Summary of medicine characteristics - KINERET 100 MG / 0.67 ML SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE
Kineret 100 mg/0.67 ml solution for injection in pre-filled syringe.
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each graduated pre-filled syringe contains 100 mg of anakinra* per 0.67 ml (150 mg/ml).
* Human interleukin-1 receptor antagonist (r-metHuIL-1ra) produced in Escherichia coli cells by recombinant DNA technology.
For the full list of excipients, see section 6.1.
Solution for injection (injection).
Clear, colourless to white solution for injection that may contain some product-related translucent-to white amorphous particles.
4.1 Therapeutic indications
Rheumatoid Arthritis (RA)
Kineret is indicated in adults for the treatment of the signs and symptoms of RA in combination with methotrexate, with an inadequate response to methotrexate alone.
Periodic fever syndromes
Kineret is indicated for the treatment of the following autoinflammatory periodic fever syndromes in adults, adolescents, children and infants aged 8 months and older with a body weight of 10 kg or above:
Cryopyrin-Associated Periodic Syndromes (CAPS)
Kineret is indicated for the treatment of CAPS, including:
– Neonatal-Onset Multisystem Inflammatory Disease (NOMID) / Chronic Infantile Neurological, Cutaneous, Articular Syndrome (CINCA) – Muckle-Wells Syndrome (MWS)
– Familial Cold Autoinflammatory Syndrome (FCAS)
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.
Still’s Disease
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 Still’s disease, including Systemic Juvenile Idiopathic Arthritis (SJIA) and AdultOnset Still’s Disease (AOSD), with active systemic features of moderate to high disease activity, or in patients with continued disease activity after treatment with non-steroidal anti-inflammatory drugs (NSAIDs) or glucocorticoids.
Kineret can be given as monotherapy or in combination with other antiinflammatory drugs and disease-modifying antirheumatic drugs (DMARDs).
4.2 Posology and method of administration
Kineret treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of RA, CAPS, FMF and Still’s disease, respectively.
Posology
RA: Adults
The recommended dose of Kineret 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.
FMF
The recommended dose for patients weighing 50 kg or more is 100 mg/day by subcutaneous injection. Patients weighing less than 50 kg should be dosed by body weight with a recommended dose of 1–2 mg/kg/day.
Still’s disease
The recommended dose for patients weighing 50 kg or more is 100 mg/ day by subcutaneous injection. Patients weighing less than 50 kg should be dosed by body weight with a starting dose of 1–2 mg/kg/day.
Response to treatment should be evaluated after 1 month: In case of persistent systemic manifestations dose may be adjusted in children or continued treatment with Kineret should be reconsidered by the treating physician.
Elderly population (> 65 years)
RA: No dose adjustment is required. Posology and administration are the same as for adults 18 to 64 years of age.
CAPS: Data in elderly patients are limited. No dose adjustments are expected to be required.
Still’s disease: Data in elderly patients are limited. No dose adjustment are expected to be required.
Paediatric population (< 18 years)
No data are available in children under the age of 8 months.
RA: The efficacy of Kineret 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.
FMF: Children weighing less than 50 kg are dosed by body weight with a recommended dose of 1–2 mg/kg/day, patients weighing 50 kg or more are dosed with 100 mg/day. In children with inadequate response the dose can be escalated up to 4 mg/kg/day.
The efficacy data of Kineret in children under 2 years of age with FMF are limited.
Still’s disease: Children weighing less than 50 kg are dosed by body weight with a starting dose of 1–2 mg/kg/day, patients weighing 50 kg or more are dosed with 100 mg/day. In children with inadequate response the dose can be escalated up to 4 mg/kg/day.
Hepatic impairment
No dose adjustment is required for patients with moderate hepatic impairment (Child-Pugh Class B). Kineret should be used with caution in patients with severe hepatic impairment.
Renal impairment
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.
Method of administration
Kineret is administered by subcutaneous injection.
Kineret is supplied ready for use in a graduated pre-filled syringe. The graduated prefilled syringe allows for doses between 20 and 100 mg. As the minimum dose is 20 mg the syringe is not suitable for paediatric patients with a body weight below 10 kg. The pre-filled syringe should not be shaken. The instructions for use and handling are given in section 6.6.
Alternating the injection site is recommended to avoid discomfort at the site of injection. Cooling of the injection site, warming the injection liquid to room temperature, use of cold packs (before and after the injection), and use of topical glucocorticoids and antihistamines after the injection can alleviate the signs and symptoms of injection site reactions.
4.3 Contraindications
Hypersensitivity to the active substance or 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).
4.4 Special warnings and precautions for use
Traceability
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
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 Kineret should be discontinued and appropriate treatment initiated.
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 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.
Serious infections
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 or FMF 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 appropriate 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.
Renal impairment
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.
Neutropenia
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.
Pulmonary Events
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.
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.
Immunosuppression
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.
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 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.
Vaccinations
In a placebo-controlled clinical trial (n = 126), no difference was detected in antitetanus 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.
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, FMF 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 Kineret and TNF-a antagonist treatment
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-a antagonists is not recommended (see section 4.5).
Sodium content
This medicinal product contains less than 1 mmol sodium (23 mg) per 100 mg dose, that is to say essentially ‘sodium-free’.
4.5 Interaction with other medicinal products and other forms of interaction
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.
Concurrent Kineret and TNF-g antagonist treatment
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-g antagonist is not recommended (see section 4.4).
Cytochrome P450 Substrates
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.
4.6 Fertility, pregnancy and lactation
Pregnancy
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.
Breast-feeding
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
4.7 Effects on ability to drive and use machines
Not relevant
4.8 Undesirable effects
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Immunosuppressants, Interleukin inhibitors, ATC code: L04AC03
Mechanism of action
Anakinra neutralises the biologic activity of interleukin-la (IL-1a) and interleukin-1 P (IL-1P) 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.
Pharmacodynamic effects
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-ip, 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.
In patients with FMF, mutation of the MEFV gene encoding for pyrin is leading to malfunctioning and overproduction of interleukin-ip (IL-ip) in the FMF inflammasome. Untreated FMF is characterized by increased CRP and SAA.
Administration of Kineret results in a decrease in acute phase reactants (e.g. CRP and SAA).
Still’s disease, in addition to various degrees of arthritis, is characterised by systemic inflammatory features such as spiking fever, skin rash, hepatosplenomegaly, serositis, and increased acute phase reactants driven by IL-1 activity. Systemically, IL-1 is known to cause the hypothalamic fever response and promote hyperalgesia. The role of IL-1 in the pathogenesis of Still’s disease has been demonstrated by ex vivo and gene expression studies.
Clinical efficacy and safety in RA
The safety and efficacy of anakinra in combination with methotrexate have been demonstrated in 1,790 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 RA 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 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).
Clinical efficacy and safety in FMF
The safety and efficacy of Kineret in the treatment of patients with colchicine resistant FMF has been demonstrated in a randomized, double-blind, and placebo-controlled published study with a treatment period of 4 months. Primary efficacy outcomes were number of attacks per month, and number of patients with a mean of <1 attack per month. 25 patients with colchicine resistant FMF were enrolled; 12 randomized to receive Kineret and 13 to receive placebo. The mean number of attacks per patient per month was significantly lower in those receiving Kineret (1.7) compared to placebo (3.5). The number of patients with <1 attack per month was significantly higher in the Kineret group; 6 patients, compared to none in the placebo group.
Additional published data in patients with FMF, intolerant to colchicine or with colchicine resistant FMF, demonstrate that the clinical effect of Kineret is evident in both clinical symptoms of attacks as well as in reduced levels of inflammatory markers, such as CRP and SAA. In the published studies the safety profile of anakinra in patients with FMF was generally similar to that in other indications.
Clinical efficacy and safety in Still’s disease
The safety and efficacy have been demonstrated in a published randomized controlled study in 24 SJIA patients treated with Kineret for up to 1 year. After a 1-month blinded phase, 8 of 12 patients in the Kineret treated group were identified as modified ACRpedi30 responders compared to 1 of 12 in the placebo group. At the same time point, 7 of 12 in the Kineret treated group were classified as ACRpedi50 and 5 of 12 as ACRpedi70 responders compared to none in the placebo group. 16 patients completed the subsequent open label phase and among 7 responders at month 12, 6 had stopped glucocorticoid treatment and 5 of them had inactive disease.
In a published prospective, uncontrolled, observational cohort study of 20 patients with new-onset SJIA Kineret was used as initial therapy after failure to respond to NSAIDs, but before the use of DMARDs, systemic glucocorticoids, or other biologic agents. Treatment with Kineret resulted in normalization of body temperature in 18 of 20 patients. At 1 year follow-up, 18 of 20 patients showed at least an adapted ACRpedi 70 response, and 17 of 20 patients reached an adapted ACRpedi 90 response as well as inactive disease.
The safety and efficacy of Kineret versus DMARD have been reported in a published 24-week multicenter, randomized, open-label study of 22 patients with glucocorticoid-dependent refractory AOSD. At Week 24, 6 of 12 patients on anakinra were in remission versus 2 of 10 patients on DMARDs. During an open-label extension phase, switching or add-on treatment with the comparator drug was possible if improvement did not occur within 24 weeks. 17 patients completed the open-label extension phase (Week 52), of which 7 of 14 Kineret-treated patients, and 2 of 3 patients on DMARDs, were in remission at that time point.
Additional published data in Still’s disease indicate that Kineret induces a rapid resolution of systemic features such as fever, rash, and elevation of acute phase reactants. Glucocorticoid doses can in many cases be reduced after initiation of Kineret therapy.
Paediatric population
Overall, the efficacy and safety profile of Kineret is comparable in adult and paediatric patients with CAPS or Still’s disease.
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 paediatric RA (JIA) patients
Kineret was studied in a single randomized, blinded multi-center trial in 86 patients with polyarticular course JIA (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 paediatric use in JIA.
Immunogenicity
See section 4.8.
5.2 Pharmacokinetic properties
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.
The median steady-state dose-normalized anakinra concentration in SJIA patients over 28 weeks was comparable to that observed in RA patients.
Hepatic impairment
A study including 12 patients with hepatic dysfunction (Child-Pugh Class B) given a single 1mg/kg intravenous dose has been performed. Pharmacokinetic parameters were not substantially different from healthy volunteers, other than a decrease in clearance of approximately 30% in comparison with data from a study with healthy volunteers. A corresponding decrease in creatinine clearance was seen in the hepatic failure population. Accordingly, the decrease in clearance is most likely explained by a decrease in renal function in this population. These data support that no dose adjustment is required for patients with hepatic dysfunction of Child-Pugh Class B. See section 4.2.
Renal impairment
The mean plasma clearance of Kineret in subjects with mild (creatinine clearance 5080 ml / min) and moderate (creatinine clearance 30–49 ml/min) renal insufficiency was reduced by 16% and 50%, respectively. In severe renal insufficiency and end stage renal disease (creatinine clearance < 30 ml/min), mean plasma clearance declined by 70% and 75%, respectively. Less than 2.5% of the administered dose of Kineret was removed by hemodialysis or continuous ambulatory peritoneal dialysis. These data support that no dose adjustment is needed for patients with mild renal impairment (CLcr 50 to 80 ml/minute). See section 4.2.
5.3 Preclinical safety data
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Citric acid, anhydrous
Sodium chloride
Disodium edetate dihydrate
Polysorbate 80
Sodium hydroxide
Water for injections
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products
6.3 Shelf life
3 years
6.4 Special precautions for storage
Store in a refrigerator (2 °C – 8 °C).
Do not freeze.
Store in the original container in order to protect from light.
For the purpose of ambulatory use, Kineret may be removed from the refrigerator for 12 hours at temperature not above 25 °C, without exceeding the expiry date. At the end of this period, the product must not be put back in the refrigerator and must be disposed of.
6.5 Nature and contents of container
0.67 ml of solution for injection in a graduated pre-filled syringe (Type I glass) with a plunger stopper (bromobutyl rubber) and 29 gauge needle. The pre-filled syringe has an outer rigid plastic needle shield attached to an inner needle cover. None of the syringe or needle shield components are made with natural rubber latex.
Pack sizes of 1, 7 or 28 (multipack containing 4 packs of 7 pre-filled syringes) prefilled syringes.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
6.6 Special precautions for disposalKineret 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.
Swedish Orphan Biovitrum AB (publ) SE 112 76 Stockholm
Sweden
8 MARKETING AUTHORISATION NUMBER(S)
PLGB 30941/0018