Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions are nausea (15.1%), headache (7.9%), acne (4.8%), herpes simplex (4.2%), blood creatine phosphokinase increased (3.8%), vomiting (3.5%), dizziness (3.4%) and abdominal pain upper (2.2%). The most frequent serious adverse reactions are infections (0.3%) (see section 4.4).

Tabulated list of adverse reactions

A total of 3,848 patients were treated with abrocitinib in clinical studies in atopic dermatitis. Among them 3,050 patients (representing 5,166 patient-years of exposure) were integrated for safety analysis. The integrated safety analysis included 1,997 patients receiving a constant dose of abrocitinib 200 mg and 1,053 patients receiving a constant dose of 100 mg. There were 2,013 patients with at least 48 weeks of exposure. Five placebo-controlled studies were integrated (703 patients on 100 mg once daily, 684 patients on 200 mg once daily and 438 patients on placebo) to evaluate the safety of abrocitinib in comparison to placebo for up to 16 weeks.

Listed in Table 2 are adverse reactions observed in atopic dermatitis clinical 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                       Very common                  Common                         Uncommon Infections and infestations                                     Herpes simplexa                 Pneumonia Herpes zosterb
Blood and lymphatic system                                                                      Thrombocytopenia disorders                                                                                       Lymphopenia Metabolism and nutrition                                                                        Hyperlipidaemiac disorders
Nervous system disorders                                        Headache Dizziness
Vascular disorders                                                                              Venous thromboembolismd
Gastrointestinal disorders             Nausea                   Vomiting Abdominal pain upper
Skin and subcutaneous tissue                                    Acne disorders
Investigations                                                  Creatine phosphokinase increased ˃ 5 × ULNe a.   Herpes simplex includes oral herpes, ophthalmic herpes simplex, genital herpes, and herpes dermatitis.
b.   Herpes zoster includes ophthalmic herpes zoster.
c.   Hyperlipidaemia includes dyslipidaemia and hypercholesterolaemia.
d.   Venous thromboembolism includes pulmonary embolism and deep vein thrombosis.
e.   Includes changes detected during laboratory monitoring (see text below).

Description of selected adverse reactions

Infections
In placebo-controlled studies, for up to 16 weeks, infections have been reported in 27.4% of patients treated with placebo and in 34.9% and 34.8% of patients treated with abrocitinib 100 mg and 200 mg, respectively. Most infections were mild or moderate. The percentage of patients reporting infection-related adverse reactions in the 200 mg and 100 mg groups compared to placebo were: herpes simplex (4.2% and 2.8% versus 1.4%), herpes zoster (1.2% and 0.6% versus 0%), pneumonia (0.1% and 0.1% versus 0%). Herpes simplex was more frequent in patients with a history of herpes simplex or eczema herpeticum. Most of the herpes zoster events involved a single dermatome and were non-serious. Most opportunistic infections were cases of herpes zoster (0.70 per 100 patient-years in the abrocitinib 100 mg group and 0.96 per 100 patient-years in the abrocitinib 200 mg group), most of which were non- serious multidermatomal cutaneous infections. Among all patients treated in clinical studies with consistent dosing regimens of either abrocitinib 100 mg or 200 mg, including the long-term extension study, the incidence rate of herpes zoster in patients treated with abrocitinib 200 mg (4.36 per 100 patient-years) was higher than that of patients treated with 100 mg (2.61 per 100 patient-years). Incidence rates for herpes zoster were also higher for patients 65 years of age and older (HR 1.76), patients with a medical history of herpes zoster (HR 3.41), patients with severe atopic dermatitis at baseline (HR 1.17), and a confirmed ALC < 1.0 × 103/mm3 prior to the event of herpes zoster (HR 2.18) (see section 4.4).

In placebo-controlled studies, for up to 16 weeks, the rate of serious infections was 1.81 per 100 patient-years in patients treated with placebo, 3.32 per 100 patient-years in patients treated with 100 mg, and 1.12 per 100 patient- years in patients treated with 200 mg. Among all patients treated in clinical studies with consistent dosing regimens of either abrocitinib 100 mg or 200 mg, including the long-term extension study, the rate of serious infections was 2.20 per 100 patient-years treated with 100 mg and 2.46 per 100 patient-years treated with 200 mg. The most commonly reported serious infections were herpes simplex, herpes zoster, and pneumonia (see section 4.4).

Venous thromboembolism
Among all patients treated in clinical studies with consistent dosing regimens of either abrocitinib 100 mg or 200 mg, including the long-term extension study, the rate of PE was 0.21 per 100 patient-years for 200 mg and 0.05 per 100 patient-years for 100 mg. The rate of DVT was 0.06 per 100 patient-years in the 200 mg group and 0.05 per 100 patient-years in the 100 mg group (see section 4.4).


Thrombocytopenia
In placebo-controlled studies, for up to 16 weeks, treatment was associated with a dose-related decrease in platelet count. Maximum effects on platelets were observed within 4 weeks, after which the platelet count returned towards baseline despite continued therapy. Confirmed platelet counts of < 50 × 103/mm3 were reported in 0.1% of patients exposed to 200 mg, and in 0 patients treated with 100 mg or placebo. Among all patients treated with clinical studies with consistent dosing regimens of either abrocitinib 100 mg or 200 mg, including the long-term extension study, the rate of confirmed platelet counts of < 50 × 103/mm3 was 0.15 per 100 patients-years for 200 mg and 0 per 100 patient-years for 100 mg, most occurring at Week 4. Patients 65 years of age and older had a higher rate of platelet counts < 75 × 103/mm3 (see section 4.4).

Lymphopenia
In placebo-controlled studies, for up to 16 weeks, confirmed ALC < 0.5 × 103/mm3 occurred in 0.3% of patients treated with 200 mg and 0% of patients treated with 100 mg or placebo. Both cases occurred in the first 4 weeks of exposure. Among all patients treated in clinical studies with consistent dosing regimens of either abrocitinib 100 mg or 200 mg, including the long-term extension, the rate of confirmed ALC < 0.5 × 103/mm3 was 0.34 per 100 patient- years for 200 mg and 0 per 100 patient-years for 100 mg, the highest rate was observed in patients 65 years of age and older (see section 4.4).

Lipid elevations
In placebo-controlled studies, for up to 16 weeks, there was a dose-related increase in low-density lipoprotein cholesterol (LDL-c), total cholesterol, and high-density lipoprotein cholesterol (HDL-c) relative to placebo at Week 4 which remained elevated through the final visit in the treatment period. There was no meaningful change in the LDL/HDL ratio in patients treated with abrocitinib relative to patients treated with placebo. Events related to hyperlipidaemia occurred in 0.4% of patients exposed to abrocitinib 100 mg, 0.6% of patients exposed to 200 mg and 0% of patients exposed to placebo (see section 4.4).

Creatine phosphokinase elevations (CPK)
In placebo-controlled studies, for up to 16 weeks, significant increases in CPK values (> 5 × ULN) occurred in 1.8% of patients treated with placebo, 1.8% of patients treated with 100 mg and 3.8% of patients treated with 200 mg of abrocitinib, respectively. Most elevations were transient and none led to discontinuation.

Nausea
In placebo-controlled studies, for up to 16 weeks, nausea was reported in 1.8% of patients treated with placebo and in 6.3% and 15.1% of patients treated with 100 mg and 200 mg, respectively. Discontinuation due to nausea occurred in 0.4% of patients treated with abrocitinib. Among patients with nausea, 63.5% of patients had onset of nausea in the first week of therapy. The median duration of nausea was 15 days. Most of the cases were mild to moderate in severity.

Paediatric population

A total of 635 adolescent patients (12 to less than 18 years of age) were treated with abrocitinib in clinical studies in atopic dermatitis representing 1,326.1 patient-years of exposure. The safety profile observed in adolescents in atopic dermatitis clinical studies 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/