Chemical formula: C₂₀H₂₃N₅O₇S₂ Molecular mass: 509.6 g/mol
Anakinra interacts in the following cases:
In a placebo-controlled clinical study (n=126), no difference was detected in anti-tetanus antibody response between the anakinra and placebo treatment groups when a tetanus/diphtheria toxoid vaccine was administered concurrently with anakinra. No data are available on the effects of vaccination with other inactivated antigens, or COVID-19 vaccines, in patients receiving anakinra.
No data are available on either the effects of live vaccination or on the secondary transmission of infection by live vaccines in patients receiving anakinra. Therefore, live vaccines should not be given concurrently with anakinra.
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 anakinra 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.
Anakinra 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 anakinra every other day should be considered.
Anakinra should be used with caution in patients with severe hepatic impairment.
In a clinical study with RA patients receiving background methotrexate, patients treated with anakinra 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 studies where anakinra was used alone. Concurrent anakinra and etanercept treatment has not demonstrated increased clinical benefit.
The concurrent administration of anakinra and etanercept or other TNF-α antagonists is not recommended.
The impact of treatment with anakinra on pre-existing malignancy has not been studied. Therefore the use of anakinra in patients with pre-existing malignancy is not recommended.
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. As a precautionary measure, it is preferable to avoid the use of anakinra during pregnancy and in woman 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 anakinra.
Not relevant.
In placebo-controlled studies in RA patients, the most frequently reported adverse reactions with anakinra were injection site reactions (ISRs), which were mild to moderate in the majority of patients. The most common reason for withdrawal from study in anakinra-treated RA patients was injection site reaction. The subject incidence of serious adverse reactions in RA studies at the recommended dose of anakinra (100 mg/day) was comparable with placebo (7.1% compared with 6.5% in the placebo group). The incidence of serious infection was higher in anakinra-treated patients compared to patients receiving placebo (1.8% vs. 0.7%). Neutrophil decreases occurred more frequently in patients receiving anakinra compared with placebo.
Adverse reactions data in COVID-19 are based on a randomized placebo-controlled study of 405 anakinra-treated patients with COVID-19 pneumonia (SAVE-MORE study). The incidence of serious adverse reactions in the anakinra-treatment group was comparable with the placebo group. Neutropenia, elevation of liver function test, rash and injection site reactions were reported more frequently in patients receiving anakinra compared with placebo. The overall safety profile in patients with COVID-19 treated with anakinra is similar to that in anakinra-treated patients with RA.
Adverse reactions data in CAPS patients are based on an open-label study of 43 patients with NOMID/CINCA treated with anakinra for up to 5 years, with a total anakinra exposure of 159.8 patient years. During the 5-year study 14 patients (32.6%) reported 24 serious events. Eleven serious events in 4 (9.3%) patients were considered related to anakinra. No patient withdrew from anakinra treatment due to adverse reactions.
Adverse events data in patients with Still’s disease is based on a partially open-label and partially blinded, placebo-controlled study of 15 SJIA patients, treated for up to 1.5 years and a randomised double blind placebo-controlled study of 11 adult and paediatric patients with Still’s disease (6 anakinra and 5 placebo) treated for 12 weeks and followed for an additional 4 weeks. In addition, a non- interventional long-term safety study in 306 paediatric patients with Still’s disease, post-marketing adverse event reports and published studies constitute supporting data.
Adverse events data in patients with FMF are based on post-marketing adverse event reports and published studies.
There are no indications either from these studies or from post-marketing adverse reaction reports that the overall safety profile in patients with CAPS, FMF or Still’s disease is different from that in patients with RA, with the exception of the postmarketing observation of a higher frequency of reported hepatic events in patients with Still’s disease. The adverse reactions table below therefore applies to anakinra treatment of RA, CAPS, FMF and Still’s disease. During long term treatment of RA, CAPS, and Still’s disease the safety profile remains unchanged over time.
Adverse reactions are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
| MedDRA Organ System | Frequency | Undesirable Effect |
|---|---|---|
| Infections and infestations | Common (≥1/100 to <1/10) | Serious infections |
| Blood and lymphatic system disorders | Common (≥1/100 to <1/10) | Neutropenia Thrombocytopenia |
| Immune system disorders | Uncommon (≥1/1 000 to <1/100) | Allergic reactions including anaphylactic reactions, angioedema, urticaria and pruritus |
| Nervous system disorders | Very common (≥1/10) | Headache |
| Hepatobiliary disorders | Uncommon (≥1/1 000 to <1/100) | Hepatic enzyme increased |
| Not known (cannot be estimated from the available data) | Non-infectious hepatitis | |
| General disorders and administration site conditions | Very common (≥1/10) | Injection site reaction |
| Skin and subcutaneous tissue disorders | Uncommon (≥1/1 000 to <1/100) | Rash |
| Not known (cannot be estimated from the available data) | Injection site amyloid deposits | |
| Investigations | Very common (≥1/10) | Blood cholesterol increased |
The incidence of serious infections in RA studies conducted at the recommended dose (100 mg/day) was 1.8% in anakinra 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 medicinal product after the infection resolved.
In the clinical study in COVID-19, secondary serious infections were common, however less frequently observed in patients treated with anakinra compared to placebo-treated patients.
In a study with 43 CAPS patients followed for up to 5 years the frequency of serious infections was 0.1/year, the most common being pneumonia and gastroenteritis. Anakinra was temporarily stopped in one patient, all other patients continued anakinra treatment during the infections.
In a study with 15 SJIA patients followed for up to 1.5 years, one patient developed a serious hepatitis in connection with a cytomegalovirus infection. In a study with 11 patients with Still’s disease (SJIA and AOSD) randomized to anakinra (6 patients) or Placebo (5 patients) and followed for 16 weeks, no serious infections were reported. In a non-interventional long-term safety study of anakinra in 306 paediatric patients with Still’s disease followed for up to more than 9 years (mean duration of a treatment course with anakinra was 17.0 (standard deviation 21.1) months and the median duration was 8.9 months), serious infections were reported in 13 patients. There are no indications from post- marketing adverse event reports and published studies that types and severity of infections in patients with FMF differ from those in patients with RA, CAPS or Still’s disease.
In clinical studies and during post-marketing use, rare cases of opportunistic infections have been observed and have included fungal, mycobacterial, bacterial, and viral pathogens. Infections have been noted in all organ systems and have been reported in patients receiving anakinra alone or in combination with immunosuppressive agents.
In placebo-controlled RA studies with anakinra, treatment was associated with small reductions in the mean values for total white blood count and absolute neutrophil count (ANC). Neutropenia (ANC <1.5 × 109/l) was reported in 2.4% patients receiving anakinra compared with 0.4% of placebo patients. None of these patients had serious infections associated with the neutropenia.
In the clinical study in COVID-19, events of neutropenia were reported in 3.0% of anakinra-treated patients and 0.5% of patients receiving placebo. All adverse events of neutropenia were mild or moderate in severity.
In a study with 43 CAPS patients followed for up to 5 years neutropenia was reported in 2 patients. Both episodes of neutropenia resolved over time with continued anakinra treatment.
In a study with 15 SJIA patients followed for up to 1.5 years, one event of transient neutropenia was reported. In a study with 11 patients with Still’s disease (SJIA and AOSD) randomized to anakinra (6 patients) or Placebo (5 patients) and followed for 16 weeks, no neutropenia was reported. In a non-interventional long-term safety study in 306 paediatric patients with Still’s disease followed for up to more than 9 years, (mean duration of treatment course with anakinra was 17.0 (standard deviation 21.1) months and the median duration was 8.9 months), 5 events of neutropenia including 1 event of febrile neutropenia, were reported.
In clinical studies in RA patients, thrombocytopenia has been reported in 1.9% of treated patients compared to 0.3% in the placebo group. The thrombocytopenias have been mild, i.e. platelet counts have been >75 × 109/l. Mild thrombocytopenia has also been observed in CAPS patients.
During post-marketing use of anakinra, thrombocytopenia has been reported, including occasional case reports indicating severe thrombocytopenia (i.e. platelet counts <10 × 109/l).
Allergic reactions including anaphylactic reactions, angioedema, urticaria, rash, and pruritus have been reported uncommonly with anakinra. The majority of these reactions were maculopapular or urticarial rashes.
In a study with 43 CAPS patients followed for up to 5 years, no allergic event was serious and no event required discontinuation of anakinra treatment.
In a study with 15 SJIA patients followed for up to 1.5 years, no allergic event was serious and no event required discontinuation of anakinra. In a study with 11 patients with Still’s disease (SJIA and AOSD) randomised to anakinra (6 patients) or Placebo (5 patients) and followed for 16 weeks, no allergic reactions were reported.
In a study with 12 FMF patients treated 4 months with anakinra in a published randomized controlled study no allergic event was reported as serious and no event required discontinuation of anakinra.
In the clinical study in COVID-19, no allergic reaction was considered related to anakinra.
In clinical studies in RA, up to 3% of adult patients tested seropositive at least once during the study for neutralizing anti-anakinra antibodies. The occurrence of antibodies was typically transient and not associated with clinical adverse reactions or diminished efficacy. In addition, in a clinical study 6% of 86 paediatric patients with JIA, whereof none of the 15 SJIA subtype patients, tested seropositive at least once during the study for neutralizing anti-anakinra antibodies. In a clinical study with 6 patients randomized to anakinra for 12 weeks for Still’s disease (SJIA and AOSD), all patients developed ADAs but none of the patients were tested seropositive for neutralizing anti anakinra antibodies.
The majority of CAPS patients in Study 03-AR-0298 developed anakinra anti-drug antibodies. This was not associated with any clinically significant effects on pharmacokinetics, efficacy, or safety.
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 serious hepatitis in connection with a cytomegalovirus infection.
During post-marketing use isolated case reports indicating non-infectious hepatitis have been received. Hepatic events during post-marketing use have mainly been reported in patients that have been treated for Still’s disease and in patients with predisposing factors, e.g. a history of transaminase elevations before start of anakinra treatment.
ISRs typically appear within 2 weeks of therapy and disappear within 4-6 weeks. The development of ISRs in patients who had not previously experienced ISRs was uncommon after the first month of therapy.
In RA patients the most common and consistently reported treatment-related adverse reactions associated with anakinra 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 RA patients developed an ISR compared to 28% of the placebo treated patients.
In a study with 43 CAPS patients followed for up to 5 years no patient permanently or temporarily discontinued anakinra treatment due to injection site reactions.
In a study with 15 SJIA patients followed for up to 1.5 years, the most common and consistently reported treatment-related adverse reactions associated with anakinra treatment were ISRs. One out of the 15 patients discontinued due to ISRs. In a placebo-controlled study with 11 patients with Still’s disease (SJIA and AOSD) randomized to anakinra (6 patients) or Placebo (5 patients) for 12 weeks, ISRs occurred in both treatment groups, of which all were mild in severity. No patient discontinued treatment due to ISRs. In a non-interventional long-term safety study in 306 paediatric patients with Still’s disease followed for up to more than 9 years (mean duration of a treatment course with anakinra was 17.0 (standard deviation 21.1) months and the median duration was 8.9 months), ISRs of moderate or severe intensity had an incidence rate of 1.6 per 100 patient years.
In patients with FMF the types and frequencies of ISRs are similar to those seen in RA and SJIA. Discontinuations due to ISRs have occurred also in patients with FMF.
In patients with COVID-19 treated with anakinra, injection site reactions were reported with low frequency.
During post-marketing use, isolated cases of injection site amyloid deposits have been reported in patients with NOMID/CINCA who received high doses of anakinra injected subcutaneously into the same area of skin over long periods of time. Rotation of injection sites is therefore recommended.
In clinical studies of RA, 775 patients treated with daily anakinra doses of 30 mg, 75 mg, 150 mg, 1 mg/kg or 2 mg/kg, there was an increase of 2.4% to 5.3% in total cholesterol levels 2 weeks after start of anakinra treatment, without a dose-response relationship. A similar pattern was seen after 24 weeks anakinra treatment. Placebo treatment (n=213) resulted in a decrease of approximately 2.2% in total cholesterol levels at week 2 and 2.3% at week 24. No data are available on LDL or HDL cholesterol.
Anakinra has been studied in 36 patients with CAPS, 21 patients with SJIA and 71 patients with other forms of JIA, aged 8 months to <18 years, for up to 5 years. With the exception of infections and related symptoms that were more frequently reported in patients <2 years of age, the safety profile was similar in all paediatric age groups. In addition, 306 paediatric patients with Still’s disease have been followed for up to more than 9 years in a non-interventional long-term safety study. The safety profile in paediatric patients was similar to that seen in adult populations and no clinically relevant new adverse reactions were seen.
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