1. Name Of The Medicinal Product
Kineret 100 mg solution for injection in a pre-filled syringe.
2. Qualitative And Quantitative Composition
Each 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 a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Solution for injection (injection) in a pre-filled syringe.
Clear, colourless-to-white solution for injection that may contain some product-related translucent-to-white amorphous particles.
4. Clinical Particulars
4.1 Therapeutic Indications
Kineret is indicated for the treatment of the signs and symptoms of rheumatoid arthritis in combination with methotrexate, in adults with an inadequate response to methotrexate alone.
4.2 Posology And Method Of Administration
Kineret treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of rheumatoid arthritis.
Posology
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.
Elderly population (
No dose adjustment is required. Posology and administration are the same as for adults 18 to 64 years of age.
Paediatric population (< 18 years)
The safety and efficacy of Kineret in children aged 0 to 18 years have not been established. No data are available.
Hepatic impairment
No dose adjustment is required.
Renal impairment
No dosage adjustment is needed for patients with mild renal impairment (CLcr 50 to 80 ml/minute). In the absence of adequate data, Kineret should be used with caution in patients with moderate renal impairment (CLcr 30 to 50 ml/minute). Kineret should not be used in patients with severe renal impairment (CLcr < 30 ml/minute) (see section 4.3).
Method of administration
Kineret is administered by subcutaneous injection.
For patient convenience, Kineret is supplied ready for use in a pre-filled syringe. 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.
4.3 Contraindications
Hypersensitivity to the active substance, any of the excipients or to E. coli derived proteins.
Kineret should not be used in patients with severe renal impairment (CLcr < 30 ml/minute) (see section 4.2).
4.4 Special Warnings And Precautions For Use
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.
The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions.
Serious infections
Kineret has been associated with an increased incidence of serious infections (1.8%) vs. placebo (0.7%). 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%). The safety and efficacy of Kineret in patients with chronic infections have not been evaluated.
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.
Neutropenia
Administration of Kineret was associated with neutropenia (ANC < 1.5 x 109/l) in 2.4% of patients compared with 0.4% of placebo patients. None of these patients had serious infections associated with the neutropenia.
Kineret 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 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 x 109/l) the ANC should be monitored closely and Kineret treatment should be discontinued.
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.
Vaccinations
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.
Elderly population (
A total of 635 patients
Concurrent Kineret and TNF antagonist treatment
Concurrent administration of Kineret and etanercept has been associated with an increased risk of serious infections and neutropenia compared to etanercept alone. This treatment combination has not demonstrated increased clinical benefit.
The concurrent administration of Kineret and etanercept or other TNF antagonists is not recommended (see section 4.5).
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 drugs, corticosteroids, and DMARDs) have not been observed.
Concurrent Kineret and TNF antagonist treatment
In a clinical trial with 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 antagonist is not recommended (see section 4.4).
For information on vaccinations see section 4.4.
4.6 Pregnancy And Lactation
There are limited amount of data from the use of anakinra in pregnant women. However, reproductive studies have been conducted with Kineret on rats and rabbits at doses up to 100 times the human dose and have revealed no evidence of impaired fertility or harm to the foetus.
Kineret is not recommended during pregnancy and in women 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.
4.7 Effects On Ability To Drive And Use Machines
Not relevant.
4.8 Undesirable Effects
In all placebo-controlled studies, the most frequently reported adverse reactionwith Kineret was injection site reaction (ISRs), which was mild to moderate in the majority of patients. The most common reason for withdrawal from study in Kineret-treated patients is injection site reaction. The subject incidence of serious adverse reactions at the recommended dose of Kineret (100 mg/day) is 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 with patients receiving placebo (1.8% vs. 0.7%). Neutrophil decreases occurred more frequently in patients receiving Kineret compared with placebo.
Adverse reactions are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (
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Serious infections
The incidence of serious infections in the 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 drug after the infection resolved. There were no on-study deaths due to serious infectious episodes.
In clinical 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 Kineret alone or in combination with immunosuppressive agents.
Neutropenia
In placebo-controlled 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 x 109/l) was reported in 2.4% patients receiving Kineret compared with 0.4% of placebo patients.
Malignancies
Rheumatoid arthritis (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.
Allergic reactions
Allergic reactions including anaphylactic reactions, angioedema, urticaria, rash, and pruritus have been reported uncommonly.
Immunogenicity
In clinical trials, 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.
Injection site reactions
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 patients developed an ISR compared to 28% of the placebo treated patients, which was typically reported within the first 4 weeks of therapy. The median duration of the above mentioned typical symptoms was 14 to 28 days. The development of ISRs in patients who had not previously experienced ISRs was uncommon after the first month of therapy.
4.9 Overdose
No dose-limiting toxicities were observed during clinical trials in rheumatoid arthritis patients.
In studies of sepsis, 1,015 patients received Kineret at doses up to 2 mg/kg/hour 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.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
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.
Clinical efficacy and safety
The safety and efficacy of anakinra in combination with methotrexate have been demonstrated in patients 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.
Immunogenicity
See section 4.8.
5.2 Pharmacokinetic Properties
The absolute bioavailability of anakinra after a 70 mg SC 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 SC injection. In subjects with RA, maximum plasma concentrations of anakinra occurred at 3 to 7 hours after SC administration of anakinra at clinically relevant doses (1 to 2 mg/kg; n = 18); the terminal half-life ranged from 4 to 6 hours. In RA patients, no unexpected accumulation of anakinra was observed after daily SC doses for up to 24 weeks.
The influence of demographic covariates on the pharmacokinetics of anakinra was studied using population pharmacokinetic analysis encompassing 341 patients receiving daily SC 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 SC bolus administration was approximately 14% higher in men than in women and approximately 10% higher in subjects < 65 years than in subjects
5.3 Preclinical Safety Data
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 Kineret alters the toxicologic or pharmacokinetic profile of methotrexate.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Sodium citrate
Sodium chloride
Disodium edetate
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 pre-filled syringe (Type I glass) with a plunger stopper (bromobutyl rubber) in pack sizes of 1, 7 or 28.
The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex).
See section 4.4
Not all pack sizes may be marketed.
6.6 Special Precautions For Disposal And Other Handling
Kineret 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.
Any unused product or waste material should be disposed of in accordance with local requirements.
7. Marketing Authorisation Holder
Swedish Orphan Biovitrum AB (publ)
SE-112 76 Stockholm
Sweden
8. Marketing Authorisation Number(S)
EU/1/02/203/001 – 1-pack
EU/1/02/203/002 – 7-pack
EU/1/02/203/003 – 28-pack
9. Date Of First Authorisation/Renewal Of The Authorisation
Date of first authorisation: 8 March 2002
Date of latest renewal: 20 March 2007
10. Date Of Revision Of The Text
02/2011
Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu
