Summary of Important Safety Information for Proleukin® (aldesleukin) for injection, for intravenous infusion

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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