Denileukin Diftitox – ONTAK®

Denileukin Diftitox - ONTAK®

Usual Diluents

Dilution Data

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 to 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:
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.

DESCRIPTION
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.

CLINICAL PHARMACOLOGY

Mechanism Of Action
Denileukin diftitox is a fusion protein designed to direct the cytocidal action of diphtheria toxin to cells which express the IL-2 receptor. Ex vivo studies report that after binding to the IL-2 receptor on the cell surface, denileukin diftitox is internalized by receptor-mediated endocytosis. The fusion protein is subsequently cleaved, releasing diphtheria toxin enzymatic and translocation domains from the IL-2 fragment, resulting in the inhibition of protein synthesis and ultimately, cell death.

1. INDICATIONS AND USAGE
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 (5.4)].

2.  DOSAGE AND ADMINISTRATION

2.1 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. 2.2 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. 3. DOSAGE FORMS AND STRENGTHS
Single-use vial containing 150 mcg/mL (300 mcg in 2 mL).

4. CONTRAINDICATIONS
None.

5.  WARNINGS AND PRECAUTIONS

5.1   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 PACKAGE INSERT FOR 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.

5.2  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)].

5.3 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.

5.4 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.

5.5 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 [see Dosage and Administration (2.1) and Warnings and Precautions (5.2)].

HOW SUPPLIED/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).