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Denileukin Diftitox (Systemic)


VA CLASSIFICATION
Primary: AN300

Commonly used brand name(s): Ontak.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antineoplastic —

Indications

Accepted

Lymphomas, cutaneous T-cell (treatment)—Denileukin diftitox is indicated for treatment of persistent or recurrent cutaneous T-cell lymphoma when malignant cells express the CD25 component of the interleukin-2 (IL-2) receptor{01}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Amino acid sequences for diptheria toxin fragments A and B (Met1-Thr387)-His followed by the sequences for interleukin-2 (IL-2; Ala1-Thr133), produced by an E. coli expression system{01}.
Molecular weight—
    58,000 daltons{01}

Mechanism of action/Effect:

Denileukin diftitox is a fusion protein that directs the cytotoxic action of diptheria toxin to cells that express the high affinity (CD25/CD122/CD152) form of the IL-2 receptor. Certain leukemias and lymphomas, including cutaneous T-cell lymphoma, contain malignant cells that express at least one subunit of the IL-2 receptor. By interacting with the high affinity IL-2 receptor on the cell surface (seen ex vivo), denileukin diftitox inhibits cellular protein synthesis, resulting in cell death{01}.

Distribution:

Volume of distribution (Vol D)—Approximately 0.06 to 0.08 liters per kg of body weight (approximates circulating blood VolD). The liver and kidneys were the primary sites of distribution of radiolabeled denileukin diftitox in rats. Systemic exposure is variable, but proportional to dose{01}.

Half-life:

Distribution phase—Approximately 2 to 5 minutes{01}.

Terminal phase—Approximately 70 to 80 minutes{01}.

Elimination:
    Clearance—Approximately 1.5 to 2 mL per minute per kg of body weight (mL/min/kg){01}.
    The development of anti-denileukin diftitox antibodies significantly increases (by two to threefold) the clearance of denileukin diftitox. This results in a 75% reduction in mean systemic exposure. Anti-denileukin diftitox antibodies developed in 41/49 patients after a single course and in 33/34 patients after three cycles of therapy{01}.


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to diptheria toxin, interleukin-2, or components of the product formulation may also be sensitive to denileukin diftitox{01}.

Note: Prior to initiation of therapy, 39% of lymphoma patients had low titers of an antibody that cross-reacted with the diptheria toxin portion of denileukin diftitox. Fifty percent of patients developed a low titer of antibodies to the IL-2 portion of denileukin diftitox. Antibody response in all patients was directed against the diptheria toxin portion of denileukin diftitox. There does not appear to be a correlation between the presence or absence of antibodies with the risk of developing acute hypersensitivity-type reactions{01}.


Carcinogenicity

Studies have not been done to evaluate the carcinogenic potential of denileukin diftitox{01}.

Mutagenicity

Denileukin diftitox was not mutagenic in the Ames test or the chromosomal aberration assay{01}.

Pregnancy/Reproduction
Fertility—
Studies in animals have not been done{01}.

Pregnancy—
Adequate and well-controlled studies in humans have not been done. Risk-benefit should be considered before use of denileukin diftitox during pregnancy{01}.

FDA Pregnancy Category C{01}.

Breast-feeding

It is not known whether denileukin diftitox is distributed into breast milk. The manufacturer recommends that patients receiving denileukin diftitox discontinue breast-feeding{01}.

Pediatrics

No information is available on the relationship of age to the effects of denileukin diftitox in pediatric patients. Safety and efficacy have not been established{01}.


Geriatrics


Certain adverse effects (anorexia, hypotension, anemia, confusion, rash, nausea, and/or vomiting) may occur more frequently and be more severe in patients over 65 years of age{01}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Drug interaction studies with denileukin diftitox have not been done. In one animal study, denileukin diftitox did not affect P450 levels{01}.



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Albumin, serum    (values may be decreased{01})


Alanine aminotransferase (ALT [SPGT]), serum
Aspartate aminotransferase (AST [SGOT]), serum    (transient increase in values may occur during first course of therapy; values usually return to normal within two weeks{01})


Creatinine, serum    (values may be increased{01})


Calcium, serum
Potassium, serum    (values may be decreased{01})


Lymphocyte count    (may be decreased during initial dosing period [days 1 to 5] with counts returning to normal by day 15. Changes in counts become less significant and recovery occurs more rapidly with subsequent courses of therapy{01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Cardiovascular disease, preexisting or
» Hypoalbuminemia    (risk of vascular leak syndrome may be increased{01})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» CD25 expression    (malignant cells should be tested for CD25 expression prior to administration of denileukin diftitox. A testing service for the assay of CD25 is available by calling 800-964-5836.{01})


» Complete blood count and
» Blood chemistry panel    (recommended prior to initiation of therapy and weekly during therapy{01})


» Albumin concentrations, serum    (recommended prior to initiation of each course of therapy; administration of denileukin diftitox should be delayed if the serum albumin levels are less than 3 grams per deciliter; the incidence of vascular leak syndrome may be predicted by decreased serum levels of albumin{01})


Blood pressure and
Edema and
Patient weight    (routine monitoring recommended{01})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent (> 15%)
    
Acute hypersensitivity reaction, including hypotension{01} (dizziness or faintness), back pain{01}
dyspnea{01} (shortness of breath), vasodilation{01} (warmth and flushing of skin), rash{01}
chest pain{01}
tachycardia{01} ( fast or irregular heartbeat), and dysphagia{01} (difficulty swallowing)— symptoms are rarely severe
    
anemia{01} (unusual tiredness or weakness)
    
asthenia{01} (loss of strength or energy)
    
flu-like syndrome, including arthralgia or myalgia{01} (pain in joints or muscles)
    
fever or chills{01}
    
nausea and vomiting{01}
    
infection{01}
    
vascular leak syndrome{01} (flushing of the skin; dizziness or faintness; swelling of face, feet, or lower legs)

Note: Acute hypersensitivity reactions were reported in 69% of patients and generally occurred within 24 hours of denileukin diftitox infusion{01}.
A flu-like syndrome occurs in 91% of patients, however, symptoms are usually mild to moderate in severity{01}.
Infections are frequently severe, however, discontinuation of therapy with denileukin diftitox is rarely necessary{01}.
Onset of vascular leak syndrome occurs within the first two weeks of infusion of denileukin diftitox. Symptoms may persist or worsen after treatment is stopped. This syndrome is usually self-limiting and treatment is warranted only if clinically indicated{01}.


Incidence less frequent (5 to 15%)
    
Leukopenia{01} (fever or chills; cough or hoarseness ; lower back or side pain; painful or difficult urination)—usually asymptomatic
    
thrombocytopenia{01} (unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)— usually asymptomatic
    
thrombotic events, including deep vein thrombosis{01} (abdominal pain, sudden, severe, or continuing; coughing up blood; headache, severe or sudden; loss of coordination, sudden; pains in groin, or leg, especially calf of leg; slurring of speech, sudden; vision changes, sudden ; weakness, numbness, or pain in arm or leg, unexplained )
    
pulmonary embolism{01} (shortness of breath, sudden, unexplained; pain in chest)
    
thrombophlebitis{01} (redness; swelling or pain at injection site)
    
urogenital symptoms, including albuminuria{01} (cloudy urine )
    
hematuria{01} (blood in urine)
    
pyuria{01} (cloudy urine)

Incidence rare (< 5%)
    
Hyperthyroidism{01} (increased heart rate)
    
hypothyroidism{01} (loss of appetite ; weight gain; dry, puffy skin; tiredness)
    
pancreatitis{01} (nausea; severe abdominal or stomach pain; vomiting)
    
renal insufficiency, acute{01} (decreased urination ; loss of appetite; nausea; unusual tiredness)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent (> 15%)
    
Anorexia{01} (loss of appetite)
    
cough{01}
    
diarrhea{01}
    
headache{01}
    
pharyngitis{01} (sore throat)
    
skin rash{01}

Note: Onset of diarrhea may be delayed and the duration of symptoms may be prolonged.{01}.
Onset of skin rashes may be acute or delayed and include macropapular, petechial, vesicular bullous, urticarial, and/or eczematous varieties{01}.


Incidence less frequent (5 to 15%)
    
Confusion{01}
    
constipation{01}
    
dyspepsia{01} (indigestion)
    
injection site reaction{01} (burning; itching; redness or swelling at place of injection)
    
insomnia{01} (trouble in sleeping )
    
paresthesia{01} (numbness or tingling of fingers, toes, or face)
    
rhinitis{01} (runny nose)





Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute effects
    
Asthenia{01} (loss of strength or energy)—usually persistent
    
chills{01}
    
fever{01}
    
nausea{01} — moderate to severe
    
vomiting{01}


Treatment of overdose
Closely monitor hepatic and renal function as well as overall fluid balance if overdose occurs{01}.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Denileukin Diftitox (Systemic).
Consider advising the patient on the following (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to diptheria toxin, interleukin-2, or other components of the product formulation

Pregnancy—Risk-benefit should be considered before use





Breast-feeding—Use is not recommended





Use in the elderly——Certain adverse events may occur frequently and be more severe in patients over 65 years of age.
Other medical problems, especially preexisting cardiovascular disease or hypoalbuminemia

Proper use of this medication

» Proper dosing

Precautions while using this medication
» Importance of close monitoring by the physician


Side/adverse effects
Signs of potential side effects, especially acute hypersensitivity reactions, anemia, asthenia, flu-like syndrome, fever or chills, nausea and vomiting, infection, vascular leak syndrome, leukopenia, thrombocytopenia, thrombotic events, pulmonary embolism, thrombophlebitis, urogenital symptoms, hyperthyroidism, hypothyroidism, pancreatitis, and acute renal insufficiency


General Dosing Information
Patients receiving denileukin diftitox should be under the supervision of a physician experienced in cancer chemotherapy.

It is recommended that patients receiving denileukin diftitox be closely monitored for an appropriate period of time in a facility equipped and staffed for cardiopulmonary resuscitation.

Denileukin diftitox is recommended for administration by intravenous infusion only. Rapid intravenous (push or bolus) administration is not recommended.

Patients should be closely monitored for signs and symptoms of infection because patients with cutaneous T-cell lymphoma may be predisposed to have cutaneous infections and denileukin diftitox may interfere with immune function by binding to activated lymphocytes and macrophages.

If an infusion-related reaction occurs, it is recommended that the infusion be discontinued or the rate of infusion be decreased, depending on the severity of the reaction.

Optimal therapy duration has not been determined; however, only 2% of patients with less than a 25% decrease in tumor size after three treatment courses responded to subsequent treatments.

For treatment of adverse effects
Acute hypersensitivity-type reactions—Infusion may be discontinued or the rate of infusion may be decreased, depending on severity of reaction. Intravenous antihistamines, corticosteroids, and epinephrine may also be required.

Flu-like syndrome—Administration of antipyretics and/or anti-emetics generally relieves symptoms of a flu-like syndrome.

Skin rashes—Antihistamines, topical and/or oral corticosteroids may be required.


Parenteral Dosage Forms

DENILEUKIN DIFTITOX INJECTION

Usual adult dose
Lymphomas, cutaneous T-cell
Intravenous infusion (over at least 15 minutes), 9 or 18 mcg per kg of body weight per day for five days, repeated every twenty-one days{01}.


Usual adult prescribing limits
Lymphoma, cutaneous T-cell
31 mcg per kg of body weight per day{01}.


Usual pediatric dose
Safety and efficacy have not been established{01}.

Strength(s) usually available
U.S.—


150 mcg per 1 mL (Rx) [Ontak (citric acid ) (EDTA) (polysorbate 20)]

Packaging and storage:
Store frozen at or below -10 °C{01}.

Preparation of dosage form:
Denileukin diftitox is prepared for intravenous use by thawing frozen solution in a refrigerator (2 to 8 °C [36 to 46 °F]) for up to 24 hours or at room temperature (25 °C [77 °F]) for 1 or 2 hours{01}. The solution can be mixed by gently swirling the vial{01}.

Denileukin diftitox is prepared for intravenous infusion by withdrawing the calculated dose from the vial and injecting it into an empty infusion bag{01}. No more than 9 mL of 0.9% sodium chloride injection (without preservatives) should be added to each 1 mL of denileukin diftitox solution in the infusion bag{01}. The concentration of denileukin diftitox should be at least 15 mcg per mL during all steps in the preparation of the intravenous infusion{01}. Discard the solution if it is not clear, colorless, or contains a precipitate{01}.

Note: Denileukin diftitox solution should not be heated, refrozen, or vigorously shaken{01}. After thawing, the solution may have a hazy appearance, which should clear after being at room temperature{01},


Stability:
Contains no preservative; any unused portion of a vial should be discarded. Denileukin diftitox solutions prepared for intravenous infusion should be administered within six hours of preparation{01}.

Incompatibilities:
Denileukin diftitox should not be mixed with any other drugs and should not be administered through an in-line filter{01}.



Developed: 09/23/1999



References
  1. Ontak package insert (Ligand Pharmaceuticals—US), Rev 2/99.
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