Hypersensitivity reactions including anaphylactoid reactions, angioedema, urticaria, rash, and pruritus have been reported with the use of anakinra. Patients with deficiency of interleukin-1 receptor antagonist (DIRA) may be at increased of hypersensitivity reactions, particularly during the first weeks of therapy; closely monitor patients during this time period. In a study of patients with DIRA, rash was 1 of the most commonly reported adverse reactions and 1 patient experienced a serious reaction of urticaria on Day 10 of therapy. Rash was also observed in 3.7% (n = 15/405) of patients who received anakinra for the treatment of COVID-19 during the clinical trials.[68123] In patients with autoinflammatory conditions, postmarketing use of anakinra has been linked to cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).[27940]

The most common adverse reaction of anakinra subcutaneous administration is injection site reaction, which usually occurs during the first 4 weeks of treatment and is more common in patients with rheumatoid arthritis (RA) than in patients with Neonatal-Onset Multisystem Inflammatory Disease (NOMID). In clinical trials of patients with RA (n= 1,565), 71% of patients developed an injection site reaction; 72.6% were characterized as mild, 24.1% as moderate, and 3.2% as severe. In an open-label trial of NOMID patients (n = 43), 16.3% experienced an injection site reaction; during the 60-month study period, 65% of the injection site reactions occurred during the first month and 76% were reported during the first 6 months; 76% were characterized as mild and 24% as moderate. In a study of 9 patients with Deficiency of Interleukin-1 Receptor Antagonist (DIRA), there was 1 report of injection site pain. These reactions typically last for 14 to 28 days and are characterized by localized erythema, ecchymosis, edema, inflammation, itching, and/or pain. To decrease pain, swelling, and bruising at the injection site, apply a cold compress before and/or after the injection and allow the solution warm to room temperature prior to injection.[27940]

Anakinra has been associated with an increased risk of serious infections during clinical trials. Anakinra may increase the risk of tuberculosis (TB) or other atypical opportunistic infections. During postmarketing observation and in clinical studies, opportunistic infections consisting of fungal, mycobacterial, and bacterial pathogens have occurred. Infections have been noted in all organ systems and have been reported in patients receiving anakinra alone or in combination with immunosuppressive agents. Discontinue anakinra in patients with rheumatoid arthritis (RA) who develop a serious infection. In anakinra-treated patients with Neonatal-Onset Multisystem Inflammatory Disease (NOMID) or Deficiency of Interleukin-1 Receptor Antagonist (DIRA), weigh the risk of a disease flare when discontinuing anakinra against the potential risk of continued treatment.[27940] There is limited information regarding the use of anakinra in patients with COVID-19 and concomitant active serious infections. The risks and benefits of treatment with anakinra in COVID-19 patients with other concurrent infections should be considered.[68123] During RA clinical trials, the incidence of infection during the first 6 months in anakinra-treated patients was 39% vs. 37% in placebo-treated patients. Reported infections in patients with RA included upper respiratory tract infections (14%), sinusitis (7%), and influenza-like symptoms (6%). Serious infections occurred in 2% of anakinra-treated patients with RA over 6 months of therapy and 3% of treated patients after over 1 year of therapy. The serious infections were primarily bacterial infections such as cellulitis, pneumonia, and bone and joint infections. In open-label extension studies, the overall rate of serious infections was comparable to that observed during controlled trials. The use of TNF blockers with anakinra should be avoided. In patients with RA who received both anakinra and a TNF blocker (etanercept) for up to 24 weeks, the incidence of serious infections was 7%. The most common infections consisted of bacterial pneumonia (4 cases) and cellulitis (4 cases). One patient with pulmonary fibrosis and pneumonia died due to respiratory failure. RA patients with asthma had a higher incidence of serious infections during treatment with anakinra versus placebo-treated patients (4.5% vs 0%). In an open-label study of 43 patients with NOMID, infections were the most common type of serious adverse event; reporting frequency was highest in pediatric patients younger than 12 years of age and those younger than 2 years had the highest incidence of infection and related symptoms. The most common infections were upper respiratory tract infection, sinusitis, ear infections (otitis media), and naso-pharyngitis (11.6%). The most common serious infections in NOMID patients were pneumonia and gastroenteritis. There were no deaths or permanent treatment discontinuation due to infection. Most NOMID patients (73%) have continued anakinra therapy once the infection resolved. In a natural history study of 9 patients (aged 1 months to 9 years) with DIRA treated for up to 10 years, infections were the most common type of serious adverse reaction with 5 events reported in 2 patients. Infections reported in patients with DIRA were upper respiratory tract infections, influenza-like illness, cellulitis, and gastroenteritis.[27940] In a placebo-controlled study in COVID-19 patients, serious infections were observed in 9.1% of patients treated with anakinra (n = 37/405) and 16.4% of patients who received placebo (n = 31/189).[68123]

Anakinra treatment has been associated with hematologic side effects, including neutropenia. Monitoring of the absolute neutrophil count (ANC) is recommended prior to and during the first year of treatment with anakinra (monitor at baseline, each month for 3 months, then quarterly). In clinical trials, 8% of patients with rheumatoid arthritis (RA) receiving anakinra had decreases in neutrophil counts of at least one World Health Organization (WHO) toxicity grade compared with 2% in the control group. Neutropenia (ANC 1,000/mm³ or less) was reported in 9 anakinra-treated patients (0.4%) and in 2% of patients treated with anakinra plus etanercept. Two of 43 (4.7%) patients with Neonatal-Onset Multisystem Inflammatory Disease (NOMID) experienced neutropenia after starting anakinra in a clinical trial; both cases resolved during continued anakinra treatment. In RA trials, a total of 9% of anakinra recipients experienced increases in eosinophil differential percentage (eosinophilia) of at least 1 WHO toxicity grade compared to 3% of placebo-treated patients. WHO toxicity grade 1 decreases in platelet counts occurred in 2% of anakinra treated-patients and 0% of placebo-treated patients. Thrombocytopenia, including severe thrombocytopenia (i.e., platelet count less than 10,000/mm³), has been reported with the postmarket use of anakinra.[27940] Hematologic adverse events observed during the clinical studies of anakinra for treatment of COVID-19 included leukopenia (3.5%; n = 14/405) and neutropenia (3%; n = 12/405).[68123]

Adverse gastrointestinal (GI) events reported in 5% or more of patients treated with anakinra during rheumatoid arthritis clinical trials include nausea (8%), diarrhea (7%), and abdominal pain (5%). In an open-label study in 43 NOMID patients, vomiting (14%) was the most common GI adverse event.[27940] During the clinical studies of anakinra for treatment of COVID-19, constipation was observed in 9.1% (n = 37/405) of drug recipients.[68123]

Headache and arthralgia are two of the most common adverse reactions to anakinra treatment. Headache occurred in 12% to 14% of patients during all clinical trials. Arthralgia occurred in 6% of anakinra-treated patients during rheumatoid arthritis (RA) clinical trials over a 6-month period and in 11.6% of 43 patients in a study of anakinra for Neonatal-Onset Multisystem Inflammatory Disease (NOMID). In the RA trials, a total of 19% of anakinra recipients experienced worsening of rheumatoid arthritis, compared to 29% of placebo recipients.[27940]

In an open-label study in 43 patients with Neonatal-Onset Multisystem Inflammatory Disease (NOMID), treatment-emergent pyrexia (fever) was reported in 11.6% of patients. In a natural history study of 9 patients with Deficiency of Interleukin-1 Receptor Antagonist (DIRA), pyrexia was 1 of the most commonly reported adverse reactions. Fever was not reported as an adverse reaction in clinical trials of patients with rheumatoid arthritis.[27940]

Cholesterol elevations were observed in some patients treated with anakinra therapy (hypercholesterolemia incidence not reported).[27940]

Elevated hepatic enzymes and non-infectious hepatitis have been reported during postmarketing use of anakinra.[27940] During the clinical studies of anakinra for treatment of COVID-19, increased transaminases and increased gamma-glutamyltransferase were observed in 30.8% (n = 125/405) and 13.8% (n = 56/405) of drug recipients, respectively.[68123]

As with all therapeutic proteins, the use of anakinra carries the risk for immunogenicity. Antibody formation to anakinra detected by the use of a highly sensitive anakinra-binding biosensor assay was present at least once over 36 months in 49% of patients with rheumatoid arthritis in 2 clinical trials. After at least 12 weeks of anakinra, 30 (2%) of the 1,615 patients with available data were seropositive in a cell-based assay for neutralizing antibodies against anakinra. Thirteen of the 30 patients had follow-up data; 5 remained positive for neutralizing antibodies at week 24. No correlation between antibody development and adverse events was noted. Immunogenicity was not evaluated in trials of patients with Neonatal-Onset Multisystem Inflammatory Disease (NOMID).[27940]

The role of interleukin-1 blockers such as anakinra in the development of new primary malignancy is unknown. In clinical trials, the number of lymphoma cases among 5,300 patients with rheumatoid arthritis treated with anakinra was 0.12 per 100 patient-years. The rate is 3.6-fold higher than the expected rate for the general population, based upon the National Cancer Institute's Surveillance Epidemiology and End Results database. In addition to lymphoma, 37 other cancers were observed including breast, melanoma, respiratory system, and digestive system.[27940]

During clinical studies of anakinra for treatment of COVID-19, anxiety was observed in 8.1% (n = 33/405) of drug recipients.[68123]

During clinical studies of anakinra for treatment of COVID-19, hypothermia was observed in 7.4% (n = 30/405) of drug recipients.[68123]

During clinical studies of anakinra for treatment of COVID-19, acute kidney injury or nephrotoxicity was observed in 6.4% (n = 26/405) of drug recipients.[68123]

Electrolyte abnormalities observed during clinical studies of anakinra for treatment of COVID-19 included hypernatremia (9.6%; n = 39/405) and hyperkalemia (9.1%; n = 37/405).[68123]

Anakinra is contraindicated in patients with E. coli protein hypersensitivity or hypersensitivity to anakinra or any components of the product. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported with the use of anakinra. Patients with deficiency of interleukin-1 receptor antagonist (DIRA) may have an increased risk for allergic reactions, particularly in the first several weeks of anakinra therapy; monitor closely during this time period. In patients with autoinflammatory conditions, treatment with anakinra has been linked to cases of serious rash, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). If a severe hypersensitivity reaction occurs, immediately discontinue anakinra, initiate appropriate therapy, and monitor the patient until signs and symptoms resolve.[27940]

Patients who receive anakinra are at increased risk for developing serious infections. Do not initate anakinra in patients with an active infection. Discontinue administration of anakinra if a patient with rheumatoid arthritis (RA) develops a serious infection. In patients with neonatal-onset multisystem inflammatory disease (NOMID) or deficiency of interleukin-1 receptor antagonist (DIRA), weigh the risk of a disease flare upon discontinuation of anakinra against the potential risk of continued treatment. In COVID-19 patients with other concurrent infections, consider the risks and benefits of treatment with anakinra. Information regarding the use of anakinra in patients with COVID-19 and concomitant active serious infections is limited.[68123] The safety and efficacy of anakinra in patients with chronic infections or immunosuppression, such as bone marrow suppression, have not been evaluated. The impact of anakinra therapy on active or chronic infections is not known. Similar to other drugs that affect the immune system, anakinra may increase the risk of tuberculosis or other atypical or opportunistic infections. In clinical studies and postmarketing experience, cases of opportunistic infections have been observed and included fungal infection, mycobacterial infection, and infection with bacterial pathogens. Infections have been noted in all organ systems and have been reported in patients receiving anakinra alone or in combination with immunosuppressive agents. Follow current CDC guidelines both to evaluate for and to treat possible latent tuberculosis infections before anakinra initiation. In RA trials, patients with asthma appeared to be at a higher risk of developing serious infections during anakinra treatment. Also, use anakinra cautiously in geriatric patients, as there is, in general, a higher incidence of infections in the elderly.[27940]

Decreases in neutrophil count and neutropenia have been reported with anakinra therapy. Neutrophil counts should be checked before anakinra receipt, every month for 3 months, and quarterly after that for a period up to 1 year.[27940] There are limited data regarding the effects of anakinra on neutrophil counts in patients with COVID-19; therefore, assess neutrophil counts prior to starting anakinra treatment for COVID-19 and monitor for neutropenia according to current clinical practices.[68123]

Anakinra is substantially excreted by the kidney; thus, patients with severe renal impairment or renal failure with a creatinine clearance (CrCl) less than 30 mL/minute may be at increased risk for adverse reactions. Consider administration of the prescribed anakinra dose every other day for these patients.[27940] For COVID-19, use of the drug has not been studied in patients with end-stage renal failure necessitating hemofiltration or peritoneal hemodialysis.[68123]

Anakinra is an immunosuppressant and treatment with immunosuppressants may result in an increased risk of cancer. The impact of anakinra on the development of a new primary malignancy is unknown, but malignancies were observed in clinical studies. Consider the risks and benefits of anakinra before initiation in patients with a history of neoplastic disease. Also, consider the risk and benefits of anakinra continuation in patients who develop a malignancy.[27940]

Avoid use of live vaccines concurrently with anakinra. No data are available on either the effects of live vaccination or the secondary transmission of infection by live vaccines in patients receiving anakinra. No data are available on the effectiveness of vaccination with inactivated antigens, other than tetanus/diphtheria toxoids vaccine, in patients receiving anakinra. In one clinical trial, no difference in the anti-tetanus antibody response to tetanus/diphtheria toxoids vaccine was noted between patients receiving anakinra and placebo. Since anakinra interferes with normal immune response mechanisms to new antigens, vaccination may not be effective. The interval between live vaccinations and initiation of anakinra therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.[27940]

Available data from retrospective studies and case reports on anakinra use during human pregnancy are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or maternal and fetal adverse events. The available data have not identified an increased frequency or pattern of birth defects, miscarriage, or adverse maternal or fetal outcomes. Published data do suggest an increased risk of adverse pregnancy outcomes in women with rheumatoid arthritis (RA) or cryopyrin-associated periodic syndromes (CAPS) who have increased disease activity. An international retrospective study of pregnancy outcomes with interleukin-1 inhibitors reported on 23 anakinra-exposed pregnancies. There were 21 live births of healthy infants, 1 miscarriage, and 1 infant with left renal agenesis. The estimated background rate of detected renal malformations is 0.2% to 2% of all newborns. Data for another retrospective study of 10 anakinra-exposed pregnancies in women with CAPS included 9 live births, 1 miscarriage, and 1 fetal death in a twin pregnancy (the surviving twin was healthy). Overall, these data cannot definitively establish or exclude any anakinra-associated risks during pregnancy. Methodological limitations of these data include small sample size and the inability to control for confounders such as the timing of drug exposure, underlying maternal disease, and concomitant medication use. Reproductive studies in animals (rats, rabbits) revealed no evidence of fetal harm at doses up to 25 times the maximum recommended human dose (MRHD) on an mg/kg basis.[27940] Guidelines suggest that until further data are available, anakinra use should be avoided during pregnancy if possible in patients with RA.[62180]

There are no data on the presence of anakinra in either human or animal milk or the effects on milk production. Limited data from a small retrospective study and postmarketing case reports do not establish an association between maternal anakinra use during lactation and adverse effects in breastfed infants. These limited data during lactation preclude a clear determination of the risk of anakinra to an infant during lactation. The developmental and health benefits of breast-feeding should be considered along with the clinical need for anakinra in the mother and any potential adverse effects to the nursing infant from anakinra or from the underlying maternal condition.[27940] Guidelines suggest that until further data are available, anakinra use in patients with RA should be approached with caution and avoided if possible during breast-feeding.[62180]

Very limited data are available describing the use of anakinra in infants; use with caution in young infants. Neonates and infants less than 1 month of age were not included in the trial for the treatment of Neonatal-Onset Multisystem Inflammatory Disease (NOMID). Anakinra prefilled syringes are unable to deliver an anakinra dosage less than 20 mg. Although anakinra has been studied in pediatric patients 2 to 17 years of age with juvenile rheumatoid arthritis (JRA)/juvenile idiopathic arthritis (JIA), the study data were insufficient to demonstrate efficacy.[27940] The emergency use of anakinra is not authorized or approved for the treatment of COVID-19 in pediatric patients younger than 18 years.[68123]

Patients who undergo surgery while taking biologic therapy, such as anakinra, may be at greater risk for postoperative infections. For elective surgeries, balance the risk of postoperative infection against the risk of developing a severe or unstable disease by stopping the biologic therapy. The American College of Rheumatology recommends holding anakinra for 2 days before undergoing total knee or total hip arthroplasties.[71153]