Denileukin Diftitox

Denileukin diftitox is a designed protein containing toxins that attach themselves to certain types of malignant cells in the body. Denileukin diftitox works by destroying these malignant cells to slow the progression of cancer.

Denileukin diftitox is used to treat leukemia and lymphomas, including cutaneous (of the skin) T-cell lymphoma.

Denileukin diftitox may also be used for purposes not listed in this medication guide.

You should not use denileukin diftitox if you have ever had an allergic reaction to a diphtheria vaccine or to medicines containing interleukin-2 (IL-2).

You may have a reaction from a denileukin diftitox injection within hours or days after receiving the injection. Call your doctor promptly if you have one or more of these symptoms: fever, chills, weakness, muscle or joint pain, nausea, vomiting, or stomach upset.

Some patients receiving denileukin diftitox have had permanent changes in their vision or ability to see colors. Talk with your doctor about your individual risk. Tell your doctor if you have any vision changes during your treatment.

You should not use denileukin diftitox if you have ever had an allergic reaction to a diphtheria vaccine or to medicines containing interleukin-2 (IL-2).

To make sure denileukin diftitox is safe for you, tell your doctor if you have heart disease.

Some patients receiving denileukin diftitox have had permanent changes in their vision or ability to see colors. Talk with your doctor about your individual risk. Tell your doctor if you have any vision changes during your treatment.

It is not known whether denileukin diftitox will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

It is not known whether denileukin diftitox passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Denileukin diftitox is injected into a vein through an IV. A healthcare provider will give you this injection.

Denileukin diftitox is usually given each day for 5 days, followed by 3 weeks off the medication.

While using denileukin diftitox, you may need frequent blood tests at your doctor's office.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Call your doctor for instructions if you miss an appointment for your denileukin diftitox injection.

Ontak (denileukin diftitox), is a recombinant DNA-derived cytotoxic protein composed of the amino acid sequences for diphtheria toxin fragments A and B (Met1 –Thr387)-His and the sequences for human interleukin-2 (IL-2; Ala1 –Thr133). It is produced in an E. coli expression system and has a molecular weight of 58 kD. Neomycin is used in the fermentation process but is undetectable in the final product. Ontak is supplied in single use vials as a sterile, frozen solution intended for intravenous (IV) administration. Each 2 mL vial of Ontak contains 300 mcg of recombinant denileukin diftitox in a sterile solution of citric acid (20 mM), EDTA (0.05 mM) and polysorbate 20 ( < 1%) in Water for Injection, USP. The solution has a pH range of 6.9 to 7.2.

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 [see WARNINGS AND PRECAUTIONS].

Dosage Forms And Strengths

Solution in a single-use vial containing 150 mcg/mL (300 mcg in 2 mL).

Storage And Handling

Ontak is supplied as 150 mcg/ml, sterile, frozen solution (300 mcg in 2 mL) in a sterile single-use vial. NDC 62856-603-01, 6 vials in a package.

Store frozen at or below -10°C (14°F).

Manufactured by: Jubilant HollisterStier. Contract: Manufacturing & Services Division: 3525 N. Regal Street, Spokane, WA 99207. Distributed by: Eisai Inc., Woodcliff Lake, NJ 07677. Revised: Aug 2011

The following adverse reactions are discussed in greater detail in other sections of the label:

• Infusion Reactions [see WARNINGS AND PRECAUTIONS]
• Capillary Leak Syndrome [see WARNINGS AND PRECAUTIONS]
• Visual Loss [see WARNINGS AND PRECAUTIONS]

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.

Table 1: Incidence of Advers e Reactions Occurring in ≥ 10% of Ontak-treated patients (18 mcg/kg group) and at a higher rate than Placebo in Study 1

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 antidiphtheria 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], 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], 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.

Read the entire FDA prescribing information for Ontak (Denileukin Diftitox)

• Cancer

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© Ontak Patient Information is supplied by Cerner Multum, Inc. and Ontak Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.

Antineoplastic agent; recombinant DNA-derived cytotoxic protein.1

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

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

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

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

No formal drug interaction studies to date.1

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