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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(de ni LOO kin DIF ti toks)
Generic Available (U.S.)
No
Index Terms
Brand Names: U.S.
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of persistent or recurrent cutaneous T-cell lymphoma (CTCL) whose malignant cells express the CD25 component of the IL-2 receptor
Use: Unlabeled/Investigational
Treatment of CTCL types mycosis fungoides (MF) and Sézary syndrome (SS); peripheral T-cell lymphoma (second-line treatment)
Pregnancy Considerations
Animal reproduction studies have not been conducted. There are no adequate and well-controlled studies in pregnant women. Should be given to a pregnant woman only if clearly needed
Lactation
Excretion in breast milk unknown/not recommended
Breast-Feeding Considerations
The excretion of denileukin diftitox in breast milk is unknown, however, it is recommended that a breast-feeding woman who is treated with denileukin diftitox should discontinue nursing.
Contraindications
There are no contraindications listed within the manufacturer's labeling.
Warnings/Precautions
Boxed warnings:
• Capillary leak syndrome: See “Concerns related to adverse effects” below.
• Infusion reactions: See “Concerns related to adverse effects” below.
• Vision loss: See “Concerns related to adverse effects” below.
Special handling:
• Hazardous agent: Use appropriate precautions for handling and disposal.
Concerns related to adverse effects:
• Capillary leak syndrome: [U.S. Boxed Warning]: Has been associated with a potentially severe, including life-threatening, capillary leak syndrome (CLS); monitor weight, edema, blood pressure, and serum albumin prior to and during treatment. Symptoms of capillary leak syndrome (hypotension, edema, hypoalbuminemia) may be delayed, occurring up to 2 weeks postinfusion; symptoms may persist or worsen after cessation of denileukin diftitox. Withhold treatment if serum albumin <3 g/dL; pre-existing low serum albumin levels may correlate with capillary leak syndrome.
• Infusion reactions: [U.S. Boxed Warning]: Serious and fatal infusion reactions have occurred. Administer in a facility appropriate for cardiopulmonary resuscitation. Discontinue immediately and permanently with serious infusion reaction. Infusion reaction symptoms usually occur within 24 hours of infusion and resolve within 48 hours of last infusion of cycle. Incidence of infusion reaction has been reported to be lower in cycles 3 and 4 (compared to cycles 1 and 2). The manufacturer recommends premedication with an antihistamine and acetaminophen; corticosteroid (eg, dexamethasone) premedication may help to reduce the incidence of hypersensitivity and edema (Foss, 2001).
• Immunogenicity: May develop immunogenicity; patients with antibodies have a two- to threefold increase in clearance. The presence of antibodies does not correlate with risk for hypersensitivity/infusion related reactions.
• Infection: Monitor closely for infection; may impair immune function; patients with CTCL are predisposed to cutaneous infection.
• Vision loss: [U.S. Boxed Warning]: Loss of visual acuity, usually associated with loss of color vision (with or without retinal pigment mottling) has been reported. Most patients have persistent visual impairment.
Special populations:
• Elderly: Use with caution in patients >65 years of age; adverse events (anemia, anorexia, confusion, hypotension, rash, nausea/vomiting) may occur more frequently.
• Pediatrics: Safety and efficacy have not been established in children.
Other warnings/precautions:
• Appropriate use: Confirm CD25 expression on malignant cells prior to treatment.
• Experienced physician: Should be administered under the supervision of an experienced cancer chemotherapy physician.
Adverse Reactions
>10%:
Cardiovascular: Capillary leak syndrome (33%; serious: 11%), peripheral edema (20% to 26%), vasodilation (22%), hypotension (7% to 16%), chest pain (4% to 13%), tachycardia (12%), thrombosis-related events (7% to 11%)
Central nervous system: Fever (49% to 64%), fatigue (44% to 47%), headache (26% to 29%), dizziness (11% to 13%), pain (11% to 13%)
Dermatologic: Rash (20% to 24%), pruritus (16% to 18%)
Endocrine & metabolic: Hypoalbuminemia (14% to 17%)
Gastrointestinal: Nausea (47% to 60%), vomiting (13% to 35%), diarrhea (22%), anorexia (9% to 20%), taste disturbance (11% to 13%)
Hematologic: Lymphopenia (70%; 24% had lymphopenia at baseline)
Hepatic: ALT increased (84%), AST increased (84%)
Neuromuscular & skeletal: Rigors (42% to 47%), myalgia (18% to 20%), weakness (18%), back pain (16% to 18%), arthralgia (13% to 16%)
Respiratory: Cough (18% to 20%), upper respiratory infection (13%), dyspnea (11% to 13%)
Miscellaneous: Antibody formation (76% to 100%) neutralizing antibodies (45% to 97%), flu-like syndrome (≤85%), infusion reaction (71%; serious: 8%), infection (48%)
1% to 10%:
Cardiovascular: Arrhythmia (6%), hypertension (6%)
Hematologic: Leukopenia (grades 3/4: 3% to 6%), neutropenia (grades 3/4: 3%), thrombocytopenia (grades 3/4: 3%)
Local: Injection site reaction (8%)
Ocular: Visual changes (serious: 4%; includes loss of visual acuity)
Renal: Serum creatinine increased (3% to 10%), proteinuria/casts/hematuria (6%)
Postmarketing and/or case reports: Acute renal insufficiency, hyper-/hypothyroidism, oral ulcer, pancreatitis, thyroiditis, thyrotoxicosis, toxic epidermal necrolysis
Metabolism/Transport Effects
None known.
Drug Interactions
BCG: Immunosuppressants may diminish the therapeutic effect of BCG. Risk X: Avoid combination
Belimumab: Denileukin Diftitox may enhance the adverse/toxic effect of Belimumab. Risk X: Avoid combination
Coccidioidin Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioidin Skin Test. Risk C: Monitor therapy
Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Risk C: Monitor therapy
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Risk D: Consider therapy modification
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Risk D: Consider therapy modification
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Risk C: Monitor therapy
Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinial infections may develop. Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Risk X: Avoid combination
Storage
Store intact vials frozen at or below -10°C (14°F); do not refreeze after thawing. Solutions ≥15 mcg/mL in NS should be used within 6 hours.
Reconstitution
Must be brought to room temperature (25°C or 77°F) before preparing the dose. Do not heat vials. Thaw in refrigerator for not more than 24 hours or at room temperature for 1-2 hours. Solution may be mixed by gentle swirling; avoid vigorous agitation. Dilute with NS to a concentration of ≥15 mcg/mL; the concentration must be ≥15 mcg/mL during all steps of preparation. Add drug to the empty sterile I.V. bag first, then add NS. Do not prepare with glass syringes or in glass containers.
Mechanism of Action
Denileukin diftitox is a fusion protein (a combination of amino acid sequences from diphtheria toxin and interleukin-2) which selectively delivers the cytotoxic activity of diphtheria toxin to targeted cells. It interacts with the high-affinity IL-2 receptor on the surface of malignant cells to inhibit intracellular protein synthesis, rapidly leading to cell death.
Pharmacodynamics/Kinetics
Distribution: Vd: 0.06-0.09 L/kg
Metabolism: Hepatic via proteolytic degradation (animal studies)
Half-life elimination: Distribution: 2-5 minutes; Terminal: 70-80 minutes
Dosage
Note: Premedicate with an antihistamine and acetaminophen prior to each infusion; corticosteroid premedication (eg, dexamethasone) may reduce the incidence of hypersensitivity and edema (Foss, 2001). Withhold treatment if serum albumin <3 g/dL.
I.V.: Adults: CTCL: 9 or 18 mcg/kg/day days 1 through 5 every 21 days for 8 cycles
Dosage adjustment for toxicity:
Serum albumin <3 g/dL: Withhold treatment
Severe infusion reaction: Permanently discontinue treatment
Administration: I.V.
For I.V. use only. Infuse over 30-60 minutes. Should not be given as a rapid I.V. bolus. Discontinue or reduce infusion rate for infusion related reactions; discontinue for severe infusion reaction. Do not administer through an in-line filter. Premedicate with an antihistamine and acetaminophen; consider corticosteroid premedication.
Administration: I.V. Detail
pH: 6.9-7.2
Monitoring Parameters
Baseline CD25 expression (on malignant cells); serum albumin level (prior to each treatment), CBC, blood chemistry panel, renal and hepatic function tests (prior to initiation of therapy and weekly during therapy). During the infusion, the patient should be monitored for symptoms of an infusion reaction. After infusion, the patient should be monitored for the development of a delayed capillary leak syndrome (usually in the first 2 weeks), including careful monitoring of weight, blood pressure, and serum albumin.
Information on assay for malignant cell CD25 expression is available at 1-877-873-4724.
Patient Education
This medication can only be administered via intravenous infusion. During infusion, report immediately any chills; chest pain, respiratory difficulty, or tightness in throat; or redness, swelling, pain, or burning at infusion site. Maintain adequate hydration, unless instructed to restrict fluids. You may be more susceptible to infection. May cause nausea, vomiting, anorexia, flatulence, constipation, diarrhea, headache, back or muscle pain, dizziness, weakness, or confusion. Report unresolved GI effects; headache or back or muscle pain; skin dryness, rash, or sores; altered urinary patterns; flu syndrome or infection (eg, weakness, fatigue, white plaques or sores in mouth, vaginal discharge, chills, fever); CNS disturbances (insomnia, dizziness, agitation, confusion, depression); unusual bleeding or bruising; blood in urine or stool; or swelling of extremities.
Additional Information
Oncology Comment: The National Comprehensive Cancer Network® (NCCN) Non-Hodgkin's Lymphoma Guidelines (v.2.2009) list denileukin diftitox as a second-line treatment option for systemic therapy of peripheral (cutaneous) T-cell lymphoma in patients who are not candidates for high dose therapy or autologous stem cell rescue. In mycosis fungoides (MF) and Sézary syndrome (SS), denileukin diftitox is a therapy option, either as monotherapy or in combination with bexarotene (Foss, 2005). Participation in a clinical trial is encouraged for this patient population.
Corticosteroids may be considered for prevention of hypersensitivity reaction. In a small study (Foss, 2001) reviewing denileukin diftitox and premedication with either prednisone 20 mg orally or dexamethasone 8 mg I.V. on day 1 followed by dexamethasone 8 mg I.V. on days 2-5, a reduction in adverse events was observed when compared to a previous (Olsen, 2001) phase III study. A statistically significant reduction in the incidence of edema was demonstrated. Improved response rates (compared to the phase III study) were noted, likely due to in increase in tolerability due to corticosteroid premedication. While some studies did not allow premedication with corticosteroids (Kuzel, 2007; Olsen, 2001) as part of the trial design, dexamethasone premedication has been utilized in other studies and case reports (Foss, 2005; Frankel, 2006; Gerena-Lewis, 2009; Talpur, 2002) with denileukin diftitox use for cutaneous T-cell lymphoma as well as other (unlabeled) uses.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
Dizziness and nervousness are common; may cause insomnia or confusion
Mental Health: Effects on Psychiatric Treatment
Hypotension and tachycardia are common; use caution with low potency antipsychotics and other psychotropics. Nausea and vomiting are common; use caution with SSRIs.
Nursing: Physical Assessment/Monitoring
Premedicate with antihistamine and acetaminophen prior to each infusion. Patient must be monitored closely for acute hypersensitivity reaction during and for 24-48 hours following infusion (resuscitation equipment should be immediately available during infusion). Discontinue permanently if serious infusion reaction occurs. Following infusion, patient should be monitored or taught to monitor for delayed vascular leak syndrome, gastrointestinal effects, fever, pain, or respiratory infection. Teach patient to report signs of infection.
Oncology: Emetic Potential
Very low (<10%)
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, solution:
ONTAK®: 150 mcg/mL (2 mL) [contains edetate disodium]
References
Foss FM, Bacha P, Osann KE, et al, “Biological Correlates of Acute Hypersensitivity Events With DAB389IL-2 (Denileukin Diftitox, Ontak®) in Cutaneous T-Cell Lymphoma: Decreased Frequency and Severity With Steroid Premedication,” Clin Lymphoma, 2001, 1(4):298-302.
Foss F, Demierre MF, and DiVenuti F, “A Phase-1 Trial of Bexarotene and Denileukin Diftitox in Patients With Relapsed or Refractory Cutaneous T-Cell Lymphoma,” Blood, 2005, 106(2):454-7.
Frankel AE, Surendranathan A, Black JH, et al, “Phase II Clinical Studies of Denileukin Diftitox Diphtheria Toxin Fusion Protein in Patients With Previously Treated Chronic Lymphocytic Leukemia,” Cancer, 2006, 106(10):2158-64.
Gerena-Lewis M, Crawford J, Bonomi P, et al, “A Phase II Trial of Denileukin Diftitox in Patients With Previously Treated Advanced Non-Small Cell Lung Cancer,” Am J Clin Oncol, 2009, 32(3):269-73.
Kuzel TM, Li S, Eklund J, et al, “Phase II Study of Denileukin Diftitox for Previously Treated Indolent Non-Hodgkin Lymphoma: Final Results of E1497,” Leuk Lymphoma, 2007 48(12):2397-402.
National Comprehensive Cancer Network® (NCCN), “Clinical Practice Guidelines in Oncology™: Non-Hodgkin's Lymphomas,” Version 2.2009. Available at http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf
Olsen E, Duvic M, Frankel A, et al, “Pivotal Phase III Trial of Two Dose Levels of Denileukin Diftitox for the Treatment of Cutaneous T-Cell Lymphoma,” J Clin Oncol, 2001, 19(2):376-88.
Polder K, Wang C, Duvic M, et al, “Toxic Epidermal Necrolysis Associated With Denileukin Diftitox (DAB389IL-2) Administration in a Patient With Follicular Large Cell Lymphoma,” Leuk Lymphoma, 2005, 46(12):1807-11.
Talpur R, Apisarnthanarax N, Ward S, et al, “Treatment of Refractory Peripheral T-Cell Lymphoma With Denileukin Diftitox (Ontak®),” Leuk Lymphoma, 2002, 43(1):121-6.
Lexi-Comp.com
Last full review/revision October 2011
Content last modified October 2011
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