Crohn’s Disease

SKYRIZI is indicated for the treatment of moderately to severely active Crohn's disease in adults.

Ulcerative Colitis

SKYRIZI is indicated for the treatment of moderately to severely active ulcerative colitis in adults.

Posology

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 360 mg administered by subcutaneous injection at Week 12, and every 8 weeks thereafter.

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.

Missed dose

If a dose is missed, the dose should be administered as soon as possible. Thereafter, dosing should be resumed at the regular scheduled time.

Special populations

Geriatric Use

Of the 6,862 subjects exposed to SKYRIZI, a total of 664 were 65 years or 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 or 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 were observed based on age.

Renal or hepatic impairment

No studies have been conducted to determine the effect of renal or hepatic impairment on the pharmacokinetics of risankizumab.

Paediatric population

The safety and effectiveness of SKYRIZI have not been established in pediatric patients.

Method of administration

SKYRIZI vial for intravenous administration is intended for administration by a healthcare provider using aseptic technique.  Please refer to section “6.6 Special precautions for disposal and other handling” for the proper injection technique.

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 Special warnings and precautions for use (4.4)]

·        Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with SKYRIZI [ see Special warnings and precautions for use (4.4)].

·        Complete all age-appropriate vaccinations as recommended by current immunization guidelines [ see Special warnings and precautions for use (4.4)].

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 (4.8)].

Infections

SKYRIZI may increase the risk of infections [see Adverse Reactions (4.8)].

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.

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 150 mg 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.

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.

Hepatotoxicity in Treatment of Inflammatory Bowel Disease

A serious adverse reaction of drug-induced liver injury was reported in a patient with Crohn’s disease (ALT 54x ULN, AST 30x ULN, and total bilirubin 2.2x ULN) following two intravenous doses of SKYRIZI 600 mg in conjunction with a rash that required hospitalization. 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.

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 in subjects with Crohn’s disease or ulcerative colitis (risankizumab 1,800 mg administered intravenously at Weeks 0, 4 and 8, i.e., 3 times and 1.5 times the dose for Crohn’s disease and ulcerative colitis, respectively).

Pregnancy

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, 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 (see Clinical Considerations).

In an enhanced pre- and post-natal developmental toxicity study, pregnant cynomolgus monkeys were administered subcutaneous doses of 5 or 50 mg/kg risankizumab 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 (see Data). 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 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.

Clinical Considerations

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 2500 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. Because risankizumab may interfere with immune response to infections, risks and benefits should be considered prior to administering live vaccines to infants exposed to SKYRIZI in utero. There are insufficient data regarding infant serum levels of risankizumab at birth and the duration of persistence of risankizumab in infant serum after birth. Although a specific timeframe to delay live virus immunizations in infants exposed in utero is unknown, a minimum of 5 months after birth should be considered because of the half-life of the product.

.

Data

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 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 -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 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 -treated groups had measurable serum concentrations of risankizumab up to 91 days postpartum. Serum concentrations were below detectable levels at 180 days postpartum.

Lactation

Risk Summary

There are no data on the presence of risankizumab in human milk, the effects on the breastfed infant, or the effects on milk production. Endogenous maternal IgG and monoclonal antibodies are transferred in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to Risankizumab are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for SKYRIZI and any potential adverse effects on the breastfed infant from SKYRIZI or from the underlying maternal condition.

Risankizumab has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The following adverse reactions are discussed in other sections of labeling [see Special warnings and precautions for use (4.4)]:

•        Hypersensitivity Reactions

•        Infections

•        Tuberculosis

•        Hepatotoxicity in Treatment of Inflammatory Bowel Disease

Tabulated list of adverse reactions

Adverse reactions for risankizumab from clinical studies (Table 1) are listed by MedDRA system organ class and are based on the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); and very rare (< 1/10 000).

Table 1: List of 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

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 studies (CD-1, CD-2) and a randomized, double-blind, placebo-controlled, dose-finding study (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 study (CD-3).

In the two induction studies (CD-1, CD-2) and the dose finding study (CD-4), 620 subjects received the SKYRIZI intravenous induction regimen. In the maintenance study (CD-3), 142 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 studies CD-1 and CD-2, received SKYRIZI subcutaneously as a maintenance regimen.

Adverse reactions reported in > 3% of subjects in induction studies and at a higher rate than placebo are shown in Table 2.

Table 2. Adverse Drug Reactions Reported in > 3% of Subjects with Crohn’s Disease Treated with SKYRIZI in Placebo-Controlled 12-Week Induction Studies

Adverse reactions reported in >3% of subjects in the maintenance study and at a higher rate than placebo are shown in Table 3.

Table 3. Adverse Reactions Reported in >3% of Subjects with Crohn’s Disease Treated with SKYRIZI in Placebo-Controlled 52-Week Maintenance Study (CD-3)

Specific Adverse Drug Reactions

Infections

In the maintenance study (CD-3) through Week 52, the rate of infections was 36.6% (60.8 events per 100 subject-years) in subjects who received SKYRIZI compared to 36.4% (60.3 events per 100 subject-years) in subjects who received placebo after SKYRIZI induction. The rate of serious infections was 5.6% (7.4 events per 100 subject-years) in subjects who received SKYRIZI compared to 2.1% (2.4 events per 100 subject-years) in subjects who received placebo after SKYRIZI induction.

Lipid Elevations
 

Elevations in lipid parameters (total cholesterol and low-density lipoprotein cholesterol [LDL-C]) were first assessed at 4 weeks following initiation of SKYRIZI in the induction trials (CD-1, CD-2). Increases from baseline and increases relative to placebo were observed at Week 4 and remained stable to Week 12. Following SKYRIZI induction, mean total cholesterol increased by 9.4 mg/dL from baseline to a mean absolute value of 175.1 mg/dL at Week 12. Similarly, mean LDL-C increased by 6.6 mg/dL from baseline to a mean absolute value of 92.6 mg/dL Week 12.

Ulcerative Colitis

SKYRIZI was studied up to 12 weeks in subjects with moderately to severely active ulcerative colitis in a randomized, double-blind, placebo-controlled induction study (UC-1) and a randomized, double-blind, placebo-controlled, dose-finding study (UC-3). Long-term safety up to 52 weeks was evaluated in subjects who responded to induction therapy in a randomized, double-blind, placebo-controlled maintenance study (UC-2).

In the induction studies (UC-1 and UC-3), 712 subjects received the SKYRIZI 1,200 mg intravenous induction regimen at Weeks 0, 4 and 8. In the maintenance study (UC-2), 347 subjects who achieved clinical response, defined as  a decrease in mMS of ≥2 points and ≥30% from baseline and a decrease in RBS ≥1 from baseline or an absolute RBS ≤1, 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.

The adverse reaction reported in ≥3% subjects treated with SKYRIZI in the ulcerative colitis induction studies (UC-1 and UC-3) and at a higher rate than placebo was arthralgia (3% SKYRIZI vs 1% placebo).

Adverse reactions reported in ≥3% of subjects treated with SKYRIZI in the maintenance study (UC-2) and at a higher rate than placebo are shown in Table 4.

Table 4. Adverse Reactions Reported in ≥3% of Subjects with Ulcerative Colitis Treated with SKYRIZI^a in Placebo-Controlled 52-Week Maintenance Study (UC-2)

Specific Adverse Drug Reactions

The rates of infections, serious infections, and lipid elevations in subjects with UC who received SKYRIZI compared to subjects who received placebo in the induction studies (UC-1 and UC-3) and maintenance study (UC-2) were similar to the rates in subjects with CD who received SKYRIZI compared to subjects who received placebo in the induction studies (CD-1, CD-2, and CD-4) and maintenance study (CD-3).

Immunogenicity

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.

Crohn’s Disease

By Week 64, approximately 3.4% (2/58) of subjects treated with SKYRIZI at the recommended induction and maintenance dosages developed antibodies to risankizumab. None of the subjects who developed antibodies to risankizumab had antibodies that were classified as neutralizing.

Ulcerative Colitis

By Week 64, antibodies to risankizumab developed in approximately 8.9% (8/90) or 4.4% (4/91) of subjects treated with SKYRIZI induction followed by the 180 mg or 360 mg maintenance regimen, respectively. Of the subjects who developed antibodies to risankizumab, 75% (6.7% of all subjects treated with SKYRIZI induction followed by the 180 mg maintenance regimen) or 50% (2.2% of all subjects treated with SKYRIZI induction followed by the 360 mg maintenance regimen), respectively, had antibodies that were classified as neutralizing.

Postmarketing Experience

The following adverse reactions have been reported during post-approval of SKYRIZI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to SKYRIZI exposure:

·        Skin and subcutaneous tissue disorders: eczema and rash

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via The The National Pharmacovigilance Centre (NPC):

·        SFDA Call Center: 19999

·        E-mail: npc.drug@sfda.gov.sa

·        Website: https://ade.sfda.gov.sa/

In the event of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment be instituted immediately.

Pharmacotherapeutic group: Immunosuppressants, interleukin inhibitors, ATC code: L04AC18

Mechanism of action

risankizumab is a humanized IgG1 monoclonal antibody that selectively binds to the p19 subunit of human 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 inhibits the release of pro-inflammatory cytokines and chemokines.

Pharmacodynamic effects

No formal pharmacodynamics studies have been conducted with risankizumab.

Clinical efficacy and safety

Induction Trials (Studies CD-1 and CD-2)

In two 12-week induction studies (CD-1; NCT03105128 and CD-2; NCT03104413), subjects with moderately to severely active Crohn’s disease were randomized to receive SKYRIZI 600 mg, SKYRIZI 1,200 mg, or placebo as an intravenous infusion at Week 0, Week 4, and Week 8. Moderately to severely active CD was defined as a Crohn’s Disease Activity Index (CDAI) of 220 to 450 and Simple Endoscopic Score for Crohn’s disease (SES-CD) ≥6 (or ≥4 for isolated ileal disease). Subjects with inadequate response, loss of response, or intolerance to oral aminosalicylates, corticosteroids, immunosuppressants, and/or biologic therapy were enrolled. 

At baseline, the median CDAI was 307 (range: 76 – 634) and 307 (range: 72 – 651), and the median SES-CD was 12 (range: 4 – 45) and 13 (range 4 – 40), in CD-1 and CD-2, respectively. In CD-1, 58% (491/850) of subjects had failed or were intolerant to treatment with one or more biologic therapies (prior biologic failure). All subjects in CD-2 had prior biologic failure. At baseline, 30% and 34% of patients were receiving corticosteroids, 24% and 23% of patients were receiving immunomodulators (azathioprine, 6-mercaptopurine, methotrexate), and 31% and 19% of patients were receiving aminosalicylates in CD-1 and CD-2, respectively. In CD-1 and CD-2 combined, the median age was 36 years (ranging from 16 to 80 years), 81% (1145/1419) of subjects were white, and 53% (753/1419) were male.

In CD-1 and CD-2, the co-primary endpoints were clinical remission and endoscopic response at Week 12. Secondary endpoints included clinical response and endoscopic remission (see Table 5 and Table 6). The SKYRIZI 1,200 mg dosage did not demonstrate additional treatment benefit over the 600 mg dosage and is not a recommended regimen [see Dosage and Administration ].

Table 5. Proportion of Subjects Meeting Efficacy Endpoints at Week 12 – Study CD-1

Table 6. Proportion of Subjects Meeting Efficacy Endpoints at Week 12 – Study CD-2^a

Onset of clinical response and clinical remission based on CDAI occurred as early as Week 4 in a greater proportion of subjects treated with the SKYRIZI 600 mg induction regimen compared to placebo.

Reductions in stool frequency and abdominal pain were observed in a greater proportion of subjects treated with the SKYRIZI 600 mg induction regimen compared to placebo at Week 12.

Study CD-3

The maintenance study CD-3 evaluated 247 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 studies CD-1 and CD-2. Subjects were randomized to receive a maintenance regimen of SKYRIZI 360 mg or placebo at Week 12 and every 8 weeks thereafter for up to an additional 52 weeks.

The co-primary endpoints in CD-3 were clinical remission and endoscopic response at Week 52 (see Table 7). 

 Table 7. Proportion of Subjects Meeting Efficacy Endpoints at Week 52 - Study CD-3

Endoscopic remission was observed at Week 52 in 41% (48/117) of subjects treated with the SKYRIZI maintenance regimen and 13% (17/130) of subjects treated with placebo. This endpoint was not statistically significant under the prespecified multiple testing procedure.

Ulcerative Colitis                     

Induction Trial (Study UC-1)

In the 12-week induction study (UC-1; NCT03398148), 966 subjects with moderately to severely active ulcerative colitis were randomized and received SKYRIZI 1,200 mg or placebo as an intravenous infusion at Week 0, Week 4, and Week 8. Disease activity was assessed by the modified Mayo score (mMS), a 3-component Mayo score (0-9) which consists of the following subscores (0 to 3 for each subscore): stool frequency (SFS), rectal bleeding (RBS), and findings on centrally read endoscopy score (ES). An ES of 2 was defined by marked erythema, lack of vascular pattern, any friability, and/or erosions; an ES of 3 was defined by spontaneous bleeding and ulceration. Enrolled subjects had a mMS between 5 and 9, with an ES of 2 or 3. Subjects with inadequate response, or intolerance to oral aminosalicylates, corticosteroids, immunomodulators, biologics, Janus Kinase inhibitors (JAKi), and/or sphingosine-1-phosphate receptor modulators (S1PRM) were enrolled. 

At baseline in UC-1, the median mMS was 7; 37% had severely active disease (mMS >7); 69% had an ES of 3. In UC-1, 52% (499/966) of subjects had failed (inadequate response or intolerance) treatment with one or more biologics, JAKi or S1PRM. Of these 499 subjects, 484 (97%) failed biologics and 90 (18%) failed JAK inhibitors.  Enrolled subjects were permitted to use a stable dose of oral corticosteroids (up to 20 mg/day prednisone or equivalent), immunomodulators, and aminosalicylates. At baseline, 36% of subjects were receiving corticosteroids, 16% of subjects were receiving immunomodulators (including azathioprine, 6-mercaptopurine, methotrexate), and 73% of subjects were receiving aminosalicylates in UC-1.

In UC-1, the primary endpoint was clinical remission defined using the mMS at Week 12 (see Table 8). Key secondary endpoints included clinical response, endoscopic improvement, and histologic endoscopic mucosal improvement (see Table 8).

Table 8. Proportion of Subjects Meeting Efficacy Endpoints at Week 12 – Study UC-1

UC-1 was not designed to evaluate the relationship of histologic endoscopic mucosal improvement at week 12 to disease progression and long-term outcomes.

Rectal Bleeding and Stool Frequency Subscores

Decreases in rectal bleeding and stool frequency subscores in subjects treated with SKYRIZI compared to placebo were observed as early as 4 weeks.

Endoscopic Assessment

Endoscopic remission was defined as ES of 0. At Week 12, a greater proportion of subjects treated with SKYRIZI compared to placebo achieved endoscopic remission (11% vs 3%).

Bowel Urgency

A greater proportion of subjects treated with the SKYRIZI 1,200 mg induction regimen compared to placebo had no bowel urgency (44% vs 27%) at Week 12.

Fatigue

In UC-1, subjects treated with SKYRIZI experienced a clinically meaningful improvement in fatigue, assessed by change from baseline in FACIT-F score, at Week 12, compared to placebo-treated subjects. The effect of SKYRIZI to improve fatigue after 12 weeks of induction has not been established.

Other UC Symptoms

The proportion of subjects who had no nocturnal bowel movements was greater in subjects treated with SKYRIZI compared to placebo at Week 12 (67% vs 43%).                

Maintenance Study UC-2

The maintenance study (UC-2; NCT03398135) evaluated 547 subjects who received one of three SKYRIZI induction regimens, including the 1,200 mg regimen, for 12 weeks in Studies UC-1 or UC-3 and demonstrated clinical response per mMS after 12 weeks. Subjects were randomized to receive a maintenance regimen of subcutaneous (SC) SKYRIZI 180 mg or SKYRIZI 360 mg or placebo at Week 12 and every 8 weeks thereafter for up to an additional 52 weeks.

In UC-2, 75% (411/547) of subjects had failed (inadequate response or intolerance) treatment with one or more biologics, JAKi, or S1PRM. Of these 411 subjects, 407 (99%) failed biologics and 78 (19%) failed JAK inhibitors.

The primary endpoint in UC-2 was clinical remission using mMS at Week 52 (see Table 9). Key secondary endpoints included corticosteroid-free clinical remission, endoscopic improvement, and histologic endoscopic mucosal improvement (see Table 9).

Table 9. Proportion of Subjects Meeting Efficacy Endpoints at Week 52 - Study UC-2

Endoscopic Assessment

Endoscopic remission was defined as ES of 0. In UC-2, a greater proportion of subjects treated with SKYRIZI 180 mg and SKYRIZI 360 mg compared to placebo achieved endoscopic remission at Week 52 (23% and 24% vs 15%).

Pharmacokinetics

Risankizumab plasma concentrations, after single dose administration increased dose proportionally from 18 mg to 360 mg when administered subcutaneously (0.1 to 2 times the lowest recommended dose and 0.05 to 1 times the highest recommended dose) and from 200 mg to 1,800 mg when administered as an up to 3-hour intravenous infusion (0.2 to 3 times the recommended dose) in healthy subject.

In subjects with Crohn’s disease treated with 600 mg IV induction dose at Weeks 0, 4, and 8 followed by 360 mg SubCutaneous maintenance dose at Week 12 and every 8 weeks thereafter, the median C_max and C_trough are estimated to be 156 and 38.8 mcg/mL respectively during the induction period (Weeks 8-12) and the median C_max and C_trough are estimated to be 28.0 and 8.13 mcg/mL respectively during the maintenance period (Weeks 40-48).

In subjects with ulcerative colitis treated with 1,200 mg intravenous induction dose at Weeks 0, 4, and 8, followed by 180 mg or 360 mg subcutaneous maintenance dose at Week 12 and every 8 weeks thereafter, the median C_max and C_trough are estimated to be 350 and 87.7 mcg/mL, respectively, during the induction period (Weeks 8-12); and the steady state median C_max­ and C_trough are estimated to be 19.6 and 4.64 µg/mL, respectively, for 180 mg or 39.2 mcg/mL and 9.29 mcg/mL, respectively, for 360 mg, during the maintenance period (Weeks 40-48).

Based on population pharmacokinetic analyses, the pharmacokinetics of risankizumab in subjects with ulcerative colitis was generally similar to that in subjects with Crohn’s disease.

Absorption

The absolute bioavailability of risankizumab was estimated to be 74 to 89% following subcutaneous injection. In healthy subjects, following administration of a single subcutaneous dose, C_max was reached by 3 to 14 days.

Distribution

The estimated steady-state volume of distribution (inter-subject CV%) was 7.68 L (64%) in subjects with Crohn’s disease.

Elimination

The estimated systemic clearance (inter-subject CV%) was 0.31 L/day (24%) and 0.30 L/day (34%) and terminal elimination half-life was approximately 21 days in subjects with Crohn’s disease,.

Metabolism

The metabolic pathway of risankizumab has not been characterized. As a humanized IgG1 monoclonal antibody, risankizumab is expected to be degraded into small peptides and amino acids via catabolic pathways in a manner similar to endogenous IgG.

Specific Populations

Risankizumab exposures (C_trough) in geriatric patients (≥65 years) are comparable to those in younger adult patients within each indication. No studies have been conducted to determine the effect of renal or hepatic impairment on the pharmacokinetics of risankizumab.

Body Weight

Risankizumab 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 in subjects with Crohn’s disease or ulcerative colitis (risankizumab 1,800 mg administered intravenously at Weeks 0, 4, and 8, i.e., 3 times and 1.5 times the recommended dose for Crohn’s disease and ulcerative colitis, respectively)..

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

No effects on male fertility parameters were observed in sexually mature male cynomolgus monkeys dosed weekly for 26 weeks with 50 mg/kg risankizumab at 4 times the exposure (AUC) in humans administered the maximum recommended induction dose (1,200 mg) and 39 times the exposure in humans administered the maximum recommended maintenance dose (360 mg).

Each SKYRIZI 600 mg/10 mL (60 mg/mL) solution for infusion vial contains:

Glacial Acetic acid (0.54 mg),

Polysorbate 20 (2 mg),

Sodium acetate(7.5 mg),

Trehalose(633.3 mg),

Water for Injection, USP.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

•    Store in a refrigerator at 2°C to 8°C.

•    Do not freeze.

•    Do not shake.

•    Keep in the original cartons to protect from light.

Storage of Diluted Solution:

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 refrigerator, the diluted SKYRIZI solution can be stored at room temperature at up to 77°F (25°C) (protected from sunlight) for 4 hours (cumulative time from dilution to start of infusion). Do not freeze.

SKYRIZI (risankizumab) solution for infusion is supplied in sterile 600 mg/10 mL single-dose glass vial containing a sterile and preservative-free, colorless to slightly yellow, and clear to slightly opalescent solution. Each single-dose glass vial is closed with a stopper and blue flip cap.

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 10 below) for a final concentration of approximately 1.2 mg/mL to 6 mg/mL. Discard any remaining solution in the vial.

Table 10. Total Volume of Diluent Required for Intravenous Induction Dose

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. The infusion should be completely administered  within 4 hours after start of infusion. 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 4 hours (cumulative time from start of dilution to start of infusion).

·        Exposure to indoor light is acceptable during room temperature storage and administration.

·        Do not freeze.