Adverse reactions : תופעות לוואי

4.8     Undesirable effects

Summary of the safety profile
In placebo-controlled studies in RA patients, the most frequently reported adverse reactions with Kineret 100 mg solution for injection were injection site reactions (ISRs), which were mild to moderate in the majority of patients. The most common reason for withdrawal from study in Kineret 100 mg solution for injection -treated RA patients was injection site reaction. The subject incidence of serious adverse reactions in RA studies at the recommended dose of Kineret 100 mg solution for injection (100 mg/day) was comparable with placebo (7.1% compared with 6.5% in the placebo group). The incidence of serious infection was higher in Kineret 100 mg solution for injection -treated patients compared to patients receiving placebo (1.8% vs. 0.7%). Neutrophil decreases occurred more frequently in patients receiving Kineret 100 mg solution for injection compared with placebo.

Adverse reactions data in CAPS patients are based on an open-label study of 43 patients with NOMID/CINCA treated with Kineret 100 mg solution for injection for up to 5 years, with a total Kineret 100 mg solution for injection exposure of 159.8 patient years. During the 5-year study, 14 patients (32.6%) reported 24 serious events. Eleven serious events in four (9.3%) patients were considered related to Kineret 100 mg solution for injection. No patient withdrew from Kineret 100 mg solution for injection treatment due to adverse reactions.


Adverse events data in patients with FMF are based on post-marketing adverse event reports and published studies.

There are no indications either from these studies or from post-marketing adverse reaction reports that the overall safety profile in patients with CAPS, FMF or Still’s disease is different from that in patients with RA, with the exception of post-marketing observation of a higher frequency of reported hepatic events in patients with Still’s disease. The adverse reactions table below therefore applies to Kineret treatment of RA, CAPS, FMF and Still’s disease. During long term treatment of RA, CAPS, and Still’s disease the safety profile remains unchanged over time.

Tabulated list of adverse reactions
Adverse reactions are listed according to MedDRA system organ class and frequency category.
Frequency categories are defined using the following convention: 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); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

MedDRA Organ System              Frequency                              Undesirable Effect Infections and infestations      Common (≥ 1/100 to < 1/10)             Serious infections Blood and lymphatic system       Common (≥ 1/100 to < 1/10)             Neutropenia disorders                                                               Thrombocytopenia Immune system disorders          Uncommon (≥ 1/1,000 to < 1/100)        Allergic reactions including anaphylactic reactions,
angioedema, urticaria and pruritus
Nervous system disorders         Very common (≥ 1/10)                   Headache Hepatobiliary disorders          Uncommon (≥ 1/1,000 to < 1/100)        Hepatic enzyme increased Not known                              Non-infectious hepatitis
(cannot be estimated from the available data)
General disorders and            Very common (≥ 1/10)                   Injection site reaction administration site conditions
Skin and subcutaneous tissue     Uncommon (≥ 1/1,000 to < 1/100)        Rash disorders                        Not known (cannot be estimated         Injection site amyloid deposits from the available data)
Investigations                   Very common (≥ 1/10)                   Blood cholesterol increased 
Serious infections
The incidence of serious infections in RA studies conducted at the recommended dose (100 mg/day) was 1.8% in Kineret 100 mg solution for injection treated patients and 0.7% in placebo-treated patients. In observations up to 3 years, the serious infection rate remained stable over time. The infections observed consisted primarily of bacterial events such as cellulitis, pneumonia, and bone and joint infections. Most patients continued on study medicinal product after the infection resolved.

In a study with 43 CAPS patients followed for up to 5 years the frequency of serious infections was 0.1/year, the most common being pneumonia and gastroenteritis. Kineret 100 mg solution for injection was temporarily stopped in one patient, all other patients continued Kineret 100 mg solution for injection treatment during the infections.


In a study with 15 SJIA patients followed for up to 1.5 years, one patient developed a serious hepatitis in connection with a cytomegalovirus infection. There are no indications from post- marketing adverse event reports and published studies that types and severity of infections in patients with FMF differ from those in RA, Still’s or CAPS disease.
In clinical studies and during post-marketing use, rare cases of opportunistic infections have been observed and have included fungal, mycobacterial, bacterial, and viral pathogens. Infections have been noted in all organ systems and have been reported in patients receiving Kineret 100 mg solution for injection alone or in combination with immunosuppressive agents.

Neutropenia
In placebo-controlled RA studies with Kineret 100 mg solution for injection, treatment was associated with small reductions in the mean values for total white blood count and absolute neutrophil count (ANC). Neutropenia (ANC < 1.5 x 109/l) was reported in 2.4% patients receiving Kineret 100 mg solution for injection compared with 0.4% of placebo patients. None of these patients had serious infections associated with the neutropenia.

In a study with 43 CAPS patients followed for up to 5 years neutropenia was reported in 2 patients. Both episodes of neutropenia resolved over time with continued Kineret 100 mg solution for injection treatment.

In a study with 15 SJIA patients followed for up to 1.5 years, one event of transient neutropenia was reported.

Thrombocytopenia
In clinical studies in RA patients, thrombocytopenia has been reported in 1.9% of treated patients compared to 0.3% in the placebo group. The thrombocytopenias have been mild, i.e. platelet counts have been > 75 x109/l. Mild thrombocytopenia has also been observed in CAPS patients.

During post-marketing use of Kineret, thrombocytopenia has been reported, including occasional case reports indicating severe thrombocytopenia (i.e. platelet counts <10 x109/l).

Allergic reactions
Allergic reactions including anaphylactic reactions, angioedema, urticaria, rash, and pruritus have been reported uncommonly with Kineret. The majority of these reactions were maculopapular or urticarial rashes.

In a study with 43 CAPS patients followed for up to 5 years, no allergic event was serious and no event required discontinuation of Kineret 100 mg solution for injection treatment.

In a study with 15 SJIA patients followed for up to 1.5 years, no allergic event was serious and no event required discontinuation of Kineret.

In a study with 12 FMF patients treated 4 months with Kineret 100 mg solution for injection in a published randomized controlled study no allergic event was reported as serious and no event required discontinuation of Kineret.

Immunogenicity
In clinical trials in RA, up to 3% of adult patients tested seropositive at least once during the study for neutralizing anti-anakinra antibodies. The occurrence of antibodies was typically transient and not associated with clinical adverse reactions or diminished efficacy. In addition, in a clinical trial 6% of 86 paediatric patients with JIA, whereof none of the 15 SJIA subtype patients, tested seropositive at least once during the study for neutralizing anti-anakinra antibodies.
The majority of CAPS patients in Study 03-AR-0298 developed anakinra anti-drug antibodies.
This was not associated with any clinically significant effects on pharmacokinetics, efficacy, or safety.

Hepatic Events
In clinical studies transient elevations of liver enzymes have been seen. These elevations have not been associated with signs or symptoms of hepatocellular damage, except for one patient with SJIA that developed serious hepatitis in connection with a cytomegalovirus infection.

During post-marketing use isolated case reports indicating non-infectious hepatitis have been received.
Hepatic events during post-marketing use have mainly been reported in patients that have been treated for Still’s disease and in patients with predisposing factors, e.g. a history of transaminase elevations before start of Kineret treatment.

Injection site reactions
ISRs typically appear within 2 weeks of therapy and disappear within 4-6 weeks. The development of ISRs in patients who had not previously experienced ISRs was uncommon after the first month of therapy.

In RA patients the most common and consistently reported treatment-related adverse reactions associated with Kineret 100 mg solution for injection were ISRs. The majority (95%) of ISRs were reported as mild to moderate. These were typically characterised by one or more of the following: erythema, ecchymosis, inflammation, and pain. At a dose of 100 mg/day, 71% of RA patients developed an ISR compared to 28% of the placebo treated patients.

In a study with 43 CAPS patients followed for up to 5 years no patient permanently or temporarily discontinued Kineret 100 mg solution for injection treatment due to injection site reactions.

In a study with 15 SJIA patients followed for up to 1.5 years, the most common and consistently reported treatment-related adverse reactions associated with Kineret treatment were ISRs. One out of the 15 patients discontinued due to ISRs.

In patients with FMF the types and frequencies of ISRs are similar to those seen in RA and SJIA.
Discontinuations due to ISRs have occurred also in patients with FMF.

Injection site amyloid deposits
During post-marketing use, isolated cases of injection site amyloid deposits have been reported in patients with NOMID/CINCA who received high doses of Kineret injected subcutaneously into the same area of skin over long periods of time. Rotation of injection sites is therefore recommended.

Blood cholesterol increase
In clinical studies of RA, 775 patients treated with daily Kineret 100 mg solution for injection doses of 30 mg, 75 mg, 150 mg, 1 mg/kg or 2 mg/kg, there was an increase of 2.4% to 5.3% in total cholesterol levels 2 weeks after start of Kineret 100 mg solution for injection treatment, without a dose-response relationship. A similar pattern was seen after 24 weeks Kineret 100 mg solution for injection treatment. Placebo treatment (n=213) resulted in a decrease of approximately 2.2% in total cholesterol levels at week 2 and 2.3% at week 24. No data are available on LDL or HDL cholesterol.
Paediatric population
Kineret 100 mg solution for injection has been studied in 36 CAPS patients, 21 SJIA patients and 71 patients with other forms of JIA, aged 8 months to <18 years, for up to 5 years. With the exception of infections and related symptoms that were more frequently reported in patients <2 years of age, the safety profile was similar in all paediatric age groups. The safety profile in paediatric patients was similar to that seen in adult populations and no clinically relevant new adverse reactions were seen.

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