Get your patient on Icotyde (Icotrokinra)

• Consider evaluating patients for tuberculosis (TB) infection prior to initiating treatment with ICOTYDE based on clinical judgment [see Warnings and Precautions (5.2) ] .
• Complete all age-appropriate vaccinations according to current immunization guidelines [see Warnings and Precautions (5.3) ] .

The recommended dosage of ICOTYDE is 200 mg administered orally once daily.

Administer ICOTYDE upon waking on an empty stomach with water. Wait at least 30 minutes after taking ICOTYDE before eating food. Swallow ICOTYDE whole. Do not crush, split, or chew tablets [see Clinical Pharmacology (12.3) ] .

If a patient misses a dose, instruct patients to take the missed dose as soon as possible with a return to normal dosing schedule the following day.

ICOTYDE 200 mg tablet can also be dispersed in water using the following instructions:

• Place one ICOTYDE tablet in a cup containing at least 120 mL (4 ounces) of water. It may take a few minutes for the tablet to disperse. The tablet may not completely disperse. The mixture may look yellow, milky, or cloudy, and small pieces may be seen in the water which are safe to swallow.
• Gently swirl the cup before drinking and swallowing the full mixture.
• Add at least 120 mL (4 ounces) of additional water to the cup and completely swallow the contents to make sure the whole dose is taken.
• Complete administration of ICOTYDE within 15 minutes of dispersion in water.

Risk Summary

The available data on the use of ICOTYDE during pregnancy are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In an animal reproduction study in rabbits, oral administration of icotrokinra to pregnant rabbits during the period of organogenesis at a dose 157 times the maximum recommended human dose (MRHD) based on AUC comparison resulted in maternal body weight loss, low food consumption, late pregnancy loss, and an increased fetal incidence of fused ribs (see Data ) .

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, and other adverse outcomes. 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.

There is a pregnancy safety study for ICOTYDE. If a patient becomes pregnant while receiving ICOTYDE, healthcare providers can report ICOTYDE exposure by calling 1-800-526-7736 or visiting www.ICOTYDE.com.

Data

Animal Data

In an embryo-fetal development study, icotrokinra was administered to pregnant rats during the period of organogenesis at oral doses of 70, 200, and 1000 mg/kg/day. No maternal or embryo-fetal toxicity was observed at doses up to 1000 mg/kg/day (297 times the MRHD based on AUC comparison). In another embryo-fetal development study, icotrokinra was administered to pregnant rabbits during the period of organogenesis at oral doses of 50, 200, and 500 mg/kg/day. Maternal body weight loss, low food consumption, late pregnancy loss, and an increased fetal incidence of fused ribs were observed at 500 mg/kg/day (157 times the MRHD based on AUC comparison). No maternal or embryo-fetal toxicity was noted at doses up to 200 mg/kg/day in rabbits (27 times the MRHD based on AUC comparison).

In a pre- and post-natal development study in rats, icotrokinra was administered to pregnant rats during pregnancy and lactation periods at oral doses of 20, 70, and 200 mg/kg/day. No maternal or developmental toxicity was noted in doses up to 200 mg/kg/day (127 times the MRHD based on AUC comparison).

Risk Summary

There are no data on the presence of icotrokinra in human milk, the effects on the breastfed infant, or the effects on milk production. When administered to lactating rats, icotrokinra was detected in the plasma of nursing pups (see Data ) . When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ICOTYDE and any potential adverse effects on the breastfed infant from ICOTYDE or from the underlying maternal condition.

Data

In a pre- and post-natal development study in rats, icotrokinra was administered orally to pregnant rats during pregnancy and lactation periods at doses up to 200 mg/kg/day (127 times the MRHD based on AUC comparison). Although not directly measured in rat milk, icotrokinra was detected in the plasma of nursing rat pups. No adverse developmental effects were observed in the nursing pups.

The safety and effectiveness of ICOTYDE have been established in pediatric patients 12 years of age and older who weigh at least 40 kg with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. Use of ICOTYDE for this indication is supported by evidence from two multi-center, randomized 52-week trials (Trial PSO-3 and Trial PSO-4) conducted in adults and pediatric subjects, including 72 pediatric subjects 12 years of age and older treated with ICOTYDE [see Adverse Reactions (6.1) and Clinical Studies (14) ].

The safety and effectiveness of ICOTYDE in pediatric patients younger than 12 years of age or who weigh less than 40 kg have not been established.

Of the 2367 subjects exposed to ICOTYDE in clinical trials for moderate-to-severe plaque psoriasis, 240 (10.1%) were 65 years of age and older, and 36 (1.5%) were 75 years of age and older. No overall differences in safety and effectiveness of ICOTYDE have been observed between subjects 65 years of age and older and younger adult subjects [see Clinical Studies (14) ] .

Monitor for potential adverse reactions when ICOTYDE is used in patients with an estimated glomerular filtration rate (eGFR) <60 mL/min [see Clinical Pharmacology (12.3) ] .

Medicines that interact with the immune system may increase the risk of infection.

In the 16-week placebo-controlled trials in subjects with moderate-to-severe plaque psoriasis, the rate of serious infections for ICOTYDE-treated subjects was 0.2% compared to 0.4% of subjects who received placebo.

Avoid treatment with ICOTYDE 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 ICOTYDE. Instruct patients to seek medical advice if signs or symptoms of clinically important infection occur. If a patient develops such an infection and/or is not responding to standard therapy, monitor the patient closely and discontinue ICOTYDE until the infection resolves.

Consider evaluating patients for tuberculosis (TB) infection prior to initiating treatment with ICOTYDE based on clinical judgment. Consider anti-TB therapy prior to initiating ICOTYDE 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 ICOTYDE treatment. Avoid administering ICOTYDE to patients with active TB.

Avoid use of live vaccines in patients during treatment with ICOTYDE. Medications that interact with the immune system may increase the risk of infection following administration of live vaccines. Prior to initiating therapy with ICOTYDE, complete immunizations according to current immunization guidelines. No data are available on the response to live or inactive vaccines.

Because clinical trials are conducted under widely varying conditions, adverse 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.

The safety of ICOTYDE was evaluated in two placebo-controlled trials (Trial PSO-3 and Trial PSO-4) and two placebo- and active-controlled trials (Trial PSO-1 and Trial PSO-2) [see Clinical Studies (14) ] . A total of 2367 adults and pediatric subjects 12 years of age and older who weigh at least 40 kg with moderate-to-severe plaque psoriasis received ICOTYDE 200 mg orally once daily. Of these, 648 subjects were treated with ICOTYDE for at least one year.

Data from these four trials were pooled to evaluate the safety of ICOTYDE compared to placebo for 16 weeks.

Adverse Reactions

Weeks 0 to 16

Adverse reactions that occurred in < 1% of subjects in the ICOTYDE group and at a higher rate than in the placebo group through Week 16 in Trials PSO-1, PSO-2, PSO-3, and PSO-4 were: gastritis, abdominal discomfort, and one fatal case involving upper gastrointestinal bleeding in a subject with underlying risk factors. A relationship of this event to ICOTYDE is not established.

Adverse Reactions in Pediatric Subjects 12 Years of Age and Older

The safety of ICOTYDE was evaluated in pediatric subjects 12 years of age and older who weigh at least 40 kg with moderate-to-severe plaque psoriasis in two placebo-controlled trials (Trial PSO-3 and Trial PSO-4). A total of 72 pediatric subjects were treated with ICOTYDE 200 mg orally once daily. Of these, 45 subjects were treated with ICOTYDE for at least one year. The adverse reactions observed in pediatric subjects were consistent with the most common adverse reactions (≥ 1%) observed in the overall population.

Icotrokinra is a peptide that selectively binds to the IL-23 receptor (IL-23R) with a dissociation constant of 7 pM and antagonizes the binding of IL-23. IL-23 is a naturally occurring cytokine that is involved in inflammatory and immune responses. Icotrokinra inhibits the IL-23/IL-23R-dependent release of proinflammatory cytokines.

Icotrokinra reduced serum levels of proinflammatory cytokines, IL-17A, IL-17F, IL-19, IL-22 and β-defensin-2, relative to pretreatment levels in evaluated subjects with moderate-to-severe plaque psoriasis based on exploratory analysis of the pharmacodynamic markers. A decrease from baseline was observed in the expression of mRNA related to IL-23/Th17 pathway and psoriasis, including molecular targets IL17A , IL17F , IL19 , IL22 , IL23A , and DEFB4A , in lesional skin biopsies up to 24 weeks post treatment in an exploratory analysis of subjects with moderate-to-severe plaque psoriasis. The relationship between these pharmacodynamic markers and the mechanism(s) by which icotrokinra exerts its clinical effects is not fully understood.

Cardiac Electrophysiology

At 5 times the maximum recommended dose of ICOTYDE, clinically significant QTc interval prolongation was not observed.

Following the administration of icotrokinra 200 mg, the mean (standard deviation) maximum concentration (C _max ) is 3.62 (1.48) ng/mL and total systemic exposure (AUC _inf ) is 44.8 (11.4) ng•h/mL. Icotrokinra C _max and AUC increase in a dose-proportional manner between 0.05 to 5 times the recommended dosage in healthy subjects. Following multiple dose administration accumulation for C _max was up to 1.6-fold and for AUC was up to 1.5-fold. Icotrokinra steady state is reached in approximately 3 days.

No clinically relevant differences in icotrokinra pharmacokinetics were observed between healthy subjects and patients with moderate-to-severe plaque psoriasis.

Absorption

Icotrokinra median (min, max) time to maximum plasma concentration (T _max ) is 2 (0.25, 8) hours.

Effect of Food

Icotrokinra AUC decreased by 43% and C _max decreased by 59% following administration with a high-fat meal (1000 calories, 50% fat) [see Dosage and Administration (2.2) ].

No clinically significant differences in icotrokinra pharmacokinetics were observed following administration of caffeine.

Distribution

Icotrokinra is 52% bound to plasma protein. Blood to plasma partition ratio is 0.53. Icotrokinra steady state apparent (oral) volume of distribution is 92800 L.

Elimination

Icotrokinra median elimination half-life is 12 hours with an apparent (oral) clearance of 6550 L/h.

Metabolism

Icotrokinra is a peptide and it is metabolized by peptide catabolism into smaller peptides.

Excretion

Following oral administration of icotrokinra to healthy subjects, approximately 37% to 81% of the dose was recovered in feces within 24 hours as unchanged icotrokinra, and 0.001% of the dose was recovered in urine as unchanged icotrokinra.

Specific Populations

No clinically significant differences in the pharmacokinetics of icotrokinra were observed based on age (range: 12 to 87 years), body weight (range: 39 to 211 kg), sex, race (76% White, 20.1% Asian, 1.7% Black), ethnicity, immunogenicity, mild (eGFR ≥60 to <90 mL/min, [calculated according to Chronic Kidney Disease Epidemiology Collaboration]) renal impairment. The effect of mild (Child-Pugh Class A) to severe (Child-Pugh Class C) hepatic impairment on icotrokinra pharmacokinetics is unknown. Hepatic impairment is unlikely to affect icotrokinra elimination since the drug is not metabolized hepatically. However, patients with severe hepatic impairment were not studied in clinical trials.

Pediatric Patients

No clinically relevant differences in icotrokinra pharmacokinetics were observed in pediatric patients with moderate-to-severe plaque psoriasis 12 years of age and older who weigh at least 40 kg compared to adults.

Patients with Renal Impairment

Icotrokinra AUC increased by 2.47-fold in patients with moderate (eGFR ≥30 to <60 mL/min, [calculated according to Chronic Kidney Disease Epidemiology Collaboration]) and 2.78-fold in severe (eGFR ≥15 to <30 mL/min) renal impairment. No clinically significant differences in the pharmacokinetics of icotrokinra were observed in patients with mild renal impairment (eGFR ≥60 to <90 mL/min) based on population pharmacokinetic analysis.

Drug Interaction Studies

Clinical Studies

No formal drug-drug interaction studies have been conducted with icotrokinra. No clinically significant drug interactions have been identified.

In Vitro Studies

CYP450 Enzymes: Icotrokinra does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. Icotrokinra does not induce CYP1A2, CYP2B6, and CYP3A4.

Transporter systems: Icotrokinra is not a substrate of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, and MATE2-K. Icotrokinra does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, MATE2-K, and BSEP.

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of ICOTYDE or of other icotrokinra products.

In four Phase 3 clinical studies through Week 52, 9.6% (199/2083) of subjects treated with ICOTYDE developed anti-drug antibodies. No neutralizing antibodies were detected.

Among ICOTYDE-treated subjects who developed anti-drug antibodies, population pharmacokinetic analysis using pooled data through Week 52 showed that icotrokinra C _max increased by 1.2-fold and AUC increased by 1.3-fold.

There was no identified clinically relevant effect of anti-drug antibodies on pharmacokinetics, pharmacodynamics, safety or effectiveness of ICOTYDE over the treatment duration of 52 weeks.

In a 6-month transgenic rasH2 mouse study, no drug-related tumors were observed at oral doses of icotrokinra up to 500 mg/kg/day (76 times the MRHD based on AUC comparison). In a 2-year rat carcinogenicity study, no drug-related tumors were observed at oral doses of 20 mg/kg/day (16 times the MRHD based on AUC comparison).

Icotrokinra was not genotoxic in an in vitro bacterial reverse mutation assay (the Ames test), an in vitro human lymphocyte chromosomal aberration assay, or an in vivo rat micronucleus and Comet assays.

In male rats, icotrokinra had no adverse effect on mating, fertility or early embryonic development of their offspring at oral doses up to 20 mg/kg/day (114 times the MRHD based on AUC comparison).

In female rats, icotrokinra had no adverse effect on estrous cyclicity, mating, fertility, or early embryonic parameters at oral doses up to 70 mg/kg/day (335 times the MRHD based on AUC comparison).

Storage and Handling

Store at 20 °C to 25 °C (68 °F to 77 °F); excursions permitted between 15 °C to 30 °C (59 °F to 86 °F) [see USP Controlled Room Temperature]. Store in original package to protect from moisture. Do not discard desiccant.