Aldesleukin

MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Aldesleukin may be confused with oprelvekin
Proleukin® may be confused with oprelvekin

High alert medication: The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.

U.S. BRAND NAMES — Proleukin®

PHARMACOLOGIC CATEGORY
Antineoplastic Agent, Miscellaneous
Biological Response Modulator

DOSING: ADULTS — Refer to individual protocols.

Renal cell carcinoma: I.V.: 600,000 int. units/kg every 8 hours for a maximum of 14 doses; repeat after 9 days for a total of 28 doses per course. Retreat if needed 7 weeks after previous course.

Melanoma:
I.V.:
Single-agent use: 600,000 int. units/kg every 8 hours for a maximum of 14 doses; repeat after 9 days for a total of 28 doses per course. Retreat if needed 7 weeks after previous course.
In combination with cytotoxic agents (unlabeled use): 24 million int. units/m2 days 12-16 and 19-23
SubQ (unlabeled route):
Single-agent doses: 3-18 million int. units/day for 5 days each week, up to 6 weeks
In combination with interferon:
5 million int. units/m2 3 times/week
1.8 million int. units/m2 twice daily 5 days/week for 6 weeks
Investigational regimen: SubQ: 11 million int. units (flat dose) daily for 4 days per week for 4 consecutive weeks; repeat every 6 weeks

DOSING: ELDERLY — Refer to adult dosing.

DOSING: RENAL IMPAIRMENT — No specific recommendations by manufacturer. Use with caution.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injection, powder for reconstitution:
Proleukin®: 22 x 106 int. units [18 million int. units/mL = 1.1 mg/mL when reconstituted]

DOSAGE FORMS: CONCISE
Injection, powder for reconstitution:
Proleukin®: 22 x 106 int. units

GENERIC EQUIVALENT AVAILABLE — No

ADMINISTRATION — Administer as I.V. infusion over 15 minutes (do not administer with an inline filter). Flush before and after with D5W, particularly if maintenance I.V. line contains sodium chloride. May also be administered by SubQ injection (unlabeled route)

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 1-5 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

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, NS, pentamidine, prochlorperazine edisylate, promethazine.

Compatibility when admixed: Incompatible with NS.

USE — Treatment of metastatic renal cell cancer, metastatic melanoma

USE - UNLABELED / INVESTIGATIONAL — HIV infection, and AIDS; non-Hodgkin's lymphoma

ADVERSE REACTIONS SIGNIFICANT
>10%:
Cardiovascular: Hypotension (71%; grade 4: 3%), peripheral edema (28%), tachycardia (23%), edema (15%), vasodilation (13%), cardiovascular disorder (11%; includes blood pressure changes, CHF and ECG changes)
Central nervous system: Chills (52%), confusion (34%), fever (29%; grade 4: 1%), malaise (27%), somnolence (22%), anxiety (12%), pain (12%), dizziness (11%)
Dermatologic: Rash (42%), pruritus (24%), exfoliative dermatitis (18%)
Endocrine & metabolic: Acidosis (12%), hypomagnesemia (12%), hypocalcemia (11%)
Gastrointestinal: Diarrhea (67%), vomiting (19% to 50%), nausea (19% to 35%), stomatitis (22%), anorexia (20%), weight gain (18%), abdominal pain (11%)
Hematologic: Thrombocytopenia (37%; grade 4: 1%), anemia (29%), leukopenia (16%)
Hepatic: Hyperbilirubinemia (40%), AST increased (23%)
Neuromuscular & skeletal: Weakness (23%)
Renal: Oliguria (63%; grade 4: 6%), creatinine increased (33%)
Respiratory: Dyspnea (43%), lung disorder (24%; includes pulmonary congestion, rales, and rhonchi), cough (11%), respiratory disorder (11%; includes acute respiratory distress syndrome, infiltrates and pulmonary changes)
Miscellaneous: Infection (13%; grade 4: 1%)

1% to 10%:
Cardiovascular: Arrhythmia (10%), cardiac arrest (grade 4: 1%), MI (grade 4: 1%), supraventricular tachycardia (grade 4: 1%), ventricular tachycardia (grade 4: 1%)
Gastrointestinal: Abdomen enlarged (10%)
Hematologic: Coagulation disorder (grade 4: 1%)
Hepatic: Alkaline phosphatase increased (10%)
Renal: Anuria (grade 4: 5%), acute renal failure (grade 4: 1%)
Respiratory: Rhinitis (10%), apnea (grade 4: 1%)
Miscellaneous: Sepsis (grade 4: 1%)

<1% (Limited to important or life-threatening): Acute tubular necrosis, allergic interstitial nephritis, allergic reactions, anaphylaxis, atrial arrhythmia, AV block, blindness (transient or permanent), bowel necrosis, bradycardia, bullous pemphigoid, BUN increased, cardiomyopathy, cellulitis, cerebral edema, cerebral lesions, cerebral vasculitis, CHF, cholecystitis, colitis, coma, crescentic IgA glomuleronephritis, Crohn's disease exacerbation, depression (severe; leading to suicide), diabetes mellitus, duodenal ulcer, encephalitis, endocarditis, extrapyramidal syndrome, gastrointestinal hemorrhage, hematemesis, hemoptysis, hemorrhage, hepatic failure, hepatitis, hepatosplenomegaly, hypertension, hyperuricemia, hyperventilation, hypothermia, hyperthyroidism, hypoventilation, hypoxia, inflammatory arthritis, injection site necrosis, intestinal obstruction, intestinal perforation, leukocytosis, malignant hyperthermia, meningitis, myocardial ischemia, myocarditis, myopathy, myositis, neuritis, neuropathy, neutropenia, oculobulbar myasthenia gravis, optic neuritis, pancreatitis, pericardial effusion, pericarditis, peripheral gangrene, phlebitis, pneumonia, pneumothorax, pulmonary edema, pulmonary embolus, renal failure, respiratory acidosis, respiratory arrest, respiratory failure, retroperitoneal hemorrhage, rhabdomyolysis, scleroderma, seizure (including grand mal), shock, Stevens-Johnson syndrome, stroke, syncope, thrombosis, thyroiditis, tracheoesophageal fistula, transient ischemic attack, urticaria, ventricular extrasystoles

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
Boxed warnings: Capillary leak syndrome (CLS): . Experienced physician: . Infection: . Lethargy/somnolence: .

Special handling: Hazardous agent: Use appropriate precautions for handling and disposal.

Concerns related to adverse effects: Adverse effects: Are frequent and sometimes fatal. Capillary leak syndrome (CLS): [U.S. Boxed Warning]: High-dose aldesleukin therapy has been associated with capillary leak syndrome (CLS) resulting 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 a history of prior cardiac or pulmonary disease. Patients must have a serum creatinine ≤ 1.5 mg/dL prior to treatment. CNS effects: Mental status changes (irritability, confusion, depression) can occur and may indicate bacteremia, hypoperfusion, CNS malignancy, or CNS toxicity. Infection: [U.S. Boxed Warning]: Impaired neutrophil function is associated with treatment; patients are at risk for sepsis, bacterial endocarditis, and central line-related gram-positive infections. 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. Lethargy/somnolence: [U.S. Boxed Warning]: Withhold treatment for patients developing moderate-to-severe lethargy or somnolence; continued treatment may result in coma.

Disease-related concerns: Autoimmune/inflammatory disorders: Use with caution in patients with autoimmune disease or inflammatory disorders; may exacerbate condition. CNS metastases: Patients should be evaluated and treated for CNS metastases and have a negative scan prior to treatment.

Concurrent drug therapy issues: Supportive care for high-dose treatment: 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.

Special populations: Pediatrics: Safety and efficacy have not been established in children.

Other warnings/precautions: Experienced physician: [U.S. Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician in a facility with cardiopulmonary or intensive specialists and intensive care facilities available.

DRUG INTERACTIONS
Contrast Media (Non-ionic): May enhance the potential for allergic or hypersensitivity reactions to Aldesleukin. Risk C: Monitor therapy

Interferons (Alfa): May enhance the adverse/toxic effect of Aldesleukin. In particular, risks of myocardial and renal toxicity may be increased by this combination. Risk D: Consider therapy modification

ETHANOL / NUTRITION / HERB INTERACTIONS — Ethanol: May increase CNS adverse effects.

PREGNANCY RISK FACTOR — C (show table)

PREGNANCY IMPLICATIONS — Maternal toxicity and embryocidal effects were noted in animal studies. 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 — Excretion in breast milk unknown/not recommended

BREAST-FEEDING CONSIDERATIONS — Due to the potential for serious adverse reactions in the nursing infant, breast-feeding should be discontinued during treatment.

PRICING — (data from drugstore.com)
Solution (reconstituted) (Proleukin)
22000000 unit (1): $855.71

MONITORING PARAMETERS
The following clinical evaluations are recommended for all patients prior to beginning treatment and then frequently during drug administration:
CBC with differential, 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; monitor for change in mental status.
Pulmonary function (baseline and periodic) basis.

CANADIAN BRAND NAMES — Proleukin®

INTERNATIONAL BRAND NAMES — Interleukina 2 (PY); Interleukina II (CN); Proleukin (AR, AT, BE, BR, CH, CO, CZ, DE, DK, EC, EG, ES, FI, FR, GB, GR, HK, HN, HU, IE, IL, IT, KP, NL, NZ, PE, PL, PT, TW, UY)

MECHANISM OF ACTION — Aldesleukin promotes proliferation, differentiation, and recruitment of T and B cells, natural killer (NK) cells, and thymocytes; causes cytolytic activity in a subset of lymphocytes and subsequent interactions between the immune system and malignant cells; can stimulate lymphokine-activated killer (LAK) cells and tumor-infiltrating lymphocytes (TIL) cells.

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

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