Adverse reactions are presented in Table 2. These data are based on adverse reactions observed in two clinical studies of 143 patients with lymphoma, including 105 patients with CTCL, treated at doses ranging from 3 to 31 mcg/kg/day.

All patients experienced one or more adverse events. Twenty-one percent of patients required hospitalization for drug-related adverse events; the most common reasons were evaluation of fever, management of vascular leak syndrome or dehydration secondary to gastrointestinal toxicity. Five percent of clinical adverse reactions were severe or life-threatening. The occurrence of adverse events tended to diminish in frequency after the first two courses, possibly related to antibody development.

Hypersensitivity:   (see WARNINGS)

Vascular Leak Syndrome:   (see WARNINGS)

Hypoalbuminemia:   (see PRECAUTIONS , Laboratory tests )

Infectious Complications:   Infections of various types were reported by 48% (69/143) of the study population, of which 23% (16/69) were considered severe. Six of the 143 patients (4%) discontinued ONTAK therapy because of infections.

Decreased lymphocyte counts (<900 cells/µL) occurred in 34% of lymphoma patients. In general, lymphocyte counts dropped during the dosing period (Days 1 to 5) and then returned to normal by Day 15. Smaller changes and more rapid recoveries were observed with subsequent courses.

Infusion-associated Reactions:   (see WARNINGS) There are two distinct clinical syndromes associated with ONTAK infusion, an acute hypersensitivity-type symptom complex and a flu-like symptom complex. Overall, 69% of patients had infusion-related, hypersensitivity-type symptoms; for additional information, see WARNINGS. A flu-like syndrome was experienced by 91% of patients within several hours to days after ONTAK infusion. The symptom complex consists of one or more of the following: fever and/or chills (81%), asthenia (66%), digestive (64%), myalgias (18%) and arthralgias (8%). In the majority of patients, these symptoms were mild to moderate and responded to treatment with antipyretics and/or anti-emetics. Antipyretics and/or anti-emetics were used to relieve flu-like symptoms; however, the usefulness of these agents in ameliorating these toxicities or as prophylactic agents to decrease the incidence of the acute, flu-like toxicities has not been prospectively studied.

Gastrointestinal:   Diarrhea was reported in 29% (42/143) of the study population. The onset of diarrhea may be delayed and the duration can be prolonged. Dehydration, usually concurrent with vomiting or anorexia, occurred in 9% (13/143) of the patients. The majority of transient hepatic transaminase elevations occurred during the first course of ONTAK, were self-limited and resolved within two weeks.

Rash:   Generalized maculopapular, petechial, vesicular bullous, urticarial and/or eczematous with both acute and delayed onset, have been reported in 34% (48/143) of patients. Antihistamines may be effective in relieving the symptoms, but more severe rashes may require the use of topical and/or oral corticosteroids.

Cardiovascular System:   Two patients, both of whom had known or suspected pre-existing coronary artery disease, sustained acute myocardial infarctions while on study. Ten additional patients (7%) experienced thrombotic events. Two patients with progressive disease and multiple medical problems experienced deep vein thrombosis. Another patient sustained a deep vein thrombosis and pulmonary embolus during hospitalization for management of congestive heart failure and vascular leak syndrome. One patient with a history of severe peripheral vascular disease sustained an arterial thrombosis. Six patients experienced less severe superficial thrombophlebitis. Thrombotic events were also observed in preclinical animal studies.

Infrequent Serious Adverse Events:   The following serious adverse events occurred at an incidence of less than 5%: pancreatitis, acute renal insufficiency, microscopic hematuria, oral ulcer, hyperthyroidism including thyroiditis and thyrotoxicosis, and hypothyroidism.

No clinical drug interaction studies have been conducted. However, in a single in vivo rodent study denileukin diftitox had no effect on P450 levels.

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