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Aldesleukin


Pronunciation

 (al des LOO kin)


U.S. Brand Names

 Proleukin®


Synonyms

 Epidermal Thymocyte Activating Factor; ETAF; IL-2; Interleukin-2; Lymphocyte Mitogenic Factor; NSC-373364; T-Cell Growth Factor; TCGF; Thymocyte Stimulating Factor


Generic Available

 No


Canadian Brand Names

 Proleukin®


Use

 Treatment of metastatic renal cell cancer, melanoma


Use - Unlabeled/Investigational

 Investigational: Multiple myeloma, HIV infection, and AIDS; may be used in conjunction with lymphokine-activated killer (LAK) cells, tumor-infiltrating lymphocyte (TIL) cells, interleukin-1, and interferons; colorectal cancer; non-Hodgkin's lymphoma


Pregnancy Risk Factor

 C


Pregnancy Implications

 There are no adequate and well-controlled studies in pregnant women; use during pregnancy only if benefits to the mother outweigh potential risk to the fetus. Contraception is recommended for fertile males or females using this medication.


Lactation

 Enters breast milk/contraindicated


Contraindications

 Hypersensitivity to aldesleukin or any component of the formulation; patients with abnormal thallium stress or pulmonary function tests; patients who have had an organ allograft; retreatment in patients who have experienced sustained ventricular tachycardia ( 5 beats), refractory cardiac rhythm disturbances, recurrent chest pain with ECG changes consistent with angina or myocardial infarction, intubation 72 hours, pericardial tamponade, renal dialysis for 72 hours, coma or toxic psychosis lasting 48 hours, repetitive or refractory seizures, bowel ischemia/perforation, GI bleeding requiring surgery


Warnings/Precautions

 High-dose aldesleukin 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. Patients must have a serum creatinine of 1.5 mg/dL prior to treatment.

Adverse effects are frequent and sometimes fatal. May exacerbate pre-existing or initial presentation of autoimmune diseases and inflammatory disorders. Patients should be evaluated and treated for CNS metastases and have a negative scan prior to treatment. Mental status changes (irritability, confusion, depression) can occur and may indicate bacteremia, hypoperfusion, CNS malignancy, or CNS toxicity.

Intensive aldesleukin treatment is associated with impaired neutrophil function (reduced chemotaxis) and with an increased risk of disseminated infection, including sepsis and bacterial endocarditis, in treated patients. Consequently, pre-existing bacterial infections should be adequately treated prior to initiation of therapy. Additionally, all patients with indwelling central lines should receive antibiotic prophylaxis effective against S. aureus . Antibiotic prophylaxis which has been associated with a reduced incidence of staphylococcal infections in aldesleukin studies includes the use of oxacillin, nafcillin, ciprofloxacin, or vancomycin.

Standard prophylactic supportive care during high-dose aldesleukin treatment includes acetaminophen to relieve constitutional symptoms and an H2 antagonist to reduce the risk of GI ulceration and/or bleeding.


Adverse Reactions

>10%:

Cardiovascular: Hypotension (85%), dose-limiting, possibly fatal; sinus tachycardia (70%); arrhythmia (22%); edema (47%); angina

Central nervous system: Mental status changes (transient memory loss, confusion, drowsiness) (73%); dizziness (17%); cognitive changes, fatigue, malaise, somnolence and disorientation (25%); headaches, insomnia, paranoid delusion

Dermatologic: Macular erythematous rash (100% of patients on high-dose therapy); pruritus (48%); erythema (41%); rash (26%); exfoliative dermatitis (14%); dry skin (15%)

Endocrine & metabolic: Fever and chills (89%); low electrolyte levels (magnesium, calcium, phosphate, potassium, sodium) (1% to 15%)

Gastrointestinal: Nausea and vomiting (87%); diarrhea (76%); stomatitis (32%); GI bleeding (13%); weight gain (23%), anorexia (27%)

Hematologic: Anemia (77%); thrombocytopenia (64%); leukopenia (34%) - may be dose-limiting; coagulation disorders (10%)

Hepatic: Transient elevations of bilirubin (64%) and enzymes (56%); jaundice (11%)

Neuromuscular & skeletal: Weakness; rigors - respond to acetaminophen, diphenhydramine, an NSAID, or meperidine

Renal: Oliguria/anuria (63%, severe in 5% to 6%), proteinuria (12%); 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: Congestion (54%); dyspnea (27% to 52%)

Miscellaneous: Pain (54%), infection (including sepsis and endocarditis) due to neutrophil impairment (23%)

1% to 10%:

Cardiovascular: Capillary leak syndrome, including peripheral edema, ascites, pulmonary infiltration, and pleural effusion (2% to 4%), may be dose-limiting and potentially fatal; MI (2%)

Central nervous system: Seizures (1%)

Endocrine & metabolic: Hypo- and hyperglycemia (2%); increased electrolyte levels (magnesium, calcium, phosphate, potassium, sodium) (1%), hypothyroidism

Hepatic: Ascites (4%)

Neuromuscular & skeletal: Arthralgia (6%), myalgia (6%)

Renal: Hematuria (9%), increased creatinine (5%)

Respiratory: Pleural effusions, edema (10%)

<1%: CHF, coma, alopecia, pancreatitis, allergic reactions, injection site reactions (SubQ doses)


Overdosage/Toxicology

 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, but may result in a less than therapeutic effect of aldesleukin.


Drug Interactions

Decreased toxicity: Corticosteroids have been shown to decrease toxicity of aldesleukin, 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 increase 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 aldesleukin

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 aldesleukin administration


Ethanol/Nutrition/Herb Interactions

 Ethanol: Avoid ethanol (due to CNS adverse effects)


Stability

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; Incompatible with NS

Gently swirl, do not shake.

Note: As with most biological proteins, solutions containing aldesleukin should not be filtered; filtration will result in significant loss of bioactivity

Recommendations for aldesleukin dilution: See table.


prior to addition
Final Dilution Concentration
(mcg/mL)		 Final Dilution Concentration
(10 6 int. units/mL)		 Stability
<30 <0.49 Albumin must be added to bag prior to addition of aldesleukin at a final concentration of 0.1% (1 mg/mL) albumin; stable at room temperature or at 32°C (89°F) for 6 days 1,2
30 to 70 0.49 to 1.1 Stable at room temperature at 6 days without albumin added or at 32°C (89°F) for 6 days only if albumin is added (0.1%) 1,2
70-100 1.2-1.6 Unstable; avoid use
>100-500 1.7-8.2 Stable at room temperature
and at 32°C (89°F) for 6 days 1,2
1 These solutions do not contain a preservative; use for more than 24 hours may not be advisable.
1,2 Continuous infusion via ambulatory infusion device raises aldesleukin to this temperature.

Compatibility

 Stable in D5W

Y-site administration: Compatible: Amikacin, amphotericin B, calcium gluconate, co-trimoxazole, diphenhydramine, dopamine, fat emulsion 10%, fluconazole, foscarnet, gentamicin, heparin, magnesium sulfate, metoclopramide, morphine, ondansetron, piperacillin, potassium chloride, ranitidine, thiethylperazine, ticarcillin, tobramycin. Incompatible: Ganciclovir, lorazepam, pentamidine, prochlorperazine edisylate, promethazine


Mechanism of Action

 Aldesleukin promotes proliferation, differentiation, and recruitment of T and B cells, natural killer (NK) cells, and thymocytes; aldesleukin also causes cytolytic activity in a subset of lymphocytes and subsequent interactions between the immune system and malignant cells; aldesleukin 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 aldesleukin) 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 aldesleukin) have been shown to be 50% more effective than LAK cells in experimental studies.


Pharmacodynamics/Kinetics

Distribution: Vd: 4-7 L; primarily in plasma and then in the lymphocytes

Bioavailability: I.M.: 37%

Half-life elimination: Initial: 6-13 minutes; Terminal: 80-120 minutes


Dosage

 Refer to individual protocols.

I.V.:

Renal cell carcinoma: 600,000 int. units/kg every 8 hours for a maximum of 14 doses; repeat after 9 days of rest for a total of 28 doses per course. Re-evaluate at 4 weeks. Retreat if needed 7 weeks after hospital discharge from previous course.

Melanoma:

Single-agent use: 600,000 int. units/kg every 8 hours for a maximum of 14 doses; repeat after 9 days of rest for a total of 28 doses per course. Re-evaluate at 4 weeks. Retreat if needed 7 weeks after hospital discharge from previous course.

In combination with cytotoxic agents: 24 million int. units/m 2 days 12-16 and 19-23

SubQ:

Single-agent doses: 3-18 million int. units/day for 5 days weekly and repeated weekly up to 6 weeks

In combination with interferon:

5 million int. units/m 2 3 times/week

1.8 million int. units/m 2 twice daily 5 days/week for 6 weeks

Investigational regimen: SubQ: 11 million int. units (flat dose) daily x 4 days per week for 4 consecutive weeks; repeat every 6 weeks


Administration

 Administer as I.V. infusion over 15 minutes; may be administered by SubQ injection

Management of symptoms related to vascular leak syndrome:

If actual body weight increases >10% above baseline, or rales or rhonchi are audible:

Administer furosemide at dosage determined by patient response

Administer dopamine hydrochloride 2-4 mcg/kg/minute to maintain renal blood flow and urine output

If patient has dyspnea at rest: Administer supplemental oxygen by face mask

If patient has severe respiratory distress: Intubate patient and provide mechanical ventilation; administer ranitidine (as the hydrochloride salt), 50 mg I.V. every 8-12 hours as prophylaxis against stress ulcers


Monitoring Parameters

The following clinical evaluations are recommended for all patients prior to beginning treatment and then frequently during drug administration:

Standard hematologic tests including CBC, differential, and platelet counts; blood chemistries including electrolytes, renal and hepatic function tests

Chest x-rays

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, cardiac monitoring for rhythm should be conducted. If an abnormal complex or rhythm is seen, an ECG 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.


Patient Education

 Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. This drug can only be administered by infusion. Avoid alcohol. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. You will be susceptible to infection (avoid crowds and exposure to infection and do not have any vaccinations without consulting prescriber). May cause increased sensitivity to sunlight (use sunblock 15 SPF or greater, wear protective clothing, avoid direct sun exposure); or nausea, vomiting, stomatitis, anorexia (frequent mouth care, small, frequent meals, chewing gum, or sucking lozenges may help). 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 or persistent GI upset or diarrhea, vaginal discharge or mouth sores, yellowing of eyes or skin, or changes in color of urine or stool. Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant. Do not breast-feed.


Additional Information

1 Cetus unit = 6 int. units

1.1 mg = 18 x 10 6 int. units (or 3 x 10 6 Cetus units)

1 Roche unit (Teceleukin) = 3 int. units


Dental Health: Effects on Dental Treatment

 Key adverse event(s) related to dental treatment: Stomatitis.


Dental Health: Vasoconstrictor/Local Anesthetic Precautions

 No information available to require special precautions


Mental Health: Effects on Mental Status

 Sedation, disorientation, delusions, and cognitive changes are common, reversible, and dose related


Mental Health: Effects on Psychiatric Treatment

 Propranolol potentiates hypotensive effects. Interaction may occur with other psychotropic given aldesleukin's effect on mental status.


Oncology: Emetic Potential

 Highly emetogenic (60% to 90%, dose-related)


Oncology: Vesicant

 No


Dosage Forms

 Injection, powder for reconstitution: 22 x 10 6 int. units [18 million int. units/mL = 1.1 mg/mL when reconstituted]


References

Atkins MB, Lotze MT, Dutcher JP, et al, "High-Dose Recombinant Interleukin 2 Therapy for Patients With Metastatic Melanoma: Analysis of 270 Patients Treated Between 1985 and 1993," J Clin Oncol , 1999, 17(7):2105-16.

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.

Sundin DJ and Wolin MJ, "Toxicity Management in Patients Receiving Low-Dose Aldesleukin Therapy," Ann Pharmacother ,1998, 32(12):1344-52.

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.


International Brand Names

 Proleukin® (AR, AT, AU, BE, CA, CH, CZ, DE, DK, ES, FR, GB, HU, IL, IT, MX, NL, PL, PT, RU, SG, TR)


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