Ontak (Denileukin Diftitox) - Warnings and Precautions

WARNINGS

Acute Hypersensitivity-type Reactions: Acute hypersensitivity reactions were reported in 98 of 143 patients (69%) during or within 24 hours of ONTAK infusion; approximately half of the events occurred on the first day of dosing regardless of the treatment cycle. The constellation of symptoms included one or more of the following, defined as the incidence (%) in these 98 patients: hypotension (50%), back pain (30%), dyspnea (28%), vasodilation (28%), rash (25%), chest pain or tightness (24%), tachycardia (12%), dysphagia or laryngismus (5%), syncope (3%), allergic reaction (1%) or anaphylaxis (1%). These events were severe in 2% of patients. Death during infusion has been reported. Management consists of interruption or a decrease in the rate of infusion (depending on the severity of the reaction); 3% of infusions were terminated prematurely and reduction in rate occurred in 4% of the infusions during the clinical trials. The administration of IV antihistamines, corticosteroids, and epinephrine may also be required; two subjects received epinephrine and 18 (13%) received systemic corticosteroids in the clinical studies. These drugs and resuscitative equipment should be readily available during ONTAK administration.

Vascular Leak Syndrome: This syndrome, characterized by 2 or more of the following 3 symptoms (hypotension, edema, hypoalbuminemia) was reported in 27% (38/143) of patients in the clinical studies. Six percent (8/143) of patients were hospitalized for the management of these symptoms. The onset of symptoms in patients with vascular leak syndrome was delayed, usually occurring within the first two weeks of infusion; symptoms may persist or worsen after the cessation of denileukin diftitox. Cases of vascular (capillary) leak with a fatal outcome have been reported. Special caution should be taken in patients with preexisting cardiovascular disease (See ADVERSE REACTIONS, Cardiovascular System).

Weight, edema, blood pressure and serum albumin levels should be carefully monitored on an outpatient basis. This syndrome is usually self-limited and treatment should be used only if clinically indicated. The type of treatment will depend on whether edema or hypotension is the primary clinical problem. Pre-existing low serum albumin levels appear to predict and may predispose patients to the syndrome (see PRECAUTIONS, Laboratory Tests).

PRECAUTIONS

General: Patients should be monitored carefully for infection since patients with CTCL have a predisposition to cutaneous infection. Also, the binding of denileukin diftitox to activated lymphocytes and macrophages can lead to cell death and may impair immune function in patients.

Immunogenicity: The immunogenicity data reflect the percentage of patients whose test results were considered positive for antibody to denileukin diftitox in ELISA assays and in a functional cellular assay. 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. Patients who develop a hypersensitivity to denileukin diftitox may have allergic or hypersensitivity reactions to other products produced in E. coli expression systems and to vaccines against diphtheria.

An immune response to denileukin diftitox was assessed using two enzyme-linked immunoassays (ELISA), one measuring reactivity directed against the intact DAB₃₈₉ IL-2 and the other 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 DAB₃₈₉ IL-2, was used to detect the presence of antibodies which inhibited functional activity. A total of 131 patients were assessed for an immune response by ELISA prior to treatment. Of these, 51 patients (39%) had antibodies to the intact fusion protein and 24 (18%) had antibodies that were directed against the IL-2 portion of the molecule. Among the 60 patients assessed prior to treatment, 27 (45%) had evidence of an immune response inhibiting activity in the cellular assay. After one cycle of treatment, 76% of the patients tested had an antibody response against DAB₃₈₉ IL-2 and 35% against the IL-2 portion by ELISA; 73% of patients had a positive immune response in the cellular assay. After 3 cycles of treatment, 97% of patients tested had an immune response to DAB₃₈₉ IL-2 in both the ELISA and the cellular assay.

The development of antibodies was correlated with a significant increase (two- to three-fold) in clearance. The increased clearance resulted in a decrease in mean systemic exposure of approximately 75%. The presence of antibodies did not correlate with risk of immediate hypersensitivity-type infusional adverse events.

Laboratory Tests: Prior to administration of this product, the patient's malignant cells should be tested for CD25 expression. A testing service for the assay of CD25 on skin biopsy samples is available. For information on this service call 800-964-5836.

A complete blood count and a blood chemistry panel, including liver and renal function and serum albumin levels, should be performed prior to initiation of ONTAK treatment and weekly during therapy.

Eighty-three percent (118/143) of patients with lymphoma experienced hypoalbuminemia, which was considered moderate or severe in 17% (20/118) of the affected patients. For most patients, the nadir for hypoalbuminemia occurs one to two weeks after ONTAK administration. Serum albumin levels should be monitored prior to the initiation of each treatment course. Administration of ONTAK should be delayed until serum albumin levels are at least 3.0 g/dL (see WARNINGS).

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

Carcinogenesis, Mutagenesis, Impairment of Fertility: There have been no studies to assess the carcinogenic potential of denileukin diftitox. Denileukin diftitox showed no evidence of mutagenicity in the Ames test and the chromosomal aberration assay. There have been no studies to assess the effect of denileukin diftitox on fertility.

Pregnancy Category C: Animal reproduction studies have not been conducted with ONTAK. It is also not known whether ONTAK can cause fetal harm when administered to a pregnant woman or affect reproductive capacity. ONTAK should be given to a pregnant woman only if clearly needed.

Nursing Mothers: It is not known whether this drug 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, patients receiving ONTAK should discontinue nursing.

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Geriatric Use: Forty-nine percent (35/71) of the patients enrolled in the randomized two dose study were 65 years of age or older, and those patients had response rates similar to those seen in younger patients. The following adverse events (regardless of causality) tended to be more frequent and/or more severe in lymphoma patients who were 65 years of age or older: anorexia, hypotension, anemia, confusion, rash, nausea and/or vomiting.