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adverse reactions
6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: Infusion Reactions [see Warnings and Precautions ( 5.1 ) ] Capillary Leak Syndrome [see Warnings and Precautions ( 5.2 ) ] Visual Loss [see Warnings and Precautions ( 5.3 ) ] The most common adverse reactions (≥20%) were pyrexia, nausea, fatigue, rigors, vomiting, diarrhea, headache, peripheral edema, cough, dyspnea and pruritus. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Eisai Inc. at 1-888-274-2378 (by fax 1-201-746-3207) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Studies Experience 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 practice. Safety data are available for 3 clinical studies in which 234 patients received Ontak at 9 mcg/kg (n=80) or 18 mcg/kg (n=154) at the recommended schedule. Of these studies, 1 was placebo-controlled and dose-ranging (Study 1, 100 Ontak-treated patients), one was a dose-comparison of 9 and 18 mcg/kg (Study 2, n=71), and the third was a single-arm study using 18 mcg/kg (n=63); all studies were limited to adult patients with CTCL. The median age of patients across the clinical studies was 60 years (range 23-91 years) and 36% (n=85) were 65 years of age or older; 55% were men and 85% were Caucasian. Across all 3 studies, the most common adverse reactions in Ontak-treated patients (≥20%) were pyrexia, nausea, fatigue, rigors, vomiting, diarrhea, headache, peripheral edema, cough, dyspnea and pruritus. The most common serious adverse reactions were capillary leak syndrome (11.1%), infusion reactions (8.1%), and visual changes including loss of visual acuity (4%). Ontak was discontinued in 28.2% (66/234) of patients due to adverse reactions. The data described in Table 1 reflect exposure to Ontak in 100 patients administered as a single agent at the recommended dosing schedule in the randomized placebo-controlled trial (Study 1). The median number of Ontak cycles was 7 (range 1-10) for the 9 mcg/kg cohort and 6 (range 1-11) for the 18 mcg/kg cohort. The median age of patients was 59 years (range 23-84 years) and 34% (n=34) were 65 years of age or older; 55% were men and 86% were Caucasian. Table 1: Incidence of Adverse Reactions Occurring in ≥10% of Ontak-treated patients (18 mcg/kg group) and at a higher rate than Placebo in Study 1 MedDRA version 6.1 Preferred Term Placebo N=44 n (%) Ontak 9 mcg/kg N=45 n (%) Ontak 18 mcg/kg N=55 n (%) Pyrexia 7 (15.9) 22 (48.9) 35 (63.6) Nausea 10 (22.7) 21 (46.7) 33 (60.0) Rigors 9 (20.5) 19 (42.2) 26 (47.3) Fatigue 14 (31.8) 21 (46.7) 24 (43.6) Vomiting 3 (6.8) 6 (13.3) 19 (34.5) Headache 8 (18.2) 13 (28.9) 14 (25.5) Edema peripheral 10 (22.7) 9 (20.0) 14 (25.5) Diarrhea 4 (9.1) 10 (22.2) 12 (21.8) Anorexia 2 (4.5) 4 (8.9) 11 (20.0) Rash 2 (4.5) 11 (24.4) 11 (20.0) Myalgia 2 (4.5) 8 (17.8) 11 (20.0) Cough 3 (6.8) 9 (20.0) 10 (18.2) Pruritus 4 (9.1) 7 (15.6) 10 (18.2) Back pain 1 (2.3) 7 (15.6) 10 (18.2) Asthenia 2 (4.5) 8 (17.8) 10 (18.2) Hypotension 1 (2.3) 3 (6.7) 9 (16.4) Upper respiratory tract infection 5 (11.4) 6 (13.3) 7 (12.7) Dizziness 5 (11.4) 5 (11.1) 7 (12.7) Arthralgia 5 (11.4) 7 (15.6) 7 (12.7) Pain 3 (6.8) 5 (11.1) 7 (12.7) Chest pain 1 (2.3) 2 (4.4) 7 (12.7) Dysgeusia 1 (2.3) 0 (0) 6 (10.9) Dyspnea 2 (4.5) 6 (13.3) 6 (10.9) Hepatobiliary Disorders: Increase in serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) from baseline occurred in 84% of subjects treated with Ontak (197/234). In the majority of subjects, these enzyme elevations occurred during either the first or the second cycle; enzyme elevation resolved without medical intervention and did not require discontinuation of Ontak. 6.2 Immunogenicity An immune response to denileukin diftitox was assessed using 2 enzyme-linked immunoassays (ELISA). The first assay measured reactivity directed against intact denileukin diftitox calibrated against anti-diphtheria toxin, and the second assay measured reactivity against the IL-2 portion of the protein. An additional in vitro cell-based assay that measured the ability of antibodies in serum to protect a human IL-2R-expressing cell line from toxicity by denileukin diftitox, was used to detect the presence of neutralizing antibodies which inhibited functional activity. The immunogenicity data reflect the percentage of patients whose test results were considered positive for antibodies to the intact fusion protein denileukin diftitox. These results are highly dependent on the sensitivity and the specificity of the assays. Additionally, the observed incidence of the antibody positivity may be influenced by several factors, including sample handling, concomitant medication, and underlying disease. For these reasons, the comparison of the incidence of antibodies to denileukin diftitox with the incidence of antibodies to other products may be misleading. In Study 1 [see Clinical Studies ( 14.1 ) ], of 95 patients treated with denileukin diftitox, 66% tested positive for antibodies at baseline probably due to a prior exposure to diphtheria toxin or its vaccine. After 1, 2, and 3 courses of treatment, 94%, 99%, and 100% of patients tested positive, respectively. Mean titers of anti-denileukin diftitox antibodies were similarly increased in the 9 and 18 mcg/kg/day dose groups after 2 courses of treatment. Meanwhile, pharmacokinetic parameters decreased substantially (C max ~57%, AUC~80%), and clearance increased 2- to 8-fold. In Study 2 [see Clinical Studies ( 14.2 ) ], 131 patients were assessed for binding antibodies. Of these, 51 patients (39%) had antibodies at baseline. Seventy-six percent of patients tested positive after 1 course of treatment and 97% after 3 courses of treatment. Neutralizing antibodies were assessed in 60 patients; 45%, 73%, and 97% had evidence of inhibited functional activity in the cellular assay at baseline and after 1 and 3 courses of treatment, respectively. 6.3 Postmarketing Experience The following adverse reactions have been identified during postapproval use of Ontak. 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. Thyroid conditions: hyperthyroidism, thyroiditis, thyrotoxicosis, and hypothyroidism.