Pharmacology Update: Anakinra Injection (Kineret — Amgen)
February 28, 2002 5 minutes read
Anakinra Injection (Kineret—Amgen)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
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The FDA has approved anakinra, a recombinant interleukin-1 receptor antagonist (IL-1Ra) for the treatment of rheumatoid arthritis (RA). The drug, which is given by daily subcutaneous injection, is indicated for RA patients who have failed disease modifying antirheumatic drugs (DMARDs). Anakinra is a competitive inhibitor of IL-1 to the IL-R1 receptor. Anakinra is produced by recombinant technology using an Escherichia coli system and is a nonglycosylated form of human IL-1Ra with methionine added to the amino terminus. It will be marketed by Amgen under the trade name "Kineret."
Indications
Anakinra is indicated for the reduction in signs and symptoms of moderately to severely active RA in adults (18 years or older) who have failed 1 or more (DMARDs). It can be used alone or in combination with DMARDs. Use in combination with agents directed against tissue necrosis factor (TNF) (ie, etanercept, infliximab) is not recommended.1
Dosage
The recommended dose is 100 mg/d given by subcutaneous injection. The dose should be given about the same time each day. The recommended sites of injection include the stomach, outer thighs, back of arms, or buttocks.1 Anakinra is available as 100-mg prefilled syringes. It should be stored in the refrigerator and should not be frozen or shaken.1
Potential Advantages
Anakinra has shown radiographic evidence of reduced progression of RA. After 24 weeks of therapy (n = 347), the number of joints with erosion increased by 1.4 in the IL-1Ra group and 7.6 in the placebo group (P = 0.004).2 The Larsen score increased by 3.8 for IL-1Ra (30 mg/d), 3.9 (75 mg/d), and 4.0 (150 mg/d) compared to 6.4 for placebo. This represented about a 40% reduction in the rate radiologic progression (P = 0.03). Similar treatment trends were also observed using the Genant/Sharp method.3-5 This method reported a 47% reduction in total score, 38% reduction in erosion, and 58% reduction in joint space narrowing. These scoring systems basically assess 14-15 areas of the hand and wrist, erosion and joint space narrowing, and other features. The Larsen score uses 2 film readers and scores one set of films at a time while the Genant/Sharp uses a single reader but assesses change in the same patient.3
Potential Disadvantages
Anakinra requires daily subcutaneous injections. The most common side effect is injection site reactions. In clinical trials, 71% of patients reported injection site reactions that included erythema, ecchymosis, inflammation, and pain. These were generally reported in the first month of therapy and lasted for 14-28 days.1 The clinical benefit of anakinra appears to be modest as assessed by American College of Rheumatology (ACR20). This represents a 20% improvement in the patient’s tender joint count and swollen joint count plus 20% or greater improvement in at least 3 of the following criteria: 1) patient’s pain assessment; 2) patient’s global assessment; 3) physician’s global assessment; 4) patient’s self-assessed disability; and 5) acute-phase reactant (ESR or CRP). As monotherapy, the percent of patients with ACR20 at 3 months was 33% for anakinra 150 mg/d or 75 mg/d compared to 23% for placebo.1,2 At 6 months it was 43% and 34% for anakinra compared to 27% for placebo (P < 0.05). Anakinra (100 mg/d) in combination with methotrexate produced ACR20 at 3 months of 34% compared to 24% and 38% vs. 22% at 6 months.1 Decrease in absolute neutrophil blood count of at least 1 WHO grade was reported in 8% of patients. The incidence of neutropenia (ANC < 1 × 109/L) was 0.3%. The incidence of serious infections was reported to be higher in patients treated with anakinra compared to placebo (1.8% vs 0.6%). Infections included bacterial cellulitis, pneumonia, and bone and joint infections.1 Preliminary data suggest that concomitant use of anakinra and etanercept increases the risk of neutropenia (3%) and serious infections (7%). Neutrophil counts should be assessed before therapy, monthly for 3 months, and then every 3 months for 1 year. The effect of long-term use of anakinra on the development of neutralizing antibodies is not known.1
Comments
Endogenous IL-1Ra is believed to play an important role in controlling proinflammatory cytokines such as IL-1 alpha and IL-1 beta. Studies in in-vitro and in animal models indicate that IL-Ra reduces the cartilage-destruction process.6 Clinical trials indicate that anakinra may have a greater effect on the radiographic evidence of response than clinical end points as measured by composite symptoms of arthritis (ACR). At 3 months, the ACR20 for anakinra ranged from 33-34% compared to 23-24% for placebo. In contrast, the response reported for etanercept at 3 months was 62% vs. 23% for placebo.7 When used in combination with methotrexate (MTX), anakinra produced ACR20 of 34 and 38% compared to 22 and 24%, respectively, at 3 and 6 months. Similarly, in an infliximab/MTX vs. placebo/MTX study ACR20 ranged from 52-58% for infliximab compared to 20% for placebo at 30 weeks.8 This seems to be consistent with the role of these cytokines as TNF may be more involved in joint swelling and IL-1 in cartilage destruction.9
The wholesale cost of anakinra is $924 for a 4-week supply.
Clinical Implications
Anakinra provides another biologic agent for the treatment of RA. It joins etanercept, a soluble receptor for tissue necrosis factor (TNF), and infliximab a monoclonal antibody against TNF. Anakinra appears to have a modest effect on clinical end points but has shown short-term radiographic evidence of slowing of disease progression. A clear graded dose response was not observed. Comparison with other biological agents is problematic due to the differences in study populations.
Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Asst. Clinical Professor of Medicine, University of California-San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Both are Associate Editors of Internal Medicine Alert.
References
1. Kineret Product Information. November 2001. Amgen Inc.
2. Bresnihan B, et al. Arthritis Rheum. 1998;41(12): 2196-2204.
3. Watt I, Cobby M. Semin Arthritis Rheum. 2001; 30(Suppl 2):21-25.
4. Genant HK. Semin Arthritis Rheum. 2001;30 (Suppl 2):26-32.
5. Jiang Y, et al. Arthritis Rheum. 2000;43(5):1001-1009.
6. Van den Berg WB. Curr Opin Rheumatol. 1997;9: 221-228.
7. Moreland LW, et al. Ann Intern Med. 1999;130(6): 478-486.
8. Maini R, et al. Lancet. 1999;354:1932-1939.
9. Kuiper S, et al. Cytokine. 1998;10(9):690-702.
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