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 Study1 [see Clinical Studies (14.1)], of 95patients 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 3courses 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 18mcg/kg/day dose groups after 2courses of treatment. Meanwhile, pharmacokinetic parameters decreased substantially (Cmax~57%, AUC~80%), and clearance increased 2- to 8-fold.
In Study2 [see Clinical Studies (14.2)], 131patients were assessed for binding antibodies. Of these, 51patients (39%) had antibodies at baseline. Seventy-six percent of patients tested positive after 1course of treatment and 97% after 3courses of treatment. Neutralizing antibodies were assessed in 60patients; 45%, 73%, and 97% had evidence of inhibited functional activity in the cellular assay at baseline and after 1 and 3courses 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.
7 DRUG INTERACTIONS
No formal drug-drug interaction studies have been conducted with Ontak.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
It is not known whether Ontak can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Animal reproduction studies have not been conducted with Ontak. Ontak should be given to a pregnant woman only if clearly needed.
8.3 Nursing Mothers
It is not known whether Ontak is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Ontak, a decision should be made whether to discontinue nursing or to discontinue Ontak, taking into account the importance of the drug to the mother.
8.4 Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
8.5 Geriatric Use
Clinical studies of Ontak did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects.
10 OVERDOSAGE
Doses of approximately twice the recommended dose (31mcg/kg/day) resulted in moderate-to-severe nausea, vomiting, fever, chills and/or persistent asthenia.
11 DESC
