Kineret

Interleukin-1 (IL-1) Inhibitors
Other Specific Antirheumatics

 
COVID-19 per the Emergency Use Authorization (EUA):
NOTE: Anakinra is not FDA-approved to treat coronavirus disease 2019 (COVID-19); however, the FDA issued an EUA allowing for use in certain patients with COVID-19. Under the EUA, health care providers are required to communicate to the patient or caregiver information consistent with the "Fact Sheet for Patients and Caregivers" prior to administration of anakinra. If providing this information delays treatment to a degree that would endanger the life of the patient, then the information must be provided as soon as practical following anakinra administration.
 
NOTE: Under the EUA, health care providers are required to report all medication errors and serious adverse events potentially related to anakinra therapy within 7 calendar days from the health care provider's awareness of the event.

Prefilled syringes are for subcutaneous administration.
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Do not use the prefilled syringe if the solution is discolored or cloudy or if foreign particulate matter is present. Trace amounts of small, translucent-to-white, amorphous particles of protein may be in the solution. However, do not use the syringe if the number of translucent-to-white, amorphous particles appears excessive.[27940]

Instructions for appropriate use should be given. Patients or patient's caregiver should not administer anakinra until they have demonstrated a thorough understanding of the procedures and the ability to inject the medication.
Inject the subcutaneous dose at about the same time(s) each day.[27940]
 
Prefilled Syringe:
Remove the prefilled syringe from the refrigerator and allow it to sit at room temperature outside of the carton for 30 minutes before the injection. Do not warm anakinra in any other way.
Wash hands before administration.
The prefilled syringe does not allow doses lower than 20 mg to be administered. For a dose that is less than 100 mg, follow the manufacturer directions for preparing the dose needed. Small air bubbles may be present in the solution and do not need to be removed prior to administration.
Pick an injection site such as the front of the middle thigh, the abdomen outside the 2 inches around the navel, the upper outer buttocks, or the outer area of the upper arm. Do not administer where skin is tender, bruised, red, or hard. Do not administer into scars or stretch marks. Do not inject near a vein that is visible under the skin surface.
Rotate injection sites with each injection.
Clean the injection site with the alcohol swab and let dry.
Gently pinch a fold of skin at the cleaned injection site. With your other hand, hold the syringe like a pencil at a 45 to 90-degree angle to the skin. With a quick, dart-like motion insert the needle into the skin.
Slowly push the plunger down to inject the dose. Use caution during injection to avoid accidental needlestick injuries. The syringe needles do not have safety guards, and the needles are not removable. When the syringe is empty, remove the needle from the skin at the same angle it was inserted. Do not recap the needle.
Dispose of used needles and syringes in an FDA-cleared sharps disposal container right away after use. The prefilled syringes do not contain preservatives and are for single-use only. If a syringe contains medicine after administration, it should be disposed of properly and not reused.[27940]

hyperkalemia / Delayed / 9.1-9.1
nephrotoxicity / Delayed / 6.4-6.4
anaphylactoid reactions / Rapid / Incidence not known
angioedema / Rapid / Incidence not known
new primary malignancy / Delayed / Incidence not known

antibody formation / Delayed / 49.0-49.0
hypernatremia / Delayed / 9.6-9.6
constipation / Delayed / 9.1-9.1
neutropenia / Delayed / 0.4-4.7
leukopenia / Delayed / 3.5-3.5
eosinophilia / Delayed / Incidence not known
thrombocytopenia / Delayed / Incidence not known
hypercholesterolemia / Delayed / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known
hepatitis / Delayed / Incidence not known

injection site reaction / Rapid / 16.3-71.0
infection / Delayed / 39.0-39.0
vomiting / Early / 14.0-14.0
headache / Early / 12.0-14.0
pharyngitis / Delayed / 0-12.0
fever / Early / 0-11.6
anxiety / Delayed / 8.1-8.1
nausea / Early / 8.0-8.0
hypothermia / Delayed / 7.4-7.4
sinusitis / Delayed / 7.0-7.0
diarrhea / Early / 0-7.0
arthralgia / Delayed / 6.0-6.0
abdominal pain / Early / 0-5.0
pruritus / Rapid / Incidence not known
rash / Early / Incidence not known
urticaria / Rapid / Incidence not known
ecchymosis / Delayed / Incidence not known

Kineret

Rx

Recombinant form of the human interleukin-1 receptor antagonist (IL-1Ra)
Used to treat adults with rheumatoid arthritis and adult and pediatric patients with Neonatal-Onset Multisystem Inflammatory Disease (NOMID) and Deficiency of Interleukin-1 Receptor Antagonist (DIRA); EUA issued for use in certain hospitalized adults with COVID-19
Increases risk of serious infections; evaluate for latent TB before use

100 mg subcutaneously once daily, at approximately the same time each day. Higher doses do not result in increased response. Anakinra may be given alone or in combination with DMARDs other than tumor necrosis factor (TNF) inhibitors.

1 to 2 mg/kg subcutaneously once daily, initially. If needed, increase by 0.5 to 1 mg/kg increments. In a clinical trial, the average maintenance dose was 3 to 4 mg/kg/day. Usually given as a single daily dose. However, splitting the daily dose into twice daily administrations may result in better symptom control for some patients. Max: 8 mg/kg/day.[27940]

1 to 2 mg/kg subcutaneously once daily, initially. If needed, increase by 0.5 to 1 mg/kg increments. In a clinical trial, the average maintenance dose was 3 to 4 mg/kg/day. Usually given as a single daily dose. However, splitting the daily dose into twice daily administrations may result in better symptom control for some patients. Max: 8 mg/kg/day. The NOMID premarket clinical trial included 36 pediatric patients, 13 of which were younger than 2 years; the youngest patient studied was 8 months of age.[27940] In a retrospective study of 10 patients (2 months to 20 years of age), the 8 oldest patients (ages 6 to 20 years) required dosages of 1 to 3 mg/kg/day, whereas the 2 youngest patients (3 and 4 months) had severe disease and required 6 and 10 mg/kg/day to control symptoms.[56308]

1 to 2 mg/kg/dose subcutaneously once daily, initially. If needed to control active inflammation, increase by 0.5 to 1 mg/kg increments up to a maximum of 8 mg/kg/day.

1 to 2 mg/kg/dose subcutaneously once daily, initially. If needed to control active inflammation, increase by 0.5 to 1 mg/kg increments up to a maximum of 8 mg/kg/day. The DIRA clinical trial included 9 pediatric patients (aged 1 month to 9 years) treated for up to 10 years. Doses were individually adjusted and the highest dose studied was 7.5 mg/kg/day.

100 mg daily via subcutaneous injection for 10 days is the EUA authorized dose. Concurrent use with TNF blocking agents and other anti-cytokine treatments has not been evaluated in COVID-19 patients. The NIH COVID-19 treatment guidelines do not give recommendations for or against the use of anakinra due to a lack of clinical data.

2 to 6 mg/kg/day subcutaneously may be considered in highly refractory patients who have failed to respond to a second IVIG infusion, an extended course of steroids, or infliximab.[61950]

5 to 10 mg/kg/day IV (preferred) or subcutaneous in 1 to 4 divided doses in patients with refractory MIS-C who do not improve within 24 hours of initial immunomodulatory therapy. Tapering over 2 to 3 weeks, or even longer, may be necessary to avoid rebound inflammation.

1 to 2 mg/kg/dose (Max: 100 mg/dose) subcutaneously once daily for several months.

1 to 2 mg/kg/dose (Max: 100 mg/dose) subcutaneously once daily for several months.

100 mg subcutaneously once daily for 5 days.

†Indicates off-label use

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

CrCl 30 mL/minute or more: No dosage adjustment needed.
CrCl less than 30 mL/minute: Increased risk of adverse reactions; consider administration of the prescribed dose every other day instead of daily for both RA and NOMID.
 
Dosage Adjustments for COVID-19 per EUA:
CrCl 30 mL/minute or more: No dosage adjustment needed.
CrCl less than 30 mL/minute: Consider 100 mg every other day for a total of 5 doses over 10 days for patients with severe renal insufficiency or end-stage renal disease. Use in COVID-19 patients with end-stage renal failure necessitating hemofiltration or peritoneal hemodialysis has not been studied.

Abatacept: (Major) Concomitant use of abatacept with biological DMARDs, such as anakinra, is not recommended because of the possibility of additive immunosuppression and increased risk of infection. There is insufficient experience to assess the safety and efficacy of abatacept administered concurrently with anakinra.
Adalimumab: (Major) Avoid the concomitant use of anakinra with biological DMARDs, such as tumor necrosis factor (TNF) modifiers; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection with no additional clinical benefit. Data suggest a higher rate of serious infections when anakinra and a TNF inhibitor is used in combination with anakinra compared with either drug given alone. Neutropenia (1,000/mcL or less) was observed in 2% of patients receiving the combination. The use of anakinra with a TNF inhibitor in combination did not yield any additional clinical benefit as compared to the use of the TNF inhibitor alone.
Bacillus Calmette-Guerin Vaccine, BCG: (Major) Avoid concurrent use of live vaccines during treatment with anakinra due to potentially increased risk of infections; clinical safety of live vaccines during anakinra treatment has not been established. Live virus vaccines should generally not be administered to an immunosuppressed patient, as they may induce the illness they are intended to prevent. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving anakinra. The interval between live vaccinations and initiation of anakinra therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.
Baricitinib: (Major) Concomitant use of baricitinib with biologic DMARDs, such as anakinra, is not recommended because of the possibility of increased immunosuppression and increased infection risk. Baricitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
Canakinumab: (Major) Concomitant use of anakinra with other drugs that also block interleukin (IL)-1, such as canakinumab, is not recommended; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
Certolizumab pegol: (Major) Avoid the concomitant use of anakinra with biological DMARDs, such as tumor necrosis factor (TNF) modifiers; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection with no additional clinical benefit. Data suggest a higher rate of serious infections when anakinra and a TNF inhibitor is used in combination with anakinra compared with either drug given alone. Neutropenia (1,000/mcL or less) was observed in 2% of patients receiving the combination. The use of anakinra with a TNF inhibitor in combination did not yield any additional clinical benefit as compared to the use of the TNF inhibitor alone.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Etanercept: (Major) Avoid the concomitant use of anakinra with biological DMARDs, such as tumor necrosis factor (TNF) modifiers; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection with no additional clinical benefit. Data suggest a higher rate of serious infections when anakinra and a TNF inhibitor is used in combination with anakinra compared with either drug given alone. Neutropenia (1,000/mcL or less) was observed in 2% of patients receiving the combination. The use of anakinra with a TNF inhibitor in combination did not yield any additional clinical benefit as compared to the use of the TNF inhibitor alone.
Golimumab: (Major) Avoid the concomitant use of anakinra with biological DMARDs, such as tumor necrosis factor (TNF) modifiers; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection with no additional clinical benefit. Data suggest a higher rate of serious infections when anakinra and a TNF inhibitor is used in combination with anakinra compared with either drug given alone. Neutropenia (1,000/mcL or less) was observed in 2% of patients receiving the combination. The use of anakinra with a TNF inhibitor in combination did not yield any additional clinical benefit as compared to the use of the TNF inhibitor alone.
Infliximab: (Major) Avoid the concomitant use of anakinra with biological DMARDs, such as tumor necrosis factor (TNF) modifiers; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection with no additional clinical benefit. Data suggest a higher rate of serious infections when anakinra and a TNF inhibitor is used in combination with anakinra compared with either drug given alone. Neutropenia (1,000/mcL or less) was observed in 2% of patients receiving the combination. The use of anakinra with a TNF inhibitor in combination did not yield any additional clinical benefit as compared to the use of the TNF inhibitor alone.
Intranasal Influenza Vaccine: (Major) Avoid concurrent use of live vaccines during treatment with anakinra due to potentially increased risk of infections; clinical safety of live vaccines during anakinra treatment has not been established. Live virus vaccines should generally not be administered to an immunosuppressed patient, as they may induce the illness they are intended to prevent. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving anakinra. The interval between live vaccinations and initiation of anakinra therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.
Live Vaccines: (Major) Avoid concurrent use of live vaccines during treatment with anakinra due to potentially increased risk of infections; clinical safety of live vaccines during anakinra treatment has not been established. Live virus vaccines should generally not be administered to an immunosuppressed patient, as they may induce the illness they are intended to prevent. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving anakinra. The interval between live vaccinations and initiation of anakinra therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Major) Avoid concurrent use of live vaccines during treatment with anakinra due to potentially increased risk of infections; clinical safety of live vaccines during anakinra treatment has not been established. Live virus vaccines should generally not be administered to an immunosuppressed patient, as they may induce the illness they are intended to prevent. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving anakinra. The interval between live vaccinations and initiation of anakinra therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.
Measles/Mumps/Rubella Vaccines, MMR: (Major) Avoid concurrent use of live vaccines during treatment with anakinra due to potentially increased risk of infections; clinical safety of live vaccines during anakinra treatment has not been established. Live virus vaccines should generally not be administered to an immunosuppressed patient, as they may induce the illness they are intended to prevent. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving anakinra. The interval between live vaccinations and initiation of anakinra therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.
Rilonacept: (Major) Concomitant use of anakinra with other drugs that also block interleukin (IL)-1, such as rilonacept, is not recommended; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
Rituximab: (Major) Utilize caution with concomitant use of rituximab with other biologic agents, such as anakinra; coadministration may result in additive immunosuppression and an increased risk of infection. Limited data are available on the safety of the use of biologic agents in rheumatoid arthritis patients exhibiting peripheral B-cell depletion following treatment with rituximab. Monitor patients closely for signs or symptoms of infection.
Rituximab; Hyaluronidase: (Major) Utilize caution with concomitant use of rituximab with other biologic agents, such as anakinra; coadministration may result in additive immunosuppression and an increased risk of infection. Limited data are available on the safety of the use of biologic agents in rheumatoid arthritis patients exhibiting peripheral B-cell depletion following treatment with rituximab. Monitor patients closely for signs or symptoms of infection.
Rotavirus Vaccine: (Major) Avoid concurrent use of live vaccines during treatment with anakinra due to potentially increased risk of infections; clinical safety of live vaccines during anakinra treatment has not been established. Live virus vaccines should generally not be administered to an immunosuppressed patient, as they may induce the illness they are intended to prevent. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving anakinra. The interval between live vaccinations and initiation of anakinra therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.
Sarilumab: (Major) Avoid using sarilumab with other biological DMARDs including interleukin-1 receptor antagonists such as anakinra; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Major) Avoid concurrent use of live vaccines during treatment with anakinra due to potentially increased risk of infections; clinical safety of live vaccines during anakinra treatment has not been established. Live virus vaccines should generally not be administered to an immunosuppressed patient, as they may induce the illness they are intended to prevent. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving anakinra. The interval between live vaccinations and initiation of anakinra therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.
Smallpox Vaccine, Vaccinia Vaccine: (Major) Avoid concurrent use of live vaccines during treatment with anakinra due to potentially increased risk of infections; clinical safety of live vaccines during anakinra treatment has not been established. Live virus vaccines should generally not be administered to an immunosuppressed patient, as they may induce the illness they are intended to prevent. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving anakinra. The interval between live vaccinations and initiation of anakinra therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.
Tocilizumab: (Major) Avoid the concomitant use of tocilizumab with biological DMARDs, including interleukin-1 receptor antagonists such as anakinra; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
Tofacitinib: (Major) Avoid concomitant use of tofacitinib with biologic DMARDs, such as anakinra; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
Tumor Necrosis Factor modifiers: (Major) Avoid the concomitant use of anakinra with biological DMARDs, such as tumor necrosis factor (TNF) modifiers; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection with no additional clinical benefit. Data suggest a higher rate of serious infections when anakinra and a TNF inhibitor is used in combination with anakinra compared with either drug given alone. Neutropenia (1,000/mcL or less) was observed in 2% of patients receiving the combination. The use of anakinra with a TNF inhibitor in combination did not yield any additional clinical benefit as compared to the use of the TNF inhibitor alone.
Typhoid Vaccine: (Major) Avoid concurrent use of live vaccines during treatment with anakinra due to potentially increased risk of infections; clinical safety of live vaccines during anakinra treatment has not been established. Live virus vaccines should generally not be administered to an immunosuppressed patient, as they may induce the illness they are intended to prevent. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving anakinra. The interval between live vaccinations and initiation of anakinra therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.
Upadacitinib: (Major) Avoid the concomitant use of upadacitinib with biologic DMARDs, such as anakinra; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
Varicella-Zoster Virus Vaccine, Live: (Major) Avoid concurrent use of live vaccines during treatment with anakinra due to potentially increased risk of infections; clinical safety of live vaccines during anakinra treatment has not been established. Live virus vaccines should generally not be administered to an immunosuppressed patient, as they may induce the illness they are intended to prevent. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving anakinra. The interval between live vaccinations and initiation of anakinra therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.
Yellow Fever Vaccine, Live: (Major) Avoid concurrent use of live vaccines during treatment with anakinra due to potentially increased risk of infections; clinical safety of live vaccines during anakinra treatment has not been established. Live virus vaccines should generally not be administered to an immunosuppressed patient, as they may induce the illness they are intended to prevent. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving anakinra. The interval between live vaccinations and initiation of anakinra therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

Kineret Subcutaneous Inj Sol: 0.67mL, 100mg

100 mg/day subcutaneously for RA; 8 mg/kg/day subcutaneously for NOMID and DIRA; 100 mg/day subcutaneously authorized for COVID-19.

100 mg/day subcutaneously for RA; 100 mg/day subcutaneously authorized for COVID-19.

8 mg/kg/day subcutaneously for NOMID and DIRA.

8 mg/kg/day subcutaneously for NOMID and DIRA.

8 mg/kg/day subcutaneously in NOMID and DIRA. Limited data available in young infants; up to 10 mg/kg/day subcutaneously has been used off-label in an infant with severe NOMID.

Safety and efficacy have not been established.

Anakinra acts similarly to the native interleukin-1 receptor antagonist (IL-1Ra). IL-1Ra blocks the effects of IL-1 by competitively inhibiting the binding of IL-1, specifically IL-1 alpha and IL-1 beta, to the interleukin-1 type 1 receptor (IL-1R1), which is expressed in a wide variety of tissues. IL-1Ra is part of the feedback loop that is designed to balance the effects of inflammatory cytokines. IL-1 is 1 of the primary pro-inflammatory cytokines associated with rheumatoid arthritis, acting synergistically with tumor necrosis factor-alpha (TNF-alpha). Both IL-1 and TNF-alpha are expressed in the synovium of rheumatoid arthritis patients, although, IL-1, specifically IL-1beta, is secreted to a greater extent than TNF-alpha. IL-1 causes cartilage degradation by inducing the rapid loss of proteoglycans and stimulating the production of neutral proteinases in chondrocytes. Since IL-1 stimulates osteoclasts, bone resorption occurs. Rheumatoid arthritis patients who have bone erosions also have higher synovial fluid concentrations of IL-1 than rheumatoid arthritis patients with no bone erosions. These higher concentrations of IL-1 cannot be overcome by endogenous IL-1Ra. By administering exogenous IL-1Ra (i.e., anakinra), the erosive bone effects and bone resorption associated with IL-1 may be inhibited.
 
The efficacy of anakinra for the treatment of familial cold autoinflammatory syndrome appears to be related to inhibition of IL-1 beta, IL-6, and IL-8 in affected skin and to inhibition of increased IL-6 serum concentrations after cold exposure. In excess, IL-1 has been shown to be a key driver of inflammation in cryopyrin-associated periodic syndromes (CAPS), which is caused by a range of mutations in the gene CIAS1 that encodes the protein cryopyrin. Cryopyrin binds with an intrinsic inhibitor and controls the activation of caspase-1. Caspase-1 cleaves pro-interleukin-1beta and IL-18 into the biologically active forms. Patients with CAPS have increased caspase activity and thus, increased biologically active IL-1 beta. Enhanced caspase-1 activity with subsequent enhanced IL-1 beta and IL-18 release has been demonstrated in a patient with chronic infantile neurologic, cutaneous, articular (CINCA) syndrome. Anakinra receipt to several patients with different CAPS phenotypes led to the reduction of many CAPS clinical manifestations.
 
Deficiency of IL-1 receptor antagonist (DIRA) is due to mutations in the IL1RN gene leading to loss of secretion of the IL-1Ra. Loss of IL-1Ra results in unopposed signaling of the proinflammatory cytokines IL-1 alpha and IL-1 beta, causing systemic inflammation with skin and bone involvement. Anakinra is the recombinant form of IL-1Ra that patients with DIRA are lacking.

Anakinra is given subcutaneously. In patients with rheumatoid arthritis (RA), no unexpected accumulation of anakinra was observed after daily subcutaneous doses for up to 24 weeks. The terminal half-life of anakinra ranges from 4 to 6 hours among patients with RA. Among patients with Neonatal Onset Multisystem Inflammatory Disease (NOMID), the median half-life was 5.7 hours (range, 3.1 to 28.2 hours). Anakinra is renally eliminated; the mean clearance of the drug increases with increasing creatinine clearance and body weight.[27940]

The absolute bioavailability of anakinra after subcutaneous injection in healthy subjects is 95%. After administration to subjects with RA, the maximum plasma concentration occurs within 3 to 7 hours. In NOMID patients (n = 16) receiving a median dose of 3 mg/kg once daily subcutaneously and a median treatment time of 3.5 years, the steady-state median (range) maximal concentration (Cmax) was 3,628 (655 to 8,511) ng/mL and the median (range) 24-hour concentration was 203 (53 to 1,979) ng/mL.

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. Guidelines suggest that until further data are available, anakinra use should be avoided during pregnancy if possible in patients with RA.

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. 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.