Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Swedish Orphan Biovitrum AB (publ), SE-112 76 Stockholm, Sweden
Hypersensitivity to the active substance or to to any of the excipients listed in section 6.1 or to E. coli derived proteins.
Kineret treatment must not be initiated in patients with neutropenia (ANC <1.5 × 109/l) (see section 4.4).
Allergic reactions, including anaphylactic reactions and angioedema have been reported uncommonly. The majority of these reactions were maculopapular or urticarial rashes.
If a severe allergic reaction occurs, administration of Kineret should be discontinued and appropriate treatment initiated.
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 a serious hepatitis in connection with a cytomegalovirus infection.
During post-marketing use hepatic events, not affecting liver function, have been reported. The majority of patients have been treated for Still’s disease or have had predisposing factors, e.g. a history of transaminase elevations. In addition cases of non-infectious hepatitis, including occasional events of acute liver failure, have been reported in patients with Still’s disease during Kineret treatment.
Hepatic events in patients with Still’s disease predominantly occur during the first month of Kineret treatment. Routine testing of hepatic enzymes during the first month should be considered, especially if the patient has pre-disposing factors or develops symptoms indicating liver dysfunction.
The efficacy and safety of Kineret in patients with AST/ALT ≥1.5 x upper level of normal have not been evaluated.
Kineret has been associated with an increased incidence of serious infections (1.8%) vs. placebo (0.7%) in RA patients. For a small number of patients with asthma, the incidence of serious infection was higher in Kineret-treated patients (4.5%) vs. placebo-treated patients (0%), these infections were mainly related to the respiratory tract.
The safety and efficacy of Kineret treatment in patients with chronic and serious infections have not been evaluated.
Kineret treatment should not be initiated in patients with active infections. Kineret treatment should be discontinued in RA patients if a serious infection develops. In Kineret treated CAPS patients, there is a risk for disease flares when discontinuing Kineret treatment. With careful monitoring, Kineret treatment can be continued also during a serious infection.
Macrophage activation syndrome (MAS) is a known, life-threatening disorder that may develop in patients with Still’s disease. If MAS occurs, or is suspected, evaluation and treatment should be started as early as possible. Physicians should be attentive to symptoms of infection or worsening of Still’s disease, as these are known triggers for MAS. Available data is limited regarding whether Kineret can be continued during serious infections in patients with Still’s disease. If Kineret treatment is continued during serious infections to reduce the risk for a disease flare, careful monitoring is required.
During post-marketing use case reports of MAS in Kineret treated patients with Still’s disease have been received. Patients with Still’s disease have an increased risk of spontaneous development of MAS. A causal relationship between Kineret and MAS has not been established.
Physicians should exercise caution when administering Kineret to patients with a history of recurring infections or with underlying conditions which may predispose them to infections.
The safety of Kineret in individuals with latent tuberculosis is unknown. There have been reports of tuberculosis in patients receiving several biological anti-inflammatory treatment regimens. Patients should be screened for latent tuberculosis prior to initiating Kineret. The available medical guidelines should also be taken into account.
Other anti-rheumatic therapies have been associated with hepatitis B reactivation. Therefore, screening for viral hepatitis should be performed in accordance with published guidelines also before starting therapy with Kineret.
Kineret is eliminated by glomerular filtration and subsequent tubular metabolism. Consequently plasma clearance of Kineret decreases with decreasing renal function.
No dose adjustment is needed for patients with mild renal impairment (CLcr 60 to 89 ml/min). Kineret should be used with caution in patients with moderate renal impairment (CLcr 30 to 59 ml/min). In patients with severe renal impairment (CLcr <30 ml/min) or end stage renal disease, including dialysis, administration of the prescribed dose of Kineret every other day should be considered.
Kineret was commonly associated with neutropenia (ANC <1.5 × 109/l) in placebo-controlled studies in RA and cases of neutropenia have been observed in patients with CAPS and Still’s disease. For more information on neutropenia see section 4.8. Kineret treatment should not be initiated in patients with neutropenia (ANC <1.5 × 109/l). It is recommended that neutrophil counts be assessed prior to initiating Kineret treatment, and while receiving Kineret, monthly during the first 6 months of treatment and quarterly hereafter. In patients who become neutropenic (ANC <1.5 × 109/l) the ANC should be monitored closely and Kineret treatment should be discontinued. The safety and efficacy of Kineret in patients with neutropenia have not been evaluated.
During post-marketing use events of interstitial lung disease, pulmonary alveolar proteinosis and pulmonary hypertension have been reported mainly in paediatric patients with Still’s disease treated with IL-6 and IL-1 inhibitors, including Kineret. Patients with trisomy 21 seem to be overrepresented. A causal relationship with Kineret has not been established.
The impact of treatment with Kineret on pre-existing malignancy has not been studied. Therefore the use of Kineret in patients with pre-existing malignancy is not recommended.
RA patients may be at a higher risk (on average 2-3 fold) for the development of lymphoma. In clinical trials, whilst patients treated with Kineret had a higher incidence of lymphoma than the expected rate in the general population, this rate is consistent with rates reported in general for RA patients.
In clinical trials, the crude incidence rate of malignancy was the same in the Kineret-treated patients and the placebo-treated patients and did not differ from that in the general population. Furthermore, the overall incidence of malignancies was not increased during 3 years of patient exposure to Kineret.
In a placebo-controlled clinical trial (n=126), no difference was detected in anti-tetanus antibody response between the Kineret and placebo treatment groups when a tetanus/diphtheria toxoid vaccine was administered concurrently with Kineret. No data are available on the effects of vaccination with other inactivated antigens in patients receiving Kineret.
No data are available on either the effects of live vaccination or on the secondary transmission of infection by live vaccines in patients receiving Kineret. Therefore, live vaccines should not be given concurrently with Kineret.
A total of 752 RA patients ≥65 years of age, including 163 patients ≥75 years of age, were studied in clinical trials. No overall differences in safety or effectiveness were observed between these patients and younger patients. There is limited experience in treating elderly CAPS and Still’s disease patients. Because there is a higher incidence of infections in the elderly population in general, caution should be used in treating elderly patients.
Concurrent administration of Kineret and etanercept has been associated with an increased risk of serious infections and neutropenia compared to etanercept alone in RA patients. This treatment combination has not demonstrated increased clinical benefit.
The concurrent administration of Kineret and etanercept or other TNF-α antagonists is not recommended (see section 4.5).
This medicinal product contains less than 1 mmol sodium (23 mg) per 100 mg dose, that is to say essentially ‘sodium-free’.
Interactions between Kineret and other medicinal products have not been investigated in formal studies. In clinical trials, interactions between Kineret and other medicinal products (including nonsteroidal anti-inflammatory medicinal products, glucocorticoids, and DMARDs) have not been observed.
In a clinical trial with RA patients receiving background methotrexate, patients treated with Kineret and etanercept were observed to have a higher rate of serious infections (7%) and neutropenia than patients treated with etanercept alone and higher than observed in previous trials where Kineret was used alone. Concurrent Kineret and etanercept treatment has not demonstrated increased clinical benefit.
The concurrent use of Kineret with etanercept or any other TNF-α antagonist is not recommended (see section 4.4).
The formation of CYP450 enzymes is suppressed by increased levels of cytokines (e.g., IL-1) during chronic inflammation. Thus, it may be expected that for an IL-1 receptor antagonist, such as anakinra, the formation of CYP450 enzymes could be normalized during treatment. This would be clinically relevant for CYP450 substrates with a narrow therapeutic index (e.g. warfarin and phenytoin). Upon start or end of Kineret treatment in patients on these types of medicinal products, it may be relevant to consider therapeutic monitoring of the effect or concentration of these products and the individual dose of the medicinal product may need to be adjusted.
For information on vaccinations see section 4.4.
There are limited amount of data from the use of anakinra in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of anakinra during pregnancy and in woman of childbearing potential not using contraception.
It is unknown whether anakinra/metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with Kineret.
Not relevant.
In placebo-controlled studies in RA patients, the most frequently reported adverse reactions with Kineret 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-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/day) was comparable with placebo (7.1% compared with 6.5% in the placebo group). The incidence of serious infection was higher in Kineret-treated patients compared to patients receiving placebo (1.8% vs. 0.7%). Neutrophil decreases occurred more frequently in patients receiving Kineret 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 for up to 5 years, with a total Kineret exposure of 159.8 patient years. During the 5-year study 14 patients (32.6%) reported 24 serious events. Eleven serious events in 4 (9.3%) patients were considered related to Kineret. No patient withdrew from Kineret treatment due to adverse reactions.
Adverse events data in patients with Still’s disease is based on a partially open-label and partially blinded, placebo-controlled study of 15 SJIA patients, treated for up to 1.5 years. In addition, postmarketing adverse event reports and published studies constitute supporting data.
There are no indications either from this study or from post-marketing adverse reaction reports that the overall safety profile in patients with CAPS or Still’s disease is different from that in patients with RA, with the exception of the risk for development of MAS in patients with Still’s disease. The adverse reactions table below therefore applies to Kineret treatment of RA, CAPS and Still’s disease. Additional information on MAS is provided below.
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.
Common (≥1/100 to <1/10): Serious infections
Common (≥1/100 to <1/10): Neutropenia, Thrombocytopenia
Uncommon (≥1/1,000 to <1/100): Allergic reactions including anaphylactic reactions, angioedema, urticaria and pruritus
Very common (≥1/10): Headache
Uncommon (≥1/1,000 to <1/100): Hepatic enzyme increased
Not known (cannot be estimated from the available data): Non-infectious hepatitis
Very common (≥1/10): Injection site reaction
Uncommon (≥1/1,000 to <1/100): Rash
Very common (≥1/10): Blood cholesterol increased
The incidence of serious infections in RA studies conducted at the recommended dose (100 mg/day) was 1.8% in Kineret 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 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 was temporarily stopped in one patient, all other patients continued Kineret treatment during the infections.
In 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 experience that types and severity of infections in patients with Still’s disease differ from those in RA or CAPS patients.
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 alone or in combination with immunosuppressive agents.
In placebo-controlled RA studies with Kineret, treatment was associated with small reductions in the mean values for total white blood count and absolute neutrophil count (ANC). Neutropenia (ANC <1.5 × 109/l) was reported in 2.4% patients receiving Kineret compared with 0.4% of placebo patients. None of these patients had serious infections associated with the neutropenia.
In 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 treatment.
In 15 SJIA patients followed for up to 1.5 years, one event of transient neutropenia was reported.
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 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 43 CAPS patients followed for up to 5 years, no allergic event was serious and no event required discontinuation of Kineret treatment.
In 15 SJIA patients followed for up to 1.5 years, no allergic event was serious and no event required discontinuation of Kineret.
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.
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.
In RA patients the most common and consistently reported treatment-related adverse reactions associated with Kineret were ISRs. The majority (95%) of ISRs were reported as mild to moderate. These were typically characterised by 1 or more of the following: erythaema, 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 43 CAPS patients followed for up to 5 years no patient permanently or temporarily discontinued Kineret treatment due to 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 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 clinical studies of RA, 775 patients treated with daily Kineret 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 treatment, without a dose-response relationship. A similar pattern was seen after 24 weeks Kineret 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.
Kineret has been studied in 36 CAPS patients, 15 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 suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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