SKYRIZI

Risankizumab is a fully humanized

IgG1 monoclonal antibody (mAb) directed against interleukin 23 (IL-23).

It gained its first global approval in Japan in March 2019, followed by approval in Canada, the US, and Europe in April 2019.

Risankizumab is used to treat plaque psoriasis, psoriatic arthritis, and Crohn's disease. 7, 9, 10 Risankizumab is being investigated for atopic dermatitis.

Risankizumab is indicated to treat: moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. 7, 9, 10 active psoriatic arthritis in adults. 7, 9, 10 In Canada and Europe, it may be used alone or in combination with a conventional non-biologic disease-modifying antirheumatic drug (cDMARD) (e.g., methotrexate). 9, 10 moderately to severely active Crohn's disease in adults. 7, 9, 10 In Canada, it is used in patients who have had an inadequate response, intolerance, or demonstrated dependence on corticosteroids; or an inadequate response, intolerance, or loss of response to immunomodulators or biologic therapies. 9 moderately to severely active ulcerative colitis in adults.

Risankizumab works to suppress the inflammatory effects of interleukin (IL)-23.

It inhibits the release of pro-inflammatory cytokines and chemokines.

In vitro, risankizumab blocked IL-17 production; 5 however, risankizumab does not actually bind to IL-17.

Drug plasma concentrations increased dose-proportionally after subcutaneous administration of a single dose over the dose range from 18 mg to 360 mg and intravenous administration over a dose range from 200 mg to 1800 mg via a 3-hour infusion.

In patients with plaque psoriasis who received a subcutaneous dose of 150 mg risankizumab, steady-state peak concentration (C max ) and trough concentration (C trough ) were 12 mcg/mL and 2 mcg/mL, respectively.

In subjects with

Crohn's disease treated with 600 mg intravenous induction dose at Weeks 0, 4, and 8, followed by 180 mg or 360 mg subcutaneous maintenance dose at Week and every 8 weeks thereafter, the median Cmax and Ctrough are estimated to be 156 mcg/mL and 38.8 mcg/mL, respectively, during Weeks 8-12; and the steady state median Cmax and Ctrough are estimated to be 14.0 mcg/mL and 4.1 mcg/mL, respectively for 180 mg or 28.0 mcg/mL and 8.1 mcg/mL, respectively, for 360 mg, during Weeks 40-48.

The absolute bioavailability of risankizumab was approximately 74-89% following subcutaneous injection.

In healthy subjects, following administration of a single subcutaneous dose, C max was reached by 3-14 days.

The estimated steady-state volume of distribution (inter-subject CV%) was 11.2 L (34%) in subjects with plaque psoriasis, and 7.68 L (64%) in subjects with Crohn's disease.

The metabolic pathway of risankizumab has not been fully characterized.

As a humanized

IgG1 monoclonal antibody, it is likely to be catabolized into small peptides and amino acids in the same way as endogenous IgG. 7, 4.

As an

IgG1 monoclonal antibody, risankizumab is not expected to be filtered by glomerular filtration in the kidneys or to be excreted as an intact molecule in the urine.

The terminal elimination half-life was approximately 28 days in patients with plaque psoriasis and 21 days in patients with Crohn's disease.

The estimated systemic clearance (inter-subject CV%) was 0.31 L/day (24%) in patients with plaque psoriasis and 0.30 L/day (34%) in patients with Crohn's disease.

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NOAEL was 50 mg/kg in monkeys following intravenous or subcutaneous administration.

There is no information available regarding the overdose of risankizumab.

is contraindicated in patients with a history of serious hypersensitivity reaction to risankizumab-rzaa or any of the excipients.

SKYRIZI is contraindicated in patients with a history of serious hypersensitivity reaction to risankizumab-rzaa or any of the excipients.

For the treatment of

Crohn’s disease and ulcerative colitis: Obtain liver enzymes and bilirubin levels prior to initiating treatment with SKYRIZI.

Complete all age-appropriate vaccinations as recommended by current immunization guidelines Recommended Dosage Plaque Psoriasis and Psoriatic Arthritis: 150 mg administered by subcutaneous injection at Week 0, Week 4, and every 12 weeks thereafter.

In patients with psoriatic arthritis

SKYRIZI can be administered alone or in combination with non-biologic disease-modifying antirheumatic drugs (DMARDs).

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.

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.

Use the lowest effective dosage to maintain therapeutic response. 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 Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with SKYRIZI.

Complete all age-appropriate vaccinations as recommended by current immunization guidelines. 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.

The recommended dosage is 150 mg administered by subcutaneous injection at Week 0, Week 4, and every 12 weeks thereafter. 2.

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.

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 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.

SKYRIZI “Instructions for Use” contains more detailed instructions on the preparation and administration of SKYRIZI.

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.

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.

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.

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 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.

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.

SKYRIZI using the on-body injector with prefilled cartridge after training in subcutaneous injection technique.

Before using the on-body injector with prefilled cartridge, remove the carton from the refrigerator and allow to reach room temperature out of direct sunlight (45 to 90 minutes) without removing the prefilled cartridge or on-body injector from the carton.

Use the on-body injector to administer

SKYRIZI 180 mg/1.2 mL or SKYRIZI 360 mg/2.4 mL prefilled cartridge subcutaneously on thigh or abdomen.

Start the injection within 5 minutes after inserting the prefilled cartridge into the On-Body Injector.

Do not inject into areas where the skin is tender, bruised, erythematous, indurated or affected by any lesions.

Instruct the patient to read the Instructions for Use before administration.

• Administer each SKYRIZI 90 mg/mL or 180 mg/1.2 mL prefilled syringe subcutaneously.

• Patients may self-inject SKYRIZI after training in subcutaneous injection technique.

• Before injecting, remove the carton from the refrigerator and without removing the prefilled syringes from the carton, allow SKYRIZI to reach room temperature out of direct sunlight (15 to 30 minutes).

• Use the 90 mg/mL or 180 mg/1.2 mL prefilled syringe(s) to administer SKYRIZI 180 mg or SKYRIZI 360 mg subcutaneously as follows: ○ 180 mg maintenance dose: ▪ SKYRIZI 90 mg/mL prefilled syringes: Two 90 mg prefilled syringes are required.

Inject one prefilled syringe after the other in different anatomic locations (such as thighs or abdomen). ▪ SKYRIZI 180 mg/1.2 mL prefilled syringe: One 180 mg prefilled syringe is required. ○ 360 mg maintenance dose: ▪ SKYRIZI 90 mg/mL prefilled syringes: Four 90 mg prefilled syringes are required.

Inject one prefilled syringe after the other in different anatomic locations (such as thighs or abdomen). ▪ SKYRIZI 180 mg/1.2 mL prefilled syringes: Two 180 mg prefilled syringes are required.

Inject one prefilled syringe after the other in different anatomic locations (such as thighs or abdomen).

• Do not inject into areas where the skin is tender, bruised, erythematous, indurated or affected by any lesions.

• If a dose is missed, administer the dose as soon as possible.

SKYRIZI (risankizumab-rzaa) injection is supplied in the following strengths: Strength Pack Size NDC Subcutaneous Injection 150 mg/mL single-dose pen Carton of 1 0074-2100-01 90 mg/mL single-dose prefilled syringe Carton of 2 0074-7040-02 Carton of 4 0074-7042-04 180 mg/1.2 mL (150 mg/mL) single-dose prefilled syringe Carton of 1 0074-8300-01 Carton of 2 0074-8350-01 150 mg/mL single-dose prefilled syringe Carton of 1 0074-1050-01 180 mg/1.2 mL (150 mg/mL) single-dose prefilled cartridge with on-body injector Kit 0074-1065-01 360 mg/2.4 mL (150 mg/mL) single-dose prefilled cartridge with on-body injector Kit 0074-1070-01 Intravenous Infusion 600 mg/10 mL (60 mg/mL) single-dose vial Carton of 1 0074-5015-01 Subcutaneous Injection SKYRIZI 150 mg/mL prefilled syringe or prefilled pen contains a sterile, preservative-free, colorless to yellow, and clear to slightly opalescent solution.

Each prefilled syringe or prefilled pen consists of a 1 mL glass syringe with a fixed 27-gauge ½ inch needle with needle guard.

SKYRIZI 90 mg/mL prefilled syringe contains a sterile, preservative-free, colorless to slightly yellow and clear to slightly opalescent solution.

Each prefilled syringe consists of a 1 mL glass syringe with a fixed 29-gauge ½ inch needle with needle guard.

SKYRIZI 180 mg/1.2 mL (150 mg/mL) prefilled syringe contains a sterile, preservative-free, colorless to yellow, and clear to slightly opalescent solution.

Each prefilled syringe consists of a 2.25 mL glass syringe with a fixed 27-gauge ½ inch needle with needle guard.

SKYRIZI 180 mg/1.2 mL (150 mg/mL) cyclic olefin polymer prefilled cartridge with a septum and cap contains a sterile, preservative-free, colorless to yellow, and clear to slightly opalescent solution for use with supplied on-body injector administration device.

SKYRIZI 360 mg/2.4 mL (150 mg/mL) cyclic olefin polymer prefilled cartridge with a septum and cap contains a sterile, preservative-free, colorless to yellow, and clear to slightly opalescent solution for use with supplied on-body injector administration device.

SKYRIZI 600 mg/10 mL (60 mg/mL) vial contains a sterile and preservative-free, colorless to slightly yellow, and clear to slightly opalescent solution.

Each glass vial is closed with a stopper and blue flip cap.

Store in a refrigerator at 36°F to 46° F (2°C to 8°C).

Do not freeze.

Do not shake.

Keep in the original cartons to protect from light.

Not made with natural rubber latex.

There is a pregnancy exposure registry that monitors outcomes in women who become pregnant while treated with SKYRIZI.

Patients should be encouraged to enroll by calling 1-877-302-2161 or visiting Risk Summary Available pharmacovigilance and clinical trial data with risankizumab use in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes.

Although there are no data on risankizumab-rzaa, monoclonal antibodies can be actively transported across the placenta, and SKYRIZI may cause immunosuppression in the in utero.

• exposed infant.

There are adverse pregnancy outcomes in women with inflammatory bowel disease.

In an enhanced pre.

• and post-natal developmental toxicity study, pregnant cynomolgus monkeys were administered subcutaneous doses of 5 or 50 mg/kg risankizumab-rzaa once weekly during the period of organogenesis up to parturition.

Increased fetal/infant loss was noted in pregnant monkeys at the 50 mg/kg dose.

The 50 mg/kg dose in pregnant monkeys resulted in approximately 5 times the exposure (AUC) in humans administered the maximum recommended induction dose (1,200 mg) and 32 times the exposure (AUC) to the maximum recommended maintenance dose (360 mg).

No risankizumab-rzaa-related effects on functional or immunological development were observed in infant monkeys from birth through 6 months of age.

The clinical significance of these findings for humans is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

The background risk of major birth defects and miscarriage for the indicated population is unknown.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Disease-associated maternal and embryo/fetal risk Published data suggest that the risk of adverse pregnancy outcomes in women with inflammatory bowel disease is associated with increased disease activity.

Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2,500 g) infants, and small for gestational age at birth.

Fetal/Neonatal adverse reactions Transport of endogenous IgG antibodies across the placenta increases as pregnancy progresses, and peaks during the third trimester.

Therefore, SKYRIZI may be present in infants exposed in utero.

The potential clinical impact of risankizumab exposure in infants exposed in utero should be considered.

An enhanced pre.

• and post-natal developmental toxicity study was conducted in cynomolgus monkeys.

Pregnant cynomolgus monkeys were administered weekly subcutaneous doses of risankizumab-rzaa of 5 or 50 mg/kg from gestation day to parturition, and the cynomolgus monkeys (mother and infants) were monitored for 6 months after delivery.

No maternal toxicity was noted in this study.

There were no treatment-related effects on growth and development, malformations, developmental immunotoxicology, or neurobehavioral development.

However, a dose-dependent increase in fetal/infant loss was noted in the risankizumab-rzaa-treated groups (32% and 43% in the 5 mg/kg and 50 mg/kg groups, respectively) compared with the vehicle control group (19%).

The increased fetal/infant loss in the 50 mg/kg group was considered to be related to risankizumab-rzaa treatment.

The no-observed adverse effect level (NOAEL) for maternal toxicity was identified as 50 mg/kg, and the NOAEL for developmental toxicity was identified as 5 mg/kg. The 5 mg/kg dose in pregnant monkeys resulted in approximately 0.6 times the exposure (AUC) in humans administered the maximum recommended induction dose (1,200 mg) and 5 times the exposure (AUC) in humans administered the maximum recommended maintenance dose (360 mg).

In the infants, mean serum concentrations increased in a dose-dependent manner and were approximately 17%-86% of the respective maternal concentrations.

Following delivery, most adult female cynomolgus monkeys and all infants from the risankizumab-rzaa-treated groups had measurable serum concentrations of risankizumab-rzaa up to 91 days postpartum.

Serum concentrations were below detectable levels at 180 days postpartum.

The safety and effectiveness of

SKYRIZI have not been established in pediatric patients.

Of the 6,862 subjects exposed to SKYRIZI, a total of were 65 years and older (243 subjects with plaque psoriasis, 246 subjects with psoriatic arthritis, 72 subjects with Crohn’s disease and 103 subjects with ulcerative colitis), and 71 subjects were 75 years and older.

Clinical studies of

SKYRIZI, within each indication, did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently from younger adult subjects.

No clinically meaningful differences in the pharmacokinetics of risankizumab-rzaa were observed based on age.