Medication Guide App

Ontak

Generic Name: Denileukin Diftitox
Class: Antineoplastic Agents
VA Class: AN900
Chemical Name: N-l-Methionyl-387-l-histidine-388-l-alanine-1-388 toxin (Corynebacterium diphtheriae strain C7) (377→2′) protein with 2-133-interleukin 2 (human clone pTIL2-21a).
Molecular Formula: C2560H4038N678O799S17
CAS Number: 173146-27-5

Warning(s)

  • Administer only under supervision of qualified clinicians experienced in use of cytotoxic therapy.1

  • Closely monitor patients in a setting equipped and staffed by health-care personnel appropriately trained in CPR.1

Introduction

Antineoplastic agent; recombinant DNA-derived cytotoxic protein.1

Uses for Ontak

Cutaneous T-cell Lymphoma

Treatment of persistent or recurrent cutaneous T-cell lymphoma (CTCL) in patients whose malignant cells express the CD25 component of the IL-2 receptor1 3 8 (designated an orphan drug by FDA for this use).5

Slideshow: Foodborne Illness: The Thanksgiving Guest Nobody Invited

Safety and efficacy in patients with CTCL whose malignant cells do not express the CD25 component of the IL-2 receptor not established but currently being studied.1 6

Ontak Dosage and Administration

General

  • Consult specialized references for procedures for proper handling and disposal of antineoplastics.

  • Prior to initiation of denileukin therapy, test patient’s malignant cells for CD25 expression.1

Premedication

  • Limited data suggest that administering oral corticosteroids (e.g., oral prednisone 20 mg) prior to each IV denileukin infusion or administering IV corticosteroids (e.g., IV dexamethasone 8 mg) on day 1 and prior to each subsequent IV denileukin infusion may minimize risk of potentially fatal acute hypersensitivity reactions.6 7

  • Not known if prophylactic administration of antipyretics, antiemetics, or antidiarrhea agents will ameliorate or decrease the incidence of flu-like syndrome.1

Administration

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by IV infusion; not for rapid (i.e., bolus) IV injection.1

Do not use in-line filter.1

Prior to administration, thaw denileukin diftitox concentrate at room temperature for 1–2 hours or under refrigeration (2–8°C) for up to 24 hours; do not heat solution.1

Must then be diluted with preservative-free 0.9% sodium chloride injection prior to administration.1

Do not admix with any other drug.1

Dilution

Use strict aseptic technique and only plastic syringes and plastic IV bags to prepare and/or administer the drug; do not use glass containers.1 (See Compatibility under Stability.)

Add appropriate volume of denileukin diftitox concentrate to an empty IV infusion bag and dilute each mL of the concentrate with no more than 9 mL of the 0.9% sodium chloride injection to provide a solution containing at least 15 mcg/mL, a concentration that must be maintained during all steps of solution preparation.1

Mix by gentle swirling; do not shake vigorously.1

Rate of Administration

Administer by IV infusion over at least 15 minutes.1

If infusion-related adverse effects occur, discontinue infusion or administer the drug over longer periods (e.g., up to 80 minutes), depending on the severity of symptoms.1 3

Dosage

Adults

Cutaneous T-cell Lymphoma
IV

9 or 18 mcg/kg daily for 5 consecutive days; repeat every 21 days.1 3

Optimum duration of therapy not established; only 2% of patients who do not experience at least a 25% decrease in tumor burden prior to the fourth course of treatment subsequently respond.1

Special Populations

No special population recommendations at this time.1

Cautions for Ontak

Contraindications

  • Known hypersensitivity to denileukin diftitox, diphtheria toxin, aldesleukin (interleukin-2), or any other ingredient in the formulation.1

Warnings/Precautions

Warnings

Administer only under supervision of qualified clinicians experienced in use of cytotoxic therapy.1

Closely monitor patients in a setting equipped and staffed by health-care personnel appropriately trained in CPR.1

Capillary Leak Syndrome

Risk of severe and/or fatal capillary leak syndrome (e.g., hypotension, edema, hypoalbuminemia).1 3 4

Syndrome usually occurs within the first 2 weeks of the infusion and may persist or worsen after completion of the treatment cycle.1 6

Use with caution in patients with preexisting cardiovascular disease and/or low serum albumin concentrations, since they appear to be at increased risk of developing this syndrome.1 3 6

Monitor weight, edema, BP, and serum albumin concentrations.1 Usually self-limiting; initiate treatment only if clinically indicated.1 6

Ocular Effects

Loss of visual acuity, usually with loss of color vision, reported; occurred with or without retinal pigment mottling.a b Although recovery was reported in some affected patients, most patients reported persistent visual impairment.a b

Sensitivity Reactions

Hypersensitivity

Potentially fatal, acute hypersensitivity reactions (e.g., hypotension, dyspnea, anaphylaxis) reported in about 69% of patients during or within 24 hours of infusion; about 50% of cases occurred on the first day of dosing, regardless of the treatment cycle.1 3 4 8

If hypersensitivity reaction occurs, discontinue immediately and/or institute appropriate therapy as indicated (e.g., IV antihistamine, epinephrine, corticosteroids).1 Have these drugs and resuscitative equipment immediately available during denileukin diftitox therapy.1

General Precautions

Adequate Patient Evaluation and Monitoring

Perform CBCs, blood chemistries, and renal and hepatic function tests prior to initiation of therapy and at weekly intervals during therapy.1 8

Immunologic Reactions

Possible development of antibodies to denileukin diftitox; may inhibit functional activity of denileukin diftitox.1

Systemic exposure to denileukin diftitox also may be decreased.1 3 (See Special Populations under Pharmacokinetics.)

Manufacturer states that presence or absence of antibodies does not correlate with the risk of immediate hypersensitivity reactions associated with IV infusion of the drug.1

Infectious Complications

May impair immune function; monitor carefully for development of possibly severe infections.1 3

Patients with CTCL may be predisposed to cutaneous infection.1

Hypoalbuminemia

Possible moderate to severe hypoalbuminemia, usually occurring 1 or 2 weeks after administration of denileukin diftitox.1

Monitor serum albumin concentrations prior to initiating each course of therapy.1 Delay administration of the drug until serum albumin concentrations are at least 3 g/dL.1

Flu-like Syndrome

Flu-like syndrome (e.g., fever and/or chills, asthenia, GI effects, myalgia, arthralgia) frequently reported within several hours to days after denileukin diftitox infusion.1 3 8

Mild to moderate symptoms generally responsive to antipyretics, antiemetics, or antidiarrhea agents.1 3

Specific Populations

Pregnancy

Category C.1

Lactation

Not known whether denileukin diftitox is distributed into milk.1 Discontinue nursing because of potential risk to nursing infants.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

No substantial differences in efficacy relative to younger adults.1

Higher incidence and greater severity of anorexia, hypotension, anemia, confusion, rash, nausea, and/or vomiting observed in patients ≥65 years of age than in younger adults.1

Common Adverse Effects

Hypoalbuminemia, chills/fever, asthenia, infection, chest pain, hypotension, vasodilation, edema, dyspnea, nausea/vomiting, anorexia, diarrhea, anemia, increase in serum aminotransferase concentrations, dizziness, pain, headache, cough, rash, pruritus.1 3 4

Interactions for Ontak

No formal drug interaction studies to date.1

No effect on CYP enzyme system in one rodent study.1

Ontak Pharmacokinetics

Distribution

Extent

Distributed into liver and kidneys in rats.1

Elimination

Metabolism

Metabolized by proteolytic degradation.1

Half-life

Biphasic; terminal half-life is approximately 70–80 minutes.1

Special Populations

In patients with denileukin diftitox antibodies, clearance may be increased twofold to threefold.1 3

Stability

Storage

Parenteral

Injection Concentrate

-10°C or less.1 Once thawed, solutions should not be refrozen.1

Use diluted solutions within 6 hours; immediately discard any unused portions.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Do not mix with other drugs.1

Manufacturer states adsorption of the drug to glass containers may occur.1

Solution Compatibility1

Compatible1

Sodium chloride 0.9% (preservative-free)

Actions

  • Recombinant DNA-derived cytotoxic protein containing domains of diphtheria toxin fragments A and B (Met1 to Thr387)-His and of interleukin-2 (IL-2; Ala1-Thr133);1 3 4 8 prepared from cultures of genetically modified Escherichia coli and purified using reverse phase chromatography followed by a multistep diafiltration process.1 6

  • Exact mechanism of action in the treatment of CTCL has not been fully elucidated but is designed to direct the cytocidal activity of diphtheria toxin to cells with high affinity IL-2 receptor on the cell surface, thereby inhibiting cellular protein synthesis, which results in cell death within hours.1

Advice to Patients

  • Risk of hypersensitivity reactions and flu-like syndrome.1

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Denileukin Diftitox

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection concentrate (frozen), for IV infusion

150 mcg per mL (300 mcg)

Ontak

Ligand

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions July 1, 2006. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Ligand. Ontak (denileukin diftitox) prescribing information. San Diego, CA; 2002 Feb.

2. Nakase K, Kita K, Nasu K et al. Differential expression of interleukin-2 receptors (alpha and beta chain) in mature lymphoid neoplasms. Am J Hematol. 1994; 46:179-83. [PubMed 7514848]

3. 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; 19:376-88. [IDIS 460619] [PubMed 11208829]

4. Kreitman RJ. Immunotoxins. Expert Opin Pharmacother. 2000; 1:1117-29. [PubMed 11249483]

5. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD; 2001 Aug 21. From FDA web site ().

6. Ligand, San Diego, CA: Personal communication.

7. 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; 1:298-302. [PubMed 11707845]

8. Anon. FDA approves novel treatment for rare form of cancer. FDA Talk Paper. Rockville, MD: Food and Drug Administration. 1999 Feb 5.

a. Ligand. Ontak (denileukin diftitox) prescribing information. San Diego, CA; 2006 Feb.

b. Ghalie R. Dear healthcare professional letter: important drug warning. San Diego, CA: Ligand; 2006 Mar 3. From FDA website ().

Hide
(web1)