Anakinra

KINERET is an interleukin-1 receptor antagonist indicated for: Rheumatoid Arthritis (RA) Reduction in signs and symptoms and slowing the progression of structural damage in moderately to severely active rheumatoid arthritis, in patients 18 years of age or older who have failed 1 or more disease modifying antirheumatic drugs (DMARDs) ( 1.1 ) Cryopyrin-Associated Periodic Syndromes (CAPS) Treatment of Neonatal-Onset Multisystem Inflammatory Disease (NOMID) ( 1.2 ) Deficiency of Interleukin-1 Receptor Antagonist (DIRA) Treatment of Deficiency of Interleukin-1 Receptor Antagonist (DIRA) ( 1.3 )

1.1 Active Rheumatoid Arthritis KINERET is indicated for the reduction in signs and symptoms and slowing the progression of structural damage in moderately to severely active rheumatoid arthritis (RA), in patients 18 years of age or older who have failed 1 or more disease modifying antirheumatic drugs (DMARDs). KINERET can be used alone or in combination with DMARDs other than Tumor Necrosis Factor (TNF) blocking agents [see Warnings and Precautions ( 5.2 )].

1.2 Cryopyrin-Associated Periodic Syndromes (CAPS) KINERET is indicated for the treatment of Neonatal-Onset Multisystem Inflammatory Disease (NOMID).

1.3 Deficiency of Interleukin-1 Receptor Antagonist (DIRA) KINERET is indicated for the treatment of Deficiency of Interleukin-1 Receptor Antagonist (DIRA)

Injection: 100 mg/0.67 mL solution in a single-use prefilled syringe for subcutaneous injection. Graduated syringe allows for doses between 20 and 100 mg. Injection: 100 mg/0.67 mL solution in a single-use prefilled syringe for subcutaneous injection. Graduated syringe allows for doses between 20 mg and 100 mg. ( 3 )

KINERET is contraindicated in patients with known hypersensitivity to E coli -derived proteins, KINERET, or any components of the product [see Hypersensitivity Reactions ( 5.3 )] . Known hypersensitivity to E coli -derived proteins, Kineret, or to any component of the product. ( 4 )

In RA, discontinue use if serious infection develops. In KINERET-treated NOMID or DIRA patients, the risk of a disease flare when discontinuing KINERET treatment should be weighed against the potential risk of continued treatment. Do not initiate KINERET in patients with active infections. ( 5.1 ) Use in combination with Tumor Necrosis Factor (TNF) blocking agents is not recommended ( 5.2 ) Hypersensitivity reactions, including anaphylactic reactions and angioedema, and serious cutaneous reactions including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) can occur; discontinue KINERET, treat promptly, and monitor until reaction resolves. Patients with DIRA may have an increased risk of allergic reactions, particularly in the first several weeks after starting KINERET treatment ( 5.3 ) The impact of treatment with KINERET on active and/or chronic infections and the development of malignancies is not known ( 5.4 ) Recommend patients to rotate injection sites to reduce the risk of injection site amyloid deposits ( 5.5 ) Live vaccines should not be given concurrently with KINERET ( 5.6 ) Neutrophil counts should be assessed prior to initiating KINERET treatment, and while receiving KINERET, monthly for 3 months, and thereafter quarterly for a period up to 1 year ( 5.7 )

5.1 Serious Infections KINERET has been associated with an increased incidence of serious infections (2%) vs. Placebo (< 1%) in clinical trials in RA. Administration of KINERET in RA should be discontinued if a patient develops a serious infection. In KINERET treated NOMID and DIRA patients the risk of a disease flare when discontinuing KINERET treatment should be weighed against the potential risk of continued treatment. Treatment with KINERET should not be initiated in patients with active infections. The safety and efficacy of KINERET in immunosuppressed patients or in patients with chronic infections have not been evaluated. Drugs that affect the immune system by blocking tumor necrosis factor (TNF) have been associated with an increased risk of reactivation of latent tuberculosis (TB). It is possible that taking drugs such as KINERET that blocks IL-1 increases the risk of TB or other atypical or opportunistic infections. Health care providers should follow current CDC guidelines both to evaluate for and to treat possible latent tuberculosis infections before initiating therapy with KINERET.

5.2 Use with TNF Blocking Agents In a 24-week study of concurrent KINERET and etanercept therapy in RA patients, the rate of serious infections in the combination arm (7%) was higher than with etanercept alone (0%). The combination of KINERET and etanercept did not result in higher ACR response rates compared to etanercept alone [see Clinical Studies ( 14 )] . Use of KINERET in combination with TNF blocking agents is not recommended.

5.3 Hypersensitivity Reactions Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported with KINERET. Serious cutaneous reactions, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported in patients with autoinflammatory conditions treated with KINERET. If a severe hypersensitivity reaction occurs, immediately discontinue KINERET; treat promptly and monitor until signs and symptoms resolve. KINERET is the recombinant form of IL-1Ra that DIRA patients are lacking. Patients with DIRA may have an increased risk of allergic reactions, particularly in the first several weeks after starting KINERET treatment. Patients should be closely monitored during this time period. If a severe allergic reaction occurs, appropriate treatment should be initiated and discontinuation of KINERET should be considered.

5.4 Immunosuppression The impact of treatment with KINERET on active and/or chronic infections and the development of malignancies is not known [see Adverse Reactions ( 6 )] .

5.5 Amyloidosis Post-marketing cases of injection site amyloid deposits [see Postmarketing Experience ( 6.4 )] have been reported in NOMID patients after receiving high doses of Kineret injected subcutaneously into the same area of skin over long periods of time. Systemic AIL1RAP (IL-1 receptor antagonist protein) amyloidosis occurred in some of these patients with injection site amyloid deposits; these patients presented with proteinuria. Recommend patients to rotate their injection sites. In patients with confirmed injection site amyloid deposits, monitor proteinuria for systemic amyloidosis.

5.6 Immunizations In a placebo-controlled clinical trial (n = 126), no difference was detected in anti-tetanus antibody response between the KINERET and placebo treatment groups when the tetanus/diphtheria toxoids vaccine was administered concurrently with KINERET. No data are available on the effects of vaccination with other inactivated antigens in patients receiving KINERET. No data are available on either the effects of live vaccination or the secondary transmission of infection by live vaccines in patients receiving KINERET. Therefore, live vaccines should not be given concurrently with KINERET.

5.7 Neutrophil Count Patients receiving KINERET may experience a decrease in neutrophil counts. Neutrophil counts should therefore be assessed prior to initiating KINERET treatment, and while receiving KINERET, monthly for 3 months, and thereafter quarterly for a period up to 1 year. In the placebo-controlled studies, 8% of RA patients receiving KINERET had decreases in neutrophil counts of at least one World Health Organization (WHO) toxicity grade compared with 2% in the placebo control group. Nine KINERET-treated patients (0.4%) experienced neutropenia (ANC < 1 x 10 9 /L). This is discussed in more detail in the Adverse Reactions ( 6 ): Hematologic Events ( 6.1 ) section. In 43 NOMID patients followed for up to 60 months 2 patients experienced neutropenia that resolved over time during continued KINERET treatment. [see Adverse Reactions ( 6.2 )]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Rheumatoid Arthritis (RA) Most common adverse reactions (incidence ≥ 5%) are injection site reaction, worsening of rheumatoid arthritis, upper respiratory tract infection, headache, nausea, diarrhea, sinusitis, arthralgia, flu like-symptoms, and abdominal pain ( 6.1 ) NOMID The most common AEs during the first 6 months of treatment (incidence > 10%) are injection site reaction, headache, vomiting, arthralgia, pyrexia, and nasopharyngitis ( 6.2 ) DIRA The most common AEs are upper respiratory tract infections, rash, pyrexia, influenza like illness, and gastroenteritis ( 6.3 ) To report SUSPECTED ADVERSE REACTIONS, contact Swedish Orphan Biovitrum at 1-866-547-0644 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Studies Experience in RA The most serious adverse reactions were: Serious Infections – [see Warnings and Precautions ( 5.1 )] Neutropenia, particularly when used in combination with TNF blocking agents The most common adverse reaction with KINERET is injection-site reactions. These reactions were the most common reason for withdrawing from studies. The data described herein reflect exposure to KINERET in 3025 patients, including 2124 exposed for at least 6 months and 884 exposed for at least one year. Studies 1 and 4 used the recommended dose of 100 mg per day. The patients studied were representative of the general population of patients with rheumatoid arthritis. Injection-site Reactions The most common and consistently reported treatment-related adverse event associated with KINERET is injection-site reaction (ISR). In Studies 1 and 4, 71% of patients developed an ISR, which was typically reported within the first 4 weeks of therapy. The majority of ISRs were reported as mild (72.6% mild, 24.1% moderate and 3.2% severe). The ISRs typically lasted for 14 to 28 days and were characterized by 1 or more of the following: erythema, ecchymosis, inflammation, and pain. Injection-site Reactions The most common and consistently reported treatment-related adverse event associated with KINERET is injection-site reaction (ISR). In Studies 1 and 4, 71% of patients developed an ISR, which was typically reported within the first 4 weeks of therapy. The majority of ISRs were reported as mild (72.6% mild, 24.1% moderate and 3.2% severe). The ISRs typically lasted for 14 to 28 days and were characterized by 1 or more of the following: erythema, ecchymosis, inflammation, and pain. Injection-site Reactions The most common and consistently reported treatment-related adverse event associated with KINERET is injection-site reaction (ISR). In Studies 1 and 4, 71% of patients developed an ISR, which was typically reported within the first 4 weeks of therapy. The majority of ISRs were reported as mild (72.6% mild, 24.1% moderate and 3.2% severe). The ISRs typically lasted for 14 to 28 days and were characterized by 1 or more of the following: erythema, ecchymosis, inflammation, and pain. Infections In Studies 1 and 4 combined, the incidence of infection was 39% in the KINERET-treated patients and 37% in placebo-treated patients during the first 6 months of blinded treatment. The incidence of serious infections in Studies 1 and 4 was 2% in KINERET-treated patients and 1% in patients receiving placebo over 6 months. The incidence of serious infection over 1 year was 3% in KINERET-treated patients and 2% in patients receiving placebo. These infections consisted primarily of bacterial events such as cellulitis, pneumonia, and bone and joint infections. Majority of patients (73%) continued on study drug after the infection resolved. No serious opportunistic infections were reported. Patients with asthma appeared to be at higher risk of developing serious infections when treated with KINERET (8 of 177 patients, 4.5%) compared to placebo (0 of 50 patients, 0%). In open-label extension studies, the overall rate of serious infections was stable over time and comparable to that observed in controlled trials. In clinical studies and postmarketing experience, cases of opportunistic infections have been observed and included fungal, mycobacterial and bacterial pathogens. Infections have been noted in all organ systems and have been reported in patients receiving KINERET alone or in combination with immunosuppressive agents. In patients who received both KINERET and 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. Malignancies Among 5300 RA patients treated with KINERET in clinical trials for a mean of 15 months (approximately 6400 patient years of treatment), 8 lymphomas were observed for a rate of 0.12 cases/100 patient years. This is 3.6 fold higher than the rate of lymphomas expected in the general population, based on the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) database. 3 An increased rate of lymphoma, up to several fold, has been reported in the RA population, and may be further increased in patients with more severe disease activity. Thirty-seven malignancies other than lymphoma were observed. Of these, the most common were breast, respiratory system, and digestive system. There were 3 melanomas observed in Study 4 and its long-term open-label extension, greater than the 1 expected case. The significance of this finding is not known. While patients with RA, particularly those with highly active disease, may be at a higher risk (up to several fold) for the development of lymphoma, the role of IL-1 blockers in the development of malignancy is not known. Hematologic Events In placebo-controlled studies with KINERET, 8% of patients receiving KINERET had decreases in total white blood counts of at least one WHO toxicity grade, compared with 2% of placebo patients. Nine KINERET-treated patients (0.4%) developed neutropenia (ANC < 1 x 10 9 /L). 9 % of patients receiving KINERET had increases in eosinophil differential percentage of at least one WHO toxicity grade, compared with 3 % of placebo patients. Of patients treated concurrently with KINERET and etanercept 2% developed neutropenia (ANC < 1 x 10 9 /L). While neutropenic, one patient developed cellulitis which recovered with antibiotic therapy. 2% of patients receiving KINERET had decreases in platelets, all of WHO toxicity grade one, compared to 0% of placebo patients. Hypersensitivity Reactions Hypersensitivity reactions including anaphylactic reactions, angioedema, urticaria, rash, and pruritus have been reported with KINERET. Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. In Studies 1 and 4, from which data is available for up to 36 months, 49% of patients tested positive for anti-anakinra binding antibodies at one or more time points using a biosensor assay. Of the 1615 patients with available data at Week 12 or later, 30 (2%) tested positive for neutralizing antibodies in a cell-based bioassay. Of the 13 patients with available follow-up data, 5 patients remained positive for neutralizing antibodies at the end of the studies. No correlation between antibody development and adverse events was observed. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assays. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including sample handling, concomitant medications, and underlying disease. […]

No drug-drug interaction studies in human subjects have been conducted. Toxicologic and toxicokinetic studies in rats did not demonstrate any alterations in the clearance or toxicologic profile of either methotrexate or KINERET when the two agents were administered together. A higher rate of serious infections has been observed in RA patients treated with concurrent KINERET and etanercept therapy than in patients treated with etanercept alone. Use of KINERET in combination with TNF blocking agents is not recommended ( 7 ) 7.1 TNF Blocking Agents A higher rate of serious infections has been observed in patients treated with concurrent KINERET and etanercept therapy than in patients treated with etanercept alone [see Warnings and Precautions ( 5.2 )] . Two percent of patients treated concurrently with KINERET and etanercept developed neutropenia (ANC < 1 x 10 9 /L). Use of KINERET in combination with TNF blocking agents is not recommended.

Pediatric use: KINERET is indicated for use in pediatric patients with NOMID and DIRA ( 8.4 ) Geriatric use: Because there is a higher incidence of infections in the elderly population in general, caution should be used in treating the elderly ( 8.5 ) Renal impairment: This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function ( 8.6 )

8.1 Pregnancy Risk Summary Available data from retrospective studies and case reports on KINERET use in pregnant women are insufficient to identify a drug associated risk of major birth defects, miscarriage, or maternal and fetal adverse events. There are risks to the mother and fetus associated with active rheumatoid arthritis or Cryopyrin-Associated Periodic Syndromes (CAPS). In animal reproduction studies, subcutaneous administration of anakinra to pregnant rats and rabbits during organogenesis demonstrated no evidence of fetal harm at doses up to 25 times the maximum recommended human dose (MRHD). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Published data suggest the risk of adverse pregnancy outcomes in women with rheumatoid arthritis or CAPS is associated with increased disease activity. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (<2500 grams), and small for gestational age at birth. Data Human Data The available data from retrospective studies and case reports of anakinra-exposed pregnancies have not identified an increased frequency or pattern of birth defects, miscarriage, or adverse maternal or fetal outcomes. An international multi-center 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 0.2-2% of all newborns. Another retrospective study reported on 10 anakinra-exposed pregnancies in women with CAPS. There were 9 live births, 1 miscarriage, and 1 fetal demise in a twin pregnancy. The surviving twin was born 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. Animal Data Animal reproduction studies were conducted in rats and rabbits. In embryo-fetal development studies, anakinra was administered throughout the period of organogenesis at the subcutaneous doses of 12.5, 50, and 200 mg/kg/day to pregnant rats from gestation days (GD) 7 to 17 and pregnant rabbits from GD 6 to 18. In these studies, anakinra at doses up to 25 times the MRHD (on a mg/kg basis at maternal subcutaneous doses up to 200 mg/kg/day) revealed no evidence of harm to the fetus.

8.2 Lactation Risk Summary There are no data on the presence of anakinra in either human or animal milk or the effects on milk production. Available published data from a small retrospective study and postmarketing case reports do not establish an association between maternal anakinra use during lactation and adverse effects on breastfed infants. The limited clinical data during lactation precludes a clear determination of the risk of KINERET to an infant during lactation. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for KINERET and any potential adverse effects on the breastfed infant from KINERET or from the underlying maternal condition.

8.4 Pediatric Use Neonatal-Onset Multisystem Inflammatory Disease (NOMID) The NOMID study included 36 pediatric patients: 13 below 2 years, 18 between 2 and 11 years, and 5 between 12 and 17 years of age. A subcutaneous KINERET starting dose of 1–2 mg/kg/day was administered in all age groups. An average maintenance dose of 3–4 mg/kg/day was adequate to maintain clinical response throughout the study irrespective of age but a higher dose was, on occasion, required in severely affected patients. The prefilled syringe does not allow doses lower than 20 mg to be administered. Deficiency of Interleukin-1 Receptor Antagonist (DIRA) The study in DIRA patients included 9 pediatric patients (ages 1 month to 9 years at start of KINERET treatment). Most patients received a starting dose of 1 to 2 mg/kg/day. Doses up to 7.5 mg/kg/day were given. The prefilled syringe does not allow doses lower than 20 mg to be administered. Juvenile Rheumatoid Arthritis (JRA) The safety and effectiveness of KINERET in the treatment of pediatric patients with Juvenile Rheumatoid Arthritis (JRA) have not been established. KINERET was studied in a single randomized, blinded multi-center trial in 86 patients with polyarticular course JRA; ages 2-17 years receiving a dose of 1 mg/kg subcutaneously daily, up to a maximum dose of 100 mg. The 50 patients who achieved a clinical response after a 12-week open-label run-in were randomized to KINERET (25 patients) or placebo (25 patients), administered daily for an additional 16 weeks. A subset of these patients continued open-label treatment with KINERET for up to 1 year in a companion extension study. An adverse event profile similar to that seen in adult RA patients was observed in these studies. These study data are insufficient to demonstrate efficacy and, therefore, KINERET is not recommended for pediatric use in JRA.

8.5 Geriatric Use A total of 752 RA patients ≥ 65 years of age, including 163 patients ≥ 75 years of age, were studied in clinical trials. No differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Because there is a higher incidence of infections in the elderly population in general, caution should be used in treating the elderly. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.

8.6 Renal Impairment This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function [see Clinical Pharmacology ( 12.3 )] .

8.7 Hepatic Impairment No formal studies have been conducted examining the pharmacokinetics of KINERET administered subcutaneously in patients with hepatic impairment.

KINERET blocks the biologic activity of IL-1 alpha and beta by competitively inhibiting IL-1 binding to the interleukin-1 type I receptor (IL-1RI), which is expressed in a wide variety of tissues and organs. IL-1 production is induced in response to inflammatory stimuli and mediates various physiologic responses including inflammatory and immunological responses. IL-1 has a broad range of activities including cartilage degradation by its induction of the rapid loss of proteoglycans, as well as stimulation of bone resorption. The levels of the naturally occurring IL-1Ra in synovium and synovial fluid from RA patients are not sufficient to compete with the elevated amount of locally produced IL-1. Spontaneous mutations in the CIAS1/NLRP3 gene have been identified in a majority of patients with cryopyrin-associated periodic syndromes such as NOMID. CIAS1/NLRP3 encodes for cryopyrin, a component of the inflammasome. The activated inflammasome results in proteolytic maturation and secretion of IL-1β, which has an important role in the systemic inflammation and manifestations of NOMID. DIRA is an autosomal recessive monogenic autoinflammatory disease caused by mutations in the IL1RN gene leading to loss of secretion of the interleukin-1 receptor antagonist (IL-1Ra). The deficiency of IL-1Ra results in unopposed IL-1α and IL-1β pro-inflammatory signaling causing systemic inflammation with skin and bone involvement.