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Black Box Warning
WARNING
See full prescribing information for complete Boxed Warning.
SERIOUS INFUSION REACTIONS, CAPILLARY LEAK SYNDROME AND LOSS OF VISUAL ACUITY.
The following adverse reactions have been reported:
Serious and fatal infusion reactions. Administer Ontak in a facility equipped and staffed for cardiopulmonary resuscitation. Immediately stop and permanently discontinue Ontak for serious infusion reactions .
Capillary leak syndrome resulting in death. Monitor weight, edema, blood pressure and serum albumin levels prior to and during Ontak treatment.
Loss of visual acuity and color vision
Overview
Denileukin diftitox is an antineoplastic agent that is FDA approved for the treatment of patients with persistent or recurrent cutaneous T-cell lymphoma whose malignant cells express the CD25 component of the IL-2 receptor.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include .
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Cutaneous T-cell lymphoma
Ontak® is indicated for the treatment of patients with persistent or recurrent cutaneous T-cell lymphoma whose malignant cells express the CD25 component of the IL-2 receptor
Dosing Schedule and Administration
Premedicate with an antihistamine and acetaminophen prior to each Ontak infusion.
Administer at 9 or 18 mcg/kg/day by intravenous infusion over 30-60 minutes for 5 consecutive days every 21 days for 8 cycles.
Do not administer as a bolus injection.
Withhold administration of Ontak if serum albumin levels are less than 3.0 g/dL.
Discontinue for adverse infusion reactions.
Preparation and Administration
Thaw vials in the refrigerator at 2 to 8°C (36 to 46°F) for not more than 24 hours or at room temperature for 1 to 2 hours.
Bring Ontak to room temperature, before preparing the dose.
Mix the solution in the vial by gentle swirling; do not shake.
Visually inspect for particulate matter and discoloration prior to administration, whenever solution and container permit. Use only if the solution is clear, colorless and without visible particulate matter. After thawing, a haze may be visible which should clear when the solution is at room temperature.
Do not refreeze Ontak after thawing.
Prepare and hold diluted Ontak in plastic syringes or soft plastic IV bags. Do not use glass containers.
Maintain concentration of Ontak at 15 mcg/mL or higher.
during all steps in the preparation of the solution for IV infusion.
Withdraw the calculated dose from the vial(s) and inject it into an empty IV infusion bag. Do not add more than 9 mL of sterile saline without preservative to the IV bag for each 1 mL of Ontak.
Do not mix Ontak with other drugs.
Do not administer Ontak through an in-line filter.
Administer prepared solutions of Ontak within 6 hours, using a syringe pump or IV infusion bag.
Discard unused portions of Ontak immediately.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
Condition1
Developed by:
Class of Recommendation:
Strength of Evidence:
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Guideline-Supported Use of Denileukin diftitox in adult patients.
Non–Guideline-Supported Use
Condition1
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Non–Guideline-Supported Use of Denileukin diftitox in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Condition1
Dosing Information
Dosage
Condition2
There is limited information regarding FDA-Labeled Use of Denileukin diftitox in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
Condition1
Developed by:
Class of Recommendation:
Strength of Evidence:
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Guideline-Supported Use of Denileukin diftitox in pediatric patients.
Non–Guideline-Supported Use
Condition1
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Non–Guideline-Supported Use of Denileukin diftitox in pediatric patients.
Contraindications
None.
Warnings
WARNING
See full prescribing information for complete Boxed Warning.
SERIOUS INFUSION REACTIONS, CAPILLARY LEAK SYNDROME AND LOSS OF VISUAL ACUITY.
The following adverse reactions have been reported:
Serious and fatal infusion reactions. Administer Ontak in a facility equipped and staffed for cardiopulmonary resuscitation. Immediately stop and permanently discontinue Ontak for serious infusion reactions .
Capillary leak syndrome resulting in death. Monitor weight, edema, blood pressure and serum albumin levels prior to and during Ontak treatment.
Loss of visual acuity and color vision
Infusion Reactions
Infusion reactions, defined as symptoms occurring within 24 hours of infusion and resolving within 48 hours of the last infusion in that course, were reported in 70.5% (165/234) of Ontak-treated patients across 3 clinical studies utilizing the approved doses and schedule. Serious infusion reactions were reported in 8.1% (19/234) of Ontak-treated patients. There have been post-marketing reports of infusion reactions resulting in death.
For patients completing at least 4 courses of Ontak treatment in Study 1 [see Clinical Studies (14.1)], the incidence of infusion reactions was lower in the 3rd and 4th cycles as compared to the 1st and 2nd cycles of Ontak.
Resuscitative equipment should be available during Ontak administration. Immediately stop and permanently discontinue Ontak for serious infusion reactions.
Capillary Leak Syndrome
Capillary leak syndrome was defined as the occurrence of at least 2 of the following 3 symptoms (hypotension, edema, serum albumin <3.0 g/dL) at any time during Ontak therapy. These symptoms were not required to occur simultaneously to be characterized as capillary leak syndrome. As defined, capillary leak syndrome was reported in 32.5% (76/234) of Ontak-treated patients. Among these 76 patients with capillary leak syndrome, one-third required hospitalization or medical intervention to prevent hospitalization. There have been post-marketing reports of capillary leak syndrome resulting in death.
The onset of symptoms in patients with capillary leak syndrome may be delayed, occurring up to 2 weeks following infusion. Symptoms may persist or worsen after the cessation of Ontak.
Regularly assess patients for weight gain, new onset or worsening edema, hypotension (including orthostatic changes) and monitor serum albumin levels prior to the initiation of each course of therapy and more often as clinically indicated. Withhold Ontak for serum albumin levels of less than 3.0 g/dL [see Warnings and Precautions (5.5)].
Visual Loss
Loss of visual acuity, usually with loss of color vision, with or without retinal pigment mottling has been reported following administration of Ontak. Recovery was reported in some of the affected patients; however, most patients reported persistent visual impairment.
CD25 Tumor Expression and Evaluation
Confirm that the patient's malignant cells express CD25 prior to administration of Ontak. A testing service for the assay of CD25 expression in tumor biopsy samples is available. For information on this service call 877-873-4724.
Laboratory Monitoring/Hypoalbuminemia
Monitor serum albumin levels prior to the initiation of each treatment course. Withhold administration of Ontak if serum albumin levels are less than 3.0 g/dL
Adverse Reactions
Clinical Trials Experience
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)]
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.
TABLE02
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.
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 (Cmax~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.
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.
Body as a Whole
Cardiovascular
Digestive
Endocrine
Hematologic and Lymphatic
Metabolic and Nutritional
Musculoskeletal
Neurologic
Respiratory
Skin and Hypersensitivy Reactions
Special Senses
Urogenital
Miscellaneous
Drug Interactions
No formal drug-drug interaction studies have been conducted with Ontak
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.
