Molecular mass: 285.351 g/mol
Ritlecitinib interacts in the following cases:
The coadministration of a single 400 mg dose of ritlecitinib increased the AUCinf of sumatriptan (an organic cation transporter [OCT]1 substrate) by approximately 1.3 to 1.5-fold relative to sumatriptan dose given alone. The increase in sumatriptan exposure is not considered clinically relevant. Caution should be exercised with concomitant use of ritlecitinib with OCT1 substrates where small concentration changes may lead to serious adverse reactions.
Multiple doses of 200 mg once daily ritlecitinib increased the AUCinf and Cmax of caffeine, a CYP1A2 substrate, by approximately 2.7-fold and 1.1-fold, respectively. Ritlecitinib is a moderate inhibitor of CYP1A2; caution should be exercised with concomitant use of ritlecitinib with other CYP1A2 substrates (e.g., tizanidine) where moderate concentration changes may lead to serious adverse reactions. Dose adjustment recommendations for the CYP1A2 substrate (e.g., theophylline, pirfenidone) should be considered.
Multiple doses of 200 mg once daily ritlecitinib increased the AUCinf and Cmax of midazolam a CYP3A4 substrate, by approximately 2.7-fold and 1.8-fold, respectively. Ritlecitinib is a moderate inhibitor of CYP3A; caution should be exercised with concomitant use of ritlecitinib with CYP3A substrates (e.g., quinidine, cyclosporine, dihydroergotamine, ergotamine, pimozide) where moderate concentration changes may lead to serious adverse reactions. Dose adjustment recommendations for the CYP3A substrate (e.g., colchicine, everolimus, tacrolimus, sirolimus) should be considered.
The risks and benefits of treatment should be considered in patients:
As there is a higher incidence of infections in elderly and in the diabetic population in general, caution should be exercised when treating the elderly and patients with diabetes, and particular attention paid with respect to occurrence of infections.
The risks and benefits of ritlecitinib treatment should be considered prior to initiating or continuing therapy in patients with a known malignancy other than a successfully treated NMSC or cervical cancer.
Periodic skin examination is recommended for patients who are at increased risk of skin cancer.
Long-term safety evaluations for ritlecitinib are ongoing. Ritlecitinib should be used with caution in patients with known risk factors for thromboembolism. In patients with a suspected thromboembolic event, discontinuation of ritlecitinib and prompt re-evaluation is recommended. The risks and benefits of ritlecitinib treatment should be considered prior to initiating therapy in patients.
There are no or limited data from the use of ritlecitinib in pregnant women. Studies in animals have shown reproductive toxicity. Ritlecitinib was teratogenic in rats and rabbits at high doses. Ritlecitinib is contraindicated during pregnancy.
Available pharmacodynamic/toxicological data in animals have shown excretion of ritlecitinib in milk. A risk to newborns/infants cannot be excluded. Ritlecitinib is contraindicated during breast-feeding.
Ritlecitinib is not recommended in women of childbearing potential not using contraception. Women of childbearing potential have to use effective contraception during treatment and for 1 month following the final dose of ritlecitinib.
The effect of ritlecitinib on human fertility has not been evaluated. There were no effects on fertility in rats at clinically relevant exposures.
Ritlecitinib has no or negligible influence on the ability to drive and use machines.
The most frequently reported adverse reactions are diarrhoea (9.2%), acne (6.2%), upper respiratory tract infections (6.2%), urticaria (4.6%), rash (3.8%), folliculitis (3.1%), and dizziness (2.3%).
A total of 1630 patients were treated with ritlecitinib in placebo-controlled studies of alopecia areata representing 2303 patient-years of exposure. Three placebo-controlled studies were integrated (130 participants on 50 mg daily and 213 participants on placebo) to evaluate the safety of ritlecitinib in comparison to placebo for up to 24 weeks after treatment initiation.
The table below lists all adverse reactions observed in alopecia areata placebo-controlled studies presented by system organ class and frequency, using the following categories: 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Adverse reactions:
| System organ class | Common | Uncommon |
|---|---|---|
| Infections and infestations | Herpes zoster Folliculitis Upper respiratory tract infections | |
| Nervous system disorders | Dizziness | |
| Gastrointestinal disorders | Diarrhoea | |
| Skin and subcutaneous tissue disorders | Acne Urticaria Rash | |
| Investigations | Blood creatine phosphokinase increased | Platelet count decreased Lymphocyte count decreased Alanine aminotransferase increased ˃3 × ULNa Aspartate aminotransferase increased ˃3 × ULNa |
a Includes changes detected during laboratory monitoring
In the placebo-controlled studies, for up to 24 weeks, overall infections have been reported in 31% of patients (80.35 per 100 patient-years) treated with placebo and 33% of patients (74.53 per 100 patient-years) treated with ritlecitinib 50 mg. In study AA-I, for up to 48 weeks, overall infections were reported in 51% of patients (89.32 per 100 patient-years) treated with ritlecitinib 50 mg or higher.
Among all patients treated with ritlecitinib in the integrated safety analysis, including the long-term study and a study in vitiligo, overall infections were reported in 45.4% of patients (50.02 per 100 patient-years) treated with ritlecitinib 50 mg or higher. Most infections were mild or moderate in severity.
In the placebo-controlled studies the percentage of patients reporting infection-related adverse reaction of herpes zoster were 1.5% in the ritlecitinib 50 mg group compared to 0 in placebo. All herpes zoster events were non-serious; 1 patient receiving ritlecitinib 200/50 mg (200 mg once daily for 4 weeks followed by 50 mg once daily) experienced an event of varicella zoster virus infection that met criteria as an opportunistic infection (multi-dermatomal herpes zoster). In study AA-I, for up to 48 weeks, 2.3% of patients (2.61 per 100 patient-years) treated with ritlecitinib 50 mg or higher reported herpes zoster Among all patients treated with ritlecitinib in the integrated safety analysis, including the long-term study and a study in vitiligo, the rate of herpes zoster was 1.10 per 100 patient-years in patients treated with ritlecitinib 50 mg or higher.
In the placebo-controlled studies, for up to 24 weeks, no serious infections were reported in patients treated with placebo or ritlecitinib 50 mg. The proportion and rate of serious infections in patients treated with ritlecitinib 200/50 mg was 0.9% (2.66 per 100 patient-years). In study AA-I, for up to 48 weeks, serious infections were reported in 0.8% of patients (0.86 per 100 patient-years) treated with ritlecitinib 50 mg or higher. Among all patients treated with ritlecitinib in the integrated safety analysis, including the long-term study and a study in vitiligo, the proportion and rate of serious infection in ritlecitinib 50 mg or higher was 0.8% (0.59 per 100 patient-years).
Opportunistic infections of multi-dermatomal herpes zoster were reported in 1 patient (0.50 per 100 patient-years) treated with ritlecitinib 200/50 mg in the placebo-controlled studies, no patients in study AA-I, for up to 48 weeks, and 2 patients (0.09 per 100 patient-years) treated with ritlecitinib 50 mg or higher in the integrated safety analysis, including the long-term study and a study in vitiligo. Cases of opportunistic herpes zoster were mild or moderate in severity.
In the placebo-controlled studies, for up to 24 weeks, and study AA-I, for up to 48 weeks, treatment with ritlecitinib was associated with a decrease in lymphocyte count. Maximum effects on lymphocytes were observed within 4 weeks, after which lymphocyte count remained stable at a lower level with continued therapy. Among all patients treated with ritlecitinib in the integrated safety analysis, including the long-term study and a study in vitiligo, confirmed ALC <0.5 × 103/mm³ occurred in 2 participants (<0.1%) treated with ritlecitinib 50 mg.
In the placebo-controlled studies, for up to 24 weeks, and study AA-I, for up to 48 weeks, treatment with ritlecitinib was associated with a decrease in platelet count. Maximum effects on platelets were observed within 4 weeks, after which platelet count remained stable at a lower level with continued therapy. Among all patients treated with ritlecitinib in the integrated safety analysis, including the long-term study and a study in vitiligo, 1 patient (<0.1%) treated with ritlecitinib 50 mg or higher had a confirmed platelet count <100 × 103/mm³.
In the placebo-controlled studies, for up to 24 weeks, events of blood CPK increased were reported in 2 patients (1.5%) treated with ritlecitinib 50 mg. In study AA-I, for up to 48 weeks, events of blood CPK increased were reported in 3.8% of patients treated with ritlecitinib 50 mg or higher. CPK elevations >5x upper limit of normal (ULN) were reported in 2 (0.9%) of patients treated with placebo and 5 (3.9%) of patients treated with ritlecitinib 50 mg. In study AA-I, for up to 48 weeks, CPK elevations >5x ULN were reported in 6.6% of patients treated with ritlecitinib 50 mg or higher. Most elevations were transient and none led to discontinuation.
In the placebo-controlled studies, for up to 24 weeks, events of increases in ALT and AST values (>3 × ULN) were reported in 3 patients (0.9%) and 2 patients (0.6%) treated with ritlecitinib 50 mg or higher, respectively. Most elevations were transient, and none led to discontinuation.
A total of 181 adolescents (12 to <18 years of age) were enrolled in ritlecitinib alopecia areata placebo-controlled studies.
The safety profile observed in adolescents was similar to that of the adult population.
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