Adverse reactions : תופעות לוואי

4.8     Undesirable effects

Summary of the safety profile

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%).

Tabulated list of adverse reactions

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.

Table 2 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.

Table 2.    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                Acne disorders                                   Urticaria
Rash
Investigations                              Blood creatine phosphokinase   Platelet count decreased increased                      Lymphocyte count decreased
Alanine aminotransferase increased ˃ 3 × ULNa
Aspartate aminotransferase increased ˃ 3 × ULNa a.    Includes changes detected during laboratory monitoring

Description of selected adverse reactions

Infections

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
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.

Decreased lymphocyte count
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.

Decreased platelet count
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.

Creatine phosphokinase (CPK) elevations
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.

Increased transaminases
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.

Paediatric population

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.

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. Any suspected adverse event should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/