Рекомбинантный рецепторный антагонист интерлейкина-1 человека

Рекомбинантный рецепторный антагонист интерлейкина-1 человека is indicated in adults for the treatment of the signs and symptoms of Rheumatoid Arthritis (RA) in combination with methotrexate, with an inadequate response to methotrexate alone.

Рекомбинантный рецепторный антагонист интерлейкина-1 человека 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)

Рекомбинантный рецепторный антагонист интерлейкина-1 человека treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of rheumatoid arthritis and CAPS, respectively.

Posology

RA: Adults

The recommended dose of Рекомбинантный рецепторный антагонист интерлейкина-1 человека is 100 mg administered once a day by subcutaneous injection. The dose should be administered at approximately the same time each day.

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.

Elderly population (> 65 years)

No dose adjustment is required in RA patients. Posology and administration are the same as for adults 18 to 64 years of age.

Data in elderly CAPS patients are limited. No dose adjustments are expected to be required.

Paediatric population (< 18 years)

RA: The efficacy of Рекомбинантный рецепторный антагонист интерлейкина-1 человека in children with RA (JIA) aged 0 to 18 years has not been established.

CAPS: Posology and administration in children and infants aged 8 months and older with a body weight of 10 kg or above are the same as for adult CAPS patients, based on body weight. No data are available in children under the age of 8 months.

Hepatic impairment

No dose adjustment is required for patients with moderate hepatic impairment (Child-Pugh Class B). Рекомбинантный рецепторный антагонист интерлейкина-1 человека should be used with caution in patients with severe hepatic impairment.

Renal impairment

Рекомбинантный рецепторный антагонист интерлейкина-1 человека must not be used in patients with severe renal impairment (CL_cr < 30 ml/minute). No dose adjustment is needed for patients with mild renal impairment (CL_cr 50 to 80 ml/minute). In the absence of adequate data, Рекомбинантный рецепторный антагонист интерлейкина-1 человека should be used with caution in patients with moderate renal impairment (CL_cr 30 to 50 ml/minute).

Method of administration

Рекомбинантный рецепторный антагонист интерлейкина-1 человека is administered by subcutaneous injection.

Рекомбинантный рецепторный антагонист интерлейкина-1 человека is supplied ready for use in a graduated pre-filled syringe.

Alternating the injection site is recommended to avoid discomfort at the site of injection. Cooling of the injection site, warming the injection liquid, use of cold packs (before and after the injection), and use of topical corticosteroids and antihistamines after the injection can alleviate the signs and symptoms of injection site reactions.

E. coli derived proteins.

Рекомбинантный рецепторный антагонист интерлейкина-1 человека must not be used in patients with severe renal impairment (CL_cr < 30 ml/minute).

Рекомбинантный рецепторный антагонист интерлейкина-1 человека treatment must not be initiated in patients with neutropenia (ANC <1.5 x 10⁹/l).

Allergic reactions

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 Рекомбинантный рецепторный антагонист интерлейкина-1 человека should be discontinued and appropriate treatment initiated.

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 Рекомбинантный рецепторный антагонист интерлейкина-1 человека treatment.

The efficacy and safety of Рекомбинантный рецепторный антагонист интерлейкина-1 человека in patients with AST/ALT >1.5 x upper level of normal have not been evaluated.

Serious infections

Рекомбинантный рецепторный антагонист интерлейкина-1 человека 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 Рекомбинантный рецепторный антагонист интерлейкина-1 человека-treated patients (4.5%) vs. placebo-treated patients (0%), these infections were mainly related to the respiratory tract.

The safety and efficacy of Рекомбинантный рецепторный антагонист интерлейкина-1 человека treatment in patients with chronic and serious infections have not been evaluated.

Рекомбинантный рецепторный антагонист интерлейкина-1 человека treatment should not be initiated in patients with active infections. Рекомбинантный рецепторный антагонист интерлейкина-1 человека treatment should be discontinued in RA patients if a severe infection develops. In Рекомбинантный рецепторный антагонист интерлейкина-1 человека treated CAPS patients, there is a risk for disease flares when discontinuing Рекомбинантный рецепторный антагонист интерлейкина-1 человека treatment. This should be taken into account when deciding on discontinuing Рекомбинантный рецепторный антагонист интерлейкина-1 человека during a severe infection.

Physicians should exercise caution when administering Рекомбинантный рецепторный антагонист интерлейкина-1 человека to patients with a history of recurring infections or with underlying conditions which may predispose them to infections.

The safety of Рекомбинантный рецепторный антагонист интерлейкина-1 человека 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 Рекомбинантный рецепторный антагонист интерлейкина-1 человека. 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 Рекомбинантный рецепторный антагонист интерлейкина-1 человека.

Neutropenia

Рекомбинантный рецепторный антагонист интерлейкина-1 человека was commonly associated with neutropenia (ANC < 1.5 x 10⁹/L) in placebo-controlled studies in RA and cases of neutropenia have been observed in CAPS patients.

Рекомбинантный рецепторный антагонист интерлейкина-1 человека treatment should not be initiated in patients with neutropenia (ANC < 1.5 x 10⁹/l). It is recommended that neutrophil counts be assessed prior to initiating Рекомбинантный рецепторный антагонист интерлейкина-1 человека treatment, and while receiving Рекомбинантный рецепторный антагонист интерлейкина-1 человека, monthly during the first 6 months of treatment and quarterly hereafter. In patients who become neutropenic (ANC < 1.5 x 10⁹/l) the ANC should be monitored closely and Рекомбинантный рецепторный антагонист интерлейкина-1 человека treatment should be discontinued. The safety and efficacy of Рекомбинантный рецепторный антагонист интерлейкина-1 человека in patients with neutropenia have not been evaluated.

Immunosuppression

The impact of treatment with Рекомбинантный рецепторный антагонист интерлейкина-1 человека on pre-existing malignancy has not been studied. Therefore the use of Рекомбинантный рецепторный антагонист интерлейкина-1 человека in patients with pre-existing malignancy is not recommended.

Vaccinations

In a placebo-controlled clinical trial (n = 126), no difference was detected in anti-tetanus antibody response between the Рекомбинантный рецепторный антагонист интерлейкина-1 человека and placebo treatment groups when a tetanus/diphtheria toxoid vaccine was administered concurrently with Рекомбинантный рецепторный антагонист интерлейкина-1 человека. No data are available on the effects of vaccination with other inactivated antigens in patients receiving Рекомбинантный рецепторный антагонист интерлейкина-1 человека.

No data are available on either the effects of live vaccination or on the secondary transmission of infection by live vaccines in patients receiving Рекомбинантный рецепторный антагонист интерлейкина-1 человека. Therefore, live vaccines should not be given concurrently with Рекомбинантный рецепторный антагонист интерлейкина-1 человека.

Elderly population (> 65 years)

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 patients. Because there is a higher incidence of infections in the elderly population in general, caution should be used in treating elderly patients.

Concurrent Рекомбинантный рецепторный антагонист интерлейкина-1 человека and TNF antagonist treatment

Concurrent administration of Рекомбинантный рецепторный антагонист интерлейкина-1 человека 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 Рекомбинантный рецепторный антагонист интерлейкина-1 человека and etanercept or other TNF antagonists is not recommended.

This medicinal product contains less than 1 mmol sodium (23 mg) per 100 mg dose, i.e. essentially 'sodium-free'.

Not relevant.

In placebo-controlled studies in RA patients, the most frequently reported adverse reactions with Рекомбинантный рецепторный антагонист интерлейкина-1 человека were injection site reactions (ISRs), which were mild to moderate in the majority of patients. The most common reason for withdrawal from study in Рекомбинантный рецепторный антагонист интерлейкина-1 человека-treated RA patients was injection site reaction. The subject incidence of serious adverse reactions in RA studies at the recommended dose of Рекомбинантный рецепторный антагонист интерлейкина-1 человека (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 Рекомбинантный рецепторный антагонист интерлейкина-1 человека-treated patients compared to patients receiving placebo (1.8% vs. 0.7%). Neutrophil decreases occurred more frequently in patients receiving Рекомбинантный рецепторный антагонист интерлейкина-1 человека compared with placebo.

Adverse reactions data in CAPS patients are based on an open-label study of 43 patients with NOMID/CINCA treated with Рекомбинантный рецепторный антагонист интерлейкина-1 человека for up to 5 years, with a total Рекомбинантный рецепторный антагонист интерлейкина-1 человека 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 Рекомбинантный рецепторный антагонист интерлейкина-1 человека. No patient withdrew from Рекомбинантный рецепторный антагонист интерлейкина-1 человека 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 Рекомбинантный рецепторный антагонист интерлейкина-1 человека treatment both in RA and CAPS patients.

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.

Serious infections

The incidence of serious infections in RA studies conducted at the recommended dose (100 mg/day) was 1.8% in Рекомбинантный рецепторный антагонист интерлейкина-1 человека 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. Рекомбинантный рецепторный антагонист интерлейкина-1 человека was temporarily stopped in one patient, all other patients continued Рекомбинантный рецепторный антагонист интерлейкина-1 человека treatment during the infections.

There were no deaths due to serious infections in RA or CAPS studies.

In clinical RA studies and post-marketing experience, rare cases of opportunistic infections have been observed and included fungal, mycobacterial, bacterial, and viral pathogens. Infections have been noted in all organ systems and have been reported in patients receiving Рекомбинантный рецепторный антагонист интерлейкина-1 человека alone or in combination with immunosuppressive agents.

Neutropenia

In placebo-controlled RA studies with Рекомбинантный рецепторный антагонист интерлейкина-1 человека, 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 Рекомбинантный рецепторный антагонист интерлейкина-1 человека 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 Рекомбинантный рецепторный антагонист интерлейкина-1 человека treatment.

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 Рекомбинантный рецепторный антагонист интерлейкина-1 человека, thrombocytopenia has been reported, including occasional case reports indicating severe thrombocytopenia (i.e. platelet counts <10 x10⁹/L).

Malignancies

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 Рекомбинантный рецепторный антагонист интерлейкина-1 человека 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 Рекомбинантный рецепторный антагонист интерлейкина-1 человека-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 Рекомбинантный рецепторный антагонист интерлейкина-1 человека.

Allergic reactions

Allergic reactions including anaphylactic reactions, angioedema, urticaria, rash, and pruritus have been reported uncommonly with Рекомбинантный рецепторный антагонист интерлейкина-1 человека. 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 Рекомбинантный рецепторный антагонист интерлейкина-1 человека treatment.

Immunogenicity

In clinical trials in RA, up to 3% of adult patients tested seropositive at least once during the study for antibodies capable of neutralising the biologic effects of anakinra. 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 paediatric patients tested seropositive at least once during the study for antibodies capable of neutralising the biologic effects of anakinra.

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 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. a history of transaminase elevations before start of Рекомбинантный рецепторный антагонист интерлейкина-1 человека treatment.

Injection site reactions

In RA patients the most common and consistently reported treatment-related adverse reactions associated with Рекомбинантный рецепторный антагонист интерлейкина-1 человека 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 Рекомбинантный рецепторный антагонист интерлейкина-1 человека 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.

Blood cholesterol increase

In clinical studies of RA, 775 patients treated with daily Рекомбинантный рецепторный антагонист интерлейкина-1 человека 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 Рекомбинантный рецепторный антагонист интерлейкина-1 человека treatment, without a dose-response relationship. A similar pattern was seen after 24 weeks Рекомбинантный рецепторный антагонист интерлейкина-1 человека 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

Рекомбинантный рецепторный антагонист интерлейкина-1 человека has been studied in 36 CAPS patients 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 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:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: [email protected]

No dose-limiting toxicities were observed during clinical trials in RA or CAPS patients.

In studies of sepsis, 1015 patients received Рекомбинантный рецепторный антагонист интерлейкина-1 человека at doses up to 2 mg/kg/hour i.v. (~35 times the recommended dose in RA) over a 72 hour treatment period. The adverse event profile from these studies show no overall difference from that seen in the rheumatoid arthritis studies.

Pharmacotherapeutic group: Immunosuppressants, Interleukin inhibitors, ATC code: L04AC03

Anakinra neutralises the biologic activity of interleukin-1α (IL-1α) and interleukin-1β (IL-1β) by competitively inhibiting their binding to interleukin-1 type I receptor (IL-1RI). Interleukin-1 (IL-1) is a pivotal pro-inflammatory cytokine mediating many cellular responses including those important in synovial inflammation.

IL-1 is found in the plasma and synovial fluid of patients with rheumatoid arthritis, and a correlation has been reported between IL-1 concentrations in the plasma and the activity of the disease.

Anakinra inhibits responses elicited by IL-1 in vitro, including the induction of nitric oxide and prostaglandin E₂ and/or collagenase production by synovial cells, fibroblasts, and chondrocytes.

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 Рекомбинантный рецепторный антагонист интерлейкина-1 человека 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.

Clinical efficacy and safety in RA

The safety and efficacy of anakinra in combination with methotrexate have been demonstrated in 1790 RA patients > 18 years of age with varying degrees of disease severity.

A clinical response to anakinra generally appeared within 2 weeks of initiation of treatment and was sustained with continued administration of anakinra. Maximal clinical response was generally seen within 12 weeks after starting treatment.

Combined anakinra and methotrexate treatment demonstrates a statistically and clinically significant reduction in the severity of the signs and symptoms of rheumatoid arthritis in patients who have had an inadequate response to methotrexate alone (38% vs. 22% responders as measured by ACR₂₀ criteria). Significant improvements are seen in the pain, tender joint count, physical function (HAQ score), acute phase reactants and in the patient's and physician's global assessment.

X-ray examinations have been undertaken in one clinical study with anakinra. These have shown no deleterious effect on joint cartilage.

Clinical efficacy and safety in CAPS

The safety and efficacy of Рекомбинантный рецепторный антагонист интерлейкина-1 человека 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 Рекомбинантный рецепторный антагонист интерлейкина-1 человека.

Рекомбинантный рецепторный антагонист интерлейкина-1 человека 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 Рекомбинантный рецепторный антагонист интерлейкина-1 человека is comparable in adult and paediatric CAPS patients.

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Safety in pediatric RA (JIA) patients

Рекомбинантный рецепторный антагонист интерлейкина-1 человека 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 Рекомбинантный рецепторный антагонист интерлейкина-1 человека (25 patients) or placebo (25 patients), administered daily for an additional 16 weeks. A subset of these patients continued open-label treatment with Рекомбинантный рецепторный антагонист интерлейкина-1 человека 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, Рекомбинантный рецепторный антагонист интерлейкина-1 человека is not recommended for pediatric use in Juvenile Rheumatoid Arthritis.

Immunogenicity

The absolute bioavailability of anakinra after a 70 mg subcutaneous bolus injection in healthy subjects (n = 11) is 95%. The absorption process is the rate-limiting factor for the disappearance of anakinra from the plasma after subcutaneous injection. In subjects with RA, maximum plasma concentrations of anakinra occurred at 3 to 7 hours after subcutaneous administration of anakinra at clinically relevant doses (1 to 2 mg/kg; n = 18). The plasma concentration decreased with no discernible distribution phase and the terminal half-life ranged from 4 to 6 hours. In RA patients, no unexpected accumulation of anakinra was observed after daily subcutaneous doses for up to 24 weeks. Mean (SD) estimates of clearance (CL/F) and volume of distribution (Vd/F) by population analysis of data from two PK studies in 35 RA patients were 105(27) mL/min and 18.5(11) L, respectively. Human and animal data demonstrated that the kidney is the major organ responsible for elimination of anakinra. The clearance of anakinra in RA patients increased with increasing creatinine clearance.

The influence of demographic covariates on the pharmacokinetics of anakinra was studied using population pharmacokinetic analysis encompassing 341 patients receiving daily subcutaneous injection of anakinra at doses of 30, 75, and 150 mg for up to 24 weeks. The estimated anakinra clearance increased with increasing creatinine clearance and body weight. Population pharmacokinetic analysis demonstrated that the mean plasma clearance value after subcutaneous bolus administration was approximately 14% higher in men than in women and approximately 10% higher in subjects < 65 years than in subjects > 65 years. However, after adjusting for creatinine clearance and body weight, gender and age were not significant factors for mean plasma clearance. No dose adjustment is required based on age or gender.

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.

Hepatic impairment

A study including 12 patients with hepatic dysfunction (Child-Pugh Class B) given a single 1mg/kg intravenous dose has been performed.

Renal impairment

The mean plasma clearance of Рекомбинантный рецепторный антагонист интерлейкина-1 человека in subjects with mild (creatinine clearance 50-80 mL/min) and moderate (creatinine clearance 30-49 mL/min) renal insufficiency was reduced by 16% and 50%, respectively.

Anakinra had no observed effect on the fertility, early development, embryo-foetal development, or peri- and postnatal development in the rat at doses up to 100 times the human dose. No effects on embryo-foetal development in the rabbit were observed at doses 100 times the human dose.

In a standard battery of tests designed to identify hazards with respect to DNA, anakinra did not induce bacterial or mammalian cell gene mutations. Neither did anakinra increase the incidence of chromosomal abnormalities or micronuclei in bone marrow cells in mice. Long-term studies have not been performed to evaluate the carcinogenic potential of anakinra. Data from mice over expressing IL-1ra and IL-1ra mutant knock-out mice, did not indicate an increased risk of tumour development.

A formal toxicologic and toxicokinetic interaction study in rats revealed no evidence that Рекомбинантный рецепторный антагонист интерлейкина-1 человека alters the toxicologic or pharmacokinetic profile of methotrexate.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Рекомбинантный рецепторный антагонист интерлейкина-1 человека is a sterile unpreserved solution. For single use only.

Do not shake. Allow the pre-filled syringe to reach room temperature before injecting.

Before administration, visually inspect the solution for particulate matter and discolouration. Only clear, colourless-to-white solutions that may contain some product-related translucent-to-white amorphous particles should be injected.

The presence of these particles does not affect the quality of the product.

The pre-filled syringe is for single use only. Discard any unused medicinal product.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.