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Pronunciation |
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(al
des LOO
kin) |
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U.S. Brand
Names |
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Proleukin® |
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Generic
Available |
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No |
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Synonyms |
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IL-2; Interleukin-2 |
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Pharmacological Index |
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Biological Response Modulator |
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Use |
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Treatment of metastatic renal cell carcinoma; also, investigated in tumors
known to have a response to immunotherapy, such as melanoma; has been used in
conjunction with LAK cells, TIL cells, IL-1, and interferon |
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Pregnancy Risk
Factor |
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C |
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Contraindications |
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Known history of hypersensitivity to interleukin-2 or any component; patients
with an abnormal thallium stress test or pulmonary function test; patients who
have had an organ allograft; retreatment in patients who have experienced
sustained ventricular tachycardia ( greater than or equal to 5 beats), cardiac
rhythm disturbances not controlled or unresponsive to management, recurrent
chest pain with EKG changes (consistent with angina or myocardial infarction),
intubation required >72 hours, pericardial tamponade; renal dysfunction
requiring dialysis >72 hours, coma or toxic psychosis lasting >48 hours,
repetitive or difficult to control seizures, bowel ischemia/perforation, GI
bleeding requiring surgery |
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Warnings/Precautions |
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High-dose IL-2 therapy has been associated with capillary leak syndrome
(CLS); CLS results in hypotension and reduced organ perfusion which may be
severe and can result in death; therapy should be restricted to patients with
normal cardiac and pulmonary functions as defined by thallium stress and formal
pulmonary function testing; extreme caution should be used in patients with
normal thallium stress tests and pulmonary functions tests who have a history of
prior cardiac or pulmonary disease. Postnephrectomy patients must have a serum
creatinine of less than or equal to 1.5 mg/dL prior to treatment.
Standard prophylactic supportive care during high-dose IL-2 treatment
includes acetaminophen to relieve constitutional symptoms and an
H2-antagonist to reduce the risk of GI ulceration and/or bleeding.
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Adverse
Reactions |
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>10%:
Cardiovascular: Sensory dysfunction, sinus tachycardia, arrhythmias,
pulmonary congestion; hypotension (dose-limiting toxicity) which may require
vasopressor support and hemodynamic changes resembling those seen in septic
shock can be seen within 2 hours of administration; angina, acute myocardial
infarction, SVT with hypotension has been reported, edema
Central nervous system: Dizziness, pain, fever, chills, cognitive changes,
fatigue, malaise, disorientation, somnolence, paranoid delusion, and other
behavioral changes; reversible and dose related; however, may continue to worsen
for several days even after the infusion is stopped
Dermatologic: Pruritus, erythema, rash, dry skin, exfoliative dermatitis,
macular erythema
Gastrointestinal: Nausea, vomiting, weight gain, diarrhea, stomatitis,
anorexia, GI bleeding
Hematologic: Anemia, thrombocytopenia, leukopenia, eosinophilia, coagulation
disorders
Hepatic: Elevated transaminase and alkaline phosphatase, jaundice
Neuromuscular & skeletal: Weakness, rigors which can be decreased or
ameliorated with acetaminophen or a nonsteroidal agent and meperidine
Renal: Oliguria, anuria, proteinuria; renal failure (dose-limiting toxicity)
manifested as oliguria noted within 24-48 hours of initiation of therapy; marked
fluid retention, azotemia, and increased serum creatinine seen, which may return
to baseline within 7 days of discontinuation of therapy; hypophosphatemia
Respiratory: Dyspnea, pulmonary edema
1% to 10%: Cardiovascular: Increase in vascular permeability: Capillary-leak
syndrome manifested by severe peripheral edema, ascites, pulmonary infiltration,
and pleural effusion; occurs in 2% to 4% of patients and is resolved after
therapy ends
<1%: Congestive heart failure, coma, seizure, alopecia, hypercalcemia,
hypocalcemia, hypomagnesemia, hypothyroidism, increased plasma levels of
stress-related hormones, acidosis, pancreatitis, polyuria, arthritis, muscle
spasm, allergic reactions |
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Overdosage/Toxicology |
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Side effects following the use of aldesleukin are dose related.
Administration of more than the recommended dose has been associated with a more
rapid onset of expected dose-limiting toxicities. Adverse reactions generally
will reverse when the drug is stopped particularly because of its short serum
half-life.
Provide supportive treatment of any continuing symptoms. Life-threatening
toxicities have been ameliorated by the I.V. administration of dexamethasone,
which may result in less of therapeutic effect of aldesleukin.
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Drug
Interactions |
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Decreased toxicity: Corticosteroids have been shown to decrease toxicity of
IL-2, but have not been used since there is concern that they may decrease the
efficacy of the lymphokine
Increased toxicity:
Aldesleukin may affect central nervous function; therefore, interactions
could occur following concomitant administration of psychotropic drugs (eg,
narcotics, analgesics, antiemetics, sedatives, tranquilizers)
Concomitant administration of drugs possessing nephrotoxic (eg,
aminoglycosides, indomethacin), myelotoxic (eg, cytotoxic chemotherapy),
cardiotoxic (eg, doxorubicin), or hepatotoxic (eg, methotrexate, asparaginase)
effects with aldesleukin may
toxicity in these organ
systems; the safety and efficacy of aldesleukin in combination with chemotherapy
agents has not been established
Beta-blockers and other antihypertensives may potentiate the hypotension seen
with Proleukin®
Iodinated contrast media: Acute reactions including fever, chills, nausea,
vomiting, pruritus, rash, diarrhea, hypotension, edema, and oliguria have
occurred within hours of contrast infusion; this reaction may occur within 4
weeks or up to several months after IL-2 administration |
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Stability |
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Store vials of lyophilized injection in a refrigerator at
2°C to 8°C
(36°F to 46°F)
Reconstituted or diluted solution is stable for up to 48 hours at
refrigerated and room temperatures 2°C to
25°C (36°F to
77°F); however, since this product contains no
preservatives, the reconstituted and diluted solutions should be stored in the
refrigerator
Compatible only with D5W
Gently swirl, do not shake
Note: As with most biological proteins, solutions containing IL-2
should not be filtered; filtration will result in significant loss of
bioactivity
Standard aldesleukin I.V. dilutions:
Dose/50-1000 mL D5W
Concentrations <1,000,000 units/mL require the addition of human albumin
to PVC bag prior to addition of IL-2
Stable for 48 hours at room temperature or refrigeration
(2°C to 8°C); refrigeration is
recommended due to lack of preservative
Incompatible with NS
Recommendations for IL-2 (Aldesleukin -
Proleukin™) dilutions in D5
W*
- Concentrations of <60 mcg/mL (<1 million units/mL), human serum
albumin must be added to bag prior to addition of IL-2. These solutions
are stable for 6 days at room temperature.**
- Concentrations of 60-100 mcg/mL (1-1.7 million units/mL) should
not be utilized as they are unstable.
- Concentrations of 100-500 mcg/mL (1.7-8.4 million units/mL) are
stable for 6 days at room temperature.**
*1.3 mg of IL-2 (aldesleukin - Proleukin™) is
equivalent to 22 million units.
**Although stability is 6 days, IL-2 does not contain a preservative and
24-hour expiration dating should be used.
Concentrations of IL-2 which fall into the unstable (60-100 mcg/mL or
1-1.7 microunits/mL) range require addition of human serum albumin (final human
serum albumin concentration of 0.1%). Volume of human serum albumin to be
added to IL-2 (aldesleukin - Proleukin™) infusions in
D5 W:
Volume of I.V. diluent 50 mL:
Add 1 mL 5% human serum albumin or 0.2 mL 25% human serum albumin
Volume of I.V. diluent 100 mL:
Add 2 mL 5% human serum albumin or 0.4 mL 25% human serum albumin
Volume of I.V. diluent 150 mL:
Add 3 mL 5% human serum albumin or 0.6 mL 25% human serum albumin
Volume of I.V. diluent 200 mL:
Add 4 mL 5% human serum albumin or 0.8 mL 25% human serum albumin
Volume of I.V. diluent 250 mL:
Add 5 mL 5% human serum albumin or 1 mL 25% human serum albumin
Volume of I.V. diluent 500 mL:
Add 10 mL 5% human serum albumin or 2 mL 25% human serum albumin
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Mechanism of
Action |
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IL-2 promotes proliferation, differentiation, and recruitment of T and B
cells, natural killer (NK) cells, and thymocytes; IL-2 also causes cytolytic
activity in a subset of lymphocytes and subsequent interactions between the
immune system and malignant cells; IL-2 can stimulate lymphokine-activated
killer (LAK) cells and tumor-infiltrating lymphocytes (TIL) cells. LAK cells
(which are derived from lymphocytes from a patient and incubated in IL-2) have
the ability to lyse cells which are resistant to NK cells; TIL cells (which are
derived from cancerous tissue from a patient and incubated in IL-2) have been
shown to be 50% more effective than LAK cells in experimental
studies. |
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Pharmacodynamics/Kinetics |
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Absorption: Oral: Not absorbed
Distribution: Vd: Has been noted to be 4-7 L; primarily into the
plasma and then into a second compartment, the lymphocytes themselves
Bioavailability: I.M.: 37%
Half-life: Initial: 6-13 minutes; Terminal: 20-120 minutes
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Usual Dosage |
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Refer to individual protocols; all orders must be written in million
International units (million IU)
Treatment consists of two 5-day treatment cycles separated by a rest period.
600,000 units/kg (0.037 mg/kg)/dose administered every 8 hours by a 15-minute
I.V. infusion for a total of 14 doses; following 9 days of rest, the schedule is
repeated for another 14 doses, for a maximum of 28 doses per course
Dose modification: In high-dose therapy of RCC, see manufacturer's
guidelines for holding and restarting therapy; hold or interrupt a dose - DO NOT
DOSE REDUCE; or refer to specific protocol
Retreatment: Patients should be evaluated for response approximately
4 weeks after completion of a course of therapy and again immediately prior to
the scheduled start of the next treatment course; additional courses of
treatment may be given to patients only if there is some tumor shrinkage or
stable disease following the last course and retreatment is not contraindicated.
Each treatment course should be separated by a rest period of at least 7 weeks
from the date of hospital discharge; tumors have continued to regress up to 12
months following the initiation of therapy
Investigational regimen: S.C.: 11 million Units (flat dose) daily x 4
days per week for 4 consecutive weeks; repeat every 6 weeks
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Monitoring
Parameters |
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The following clinical evaluations are recommended for all patients prior
to beginning treatment and then daily during drug administration:
Standard hematologic tests including CBC, differential, and platelet counts
Blood chemistries including electrolytes, renal and hepatic function tests
Chest x-rays
Daily monitoring during therapy should include vital signs (temperature,
pulse, blood pressure, and respiration rate) and weight; in a patient with a
decreased blood pressure, especially <90 mm Hg, constant cardiac monitoring
for rhythm should be conducted. If an abnormal complex or rhythm is seen, an EKG
should be performed; vital signs in these hypotension patients should be taken
hourly and central venous pressure (CVP) checked.
During treatment, pulmonary function should be monitored on a regular basis
by clinical examination, assessment of vital signs and pulse oximetry. Patients
with dyspnea or clinical signs of respiratory impairment (tachypnea or rales)
should be further assessed with arterial blood gas determination. These tests
are to be repeated as often as clinically indicated.
Cardiac function is assessed daily by clinical examination and assessment of
vital signs. Patients with signs or symptoms of chest pain, murmurs, gallops,
irregular rhythm or palpitations should be further assessed with an EKG
examination and CPK evaluation. If there is evidence of cardiac ischemia or
congestive heart failure, a repeat thallium study should be done.
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Mental Health: Effects
on Mental Status |
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Sedation, disorientation, delusions, and cognitive changes are common,
reversible, and dose related |
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Mental Health:
Effects on Psychiatric
Treatment |
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Propranolol potentiates hypotensive effects. Interaction may occur with other
psychotropic given aldesleukin's effect on mental status. |
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Dental Health: Local
Anesthetic/Vasoconstrictor
Precautions |
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No information available to require special precautions |
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Dental Health:
Effects on Dental Treatment |
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Stomatitis in >10% of patients |
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Patient
Information |
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This drug can only be administered by infusion. Avoid alcohol and all OTC or
prescription drugs unless approved by your oncologist. You will be sensitive to
sunlight; use of sunblock (15 SPF or greater), wear protective clothing, or
avoid direct sun exposure. You will be susceptible to infection; avoid crowds or
infected persons or persons with contagious diseases. Frequent mouth care and
small frequent meals may help counteract any GI effects you may experience and
will help maintain adequate nutrition and fluid intake. This drug may result in
many side effects; you will be monitored and assessed closely during therapy,
however, it is important that you report any changes or problems for evaluation.
Report any changes in urination, unusual bruising or bleeding, chest pain or
palpitations, acute dizziness, respiratory difficulty, fever or chills, changes
in cognition, rash, feelings of pain or numbness in extremities, severe GI upset
or diarrhea, vaginal discharge or mouth sores, yellowing of eyes or skin, or any
changes in color of urine or stool. Pregnancy/breast-feeding
precautions: Inform prescriber if you are pregnant. Do not
breast-feed. |
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Nursing
Implications |
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Prior to treatment: Standard hematologic tests, blood chemistries,
chest x-rays
During treatment: Pulmonary function, assessment of vital signs and
pulse oximetry. Patients with dyspnea or clinical signs of respiratory
impairment: Arterial blood gas determination |
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Dosage Forms |
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Powder for injection, lyophilized: 22 x 106 international units
[18 million international units/mL = 1.1 mg/mL when
reconstituted] |
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References |
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Foa R, "Interleukin 2 in the Management of Acute Leukaemia," Br J
Haematol, 1996, 92(1):1-8.
Kintzel PE and Calis KA,
"Recombinant Interleukin-2: Biological Response Modifier," Clin Pharm,
1991, 10(2):110-28.
Lotz MT and Rosenberg SA,
"Interleukin-2: Clinical Applications in Biologic Therapy of Cancer," DeVita VT,
Hellman S, Rosenberg, eds, J.B. Lippincott Company: Philadelphia, PA, 1991,
159-77.
Lotze MT, "Interleukin-2: Basic Principles in Biologic Therapy of Cancer,"
DeVita VT, Hellman S, Rosenberg, eds, J.B. Lippincott Company: Philadelphia, PA,
1991, 123-41.
Mule JJ, "Interleukin-2: Preclinical Trials in Biologic Therapy of Cancer,"
DeVita VT, Hellman S, Rosenberg, eds, J.B. Lippincott Company: Philadelphia, PA,
1991, 142-58.
Whittington R and Faulds D,
"Interleukin-2: A Review of Its Pharmacological Properties and Therapeutic Use in Patients With Cancer,"
Drugs, 1993, 46(3):446-514.
Yang JC, Topalian SL, Parkinson D, et al,
"Randomized Comparison of High-Dose and Low-Dose Intravenous Interleukin-2 for the Therapy of Metastatic Renal Cell Carcinoma: An Interim Report,"
J Clin Oncol, 1994, 12(8):1572-6.
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