WARNINGS
Therapy with Proleukin® (aldesleukin) 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.
Proleukin 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
must be available.
Proleukin administration 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, gastrointestinal bleeding or infarction,
renal insufficiency, edema, and mental status changes.
Proleukin treatment is associated with impaired neutrophil function (reduced chemotaxis)
and with an increased risk of disseminated infection, including sepsis and bacterial
endocarditis. Consequently, preexisting bacterial infections should be adequately
treated prior to initiation of Proleukin 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.
Proleukin administration should be withheld in patients developing moderate to severe
lethargy or somnolence; continued administration may result in coma.
INDICATION AND USAGE
Proleukin® (aldesleukin) is indicated for the treatment of adults with
metastatic renal cell carcinoma (metastatic RCC).
Proleukin is indicated for the treatment of adults with metastatic melanoma.
Careful patient selection is mandatory prior to the administration of Proleukin.
Evaluation of clinical studies to date reveals that patients with more favorable
ECOG performance status (ECOG PS 0) at treatment initiation respond better to Proleukin,
with a higher response rate and lower toxicity. Therefore, selection of patients
for treatment should include assessment of performance status.
Experience in patients with ECOG PS >1 is extremely limited.
CONTRAINDICATIONS
Proleukin® (aldesleukin) is contraindicated in patients with a known
history of hypersensitivity to interleukin-2 or any component of the Proleukin formulation.
Proleukin is contraindicated in patients with an abnormal thallium stress test or
abnormal pulmonary function tests and those with organ allografts. Retreatment with
Proleukin is contraindicated in patients who have experienced the following drug-related
toxicities while receiving an earlier course of therapy: Sustained ventricular tachycardia
(≥5 beats), Cardiac arrhythmias not controlled or unresponsive to management, Chest
pain with ECG changes, consistent with angina or myocardial infarction, Cardiac
tamponade, Intubation for >72 hours, Renal failure requiring dialysis >72 hours,
Coma or toxic psychosis lasting >48 hours, Repetitive or difficult to control seizures,
Bowel ischemia/perforation, GI bleeding requiring surgery.
WARNINGS
Because of the severe adverse events which generally accompany Proleukin®
(aldesleukin) therapy at the recommended dosages, thorough clinical evaluation should
be performed to identify patients with significant cardiac, pulmonary, renal, hepatic,
or CNS impairment in whom Proleukin is contraindicated. Patients with normal cardiovascular,
pulmonary, hepatic, and CNS function may experience serious, life threatening or
fatal adverse events. Adverse events are frequent, often serious, and sometimes
fatal.
Should adverse events, requiring dose modification occur, dosage should be withheld
rather than reduced.
Proleukin has been associated with exacerbation of pre-existing autoimmune disease
and inflammatory disorders. In some cases, the onset of new autoimmune diseases,
such as vitiligo, may occur. Symptomatic hyperglycemia and/or diabetes mellitus
have been reported during Proleukin therapy.
All patients should have thorough evaluation and treatment of CNS metastases and
have a negative scan prior to receiving Proleukin therapy. New neurologic signs,
symptoms, and anatomic lesions following Proleukin therapy have been reported in
patients without evidence of CNS metastases. Neurologic signs and symptoms associated
with Proleukin therapy usually improve after discontinuation of Proleukin therapy;
however, there are reports of permanent neurologic defects. In patients with known
seizure disorders, extreme caution should be exercised as Proleukin may cause seizures.
PRECAUTIONS
Patients should have normal cardiac, pulmonary, hepatic, and CNS function at the
start of therapy. Capillary leak syndrome (CLS) begins immediately after Proleukin®
(aldesleukin) treatment starts and is marked by increased capillary permeability
to protein and fluids and reduced vascular tone.
Proleukin® (aldesleukin) treatment should be withheld for failure to
maintain organ perfusion as demonstrated by altered mental status, reduced urine
output, a fall in the systolic blood pressure below 90 mm Hg or onset of cardiac
arrhythmias.
Recovery from CLS begins soon after cessation of Proleukin therapy. Usually, within
a few hours, the blood pressure rises, organ perfusion is restored and reabsorption
of extravasated fluid and protein begins.
Kidney and liver function are impaired during Proleukin treatment. Use of concomitant
nephrotoxic or hepatotoxic medications may further increase toxicity to the kidney
or liver.
Mental status changes including irritability, confusion, or depression which occur
while receiving Proleukin may be due to bacteremia or early bacterial sepsis, hypoperfusion,
occult CNS malignancy, or direct Proleukin-induced CNS toxicity. Patients should
be evaluated for these and other causes of mental status changes. Alterations in
mental status due solely to Proleukin therapy may progress for several days before
recovery begins. Rarely, patients have sustained permanent neurologic deficits.
Proleukin enhancement of cellular immune function may increase the risk of allograft
rejection in transplant patients.
Serious manifestations of eosinophilia involving eosinophilic infiltration of cardiac
and pulmonary tissues can occur following Proleukin.
ADVERSE REACTIONS
The rate of drug-related deaths in the 255 metastatic RCC patients who received
single-agent Proleukin® (aldesleukin) was 4% (11/255); the rate of drug-related
deaths in the 270 metastatic melanoma patients who received single-agent PROLEUKIN
was 2% (6/270).
In clinical trials, the following life-threatening (Grade 4) adverse events were
seen in >1% of 525 patients (255 with metastatic renal cell cancer and 270 with
metastatic melanoma) treated with PROLEUKIN: oliguria (6%), anuria (5%), hypotension
(3%), respiratory disorder (3%), bilirubinemia (2%), coma (2%), diarrhea (2%), acidosis
(1%), acute kidney failure (1%), apnea (1%), cardiovascular disorder (1%), coagulation
disorders (1%), confusion (1%), creatinine increase (1%), dyspnea (1%), fever (1%),
heart arrest (1%), infection (1%), myocardial infarct (1%), psychosis (1%), sepsis
(1%), SGOT increase (1%), stupor (1%), supraventricular tachycardia (1%), thrombocytopenia
(1%), ventricular tachycardia (1%), and vomiting (1%). From the same trials, the
following adverse events (Grades 1-4) were seen in ≥30% of 525 patients (255 with
metastatic renal cell cancer and 270 with metastatic melanoma) treated with PROLEUKIN:
hypotension (71%), diarrhea (67%), oliguria (63%), chills (52%), vomiting (50%),
dyspnea (43%), rash (42%), bilirubinemia (40%), thrombocytopenia (37%), nausea (35%),
confusion (34%), and creatinine increase (33%).
Please see the full Prescribing Information, including Boxed Warning, for Proleukin®
(aldesleukin) for injection, for intravenous infusion.
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