Icotrokinra Hydrochloride: prescribing information – dosing, contraindications, interactions, side effects

ICOTYDE is indicated for the treatment of moderate to severe plaque psoriasis in adults, and adolescents 12 years of age and older and weighing at least 40 kg, who are candidates for systemic therapy.

Treatment should be initiated under the guidance and supervision of a physician experienced in the diagnosis and treatment of plaque psoriasis.

Adults and adolescents weighing at least 40 kg

The recommended dose of ICOTYDE is 200 mg orally once daily on an empty stomach (see Method of administration).

If a patient shows no evidence of therapeutic benefit after 24 weeks, treatment discontinuation should be considered. The patient's response to treatment should be evaluated on a regular basis. Some plaque psoriasis patients with initial partial response may subsequently improve with continued treatment beyond 24 weeks.

Missed dose
If a dose is missed, patients should be instructed to take the dose on the same day as soon as possible and then resume normal dosing schedule the following day.

Special populations

Elderly
No dose adjustment is required in elderly patients aged 65 years and older (see section 5.2).

Renal impairment
No dose adjustment is recommended for patients with mild, moderate or severe renal impairment.
ICOTYDE has not been studied in patients with end-stage renal disease and should only be used in these patients if the benefit outweighs the possible risk (see section 5.2).

Hepatic impairment
No dose adjustment is recommended in patients with mild, moderate, or severe hepatic impairment (see section 5.2).

Paediatric population
In children aged 12 years to less than 18 years and weighing at least 40 kg, the recommended dose is the same as in adults (see above).

The safety and efficacy of ICOTYDE in children younger than 12 years of age or children weighing less than 40 kg have not yet been established. No data are available.

Method of administration

For oral use.

ICOTYDE film-coated tablets should be taken upon waking on an empty stomach with water at least 30 min before eating food (see section 5.2). Film-coated tablet must be swallowed whole.

Alternative method of administration
For patients who have difficulty swallowing tablets whole, ICOTYDE 200 mg film-coated tablet can be dispersed in water.

Patients should place one ICOTYDE 200 mg film-coated tablet in a cup containing at least 120 mL of water. It may take a few minutes for the film-coated tablet to disperse. The film-coated 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. The cup should be gently swirled before drinking. The full mixture should be swallowed.

Patients should fill the cup with at least an additional 120 mL of water to make sure the whole dose is taken and should swallow contents completely. ICOTYDE film-coated tablet should be taken as soon as possible after dispersion in water.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Clinically important active infections (e.g. active tuberculosis, see section 4.4).

Summary of the safety profile

The most frequently reported adverse reactions were fungal infections (1.1%).

Tabulated list of adverse reactions

Adverse reactions for icotrokinra from clinical studies are listed (see Table 1) by MedDRA System Organ Class and are based on the following conventions: 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); very rare (< 1/10 000) and not known (cannot be estimated from the available data).

Table 1:
List of adverse reactions
System Organ Class
Frequency
Adverse reaction
Infections and infestations
Common
Fungal infectionsa
Uncommon
Diverticulitis a
Fungal infections include 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), and laryngitis fungal (n=1).

Paediatric patients

A total of 72 paediatric patients 12 to less than 18 years of age have been treated with icotrokinra 200 mg orally once daily in two clinical studies in moderate to severe plaque psoriasis. Of these, 71 patients were exposed to icotrokinra for at least 6 months and 67 patients were exposed to icotrokinra for at least one year. The safety profile in adolescents was consistent with the safety profile observed in the overall study population.

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 national reporting system listed in Appendix V.

Immunisations

No data on the response to immunisations under icotrokinra treatment are available. As a precautionary measure, prior to treatment initiation, completion of all age-appropriate immunisations according to the current immunisation guidelines should be considered. Administration of live vaccines is not recommended during treatment with icotrokinra and within 3 days after discontinuation of icotrokinra.

For recommendations on administration of live vaccines in newborns potentially exposed during pregnancy, see section 4.6.

Infections

Medicines that interact with the immune system may increase the risk of infection. Treatment should not be initiated in patients with any clinically important active infection until the infection resolves or is adequately treated. Patients should be instructed to seek medical advice if signs or symptoms suggestive of a clinically relevant chronic or acute infection occur. If a patient develops such an infection and/or is not responding to standard therapy, monitor the patient closely and discontinue icotrokinra until the infection resolves.

Live vaccines/therapeutic infectious agents

Live vaccines should not be administered to patients during treatment with icotrokinra and within 3 days after discontinuation of icotrokinra (see sections 4.4 and 4.6).

Interaction with other medicinal products

No clinical drug-drug interaction studies with icotrokinra have been performed.

Based on in vitro studies, icotrokinra is not a CYP enzyme substrate, inhibitor, or inducer. Icotrokinra is not a substrate or inhibitor of P-glycoprotein (P-gp) or other major drug transporters. Therefore, no drug interactions are expected.

Pregnancy

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of icotrokinra in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of ICOTYDE during pregnancy.

It is unknown if icotrokinra crosses the placenta. As a precautionary measure, administration of live vaccines to newborns potentially exposed to icotrokinra during pregnancy within the first 3 days after birth is not recommended. If there is a clear clinical benefit for the individual infant, administration of a live vaccine might be considered (see sections 4.4 and 4.5).

Breast-feeding

It is unknown whether icotrokinra/metabolites are excreted in human milk. Available pharmacokinetic data in animals have shown the presence of icotrokinra in the plasma of nursing rat pups (see section 5.3). A risk to the newborn/infant cannot be excluded. A decision must be made whether to discontinue breast-feeding or discontinue/abstain from ICOTYDE therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

The effect of icotrokinra on human fertility has not been evaluated. Animal studies do not indicate direct or indirect harmful effects with respect to fertility (see section 5.3).

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

In clinical studies, single oral icotrokinra doses up to 1 000 mg have been administered to healthy subjects without adverse reactions.

There is no specific treatment in the event of an overdose. In the event of an overdose, administer appropriate symptomatic treatment.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Immunosuppressants, interleukin inhibitors, ATC code: L04AC28.

Mechanism of action

Icotrokinra is a peptide that binds selectively to the IL-23 receptor (IL-23R) with high affinity and competitively antagonizes the binding of IL-23. IL-23 is a naturally occurring cytokine that is involved in inflammatory and immune responses, but when produced in excess contributes to chronic

inflammation associated with plaque psoriasis. Icotrokinra inhibits the IL-23/IL-23R-dependent release of proinflammatory cytokines.

Pharmacodynamic effects

In evaluated patients with plaque psoriasis serum levels of IL-17A, IL-17F, IL-22, β-defensin-2 and IL-19 were reduced after treatment with icotrokinra. Gene expression levels of IL-17A, IL-17F, IL-22, DEFB4A and IL-19 in psoriatic skin, were normalised to non-lesional skin. Reductions in epidermal thickness and densities of T cells, including CD8+ tissue resident memory T cells, were also observed.

Immunogenicity

Consistent with the potential immunogenic properties of medicinal products containing proteins or peptides, patients may develop antibodies following treatment with icotrokinra.

In four Phase III clinical studies through Week 52, 12.2% (291/2 387) of patients treated with icotrokinra developed antibodies to icotrokinra. Of these patients who developed antibodies to icotrokinra, none had antibodies that were classified as neutralizing antibodies.

In two Phase III clinical studies (ICONIC-LEAD and ICONIC-TOTAL) through Week 52, 32.4% (23/71) of adolescent patients treated with icotrokinra developed antibodies to icotrokinra.

There was no identified clinically significant effect of anti-drug antibodies on pharmacokinetics, safety or effectiveness of icotrokinra through Week 52.

Clinical efficacy

Plaque psoriasis

The efficacy of icotrokinra 200 mg orally once daily was evaluated in 2 492 patients (2 420 adult patients and 72 adolescent patients 12 years to less than 18 years of age and weighing at least 40 kg) with plaque psoriasis who were eligible for systemic therapy or phototherapy in four Phase III randomised, multi-centre, double-blind, placebo and/or active comparator-controlled studies ICONIC- LEAD, ICONIC-TOTAL, ICONIC-ADVANCE 1, and ICONIC-ADVANCE 2.

Adult and adolescent patients with moderate to severe plaque psoriasis

ICONIC-LEAD enrolled 684 patients (618 adult and 66 adolescent patients 12 years of age and older) with moderate to severe plaque psoriasis. Patients were randomised to either icotrokinra 200 mg orally once daily or placebo for 16 weeks.

ICONIC-ADVANCE 1 and ICONIC-ADVANCE 2 evaluated 1 497 adult patients with moderate to severe plaque psoriasis. Patients were randomised to either icotrokinra 200 mg orally once daily, deucravacitinib 6 mg orally once daily or placebo.

Absorption

Icotrokinra is a compound with low solubility and low permeability.

The median (range) Tmax of icotrokinra after oral administration is 2.00 (0.25-8.00) hours in healthy subjects. The mean Cmax and mean AUC∞ of icotrokinra were 3.62 ng/mL and 44.8 ng.h/mL, respectively.

After repeat once daily dosing of icotrokinra, steady-state icotrokinra is expected within 3 days with minimal accumulation, consistent with its terminal half-life.

Inter-subject variability of Cmax and AUC∞ was estimated to be 26.7% and 19.6%, respectively.
Intra-subject variability of Cmax and AUC∞ was estimated to be 35.6% and 20.7%, respectively.

Based on nonclinical data, the absolute bioavailability of icotrokinra was < 1%.

Food effect
In healthy subjects, co-administration of a single icotrokinra 200 mg dose orally with a high-calorie, high-fat meal decreased icotrokinra AUC∞ and Cmax by 43% and 59%, respectively, relative to fasted state. Icotrokinra should be taken upon waking at least 30 minutes before eating food.

Oral administration of a single icotrokinra 200 mg tablet with caffeine resulted in no difference in exposure.

Co-administration of a single icotrokinra 200 mg tablet orally with whole milk decreased Cmax by 33% and AUC∞ by 24% compared with co-administration with water.

Distribution

Icotrokinra is 52% bound to plasma protein. Blood to plasma partition ratio was 0.53. The volume of distribution (V/F) at steady state is 92 800 L.

Biotransformation

Icotrokinra is a peptide, and intact active substance is the main medicine-related species in plasma.
Icotrokinra is metabolised by peptide catabolism into smaller peptides and is not metabolised by CYP enzymes.

Elimination

The median terminal half-life (t1/2) of icotrokinra is 12 hours. Clearance following oral dosing (Cl/F) is 6 550 L/h.