Risankizumab

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# Overview
Risankizumab is an interleukin-23 antagonist that is FDA approved for the treatment of moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy.   Common adverse reactions include upper respiratory infections, headache, fatigue, injection site reactions, and tinea infections.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
Indication
- Risankizumab is indicated for the treatment of moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy.
Dosage
- 150 mg (two 75 mg injections) administered by subcutaneous injection at Week 0, Week 4 and every 12 weeks thereafter.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding risankizumab Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding risankizumab Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
The safety and efficacy of risankizumab in pediatric patients less than 18 years of age have not yet been established.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding risankizumab Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding risankizumab Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.

# Contraindications
None.

# Warnings
- Risankizumab may increase the risk of infections. In clinical studies, infections occurred in 22.1% of the risankizumab group compared to 14.7% of the placebo group through 16 weeks of treatment. Upper respiratory tract infections and tinea infections occurred more frequently in the risankizumab group than in the placebo group. Subjects with known chronic or acute infections were not enrolled in clinical studies.
- The rate of serious infections for the risankizumab group and the placebo group was  0.4%. Treatment with risankizumab 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 risankizumab. 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 risankizumab until the infection resolves.
- Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with risankizumab. Across the Phase 3 psoriasis clinical studies, of the 72 subjects with latent TB who were concurrently treated with risankizumab and appropriate TB prophylaxis during the studies, none developed active TB during the mean follow-up of 61 weeks on risankizumab. Two subjects taking isoniazid for treatment of latent TB discontinued treatment due to liver injury. Of the 31 subjects from the IMMHANCE 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 risankizumab. Consider anti-TB therapy prior to initiating risankizumab 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 risankizumab treatment. Do not administer risankizumab to patients with active TB.
- Prior to initiating therapy with risankizumab, consider completion of all age appropriate immunizations according to current immunization guidelines. Avoid use of live vaccines in patients treated with risankizumab. No data are available on the response to live or inactive vaccines.

# Adverse Reactions

## 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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- A total of 2234 subjects were treated with risankizumab in clinical development studies in plaque psoriasis. Of these, 1208 subjects with psoriasis were exposed to risankizumab for at least one year.
- Data from placebo- and active-controlled studies were pooled to evaluate the safety of risankizumab for up to 16 weeks. In total, 1306 subjects were evaluated in the risankizumab 150 mg group.
- Table 1 summarizes the adverse drug reactions that occurred at a rate of at least 1% and at a higher rate in the risankizumab group than the placebo group during the 16-week controlled period of pooled clinical studies.
- Adverse drug reactions that occurred in  0.1% of subjects in the risankizumab 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 risankizumab group (90.8 events per 100 subject-years) compared to 14.7% of the placebo group (56.5 events per 100 subject-years) and did not lead to discontinuation of risankizumab. The rates of serious infections for the risankizumab group and the placebo group were 0.4%. Serious infections in the risankizumab group included cellulitis, osteomyelitis, sepsis and herpes zoster. In ULTIMMA-1 and ULTIMMA-2, through Week 52, the rate of infections (73.9 events per 100 subject-years) was similar to the rate observed during the first 16 weeks of treatment.
Safety through 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 study discontinuation included pneumonia.
- As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other products, including other risankizumab products, may be misleading.
- By Week 52, approximately 24% (263/1079) of subjects treated with risankizumab at the recommended dose developed antibodies to risankizumab-rzaa. Of the subjects who developed antibodies to risankizumab-rzaa, approximately 57% (14% of all subjects treated with risankizumab) had antibodies that were classified as neutralizing. Higher antibody titers in approximately 1% of subjects treated with risankizumab were associated with lower risankizumab-rzaa concentrations and reduced clinical response.

## Postmarketing Experience
There is limited information regarding Risankizumab Postmarketing Experience in the drug label.

# Drug Interactions
- Avoid use of live vaccines in patients treated with risankizumab.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): 
Risk Summary
- Limited available data with risankizumab use in pregnant women are insufficient to evaluate a drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcome. Human IgG is known to cross the placental barrier; therefore, risankizumab may be transmitted from the mother to the developing fetus.
- In an enhanced pre- and post-natal developmental toxicity study, pregnant cynomolgus monkeys were administered subcutaneous doses of 5 and 50 mg/kg risankizumab-rzaa once weekly during the period of organogenesis up to parturition. At the 50 mg/kg dose , increased fetal/infant loss was noted in pregnant monkeys (see Data). 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 estimated 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.
Animal Data
- 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 20 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 to 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 (20 times the MRHD, based on mg/kg comparison) and the NOAEL for developmental toxicity was identified as 5 mg/kg (2 times the MRHD, based on mg/kg comparison). 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-rzaatreated groups had measurable serum concentrations of risankizumab-rzaa up to 91 days postpartum. Serum concentrations were below detectable levels at 180 days postpartum.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Risankizumab in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Risankizumab during labor and delivery.

### Nursing Mothers
- There are no data on the presence of risankizumab-rzaa in human milk, the effects on the breastfed infant, or the effects on milk production. Maternal IgG is known to be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for risankizumab and any potential adverse effects on the breastfed infant from risankizumab or from the underlying maternal condition.

### Pediatric Use
- The safety and efficacy of risankizumab in pediatric patients less than 18 years of age have not yet been established.

### Geriatic Use
- Of the 2234 subjects with plaque psoriasis exposed to risankizumab, 243 subjects were 65 years or older and 24 subjects were 75 years or older. No overall differences in risankizumab-rzaa exposure, safety or effectiveness were observed between older and younger subjects who received risankizumab. However, the number of subjects aged 65 years and older was not sufficient to determine whether they respond differently from younger subjects.

### Gender
There is no FDA guidance on the use of Risankizumab with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Risankizumab with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Risankizumab in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Risankizumab in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Risankizumab in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Risankizumab in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- The recommended dose is 150 mg (two 75 mg injections) administered by subcutaneous injection at Week 0, Week 4, and every 12 weeks thereafter.
- Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with risankizumab.
- Administer risankizumab subcutaneously. Inject two separate 75 mg single-dose prefilled syringes for the full 150 mg dose. Discard prefilled syringes after use. Do not reuse.
- For each dose, administer the injections at different anatomic locations (such as thighs or abdomen), and not into areas where the skin is tender, bruised, erythematous, indurated or affected by psoriasis. Administration of risankizumab 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.
- Risankizumab is intended for use under the guidance and supervision of a healthcare professional. Patients may self-inject risankizumab after training in subcutaneous injection technique. Provide proper training to patients and/or caregivers on the subcutaneous injection technique of risankizumab. Instruct the patient that two separate 75 mg single-dose injections are required to achieve the 150 mg dose.
- The risankizumab Instructions for Use contains more detailed instructions on the preparation and administration of risankizumab. Instruct the patient to read the Instructions for Use before administration (see Patient Counseling Information).
- Before injecting, patients may remove the carton from the refrigerator and allow to reach room temperature out of direct sunlight (15 to 30 minutes) without removing the prefilled syringes from the carton.
- Visually inspect risankizumab for particulate matter and discoloration prior to administration. Risankizumab is a colorless to slightly yellow and clear to slightly opalescent solution. It may contain a few translucent to white particles. Do not use if the solution contains large particles or is cloudy or discolored.

### Monitoring
There is limited information regarding Risankizumab Monitoring in the drug label.

# IV Compatibility
There is limited information regarding the compatibility of Risankizumab and IV administrations.

# Overdosage
- In the event of overdosage, monitor the patient for any signs or symptoms of adverse reactions and administer appropriate symptomatic treatment immediately.

# Pharmacology

## Mechanism of Action
- Risankizumab-rzaa is a humanized immunoglobulin G1 (IgG1) monoclonal antibody that selectively binds to the p19 subunit of human interleukin 23 (IL-23) cytokine and inhibits its interaction with the IL-23 receptor. IL-23 is a naturally occurring cytokine that is involved in inflammatory and immune responses.
- Risankizumab-rzaa inhibits the release of pro-inflammatory cytokines and chemokines.

## Structure
There is limited information regarding Risankizumab Structure in the drug label.

## Pharmacodynamics
- No formal pharmacodynamics studies have been conducted with risankizumab-rzaa.

## Pharmacokinetics
- Risankizumab-rzaa plasma concentrations increased dose-proportionally from 90 to 180 mg and from 18 to 300 mg (0.6 to 1.2 and 0.12 to 2.0 times the approved recommended dosage) following subcutaneous administration in subjects with plaque psoriasis and healthy volunteers, respectively. Steady-state concentrations were achieved by Week 16 following subcutaneous administration of risankizumab-rzaa at Weeks 0, 4, and every 12 weeks thereafter. At the 150 mg dose, the estimated steady-state peak concentration (Cmax) and trough concentration (Ctrough) were approximately 12 mcg/mL and 2 mcg/mL, respectively.
Absorption
- The absolute bioavailability of risankizumab-rzaa was estimated to be 89% following subcutaneous injection. Cmax was reached by 3-14 days.
Distribution
- The estimated steady-state volume of distribution (inter-subject CV%) was 11.2 L (34%) in subjects with plaque psoriasis.
Elimination
- The estimated systemic clearance (inter-subject CV%) was 0.31 L/day (24%) and terminal elimination half-life was approximately 28 days in subjects with plaque psoriasis.
Metabolism
- The metabolic pathway of risankizumab-rzaa has not been characterized. As a humanized IgG1 monoclonal antibody, risankizumab-rzaa is expected to be degraded into small peptides and amino acids via catabolic pathways in a manner similar to endogenous IgG.
Specific Populations
- No clinically significant differences in the pharmacokinetics of risankizumab-rzaa were observed based on age (18 years). No specific studies have been conducted to determine the effect of renal or hepatic impairment on the pharmacokinetics of risankizumab-rzaa.
Body Weight
- Risankizumab-rzaa clearance and volume of distribution increase and plasma concentrations decrease as body weight increases; however, no dose adjustment is recommended based on body weight.
Drug Interaction Studies
- Cytochrome P450 Substrates: No clinically significant changes in exposure of caffeine (CYP1A2 substrate), warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate), metoprolol (CYP2D6 substrate), or midazolam (CYP3A substrate) were observed when used concomitantly with risankizumab-rzaa 150 mg administered subcutaneously at Weeks 0, 4, 8 and 12 (more frequent than the approved recommended dosing frequency) in subjects with plaque psoriasis.

## Nonclinical Toxicology
- Carcinogenicity and mutagenicity studies have not been conducted with risankizumab.
- No effects on male fertility parameters were observed in sexually mature male cynomolgus monkeys subcutaneously treated with 50 mg/kg risankizumab-rzaa (at 20 times the clinical exposure at the MRHD, based on mg/kg comparison) once weekly for 26 weeks.

# Clinical Studies
- Four multicenter, randomized, double-blind studies  enrolled 2109 subjects 18 years of age and older with moderate to severe plaque psoriasis who had a body surface area (BSA) involvement of 10%, a static Physicians Global Assessment (sPGA) score of 3 (moderate) in the overall assessment (plaque thickness/induration, erythema, and scaling) of psoriasis on a severity scale of 0 to 4, and a Psoriasis Area and Severity Index (PASI) score 12.
- Overall, subjects had a median baseline PASI score of 17.8 and a median BSA of 20.0%. Baseline sPGA score was 4 (severe) in 19% of subjects. A total of 10% of study subjects had a history of diagnosed psoriatic arthritis.
- Across all studies, 38% of subjects had received prior phototherapy, 48% had received prior non-biologic systemic therapy, and 42% had received prior biologic therapy for the treatment of psoriasis.
ULTIMMA-1 and ULTIMMA-2
- In ULTIMMA-1 and ULTIMMA-2, 997 subjects were enrolled (including 598 subjects randomized to the risankizumab 150 mg group, 200 subjects randomized to the placebo group, and 199 to the biologic active control group). Subjects received treatment at Weeks 0, 4, and every 12 weeks thereafter.
- Both studies assessed the responses at Week 16 compared to placebo for the two co-primary endpoints:
the proportion of subjects who achieved an sPGA score of 0 (clear) or 1 (almost clear)
the proportion of subjects who achieved at least a 90% reduction from baseline PASI (PASI 90)
- the proportion of subjects who achieved an sPGA score of 0 (clear) or 1 (almost clear)
- the proportion of subjects who achieved at least a 90% reduction from baseline PASI (PASI 90)
- Secondary endpoints included the proportion of subjects who achieved PASI 100, sPGA 0, and PSS 0 at Week 16.
- The results are presented in Table 2.
- Examination of age, gender, race, body weight, baseline PASI score and previous treatment with systemic or biologic agents did not identify differences in response to risankizumab among these subgroups at Week 16.
- In ULTIMMA-1 and ULTIMMA-2 at Week 52, subjects receiving risankizumab achieved sPGA 0 (58% and 60%, respectively), PASI 90 (82% and 81%, respectively), and PASI 100 (56% and 60%, respectively).
Patient Reported Outcomes
- Improvements in signs and symptoms related to pain, redness, itching and burning at Week 16 compared to placebo were observed in both studies as assessed by the Psoriasis Symptom Scale (PSS). In ULTIMMA-1 and ULTIMMA-2, about 30% of the subjects who received risankizumab achieved PSS 0 (none) at Week 16 compared to 1% of the subjects who received placebo.
IMMHANCE
- IMMHANCE enrolled 507 subjects (407 randomized to risankizumab 150 mg and 100 to placebo). Subjects received treatment at Weeks 0, 4, and every 12 weeks thereafter.
- At Week 16, risankizumab was superior to placebo on the co-primary endpoints of sPGA 0 or 1 (84% risankizumab and 7% placebo) and PASI 90 (73% risankizumab and 2% placebo). The respective response rates for risankizumab and placebo at Week 16 were: sPGA 0 (46% risankizumab and 1% placebo); PASI 100 (47% risankizumab and 1% placebo); and PASI 75 (89% risankizumab and 8% placebo).
Maintenance and Durability of Response
- In ULTIMMA-1 and ULTIMMA-2, among the subjects who received risankizumab and had PASI 100 at Week 16, 80% (206/258) of the subjects who continued on risankizumab had PASI 100 at Week 52. For PASI 90 responders at Week 16, 88% (398/450) of the subjects had PASI 90 at Week 52.
- In IMMHANCE, subjects who were originally on risankizumab and had sPGA 0 or 1 at Week 28 were re-randomized to continue risankizumab every 12 weeks or withdrawal of therapy. At Week 52, 87% (97/111) of the subjects re-randomized to continue treatment with risankizumab had sPGA 0 or 1 compared to 61% (138/225) who were re-randomized to withdrawal of risankizumab.

# How Supplied
- Risankizumab injection is a sterile, preservative-free, colorless to slightly yellow and clear to slightly opalescent solution. The product is supplied in a 1 mL glass syringe with a fixed 29 gauge 12 inch needle with needle guard.
-ne carton containing two prefilled syringes and two alcohol pad
- one carton containing two prefilled syringes and two alcohol pad

## Storage
- Store in a refrigerator at 2C to 8C (36F to 46 F).
- Do not freeze.
- Do not shake.
- Keep the prefilled syringes in the outer carton to protect from light.
- Not made with natural rubber latex.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use) before starting risankizumab therapy and to reread the Medication Guide each time the prescription is renewed. Advise patients of the potential benefits and risks of risankizumab.
Infections
- Inform patients that risankizumab may lower the ability of their immune system to fight infections. Instruct patients of the importance of communicating any history of infections to the healthcare provider and contacting their healthcare provider if they develop any symptoms of an infection.
Administration Instruction
- Instruct patients or caregivers to perform the first self-injected dose under the supervision and guidance of a qualified healthcare professional for training in preparation and administration of risankizumab, including choosing anatomical sites for administration, and proper subcutaneous injection technique.
- Instruct patients or caregivers to administer two 75 mg single-dose syringes to achieve the 150 mg dose of risankizumab.
- Instruct patients or caregivers in the technique of needle and syringe disposal.

# Precautions with Alcohol
Alcohol-Risankizumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

# Brand Names
Skyrizi

# Look-Alike Drug Names
There is limited information regarding Risankizumab Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price