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The safety of Kineret® (anakinra) has been collated from randomised, placebo-controlled clinical studies involving a total of 2,606 patients with rheumatoid arthritis (RA).1 In addition to the safety data obtained from the European Monotherapy Study, the Methotrexate (MTX) Combination Study and the Confirmatory Efficacy Study, a 3-year Safety Study is being conducted to evaluate the overall safety of Kineret® (anakinra) in a population of patients with RA.2,3
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Over 2,600 RA patients have been treated with Kineret® ( anakinra) in large, well-controlled clinical trials
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The Safety Study was designed to parallel patient presentation in the average clinical practice, by including patients receiving a variety of concurrent RA medications including multiple disease-modifying antirheumatic drugs (DMARDs), as well as patients who were DMARD-free.2,3 Concurrent DMARDs included MTX, sulphasalazine, hydroxychloroquine, gold, penicillamine, leflunomide and azathioprine.2,3 However, patients treated with etanercept or infliximab were specifically excluded.2,3 The study population also included patients predisposed to infection because of a history of underlying disease such as pneumonia, asthma, controlled diabetes and chronic obstructive pulmonary disease.2,3 Patients with comorbidities such as hypertension, coronary artery disease and congestive heart failure were also included.2,3 The primary endpoint of the trial was safety, evaluated by death, serious and severe infection, and discontinuation from the study due to adverse events.
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Kineret® ( anakinra) has been assessed in a safety study involving 1,399 patients with existing comorbidities receiving multidrug RA therapies, including DMARDs
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Adverse Events
Of the 2,606 patients treated with Kineret® (anakinra) across the RA studies, 1,812 were exposed for at least 6 months and 570 exposed for at least 1 year. Of these patients, 1,379 have been exposed to greater than or equal to the recommended dose of Kineret® (anakinra; 100 mg/day) for at least 6 months and 237 for at least 1 year.1 Commonly reported adverse events with Kineret® (anakinra) from the Safety Study and Confirmatory Efficacy Study at the recommended dosage of 100 mg/day (those reported in at least 5% of patients) are few and can be seen in Table 1.1-3
Table 1. Adverse events occurring at a frequency of >5% (combined results of the Safety Study and Confirmatory Efficacy Study)5
Injection-Site Reactions
The most frequently reported adverse event with Kineret® (anakinra) was injection-site reactions (ISRs; Table 1). Of the subjects who experienced ISRs in the randomised, placebo-controlled studies (64.4%, n = 1,399), 95.3% (n = 1,333) were reported to be mild-to-moderate and characterised as erythema, ecchymosis, inflammation, and/or pain.1,4
In both the Safety Study and the Confirmatory Efficacy Study, 71% of patients who received Kineret® (anakinra) 100 mg/day developed an ISR, which was typically reported within the first 4 weeks of therapy (Table 1).1-5 The reaction was generally short-lived, with a median duration of 14 to 28 days. The development of ISRs in patients who had not previously experienced ISRs was uncommon after the first month of therapy.1,4
Infections
For both the MTX Combination and the Confirmatory Efficacy Studies, the combined rate of infection occurred with similar frequency among patients treated with either Kineret® (anakinra) or placebo (40% vs 35%, respectively).6 The most frequently reported infections included upper respiratory infections, sinusitis and influenza-like symptoms (Table 1).1,4
The incidence of serious infection, while relatively low overall, was slightly higher in patients treated with Kineret® (anakinra; 1.8%) than patients receiving placebo (0.7%).1,4 These infections consisted primarily of events caused by bacteria, such as cellulitis, pneumonia, and bone and joint infections, rather than opportunistic, fungal or viral infections. Most patients who had discontinued treatment because of infection subsequently resumed treatment with the study drug after the infection had resolved. There were no on-study deaths due to serious infectious episodes in either study.1,4 In clinical studies, the risk of serious infection was higher for patients with a history of asthma than for patients without a history of asthma. The safety and efficacy of Kineret® (anakinra) in patients with chronic infections have not been evaluated.
A total of 635 patients aged >65 years, including 131 patients >75 years, were studied in clinical trials. No overall differences in safety or effectiveness were observed between these patients and younger patients. Because there is a higher incidence of infections in the elderly population in general, caution should be used in treating the elderly.4
Physicians should exercise caution when administering Kineret® (anakinra) to patients with a history of recurrent infections or with underlying conditions that may predispose them to infection.4
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The rate of infection was similar with Kineret® ( anakinra) and placebo, with no increase in the incidence of sepsis, or unusual or opportunistic infections observed
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Neutropenia
Patients with RA often show increases in their white blood cell count owing to the inflammatory aspects of their disease. Kineret® (anakinra), through its anti-inflammatory action, would be expected to cause a decrease in neutrophil count. Kineret® (anakinra) treatment was associated with a non-progressive reduction in total white blood cell count and absolute neutrophil count (ANC). Administration of Kineret® (anakinra) 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.1,4 It is recommended that neutrophil counts be assessed prior to initiating Kineret® (anakinra) treatment, and while receiving Kineret® (anakinra) at monthly periods during the first 6 months of treatment and quarterly thereafter. Kineret® (anakinra) treatment should not be initiated in patients with neutropenia (ANC <1.5 x 109/L). In patients who become neutropenic (ANC <1.5 x 109/L), the ANC should be monitored closely and Kineret® (anakinra) treatment should be discontinued.4
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No serious infectious events with Kineret® ( anakinra) were associated with neutropenia
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Immunosuppression
It is unknown if chronic exposure to Kineret® (anakinra) can increase the incidence of malignancies. The use of Kineret® (anakinra) in patients with pre-existing malignancy is not recommended.4
Vaccinations
No data are available on the effects of vaccination in patients receiving Kineret® (anakinra). Live vaccines should not be given concurrently with Kineret® (anakinra).4
Combination therapy with Kineret® (anakinra) and Enbrel® (etanercept)
Two clinical trials have evaluated the safety of Kineret® (anakinra) in combination with the human TNF receptor p75 Fc fusion protein Enbrel® (etanercept). In a 24-week open-label, single-arm study, 58 patients with active RA receiving Enbrel® (etanercept) 25 mg twice weekly were administered concomitant Kineret® (anakinra) 1 mg/kg/day. Serious adverse events were reported in seven patients (12.1%), all of which resolved. These included four serious infectious episodes: two cases of pneumonia and two of cellulitis. In addition, one case of accidental electrocution, one case of withdrawal syndrome from combination opiates and barbiturates, and one gastric ulcer haemorrhage were reported. There were no reports of tuberculosis or opportunistic infection and there were no deaths during the study.7 The safety and efficacy of combination therapy was further investigated in a 24-week placebo-controlled trial involving 242 active RA patients who were naïve to biological agents and were receiving background MTX. Patients were randomised to one of three treatment arms: Enbrel® (etanercept) 25 mg administered twice weekly + placebo; Enbrel® (etanercept) 25 mg once weekly + Kineret® (anakinra) 100 mg/day; or Enbrel® (etanercept) 25 mg twice weekly + Kineret® (anakinra) 100 mg/day. A higher incidence of serious adverse events, including serious infectious episodes, was observed in the combination therapy groups compared with the group receiving Enbrel® (etanercept) alone (Table 2). Serious infectious episodes in the combination arms included: cellulitis (3 cases), pneumonia (3 cases), pneumonitis (1 case), Herpes zoster (1 case), and pyelonephritis (1 case). No serious infectious episodes were reported in patients receiving Enbrel® (etanercept) as monotherapy.8,9
Table 2. Summary of adverse events occurring with Kineret® (anakinra) in combination with Enbrel®
(etanercept)9
Across the two combination therapy studies, 3/139 patients (2%) developed neutropenia (ANC < 1.0 x 109/L) and, while neutropenic, one patient developed cellulitis that resolved after hospitalisation.8
Because concurrent administration of Kineret® (anakinra) and Enbrel® (etanercept) has been associated with an increased risk of serious infections, an increased risk of neutropenia, and has not demonstrated any additional therapeutic benefit compared with monotherapy, concurrent use of these agents is not recommended. The safety and efficacy of Kineret® (anakinra) used in combination with other TNF antagonists has not been established and their combined use is, therefore, also not recommended.8
Drug Interactions
Toxicological and toxicokinetic interaction studies in rats did not demonstrate any alterations in the clearance or toxicological profile of either MTX or Kineret® (anakinra) when the two agents were administered together.1,4 No formal drug-drug interaction studies in human subjects have been conducted.1,4 However, in clinical trials, interactions between Kineret® (anakinra) and other medicinal products (including NSAIDs, corticosteroids and DMARDs) have not been observed.4
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