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adverse reactions
6 ADVERSE REACTIONS 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. For these reasons, comparison of the incidence of antibodies to KINERET with the incidence of antibodies to other products may be misleading. Lipids Cholesterol elevations were observed in some patients treated with KINERET. Other Adverse Events Table 1 reflects adverse events in Studies 1 and 4, that occurred with a frequency of ≥ 5% in KINERET-treated patients over a 6-month period. Table 1: Percent of RA Patients Reporting Adverse Events (Studies 1 and 4) Placebo KINERET 100 mg/day Preferred term (n = 733) (n = 1565) Injection Site Reaction 29% 71% Worsening of RA 29% 19% Upper Respiratory Tract Infections 17% 14% Headache 9% 12% Nausea 7% 8% Diarrhea 5% 7% Sinusitis 7% 7% Arthralgia 6% 6% Flu Like Symptoms 6% 6% Abdominal Pain 5% 5% 6.2 Clinical Study Experience in NOMID The data described herein reflect an open-label study in 43 NOMID patients exposed to KINERET for up to 60 months adding up to a total exposure of 159.8 patient years. Patients were treated with a starting dose of 1 to 2 mg/kg/day and an average maintenance dose of 3-4 mg/kg/day adjusted depending on the severity of disease. Among pediatric NOMID patients, doses up to 7.6 mg/kg/day have been maintained for up to 15 months. There were 24 serious adverse events (SAEs) reported in 14 of the 43 treated patients. The most common type of SAEs reported were infections [see Warnings and Precautions ( 5.1 )] . Five SAEs were related to lumbar puncture, which was part of the study procedure. There were no permanent discontinuations of study drug treatment due to AEs. Doses were adjusted in 5 patients because of AEs; all were dose increases in connection with disease flares. The reporting frequency of AEs was highest during the first 6 months of treatment. The incidence of AEs did not increase over time, and no new types of AEs emerged. The most commonly reported AEs during the first 6 months of treatment (incidence >10%) were injection site reaction (ISR), headache, vomiting, arthralgia, pyrexia, and nasopharyngitis ( Table 2 ). The most commonly reported AEs during the 60-month study period, calculated as the number of events/patient years of exposure, were arthralgia, headache, pyrexia, upper respiratory tract infection, nasopharyngitis, and rash. The AE profiles for different age groups <2 years, 2-11 years, and 12-17 years corresponded to the AE profile for patients ≥18 years, with the exception of infections and related symptoms being more frequent in patients <2 years. Infections The reporting rate for infections was higher during the first 6 months of treatment (2.3 infections/patient-year) compared to after the first 6 months (1.7 infections/patient year). The most common infections were upper respiratory tract infection, sinusitis, ear infections, and nasopharyngitis. There were no deaths or permanent treatment discontinuations due to infections. In one patient KINERET administration was temporarily stopped during an infection and in 5 patients the dose of KINERET was increased due to disease flares in connection with infections. Thirteen infections in 7 patients were classified as serious, the most common being pneumonia and gastroenteritis occurring in 3 and 2 patients, respectively. No serious opportunistic infections were reported. The reporting frequency for infections was highest in patients <12 years of age. Hematologic Events After start of KINERET treatment neutropenia was reported in 2 patients. One of these patients experienced an upper respiratory tract infection and an otitis media infection. Both episodes of neutropenia resolved over time with continued KINERET treatment. Injection Site Reactions In total, 17 injection site reactions (ISRs) were reported in 10 patients during the 60-month study period. Out of the 17 ISRs, 11 (65%) occurred during the first month and 13 (76%) were reported during the first 6 months. No ISR was reported after Year 2 of treatment. The majority of ISRs were reported as mild (76% mild, 24% moderate). No patient permanently or temporarily discontinued KINERET treatment due to injection site reactions. Immunogenicity The immunogenicity of KINERET in NOMID patients was not evaluated. Table 2. Most common (>10% of patients) treatment-emergent adverse events during the first 6 months of KINERET treatment Safety population (N=43) Total exposure in patient years= 20.8 Preferred term N (%) Number of events /patient year Injection site reaction 7 (16.3%) 0.5 Headache 6 (14.0%) 0.7 Vomiting 6 (14.0%) 0.6 Arthralgia 5 (11.6%) 0.6 Pyrexia 5 (11.6%) 0.4 Nasopharyngitis 5 (11.6%) 0.3 The most common adverse reactions occurring after the first 6-month period of treatment with KINERET (up to 60 months of treatment) included: arthralgia, headache, pyrexia, upper respiratory tract infection, nasopharyngitis, and rash. 6.3 Clinical Study Experience in DIRA The safety data described in this section reflect exposure to KINERET in 9 patients with DIRA treated for up to 10 years in a natural history study (study 17-I-0016). Most patients received a starting dose of 1 to 2 mg/kg/day and thereafter doses were individually adjusted to reach a stable efficacious dose. The highest dose given was 7.5 mg/kg/day. Overall, the safety profile observed in patients with DIRA treated with KINERET was consistent with the safety profile in NOMID patients. There were 16 serious adverse events (SAEs) reported in 4 out of 9 treated patients. The most common type of SAEs reported (5 events in 2 patients) were infections [see Warnings and Precautions ( 5.1 )] . The most common adverse events in patients with DIRA were upper respiratory tract infections, rash, pyrexia, influenza like illness and gastroenteritis. There were no permanent discontinuations of KINERET treatment due to AEs. Infections There were 16 infections in 5 patients (reporting rate: 0.28 infections / patient year). The most common infections were upper respiratory tract infections, cellulitis and gastroenteritis. Hypersensitivity Reactions One patient with DIRA had a serious event of urticaria on day 10 of KINERET treatment [see Warnings and Precautions ( 5.3 )] . Injection Site Reactions There was one report of injection site pain, which did not cause discontinuation of KINERET treatment. 6.4 Postmarketing Experience The following adverse reactions have been identified during postapproval use of KINERET. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hepato-biliary disorders: elevations of transaminases, non-infectious hepatitis Hematologic events: thrombocytopenia, including severe thrombocytopenia (i.e platelet counts <10x10 9 /L) Skin and subcutaneous tissue disorders: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings & Precautions ( 5.3 )] injection site amyloid deposits [see Warnings & Precautions ( 5.5 )]