Usual Adult Dose for Renal Cell Carcinoma

0.037 mg/kg (600,000 IU/kg) every 8 hours via a 15-minute IV infusion for a maximum of 14 doses; the schedule is repeated for another 14 doses after 9 days of rest.

Maximum Dose: 28 doses per course, as tolerated

Therapy Duration: During the first therapy course, metastatic RCC patients received a median of 20 doses and metastatic melanoma patients received a median of 18 doses.

Comments:

• Each treatment course consists of two 5-day treatment cycles separated by a rest period.
• Patient selection should include assessment of ECOG PS (Eastern Cooperative Oncology Group performance status).

• Metastatic melanoma
• Metastatic renal cell carcinoma (metastatic RCC)

Usual Adult Dose for Melanoma - Metastatic

0.037 mg/kg (600,000 IU/kg) every 8 hours via a 15-minute IV infusion for a maximum of 14 doses; the schedule is repeated for another 14 doses after 9 days of rest.

Maximum Dose: 28 doses per course, as tolerated

Therapy Duration: During the first therapy course, metastatic RCC patients received a median of 20 doses and metastatic melanoma patients received a median of 18 doses.

Comments:

• Each treatment course consists of two 5-day treatment cycles separated by a rest period.
• Patient selection should include assessment of ECOG PS (Eastern Cooperative Oncology Group performance status).

• Metastatic melanoma
• Metastatic renal cell carcinoma (metastatic RCC)

Renal Dose Adjustments

• Decisions to stop, hold, or restart therapy should be made after performing a global patient assessment; dose reductions are not recommended.
• Life-threatening toxicities may be ameliorated with IV dexamethasone, which may also cause this drug to lose its therapeutic effects.
• Retreatment is contraindicated in patients who have experienced these toxicities.

• HOLD DOSE: Serum creatinine (Scr) greater than 4.5 mg/dL or 4 mg/dL or greater in the presence of severe volume overload, acidosis, or hyperkalemia; persistent oliguria, urine output of less than 10 mL/hr for 16 to 24 hours with rising SCr.
• RESTART DOSE: SCr less than 4 mg/dL and stable fluid and electrolyte status; urine output greater than 10 mL/hr with a decrease of SCr greater than 1.5 mg/dL or normalization of SCr.

Liver Dose Adjustments

• HOLD DOSE: Signs of hepatic failure including encephalopathy, increasing ascites, liver pain, hypoglycemia.
• RESTART DOSE: All signs of hepatic failure have resolved; discontinue all further treatment for that course; a new treatment course (if warranted) should be initiated no sooner than 7 weeks after cessation of adverse event and hospital discharge.

Dose Adjustments

DOSE MODIFICATIONS FOR TOXICITY:

• Decisions to stop, hold, or restart therapy should be made after performing a global patient assessment; dose reductions are not recommended.
• Life-threatening toxicities may be ameliorated with IV dexamethasone, which may also cause this drug to lose its therapeutic effects.

• Sustained ventricular tachycardia (5 beats or greater)
• Cardiac rhythm disturbances not controlled or unresponsive to management
• Chest pain with ECG changes, consistent with angina or myocardial infarction
• Cardiac tamponade

• Intubation for longer than 72 hours

• Renal failure requiring dialysis longer than 72 hours

• Coma or toxic psychosis lasting longer than 48 hours
• Repetitive or difficult to control seizures

• Bowel ischemia/perforation
• GI bleeding requiring surgery

• Hold dose for atrial fibrillation, supraventricular tachycardia, or bradycardia that requires treatment or is recurrent or persistent; subsequent doses may be given if patient is asymptomatic with full recovery to normal sinus rhythm.
• Hold dose for systolic BP less than 90 mm Hg with increasing requirements for pressors; subsequent doses may be given if systolic BP is 90 mm Hg or greater and stable or improving requirements for pressors
• Hold dose for any ECG change consistent with MI, ischemia, or myocarditis with or without chest pain, suspicion of cardiac ischemia; subsequent doses may be given if patient is asymptomatic, MI and myocarditis have been ruled out, clinical suspicion of angina is low; there is no evidence of ventricular hypokinesia

• Hold dose for O2 saturation less than 90%; subsequent doses may be given if O2 saturation is greater than 90%

• Hold dose for mental status changes including moderate confusion or agitation; subsequent doses may be given if mental status changes are completely resolved

• Hold dose for sepsis syndrome (patient is clinically unstable); subsequent doses may be given if sepsis syndrome has resolved, patient is clinically stable, and infection is being treated

• Hold dose for serum creatinine greater than 4.5 mg/dL or a serum creatinine of 4 mg/dL or greater in the presence of severe volume overload, acidosis, or hyperkalemia; subsequent doses may be given if serum creatinine is less than 4 mg/dL and fluid and electrolyte status is stable
• Hold dose for persistent oliguria, urine output of less than 10 mL/hour for 16 to 24 hours with rising serum creatinine; subsequent doses may be given if urine output is greater than 10 mL/hour with a decrease of serum creatinine greater than 1.5 mg/dL or normalization of serum creatinine

• Hold dose for signs of hepatic failure including encephalopathy, increasing ascites, liver pain, hypoglycemia; subsequent doses may be given if all signs of hepatic failure have resolved; discontinue all further treatment for that course; a new course of therapy should be initiated no sooner than 7 weeks after cessation of adverse event and hospital discharge

Precautions

US BOXED WARNINGS:

• Therapy should be restricted to patients with normal cardiac and pulmonary functions as defined by thallium stress testing and formal pulmonary function testing.
• Extreme caution should be used in patients with a normal thallium stress test and a normal pulmonary function test who have a history of cardiac or pulmonary disease.
• This drug should be administered in a hospital setting under the supervision of a qualified physician experienced in the use of anticancer agents. An intensive care facility and specialists skilled in cardiopulmonary or intensive care medicine should be available.
• Administration of this drug has been associated with capillary leak syndrome (CLS) which is characterized by a loss of vascular tone and extravasation of plasma proteins and fluid into the extravascular space. CLS results in hypotension and reduced organ perfusion which may be severe and can result in death. CLS may be associated with cardiac arrhythmias (supraventricular and ventricular), angina, myocardial infarction, respiratory insufficiency requiring intubation, GI bleeding or infarction, renal insufficiency, edema, and mental status changes.
• This drug is associated with impaired neutrophil function (reduced chemotaxis) and with an increased risk of disseminated infection, including sepsis and bacterial endocarditis. Preexisting bacterial infections should be treated prior to initiation of therapy. Patients with indwelling central lines are particularly at risk for infection with gram positive microorganisms. Antibiotic prophylaxis with oxacillin, nafcillin, ciprofloxacin, or vancomycin has been associated with a reduced incidence of staphylococcal infections.
• Withhold therapy in patients developing moderate to severe lethargy or somnolence; continued administration may result in coma.

• Hypersensitivity to the active component or any of the ingredients
• In patients with an abnormal thallium stress test or abnormal pulmonary function tests and those with organ allografts
• Retreatment in patients who have experienced the following drug-related toxicities while receiving an earlier course of therapy:
• Sustained ventricular tachycardia (5 beats or greater)
• Cardiac arrhythmias not controlled or unresponsive to management
• Chest pain with ECG changes, consistent with angina or myocardial infarction
• Cardiac tamponade
• Intubation for longer than 72 hours
• Renal failure requiring dialysis for longer than 72 hours
• Coma or toxic psychosis lasting longer than 48 hours
• Repetitive or difficult to control seizures
• Bowel ischemia/perforation
• GI bleeding requiring surgery

Dialysis

This drug is contraindicated in renal failure requiring dialysis for longer than 72 hours.

Other Comments

Administration Advice:

• Patients should be evaluated for response approximately 4 weeks after therapy course completion and again immediately prior to the next treatment course.
• Each treatment course should be separated by a rest period of at least 7 weeks from the date of hospital discharge.
• Additional treatment courses should be given only if there is some tumor shrinkage following the last course and retreatment is not contraindicated.
• Patients should have normal cardiac, pulmonary, hepatic, and CNS function at the start of therapy.
• In-line filters should not be used.
• This drug should be administered within 48 hours of reconstitution.
• This drug should not be coadministered with other drugs in the same container.
• This drug should be brought to room temperature before administration.

• This drug should be kept in its original package; protected from light; and refrigerated at 2 to 8 degrees Celsius (36 to 46 Fahrenheit) before and after reconstitution and dilution.
• Unused drug should be discarded.

• The manufacturer product information should be consulted.

• Clinical studies show patients with ECOG PS 0 at treatment initiation have a higher response rate and experience lower toxicity; data in patients with ECOG PS greater than 1 is extremely limited.
• The impact of anti-aldesleukin antibody formation on clinical efficacy and safety is unknown.
• The relationship between potency and protein mass: 18 million IUs aldesleukin equals 1.1 mg protein.
• Each vial contains 22 million IUs (1.3 mg) of drug and no preservatives.
• The solubilizing agent sodium dodecyl sulfate may have an effect on the kinetic properties of this drug.
• This drug is produced by recombinant DNA technology using a genetically engineered E. coli strain containing an analog of the human IL-2 gene.
• The potential for mutagenicity or carcinogenicity is considered low given the similarities between this drug and endogenous IL-2.
• The manufacturer product information should be consulted for concomitant medications shown to be useful in managing adverse effects experienced by patients.

• Cardiovascular: Vital signs, clinical exams, organ function monitoring (daily); hypovolemia (via catheterization and central pressure monitoring)
• Endocrine: Thyroid abnormalities and other potential autoimmune phenomena, blood glucose
• Hematological: CBC with differential, platelet counts, and other standard tests (daily); blood chemistries [e.g., fluid and electrolyte balance, renal, and hepatic function tests] (daily)
• Respiratory: Pulmonary function (via clinical exams, vital signs, pulse oximetry)

• This drug may cause side effects such as confusion and drowsiness that can affect your ability to perform certain activities; avoid driving and activities such as operating machinery until you know how this drug affects you.