liver specialist should be consulted if detection of hepatitis B virus DNA occurs during treatment with Rinvoq. 

Mortality 

The prescribing information for Rinvoq includes a Boxed Warning regarding the increased risk of all-cause mortality. Findings of a postmarketing safety study in patients with rheumatoid arthritis revealed another JAK inhibitor to be associated with a higher rate of all-cause mortality, including sudden cardiovascular death, compared with TNF blockers. The risks and benefits of treatment with Rinvoq should be considered for each individual patient. 

Malignancy and Lymphoproliferative Disorders

The prescribing information for Rinvoq includes a Boxed Warning regarding the incidence of malignancies, including lymphomas, observed during clinical trials in patients treated with Rinvoq. A postmarketing safety study observed an increased rate of malignancies (excluding nonmelanoma skin cancer [NMSC]) in patients with rheumatoid arthritis who received treatment with another JAK inhibitor compared with patients who received TNF blockers. Similarly, the rate of lung cancers was found to be higher among patients who smoked or had a history of smoking who were treated with a JAK inhibitor compared with those who received TNF blockers. Findings of this study also observed an additional increased risk of overall malignancies in current or past smokers.  

The risks and benefits of treatment with Rinvoq should be considered for each individual patient, especially in patients with a known malignancy (excluding cases of NMSC that are effectively managed), in patients who develop a malignancy during treatment, and in patients who smoke or have a history of smoking.

There have been reports of cases of NMSC in patients receiving Rinvoq. For patients with an increased skin cancer risk, periodic skin examinations are recommended. Protective clothing and broad-spectrum sunscreen should be utilized to limit exposure to sunlight and ultraviolet (UV) light. 

Major Adverse Cardiovascular Events

The prescribing information for Rinvoq includes a Boxed Warning regarding the increased risk of major adverse cardiovascular events (MACE), which is defined as cardiovascular death, nonfatal myocardial infarction (MI), and nonfatal stroke. A large postmarketing safety study observed an increased risk of MACE associated with the use of another JAK inhibitor in patients with rheumatoid arthritis who were 50 years of age and older with at least 1 cardiovascular risk factor compared with those who received TNF blockers. An additional increased risk was observed in current or past smokers.

The risks and benefits of treatment with Rinvoq should be considered for each individual patient, especially in those with cardiovascular risk factors and those who smoke or have a history of smoking. Patients should be counseled on the symptoms and management of serious cardiovascular events. Rinvoq should be discontinued in patients who have experienced an MI or stroke. 

Thrombosis

The prescribing information for Rinvoq includes a Boxed Warning regarding the increased risk of thrombosis. Cases of thrombosis (deep venous thrombosis [DVT], pulmonary embolism [PE], and arterial thrombosis) have been reported in patients who received JAK inhibitors for the treatment of inflammatory conditions. A large number of these cases were considered to be serious, with some resulting in death. 

A large postmarketing safety study observed an increased risk of thrombosis, DVT, and PE associated with the use of another JAK inhibitor in patients with rheumatoid arthritis who were 50 years of age and older with at least 1 cardiovascular risk factor compared with those who received TNF blockers. 

Rinvoq should be avoided in patients at increased risk for thrombosis. Discontinuation of Rinvoq as well as prompt evaluation and treatment are recommended in patients who present with symptoms of thrombosis. 

Hypersensitivity Reactions

In clinical trials, cases of serious hypersensitivity reactions, including anaphylaxis and angioedema, have occurred in patients receiving Rinvoq. Rinvoq should be discontinued in patients who experience a clinically significant hypersensitivity reaction, and appropriate therapy should be initiated. 

Gastrointestinal Perforations

In clinical trials, cases of gastrointestinal perforations were reported in patients receiving Rinvoq. In these trials, a large number of patients were receiving nonsteroidal antiinflammatory drugs (NSAIDs) as background therapy. Patients receiving Rinvoq who are at increased risk for gastrointestinal perforation should be monitored closely and evaluated immediately if new-onset abdominal pain occurs. 

Laboratory Abnormalities

Laboratory abnormalities have been observed in patients receiving Rinvoq (Figure 2). 

Embryo-Fetal Toxicity

Based on findings from animal studies, Rinvoq has the potential to cause fetal harm if administered to a pregnant woman. Increases in fetal malformations were observed when upadacitinib was administered to rats and rabbits during organogenesis. 

The pregnancy status of patients of reproductive potential should be verified prior to the initiation of Rinvoq. Female patients of reproductive potential should be advised on the potential risk to the fetus and the importance of using effective contraception during Rinvoq treatment, as well as for 4 weeks following the last dose.

Vaccinations

Use of live vaccines should be avoided immediately prior to as well as during Rinvoq therapy. It is recommended that patients be brought up to date on all immunizations prior to initiating therapy. 

Strong CYP3A4 Inhibitors

Co-administration of Rinvoq with a strong CYP3A4 inhibitor increases drug exposure as well as the risk of adverse events. Although no dose modification is required, patients should be monitored closely for adverse events during coadministration of Rinvoq 15 mg with a strong CYP3A4 inhibitor.  It is recommended that coadministration of Rinvoq 30 mg with a strong CYP3A4 inhibitor be avoided.

Strong CYP3A4 Inducers

Co-administration of Rinvoq with a strong CYP3A4 inducer decreases drug exposure and reduces its therapeutic effect. It is recommended to avoid coadministration of Rinvoq with strong CYP3A4 inducers. 

No data currently exist on the presence of Rinvoq in breast milk, its effect in a breastfed child, or its effect on milk production/excretion. Based on animal study data, Rinvoq is excreted in milk. Due to its potential for excretion into human milk and its risk of harm to an infant, patients should be advised to avoid breastfeeding during treatment with Rinvoq and for 6 days following the last dose.  

The efficacy and safety of Rinvoq have not been established in pediatric patients with psoriatic arthritis.

Findings of the 2 phase 3 psoriatic arthritis clinical trials showed no difference in treatment efficacy in patients with increasing age when analyzing patients 65 years of age and older. Results of these studies did find, however, a higher rate of overall adverse events, including serious infections, in older patients. 

For patients with psoriatic arthritis, no dose adjustment is recommended with mild, moderate, or severe renal impairment. 

No dose adjustment is recommended for patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment. Rinvoq is not recommended in patients with severe hepatic impairment (Child Pugh C) as it has not been studied in this population. 

Reference

Rinvoq. Package insert. AbbVie, Inc.; 2021. Accessed January 25, 2022. https://www.rxabbvie.com/pdf/rinvoq_pi.pdf

Posted by Haymarket’s Clinical Content Hub. The editorial staff of MPR had no role in this content’s preparation.

Reviewed March 2022