IUPAC_name = Recombinant human Interleukin-1 receptor antagonist protein; syn. N2-l-methionyl-interleukin 1 receptor antagonist (human isoform x reduced)
width = 220
CAS_number = 143090-92-0
ATC_prefix = L04
ATC_suffix = AA14
DrugBank = BTD00060
C=759 | H=1186 | N=208 | O=232 | S=10
molecular_weight = 17,257.6 g/mol
bioavailability = 95%
metabolism = predominantly renal
elimination_half-life = 4-6 hrs
pregnancy_category = B (in some countries : contraindicated)
legal_status = Rx only, not a controlled substance
routes_of_administration = s.c. injection only
Anakinra is a
drug, mostly used to treat rheumatoid arthritis.
Basic chemical, pharmacological and marketing Data
Anakinra is an
interleukin-1(IL-1) receptor antagonist. The anakinra molecule is a recombinant, non glycosolated version of human IL-1RA (RA for receptor antagonist). It consists of 153 amino acids and has a molecular weight of 17,257.6 g/mol (approx. 17.3 kilodaltons) and differs from native human IL-1RA in that it has the addition of a single methionine residue on its amino terminus.
The substance is a biologic response modifier. It is prepared from cultures of genetically modified "
Escherichia coli" using recombinant DNA technology.
Anakinra blocks the biologic activity of naturally occurring IL-1, including
inflammationand cartilage degradation associated with rheumatoid arthritis, by competitively inhibiting the binding of IL-1 to the Interleukin-1 type receptor, which is expressed in many tissues and organs. IL-1 is produced in response to inflammatory stimuli and mediates various physiologicresponses, including inflammatoryand immunologic reactions. IL-1 additionally stimulates bone resorptionand induces tissue damage like cartilage degradation as a result of loss of proteoglycans. In patients with rheumatoid arthritis the natural IL-1 receptor antagonist is not found in effective concentrations in synoviumand synovial fluidto counteract the elevated IL-1 concentrations in these patients.
Anakinra had an absolute bioavailability of 95% for healthy adults (n = 11) after a 70 mg subcutaneous bolus injection. Peak plasma concentrations of Kineret generally occurred 3 to 7 hours after s.c. administration of clinically relevant doses (1 to 2 mg/kg: n = 18) for patients with rheumatoid arthritis. The terminal half-life ranged from 4 to 6 hours. After daily s.c. dosing for up to 24 weeks, no unexpected accumulations of Kineret were observed in the plasma samples of rheumatoid arthritis patients.
This drug is sold under the
tradename"Kineret" and is produced by the pharmaceutical company Amgen. It is delivered as injection concentrate containing 100mg each single dose.
Anakinra is indicated as monotherapeutic agent or in combination with other disease-modifying agents (DMARDs) other than
tumor necrosis factor α(TNF-α) blocking agents for the management of signs and symptoms of rheumatoid arthritis and to inhibit the progression of structural damage associated with the disease in adults with moderately to severely active disease who have had an absence of clinical improvement of symptoms or inadequate response in therapy with one or more DMARDs. Anakinra should not be used in combination with etanercept(E mnbrel), infliximab(Remicade) or adalimumab(Humira).
Kineret showed moderate but statistically significant therapeutic efficacy; in most studies
methotrexatewas administered concomitantly. In the methotrexate plus anakinra group 38% of 250 patients reached an improvement/relief of symptoms of at least 20% within 24 weeks. In the control group of 251 patients under methotrexate treatment alone response was seen in 22% only. The clinical response was measured according to ACR-criteria (20, 50, and 70).
There are no direct studies comparing anakinra with TNF-α inhibitors, but indirect data suggests that anakinra may be inferior to TNF-α inhibitors. In a study with infliximab plus methotrexate 50% of all patients had significant remission (according to at least ACR 20 criteria) after a 30-week treatment period.
Contraindications and precautions
Hypersensitivityto anakinra, other E. coli derived proteins, or to any other ingredient (absolute contraindication).
* Preexisting malignant diseases (e.g., solid
cancers, leukemia): absolutely contraindicated (anakinra may be a human carcinogen and the suppression of immune function may worsen already existing malignancies).
* Patients with
neutropeniadue to any reason : absolutely contraindicated. Neutrophil counts should be obtained before initiating therapy and regularly thereafter (see recommended laboratory tests).
* Severely impaired
renal function(creatinine clearance less than 30 ml/minute): absolutely contraindicated.
* Preexisting active
tuberculosis(disease may be worsened – see side-effects).
* Concomitant application of live-virus vaccines (see Interactions).
Lactation: it is unknown if anakinra is distributed into human milk. Nursing mothers should either discontinue the drug or breast-feeding, taking into account the importance of the drug to the mother.
* Pediatric patients: no well controlled human data exists in patients under age 18. Therefore, therapy is contraindicated in those patients.
* Geriatric patients (over 65 yrs of age): risk of infections is increased.
Asthma: increased risk of severe infections.
* Women of childbearing potential should use effective
* Pregnancy: animal studies showed no adverse effects. Human data is not available. The drug should be applied to pregnant women only if clearly indicated.
* Mild to moderately impaired renal function: caution.
* GIT : Frequently, nausea (8%), diarrhea (7%), unspecific abdominal pain (5%).
Allergy: Rare cases of allergic reactions including severe anaphylaxishave been noticed. If necessary, the usual symptomatic therapy with corticosteroids, epinephrine, antihistaminics and i.v. fluid correction should be initiated as soon as possible. Rare cases of allergic skin rashhave also been seen.
Respiratory tract: Frequently, infections of upper respiratory tract (13%), sinusitis(7%), flu-like syndrome (6%), Infrequently, pneumoniaand tuberculosis.
Skin: Frequently ecchymoses, infrequently skin mycosis, Lupus-erythematodes-like syndrome, urticaria, and isolated cases of melanoma (see malignancies).
Immune system: Frequently, infections (40%, severe in 2%). Infrequently, production of antibodieswith neutralizing activity.
* Blood and blood forming organs : Frequently, decrease in neutrophil counts (8% under anakinra, placebo 2%), infrequent significant neutropenia (0.4% under anakinra), moderate
eosinophilia, moderate thrombocytopenia, and malignant lymphomas (0.12 cases/patient year) (see malignancies).
* Musculosceletal system : Infrequent are arthritic symptoms, arthritic symptoms associated with inflammation, bony infections.
* Pain, inflammation, and erythema at injection sites : Very frequently (70% of patients), usually during first 4 weeks of therapy, reversible within 1 to 2 weeks. These reactions are reasons why many patients discontinue therapy.
Recommended Laboratory Tests
In patients receiving Kineret a decrease in neutrophil counts may be found. In the placebo-controlled studies 8% of patients receiving anakinra had decreases in neutrophil counts of at least 1
World Health Organization(WHO) toxicity grade compared with 2% in the placebo control group. Kineret-treated patients experienced defined neutropenia (ANC < 1 x 109/L) in 0.4%.
Neutrophil counts should be assessed prior to initiating Kineret treatment, and while receiving Kineret, monthly for 3 months, and thereafter quarterly for a period up to 1 year.
Among 5,300 rheumatoid arthritis patients treated with Kineret in clinical trials for a mean of 15 months (approximately 6,400 patient years of treatment), 8 cases of lymphomas were observed resulting in a rate of 0.12 cases/100 patient years. This is 3.6 fold higher than the rate of lymphomas expected in the general population. However, the 'natural' incidence of lymphomas in patients with rheumatoid arthritis is considerably increased and may even be higher in patients with high disease activity.
Additionally, 37 solid tumors of different origination have been found. Of these, the number of 3 melanomas reported in study 4 is significant (1 case expected), but the clear association to anakinra therapy remains unclear.
At this stage it cannot be ruled out that anakinra is a human carcinogen.
* TNF-Blocking Agents: An increased incidence of serious infections and an increased risk of neutropenia have been seen when anakinra and etanercept were used concomitantly in patients with rheumatoid arthritis. Similar interactions can be anticipated for the combination therapy of anakinra together with other agents blocking TNF (alpha) (e.g., adalimumab, infliximab). Therefore, combined drug therapy with anakinra and any TNF-blocking agent is not recommended and should be avoided. Moreover, in a 24-week clinical study a regime with anakinra and etanercept did not provide any additional benefit to the patients.
* Methotrexate:Methotrexate has been coadministered with anakinra in quite extended clinical studies. Neither specific drug interactions nor increased toxicity of anakinra and/or methotrexate have been noticed. In animal models (rats) studying the effects of both drugs when coadminstered, no effects on clearing of both drugs form plasma or on the respective toxicologic properties have been seen. Therefore, the concomitant use of both disease modifiers in patients with rheumatoid arthritis can be regarded as safe.
* Vaccines:Live-virus vaccines should not be given to patients during anakinra treatment. Information is not available, if anakinra would affect the rate of secondary transmission of vaccine virus (e.g., measles or poliomyelitis viruses) following administration of a live virus vaccine or regarding any other effect of vaccination on patients receiving the drug. Due to the fact that anakinra decreases the immune response to antigens in general, vaccine efficacy may be reduced in patients receiving anakinra.
The usual dosage is 100mg subcutaneosly (s.c.) once a day. Dose reduction to 100mg s.c. every other day should be considered in patients with severe renal impairment, if these are treated in exceptional cases (see contraindications and precautions). No additional benefits of doses exceeding 100mg daily have been seen.
Duration of treatment
In the pre-clinical and clinical studies the usual duration of therapy was 24 weeks. It is possible to extend therapy to 48 weeks in patients with satisfying remission after 24 weeks to maintain clinically evident improvements. Under continued therapy anakinra has been shown to slow progression of disease over a period of at least 12 month evidenced by X-ray studies or other clinical examinations. Some experience with 48 to 60 weeks (15 months) treatment duration has already been gained and no evidence has been seen regarding additional toxicity.
Possible future indications
Due to the specific mechanism of action of anakinra, a possible efficiency may be anticipated in patients with inflammatory joint diseases such as
psoriatic arthritis, and spondylarthritis. Possibly, anakinra may even benefit patients with destructive osteoarthritisin inflammatory phases. Kineret may also be effective in pediatric patients with juvenile rheumatoid arthritis(JRA). Clinical studies have not been initiated so far regarding these diseases. Currently, the use of anakinra in these patients is therefore not recommended.
On April 12, 2007 an [http://uk.reuters.com/article/healthNews/idUKCOL24490420070412 article] in the
New England Journal of Medicinediscussed the possibility of using anakinra for treatment of type 2 diabetes.
References and external links
* AHFS Database Online
* Arzneimittel Datenbank (in German)
* [http://www.kineretrx.com/ Kineret homepage]
* http://www.rheuma-online.de/medikamente/anakinra-kineret/anakinra-zb-kineret/tumorrisiko.html (on the risk of cancerogenity (in German))
* http://www.rheuma-online.de/medikamente/anakinra-kineret/anakinra-zb-kineret/ausblicke-moegliche-zukuenftige-anwendungen-von-anakinra-kineret.html (same site on future indications)
* http://www.rheuma-online.de/medikamente/anakinra-kineret/anakinra-zb-kineret/anakinra-kineret-in-der-kinderrheumatologie.html (same site on possible pediatric indications)
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