Kineret 100 mg/0.67 ml solution for injection in pre-filled syringe

Change to section 4.8 - Addition of text on Injection site amyloid deposits

Change to section 4 - Addition of text on Injection site amyloid deposits

Removed the potential risk of MAS

Still’s disease :

The serious skin reaction, DRESS (drug reaction with eosinophilia and systemic symptoms), has rarely been reported in association with Kineret treatment, predominantly in patients with systemic juvenile idiopathic arthritis (SJIA). Seek medical attention immediately if you notice an atypical, widespread rash, which may occur in conjunction with high body temperature and enlarged lymph nodes.

06/08/2021 

addition of the following information to section 4.4:

Drug reaction with eosinophilia and systemic symptoms (DRESS) 

Drug reaction with eosinophilia and systemic symptoms (DRESS) has rarely been reported in patients treated with Kineret, predominantly in patients with systemic juvenile idiopathic arthritis (SJIA). Patients with DRESS may require hospitalization, as this condition may be fatal. If signs and symptoms of DRESS are present and an alternative aetiology cannot be established, Kineret should be discontinued and a different treatment considered. 

revision of text date:06/08/2021 

Familial Mediterranean Fever (FMF)

Kineret is indicated for the treatment of Familial Mediterranean Fever (FMF). Kineret should be given in combination with colchicine, if appropriate.

Update of section 4.4 of the SmPC in order to add a warning on pulmonary events based on post-marketing data. The package leaflet is updated accordingly.

Furthermore, the Sobi took the opportunity to move the text about macrophage activation syndrome (MAS) and malignancies from section 4.8 to 4.4 of the SmPC.

10.       DATE OF REVISION OF THE TEXT

Inserted: 05/10/2017

Deleted: 28^th January 2016

‐filled syringe contains dry natural rubber (a derivative of latex), which may cause

severe allergic reactions.

[Text deleted]

 1/100 to < 1/10) Thrombocytopenia [added]

[Added]

Investigations Very common (

1/10) Blood cholesterol increased

[Added]

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 x10

9/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 x10

9/L).

[Added]

Blood cholesterol increase

In clinical studies of RA, 775 patients treated with daily Kineret doses of 30mg, 75mg, 150mg, 1mg/kg or 2mg/kg, there

was an increase of 2.4% to 5.3% in total cholesterol levels 2 weeks after start of Kineret treatment, without a doseresponse

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.

 The former needle shield of natural rubber is replaced by a synthetic rubber shield, not manufactured using natural rubber latex.

4.1 . Kineret is indicated in adults, adolescents, children and infants aged 8 months and older with a body weight of 10 kg or above for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), including:

-        Neonatal-Onset Multisystem Inflammatory Disease (NOMID) / Chronic Infantile Neurological, Cutaneous, Articular Syndrome (CINCA)

-        Muckle-Wells Syndrome (MWS)

-        Familial Cold Autoinflammatory Syndrome (FCAS)

 4.2

CAPS: Adults, adolescents, children and infants aged 8 months and older with a body weight of 10 kg or above

Starting dose:

The recommended starting dose in all CAPS subtypes is 1-2 mg/kg/day by subcutaneous injection. The therapeutic response is primarily reflected by reduction in clinical symptoms such as fever, rash, joint pain, and headache, but also in inflammatory serum markers (CRP/SAA levels), or occurrence of flares.

Maintenance dose in mild CAPS (FCAS, mild MWS):

Patients are usually well-controlled by maintaining the recommended starting dose (1-2 mg/kg/day).

Maintenance dose in severe CAPS (MWS and NOMID/CINCA):

Dose increases may become necessary within 1-2 months based on therapeutic response. The usual maintenance dose in severe CAPS is 3-4 mg/kg/day, which can be adjusted to a maximum of 8 mg/kg/day.

In addition to the evaluation of clinical symptoms and inflammatory markers in severe CAPS, assessments of inflammation of the CNS, including the inner ear (MRI or CT, lumbar puncture, and audiology) and eyes (ophthalmological assessments) are recommended after an initial 3 months of treatment, and thereafter every 6 months, until effective treatment doses have been identified. When patients are clinically well-controlled, CNS and ophthalmological monitoring may be conducted yearly.

Hepatic Events

In clinical studies in RA and CAPS patients, transient elevations of liver enzymes have been seen uncommonly. These elevations have not been associated with signs or symptoms of hepatocellular damage. 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 with predisposing factors, e.g history of transaminase elevations before start of Kineret treatment.

The efficacy and safety of Kineret in patients with AST/ALT ≥1.5 x upper level of normal have not been evaluated.

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. There are no indications either from this study or from post marketing adverse reaction reports that the overall safety profile in CAPS patients is different from that in RA patients. The adverse reactions table below therefore applies to Kineret treatment both in RA and CAPS patients.

Spontaneous mutations in the CIAS1/NLRP3 gene have been identified in a majority of patients with CAPS. CIAS1/NLRP3 encodes for cryopyrin, a component of the inflammasome. The activated inflammasome results in proteolytic maturation and secretion of IL-1β, which has a broad range of effects including systemic inflammation. Untreated CAPS patients are characterized by increased CRP, SAA and IL-6 relative to normal serum levels. Administration of Kineret results in a decrease in the acute phase reactants and a decrease in IL-6 expression level has been observed. Decreased acute phase protein levels are noted within the first weeks of treatment.

5.1

Clinical efficacy and safety in CAPS

The safety and efficacy of Kineret have been demonstrated in CAPS patients with varying degrees of disease severity. In a clinical study including 43 adult and paediatric patients (36 patients aged 8 months to < 18 years) with severe CAPS (NOMID/CINCA and MWS), a clinical response to anakinra was seen within 10 days after initiation of treatment in all patients and was sustained for up to 5 years with the continued administration of Kineret.

Kineret treatment significantly decreases the manifestations of CAPS, including a reduction in frequently occurring symptoms as fever, rash, joint pain, headache, fatigue, and eye redness. A rapid and sustained decrease in the levels of the inflammatory biomarkers; serum amyloid A (SAA), C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), and a normalization of inflammatory hematological changes are seen. In the severe form of CAPS, long-term treatment improves the systemic inflammatory organ manifestations of the eye, inner ear, and CNS. Hearing and visual acuity did not deteriorate further during anakinra treatment.

Analysis of treatment-emergent AEs classified by presence of CIAS1 mutation showed that there were no major differences between the CIAS1 and non-CIAS1 groups in overall AE reporting rates, 7.4 and 9.2, respectively. Similar rates were obtained for the groups on the SOC level, except for eye disorders with 55 AEs (rate 0.5), whereof 35 ocular hyperemia (which could also be a symptom of CAPS) in the CIAS1 group, and 4 AEs in the non-CIAS1 group (rate 0.1).

Paediatric population

Overall, the efficacy and safety profile of Kineret is comparable in adult and paediatric CAPS patients. 

The European Medicines Agency has waived the obligation to submit the results of studies with Kineret in one or more subsets of the paediatric population in CAPS and RA (JIA) (see section 4.2 for information on paediatric use).

Safety in pediatric RA (JIA) patients

Kineret was studied in a single randomized, blinded multi-center trial in 86 patients with polyarticular course Juvenile Rheumatoid Arthritis (JRA; ages 2-17 years) receiving a dose of 1 mg/kg subcutaneously daily, up to a maximum dose of 100 mg. The 50 patients who achieved a clinical response after a 12-week open-label run-in were randomized to Kineret (25 patients) or placebo (25 patients), administered daily for an additional 16 weeks. A subset of these patients continued open-label treatment with Kineret for up to 1 year in a companion extension study. An adverse event profile similar to that seen in adult RA patients was observed in these studies. These study data are insufficient to demonstrate efficacy and, therefore, Kineret is not recommended for pediatric use in Juvenile Rheumatoid Arthritis.

 

5.2

In general the pharmacokinetics in CAPS patients is similar to that in RA patients. In CAPS patients approximate dose linearity with a slight tendency to higher than proportional increase has been noted. Pharmacokinetic data in children < 4 years are lacking, but clinical experience is available from 8 months of age, and when started at the recommended daily dose of 1-2 mg/kg, no safety concerns have been identified. Pharmacokinetic data are lacking in older CAPS patients. Distribution into the cerebrospinal fluid has been demonstrated.

10.

06/2014