ICOTYDE Film-coated tablet Ref.[116431] Active ingredients: Icotrokinra

5.1 Infections

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.

5.2 Tuberculosis

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.

5.3 Immunizations

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

Table 1. Adverse Reactions that Occurred in ≥1% of Subjects in the ICOTYDE Group and More Frequently than in the Placebo Group in Trials PSO-1, PSO-2, PSO-3, and PSO-4 through Week 16*:

^* percentages based on Cochran-Mantel-Haenszel (CMH) adjusted proportions.
^† Fungal infection includes tinea pedis (n=4), tinea versicolor (n=2), oral candidiasis (n=2), onychomycosis (n=1), skin candida (n=1), urinary tract candidiasis (n=1), vulvovaginal candidiasis (n=1), fungal skin infection (n=1), genital infection fungal (n=1), ear infection fungal (n=1), laryngitis fungal (n=1). Two subjects experienced more than 1 event.

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.

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.

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)].