Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions with baricitinib are increased LDL cholesterol (26.0 %), upper respiratory tract infections (16.9 %), headache (5.2 %), herpes simplex (3.2 %), and urinary tract infections (2.9 %). Serious pneumonia and serious herpes zoster occurred uncommonly in patients with rheumatoid arthritis.

Tabulated list of adverse reactions

Frequency estimate: 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). The frequencies in Table 2 are based on integrated data from clinical trials in adults and/or postmarketing setting across rheumatoid arthritis, atopic dermatitis, and alopecia areata indications unless stated otherwise; where notable differences in frequency between indications are observed, these are presented in the footnotes below the table.

Table 2. Adverse reactions

System organ        Very common                    Common                      Uncommon class

Infections and      Upper respiratory tract        Herpes zosterb infestations        infections                     Herpes simplex
Gastroenteritis
Urinary tract infections
Pneumoniad
Folliculitisg
Blood and                                          Thrombocytosis              Neutropaenia lymphatic                                          > 600 x 109 cells/La, d     < 1 x 109 cells/La system disorders
Immune system                                                                  Swelling of the face, disorders                                                                      Urticaria Metabolism and      Hypercholesterolaemiaa                                     Hypertriglyceridaemiaa nutrition disorders
Nervous system                                     Headache disorders
Vascular                                                                       Deep vein thrombosisb disorders
Respiratory,                                                                   Pulmonary embolismf thoracic,
mediastinal disorders
Gastrointestinal                                   Nausead                     Diverticulitis disorders                                          Abdominal paind
Hepatobiliary                                      ALT increased               AST increased ≥ 3 x ULNa, e disorders                                          ≥ 3 x ULNa, d
Skin and                                           Rash subcutaneous                                       Acnec tissue disorders
Investigations                                  Creatine phosphokinase      Weight increased increased > 5 x ULNa, c a
Includes changes detected during laboratory monitoring (see text below).
b
Frequency for herpes zoster and deep vein thrombosis is based on rheumatoid arthritis clinical trials.

c
In rheumatoid arthritis clinical trials, the frequency of acne and creatine phosphokinase increased > 5 x ULN was uncommon.
d
In atopic dermatitis clinical trials, the frequency of nausea, and ALT ≥3 x ULN was uncommon. In alopecia areata clinical trials, the frequency of abdominal pain was uncommon. In atopic dermatitis and alopecia areata clinical trials, the frequency of pneumonia and thrombocytosis > 600 x 109 cells/L was uncommon.
e
In alopecia areata clinical trials, the frequency of AST ≥ 3 x ULN was common.
f
Frequency for pulmonary embolism is based on rheumatoid arthritis and atopic dermatitis clinical trials.
g
Folliculitis was observed in alopecia areata clinical trials. It was usually localized in the scalp region associated with hair regrowth.

Description of selected adverse reactions

Gastrointestinal disorders
In rheumatoid arthritis clinical studies, in treatment-naïve patients, through 52 weeks, the frequency of nausea was greater for the combination treatment of methotrexate and baricitinib (9.3 %) compared to methotrexate alone (6.2 %) or baricitinib alone (4.4 %). In the integrated data from rheumatoid arthritis, atopic dermatitis and alopecia areata clinical trials, nausea was most frequent during the first 2 weeks of treatment.

Cases of abdominal pain were usually mild, transient, not associated with infectious or inflammatory gastrointestinal disorders, and did not lead to treatment interruption.

Infections
In the integrated data from rheumatoid arthritis, atopic dermatitis and alopecia areata clinical trials, most infections were mild to moderate in severity. In studies which included both doses, infections were reported in 31.0 %, 25.7 % and 26.7 % of patients in the 4 mg, 2 mg and placebo groups, respectively. In rheumatoid arthritis clinical studies, combination with methotrexate resulted in increased frequency of infections compared to baricitinib monotherapy. Frequency of herpes zoster was common in rheumatoid arthritis, very rare in atopic dermatitis and uncommon in alopecia areata.
In atopic dermatitis clinical trials, there were less skin infections requiring antibiotic treatment with baricitinib than with placebo.

The incidence of serious infections with baricitinib was similar to placebo. The incidence of serious infections remained stable during long term exposure. The overall incidence rate of serious infections in the clinical trial programme was 3.2 per 100 patient-years in rheumatoid arthritis, 2.1 in atopic dermatitis and 0.8 in alopecia areata. Serious pneumonia and serious herpes zoster occurred uncommonly in patients with rheumatoid arthritis.

Hepatic transaminase elevations
Dose dependent increases in blood ALT and AST activity were reported in studies extended over week 16. Elevations in mean ALT/AST remained stable over time. Most cases of hepatic transaminase elevations ≥ 3 x ULN were asymptomatic and transient.

In patients with rheumatoid arthritis, the combination of baricitinib with potentially hepatotoxic medicinal products, such as methotrexate, resulted in increased frequency of these elevations.

Lipid elevations
In the integrated data from rheumatoid arthritis, atopic dermatitis and alopecia areata clinical trials, baricitinib treatment was associated with dose-dependent increases in lipid parameters including total cholesterol, LDL cholesterol, and high density lipoprotein (HDL) cholesterol. There was no change in the LDL/HDL ratio. Elevations were observed at 12 weeks and remained stable thereafter at a higher value than baseline including in the long-term extension study in rheumatoid arthritis. Mean total and LDL cholesterol increased through week 52 in patients with atopic dermatitis and alopecia areata. In rheumatoid arthritis clinical trials, baricitinib treatment was associated with dose-dependent increases in triglycerides. There was no increase in triglycerides levels in atopic dermatitis and alopecia areata clinical trials.

Elevations in LDL cholesterol decreased to pre-treatment levels in response to statin therapy.

Creatine phosphokinase (CPK)
Baricitinib treatment was associated with dose-dependent increases in CPK. Mean CPK was increased at week 4 and remained at a higher value than baseline thereafter. Across indications, most cases of CPK elevations > 5 x ULN were transient and did not require treatment discontinuation.

In clinical trials, there were no confirmed cases of rhabdomyolysis.

Neutropaenia
Mean neutrophil counts decreased at 4 weeks and remained stable at a lower value than baseline over time. There was no clear relationship between neutropaenia and the occurrence of serious infections.
However, in clinical studies, treatment was interrupted in response to ANC < 1 x 109 cells/L.

Thrombocytosis
Dose-dependent increases in mean platelet counts were observed and remained stable at a higher value than baseline over time.

Paediatric population

Juvenile idiopathic arthritis
A total of 220 patients from 2 to less than 18 years of age were exposed to any dose of baricitinib in the juvenile idiopathic arthritis clinical trial programme, representing 326 patient years’ exposure.

In paediatric patients treated with baricitinib in the placebo-controlled double-blind randomised withdrawal period of the juvenile idiopathic arthritis clinical trial (n=82), headache was very common (11 %), neutropenia < 1000 cells/mm3 was common (2.4 %, one patient) and pulmonary embolism was common (1.2 %, one patient).

Paediatric atopic dermatitis
The safety assessment in children and adolescents is based on the safety data of the phase III trial BREEZE-AD-PEDS in which 466 patients between 2 and 18 years of age received any dose of baricitinib. Overall, the safety profile in these patients was comparable to that observed in the adult population. Neutropaenia (< 1 x 109 cells/L) was more common (1.7%) compared to adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il