Risankizumab for Gastrointestinal Bleeding

INDICATIONS AND USAGE SKYRIZI is an interleukin-23 antagonist indicated for the treatment of: moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. ( 1.1 ) active psoriatic arthritis in adults. ( 1.2 ) moderately to severely active Crohn's disease in adults. ( 1.3 ) moderately to severely active ulcerative colitis in adults. ( 1.4 ) 1.1 Plaque Psoriasis SKYRIZI ® is indicated for the treatment of moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. 1.2 Psoriatic Arthritis SKYRIZI is indicated for the treatment of active psoriatic arthritis in adults. 1.3 Crohn’s Disease SKYRIZI is indicated for the treatment of moderately to severely active Crohn's disease in adults. 1.4 Ulcerative Colitis SKYRIZI is indicated for the treatment of moderately to severely active ulcerative colitis in adults.

DOSAGE AND ADMINISTRATION For the treatment of Crohn’s disease and ulcerative colitis: Obtain liver enzymes and bilirubin levels prior to initiating treatment with SKYRIZI. ( 2.1 , 5.4 ) Complete all age-appropriate vaccinations as recommended by current immunization guidelines ( 2.1 , 5.5 ) Recommended Dosage Plaque Psoriasis and Psoriatic Arthritis: 150 mg administered by subcutaneous injection at Week 0, Week 4, and every 12 weeks thereafter. ( 2.3 , 2.4 ) In patients with psoriatic arthritis SKYRIZI can be administered alone or in combination with non-biologic disease-modifying antirheumatic drugs (DMARDs). ( 2.4 ) Crohn’s Disease: The recommended induction dosage is 600 mg administered by intravenous infusion over at least one hour at Week 0, Week 4, and Week 8. The recommended maintenance dosage is 180 mg or 360 mg administered by subcutaneous injection at Week 12, and every 8 weeks thereafter. Use the lowest effective dosage to maintain therapeutic response. ( 2.6 ) Ulcerative Colitis: The recommended induction dosage is 1,200 mg administered by intravenous infusion over at least two hours at Week 0, Week 4, and Week 8. The recommended maintenance dosage is 180 mg or 360 mg administered by subcutaneous injection at Week 12, and every 8 weeks thereafter. Use the lowest effective dosage to maintain therapeutic response. ( 2.7 ) 2.1 Procedures Prior to Treatment Initiation For the treatment of Crohn’s disease and ulcerative colitis, obtain liver enzymes and bilirubin levels prior to initiating treatment with SKYRIZI [see Warnings and Precautions ( 5.4 )] Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with SKYRIZI [see Warnings and Precautions ( 5.3 )] . Complete all age-appropriate vaccinations as recommended by current immunization guidelines [see Warnings and Precautions ( 5.5 )]. 2.2 General Considerations for Administration • Visually inspect SKYRIZI for particulate matter and discoloration prior to administration. The solution may contain a few translucent to white particles. ○ SKYRIZI 150 mg/mL prefilled pen or prefilled syringe, 180 mg/1.2 mL prefilled syringe or prefilled cartridge, and 360 mg/2.4 mL prefilled cartridge: a colorless to yellow, and clear to slightly opalescent solution. ○ SKYRIZI 90 mg/mL prefilled syringe and 600 mg/10 mL vial: a colorless to slightly yellow, and clear to slightly opalescent solution. ○ Do not use if the solution contains large particles or is cloudy or discolored. • Discard after use. Do not reuse. 2. 3 Recommended Dosage for Plaque Psoriasis The recommended dosage is 150 mg administered by subcutaneous injection at Week 0, Week 4, and every 12 weeks thereafter. 2. 4 Recommended Dosage for Psoriatic Arthritis The recommended dosage is 150 mg administered by subcutaneous injection at Week 0, Week 4, and every 12 weeks thereafter. SKYRIZI may be administered alone or in combination with non-biologic disease-modifying antirheumatic drugs (DMARDs). 2. 5 Preparation and Administration Instruction s (Plaque Psoriasis and Psoriatic Arthritis) Administer SKYRIZI 150 mg/mL prefilled pen or prefilled syringe subcutaneously. Patients may self-inject SKYRIZI after training in subcutaneous injection technique. Provide proper training to patients and/or caregivers on the subcutaneous injection technique of SKYRIZI. Before injecting, remove the carton with SKYRIZI from the refrigerator and without removing the prefilled pen or prefilled syringe from the carton, allow SKYRIZI to reach room temperature out of direct sunlight (30 to 90 minutes for the prefilled pen and 15 to 30 minutes for the prefilled syringe). Do not inject into areas where the skin is tender, bruised, erythematous, indurated or affected by psoriasis. Administration of SKYRIZI in the upper, outer arm may only be performed by a healthcare professional or caregiver. If a dose is missed, administer the dose as soon as possible. Thereafter, resume dosing at the regular scheduled time. The SKYRIZI “Instructions for Use” contains more detailed instructions on the preparation and administration of SKYRIZI [see Instructions for Use ] . Instruct the patient to read the Instructions for Use before administration. 2.6 Recommended Dosage for Crohn’s Disease Adult Patients: Induction The recommended induction dosage of SKYRIZI is 600 mg administered by intravenous infusion over a period of at least one hour at Week 0, Week 4, and Week 8. Adult Patients: Maintenance The recommended maintenance dosage of SKYRIZI is 180 mg or 360 mg administered by subcutaneous injection at Week 12, and every 8 weeks thereafter. Use the lowest effective dosage needed to maintain therapeutic response. 2.7 Recommended Dosage for Ulcerative Colitis Adult Patients: Induction The recommended induction dosage of SKYRIZI is 1,200 mg administered by intravenous infusion over a period of at least two hours at Week 0, Week 4, and Week 8. Adult Patients: Maintenance The recommended maintenance dosage of SKYRIZI is 180 mg or 360 mg administered by subcutaneous injection at Week 12, and every 8 weeks thereafter. Use the lowest effective dosage needed to maintain therapeutic response. 2.8 Preparation and Administration Instructions (Crohn’s Disease and Ulcerative Colitis) Intravenous Induction Dosing Regimen: 1. SKYRIZI vial for intravenous administration is intended for administration by a healthcare provider using aseptic technique. 2. Prior to intravenous administration, determine the dose and number of SKYRIZI vials needed based on the patient’s indication (see table below). Withdraw 10 mL of SKYRIZI solution from a vial (600 mg/10 mL) and inject into an intravenous infusion bag or glass bottle containing 5% Dextrose Injection or 0.9% Sodium Chloride Injection (see Table 1 below) for a final concentration of approximately 1.2 mg/mL to 6 mg/mL. Discard any remaining solution in the vial. Table 1. Total Volume of Diluent Required for Intravenous Induction Dose Indication I ntravenous Induction Dose Number of SKYRIZI 600 mg/10 mL Vials Total Volume of 5% Dextrose or 0.9% Sodium Chloride Injection Crohn’s disease 600 mg 1 100 mL, or 250 mL, or 500 mL Ulcerative colitis 1,200 mg 2 250 mL, or 500 mL 3. Infuse the diluted solution intravenously over a period of at least one hour for the SKYRIZI 600 mg dose; at least two hours for the SKYRIZI 1,200 mg dose. If stored refrigerated, allow the diluted SKYRIZI solution in the infusion bag or glass bottle to warm to room temperature prior to the start of the intravenous infusion. 4. Do not administer SKYRIZI diluted solution concomitantly in the same intravenous line with other medicinal products. Handling and Storage of the Vial and the Diluted Solution: Do not shake the vial or diluted solution in the infusion bag or glass bottle. Use the prepared infusion immediately. If not used immediately, store the diluted SKYRIZI solution refrigerated and protected from light for up to 20 hours between 36°F to 46°F (2°C to 8°C). Immediately after preparation or removal from refrigeration, the diluted SKYRIZI solution can be stored at room temperature at up to 77°F (25°C) (protected from sunlight) for up to 8 hours. Storage time at room temperature begins once the diluted solution has been prepared. The infusion should be completed within 8 hours after dilution in the infusion bag. Exposure to indoor light is acceptable during room temperature storage and administration. Do not freeze. Subcutaneous Maintenance Dosing Regimen: Using the single-dose 180 mg or 360 mg prefilled cartridge with On-Body Injector: SKYRIZI is intended for use under the guidance and supervision of a healthcare professional. Patients may self-inject SKYRIZI using the on-body injector with prefilled cartridge after training in subcutaneous injection technique. Provide proper training to patients and/or caregivers on the subcutaneous injection technique of SKYRIZI. Before using the on-body injector with prefilled cartridge, remove the carton from the refrigerato

WARNINGS AND PRECAUTIONS Hypersensitivity Reactions: Serious hypersensitivity reactions, including anaphylaxis, may occur. ( 5.1 ) Infections: SKYRIZI may increase the risk of infection. Instruct patients to seek medical advice if signs or symptoms of clinically important infection occur. If such an infection develops, do not administer SKYRIZI until the infection resolves. ( 5.2 ) Tuberculosis (TB): Evaluate for TB prior to initiating treatment with SKYRIZI. ( 5.3 ) Hepatotoxicity in Treatment of Inflammatory Bowel Disease: Drug-induced liver injury during induction has been reported. Monitor liver enzymes and bilirubin levels at baseline and, during induction, up to at least 12 weeks of treatment. Monitor thereafter according to routine patient management. ( 5.4 ) Administration of Vaccines: Avoid use of live vaccines. ( 5.5 ) 5.1 Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylaxis, have been reported with use of SKYRIZI. If a serious hypersensitivity reaction occurs, discontinue SKYRIZI and initiate appropriate therapy immediately [see Adverse Reactions ( 6.1 )]. 5. 2 Infections SKYRIZI may increase the risk of infections [see Adverse Reactions ( 6.1 )] . Treatment with SKYRIZI should not be initiated in patients with any clinically important active infection until the infection resolves or is adequately treated. In patients with a chronic infection or a history of recurrent infection, consider the risks and benefits prior to prescribing SKYRIZI. Instruct patients to seek medical advice if signs or symptoms of clinically important infection occur. If a patient develops such an infection or is not responding to standard therapy, monitor the patient closely and do not administer SKYRIZI until the infection resolves. 5. 3 Tuberculosis Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with SKYRIZI. Across the Phase 3 psoriasis clinical studies, of the 72 subjects with latent TB who were concurrently treated with SKYRIZI and appropriate TB prophylaxis during the studies, none developed active TB during the mean follow-up of 61 weeks on SKYRIZI. Two subjects taking isoniazid for treatment of latent TB discontinued treatment due to liver injury. Of the 31 subjects from the PsO-3 study with latent TB who did not receive prophylaxis during the study, none developed active TB during the mean follow-up of 55 weeks on SKYRIZI. Consider anti-TB therapy prior to initiating SKYRIZI in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Monitor patients for signs and symptoms of active TB during and after SKYRIZI treatment. Do not administer SKYRIZI to patients with active TB. 5. 4 Hepatotoxicity in Treatment of Inflammatory Bowel Disease A serious adverse reaction of drug-induced liver injury in conjunction with a rash that required hospitalization was reported in a patient with Crohn’s disease (ALT 54x ULN, AST 30x ULN, and total bilirubin 2.2x ULN) following two 600 mg intravenous doses of SKYRIZI. The liver test abnormalities resolved following administration of steroids. SKYRIZI was subsequently discontinued. For the treatment of Crohn’s disease and ulcerative colitis, evaluate liver enzymes and bilirubin at baseline, and during induction at least up to 12 weeks of treatment. Monitor thereafter according to routine patient management. Consider other treatment options in patients with evidence of liver cirrhosis. Prompt investigation of the cause of liver enzyme elevation is recommended to identify potential cases of drug-induced liver injury. Interrupt treatment if drug-induced liver injury is suspected, until this diagnosis is excluded. Instruct patients to seek immediate medical attention if they experience symptoms suggestive of hepatic dysfunction. 5.5 Administration of Vaccines Avoid use of live vaccines in patients treated with SKYRIZI. Medications that interact with the immune system may increase the risk of infection following administration of live vaccines. Prior to initiating therapy with SKYRIZI, complete all age-appropriate vaccinations according to current immunization guidelines. No data are available on the response to live or inactive vaccines.

ADVERSE REACTIONS The following adverse reactions are discussed in other sections of labeling: Hypersensitivity Reactions [see Warnings and Precautions ( 5.1 )] Infections [see Warnings and Precautions ( 5.2 )] Tuberculosis [see Warnings and Precautions ( 5.3 )] Hepatotoxicity in Treatment of Inflammatory Bowel Disease [see Warnings and Precautions ( 5.4 )] Most common adverse reactions are: Plaque Psoriasis and Psoriatic Arthritis (≥ 1%): upper respiratory infections, headache, fatigue, injection site reactions, and tinea infections. ( 6.1 ) Crohn’s Disease (>3%): ◦ Induction : upper respiratory infections, headache, and arthralgia. ( 6.1 ) ◦ Maintenance : arthralgia, abdominal pain, injection site reactions, anemia, pyrexia, back pain, arthropathy, and urinary tract infection. ( 6.1 ) Ulcerative Colitis (≥3%): ◦ Induction : arthralgia. ( 6.1 ) ◦ Maintenance : arthralgia, pyrexia, injection site reactions, and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse drug reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Plaque Psoriasis A total of 2234 subjects were treated with SKYRIZI in clinical development trials in plaque psoriasis. Of these, 1208 subjects with psoriasis were exposed to SKYRIZI for at least one year. Data from placebo- and active-controlled trials were pooled to evaluate the safety of SKYRIZI for up to 16 weeks. In total, 1306 subjects were evaluated in the SKYRIZI 150 mg group. Table 2 summarizes the adverse drug reactions that occurred at a rate of at least 1% and at a higher rate in the SKYRIZI group than the placebo group during the 16-week controlled period of pooled clinical trials. Table 2. Adverse Drug Reactions Occurring in ≥ 1% of Subjects with Plaque Psoriasis on SKYRIZI through Week 16 Adverse Drug Reactions SKYRIZI N = 1306 n (%) Placebo N = 300 n (%) Upper respiratory infections a 170 (13.0) 29 (9.7) Headache b 46 (3.5) 6 (2.0) Fatigue c 33 (2.5) 3 (1.0) Injection site reactions d 19 (1.5) 3 (1.0) Tinea infections e 15 (1.1) 1 (0.3) a Includes: respiratory tract infection (viral, bacterial or unspecified), sinusitis (including acute), rhinitis, nasopharyngitis, pharyngitis (including viral), tonsillitis b Includes: headache, tension headache, sinus headache, cervicogenic headache c Includes: fatigue, asthenia d Includes: injection site bruising, erythema, extravasation, hematoma, hemorrhage, infection, inflammation, irritation, pain, pruritus, reaction, swelling, warmth e Includes: tinea pedis, tinea cruris, body tinea, tinea versicolor, tinea manuum, tinea infection, onychomycosis Adverse drug reactions that occurred in < 1% but > 0.1% of subjects in the SKYRIZI group and at a higher rate than in the placebo group through Week 16 were folliculitis and urticaria. Specific Adverse Drug Reactions Infections In the first 16 weeks, infections occurred in 22.1% of the SKYRIZI group (90.8 events per 100 patient-years) compared with 14.7% of the placebo group (56.5 events per 100 patient-years) and did not lead to discontinuation of SKYRIZI. The rates of serious infections for the SKYRIZI group and the placebo group were ≤0.4%. Serious infections in the SKYRIZI group included cellulitis, osteomyelitis, sepsis, and herpes zoster. In Trials PsO-1 and PsO-2, through Week 52, the rate of infections (73.9 events per 100 patient-years) was similar to the rate observed during the first 16 weeks of treatment. Safety T hrough Week 52 Through Week 52, no new adverse reactions were identified, and the rates of the adverse reactions were similar to those observed during the first 16 weeks of treatment. During this period, serious infections that led to trial discontinuation included pneumonia. Plaque Psoriasis of the Scalp or Genital Area The overall safety profile observed in clinical trials of subjects with moderate to severe plaque psoriasis of the scalp or genital area treated with SKYRIZI is generally consistent with the safety profile observed in previous clinical trials of subjects with moderate to severe plaque psoriasis [see Clinical Studies ( 14.1 )] . Psoriatic Arthritis The overall safety profile observed in subjects with psoriatic arthritis treated with SKYRIZI is generally consistent with the safety profile in subjects with plaque psoriasis. Additionally, in the Phase 3 placebo-controlled trials the incidence of hepatic events was higher in the SKYRIZI group (5.4%, 16.7 events per 100 patient-years) compared to the placebo group (3.9%, 12.6 events per 100 patient-years). Of these, the most common events that were reported more frequently in both the placebo group and the SKYRIZI group were ALT increased (placebo: n=12 (1.7%); SKYRIZI: n=16 (2.3%)), AST increased (placebo: n=9 (1.3%); SKYRIZI: n=13 (1.8%)), and GGT increased (placebo: n=5 (0.7%); SKYRIZI: n=8 (1.1%)). There were no serious hepatic events reported. The incidence of hypersensitivity reactions was higher in the SKYRIZI group (n=16, 2.3%) compared to the placebo group (n=9, 1.3%). In the Phase 3 placebo-controlled trials, hypersensitivity reactions reported at a higher rate in the SKYRIZI group included rash (placebo: n=4 (0.6%); SKYRIZI: n=5 (0.7%), allergic rhinitis (placebo: n=1 (0.1%); SKYRIZI: n=2 (0.3%), and facial swelling (placebo: n=0 (0.0%); SKYRIZI n=1 (0.1%). One case of anaphylaxis was reported in a subject who received SKYRIZI in the Phase 2 clinical trial. Crohn’s Disease SKYRIZI was studied up to 12 weeks in subjects with moderately to severely active Crohn’s disease in two randomized, double-blind, placebo-controlled induction trials (CD-1, CD-2) and a randomized, double-blind, placebo-controlled, dose-finding trial (CD-4; NCT02031276). Long-term safety up to 52 weeks was evaluated in subjects who responded to induction therapy in a randomized, double-blind, placebo-controlled maintenance trial (CD-3) [see Clinical Studies ( 14.3 )] . In the two induction trials (CD-1, CD-2) and the dose finding trial (CD-4), 620 subjects received the SKYRIZI intravenous induction regimen at Weeks 0, 4 and 8. In the maintenance trial (CD-3), 297 subjects who achieved clinical response, defined as a reduction in CDAI of at least 100 points from baseline after 12 weeks of induction treatment with intravenous SKYRIZI in trials CD-1 and CD-2, received a maintenance regimen of SKYRIZI either 180 mg or 360 mg subcutaneously at Week 12 and every 8 weeks thereafter for up to an additional 52 weeks. Adverse reactions reported in > 3% of subjects in induction trials and at a higher rate than placebo are shown in Table 3. Table 3. Adverse Drug Reactions Reported in > 3% of Subjects with Crohn’s Disease Treated with SKYRIZI in Placebo-Controlled 12-Week Induction Trials (CD-1, CD-2, and CD-4) Adverse Drug Reactions SKYRIZI 600 mg Intravenous Infusion a N = 620 n (%) Placebo N = 432 n (%) Upper respiratory infections b 66 (10.6) 40 (9.3) Headache c 41 (6.6) 24 (5.6) Arthralgia 31 (5.0) 19 (4.4) a SKYRIZI 600 mg as an intravenous infusion at Week 0, Week 4, and Week 8. b Includes: influenza like illness, nasopharyngitis, influenza, pharyngitis, upper respiratory tract infection, viral upper respiratory tract infection, COVID-19, nasal congestion, respiratory tract infection viral, viral pharyngitis, tonsillitis, upper respiratory tract inflammation c Includes: headache, tension headache Adverse reactions reported in >3% of subjects in the maintenance trial and at a higher rate than placebo are shown in Table 4. Table 4. Adverse Reactions Reported in >3% of Subjects with Crohn’s Disease Treated with SKYRIZI a in Placebo-Controlled 52-Week Maintenance Trial (CD-3) Adverse Drug Reactions SKYRIZI 180 mg Subcutaneous Injection N = 155 n (%) SKYRIZI