PROLEUKIN® (aldesleukin) Recombinant IL-2

Capillary Leak Syndrome

Severe and life-threatening capillary leak syndrome (CLS) characterized by hypotension, dyspnea, edema, and hypoalbuminemia can occur with PROLEUKIN, and can result in end organ toxicity including cardiac, respiratory, renal, hepatic toxicity, or death. Do not administer PROLEUKIN to patients with significant cardiac, pulmonary, renal, or hepatic impairment. Avoid concomitant use of PROLEUKIN with other products known to cause hypotension including antihypertensive drugs, those that cause renal toxicity, or hepatotoxicity.

CLS may begin immediately after PROLEUKIN treatment is initiated. Monitor for signs and symptoms of CLS including assessments of vital signs, weight, fluid intake, albumin levels and urine output.

Withhold or discontinue PROLEUKIN for failure to maintain organ perfusion as demonstrated by altered mental status, reduced urine output, oxygen saturation <90%, a fall in the systolic blood pressure below 90 mm Hg, or onset of cardiac arrhythmias. Initiate standard management for CLS, which may include intensive care.

Neurologic Toxicity

PROLEUKIN can cause neurologic toxicities including mental status changes, speech difficulties, cortical blindness, limb or gait ataxia, hallucinations, agitation, obtundation, demyelinating polyneuropathy, and coma. Alterations in mental status may progress for several days before recovery begins. Permanent neurologic deficits have occurred. Radiological findings included multiple and, less commonly, single cortical lesions on MRI and evidence of demyelination. One case of possible cerebral vasculitis has been reported.

Monitor patients for signs and symptoms of neurological toxicity during PROLEUKIN treatment. Withhold PROLEUKIN in patients developing moderate to severe lethargy or somnolence; continued administration may result in coma. Permanently discontinue PROLEUKIN for coma or toxic psychosis lasting >48 hours or for repetitive or difficult to control seizures.

Evaluate and treat CNS metastases prior to initiation of PROLEUKIN. If possible, avoid concomitant use of PROLEUKIN with other product(s) with a known potential to cause neurotoxicity, and avoid PROLEUKIN in patients with seizure disorders or abnormal intracranial imaging. Concomitant use of PROLEUKIN with other products that cause neurotoxicity may result in a greater risk of severe neurotoxicity.

Serious Infections Including Sepsis

PROLEUKIN can cause impaired neutrophil function (reduced chemotaxis) and an increased risk of disseminated infection, including sepsis and bacterial endocarditis. Treat pre-existing bacterial infections prior to initiating PROLEUKIN. Consider antibiotic prophylaxis in patients with indwelling central lines. Monitor patients for the development of signs and symptoms of infection during treatment and withhold PROLEUKIN based on severity.

Renal Toxicity

Serious renal toxicity, including oliguria and renal failure can occur with PROLEUKIN. Pre-existing renal impairment or coadministration of PROLEUKIN with other products known to cause renal toxicity may increase this risk. If possible, avoid concomitant use of PROLEUKIN with other product(s) with a known potential to cause renal toxicity. Serum creatinine should be ≤ 1.5 mg/dL before beginning PROLEUKIN. Monitor serum creatinine at baseline and daily throughout each course of therapy. Withhold PROLEUKIN, or permanently discontinue, based on severity.

Immune-mediated Adverse Reactions

Exacerbation of pre-existing autoimmune disease or initial presentation of autoimmune and inflammatory disorders has been reported following treatment with PROLEUKIN. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. These have included exacerbation of Crohn's disease, colitis, scleroderma, thyroiditis, inflammatory arthritis, diabetes mellitus, oculo-bulbar myasthenia gravis, crescentic IgA glomerulonephritis, cholecystitis, cerebral vasculitis, Stevens-Johnson syndrome, bullous pemphigoid, myocarditis, myositis, and neuritis including optic neuritis resulting in blindness.

PROLEUKIN may increase the risk of allograft rejection in transplant patients. Hypothyroidism, sometimes preceded by hyperthyroidism, has been reported following PROLEUKIN treatment. Evaluate thyroid function at baseline and periodically during treatment and initiate thyroid replacement therapy as clinically indicated.

Hyperglycemia and/or diabetes mellitus has been reported during PROLEUKIN therapy. Monitor patients for hyperglycemia and initiate treatment with insulin as clinically indicated.

Embryo-Fetal Toxicity

Based on findings in an animal study and its mechanism of action, PROLEUKIN may cause fetal harm or loss of pregnancy when administered to a pregnant woman. In pregnant rats, aldesleukin has been shown to have embryolethal effects at doses 27 times and maternal toxicities at doses 2.1 times the human exposure at the recommended clinical dose. Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to use effective contraception during treatment with PROLEUKIN.

Serious Manifestations of Eosinophilia

Serious manifestations of eosinophilia involving eosinophilic infiltration of cardiac and pulmonary tissues can occur following PROLEUKIN.

Delayed Adverse Reactions to Iodinated Contrast Media

A review of the literature revealed that 12.6% (range 11-28%) of 501 patients treated with various interleukin-2-containing regimens who were subsequently administered radiographic iodinated contrast media experienced acute, atypical adverse reactions. The onset of symptoms usually occurred within hours (most commonly 1 to 4 hours) following the administration of contrast media. These reactions include fever, chills, nausea, vomiting, pruritus, rash, diarrhea, hypotension, edema, and oliguria. These reactions may resemble the immediate side effects caused by interleukin-2 administration. Most events were reported to occur when contrast media was given within 4 weeks after the last dose of interleukin-2. These events were also reported to occur when contrast media was given several months after interleukin-2 treatment.

Severe Hypersensitivity Reactions

PROLEUKIN can cause severe hypersensitivity reactions, including anaphylactic reactions. Permanently discontinue PROLEUKIN in patients who experience a severe hypersensitivity reaction.

Infusion-Related Reactions

PROLEUKIN can cause fevers, chills, or rigors. Premedicate patients with an antipyretic prior to beginning PROLEUKIN and continue during treatment as needed for fever.

Drug Interactions

Drug interaction studies with PROLEUKIN have not been conducted. The drug interaction information described below have been observed post-marketing.

Avoid concomitant use of glucocorticoids. Coadministration with glucocorticoids may reduce aldesleukin antitumor effectiveness.

Monitor for delayed adverse reactions in patients receiving iodinated contrast media following PROLEUKIN. Administration of radiographic iodinated contrast media following administration of interleukin-2 resulted in acute, atypical adverse reactions that resemble the immediate side effects caused by PROLEUKIN in some patients.

For certain CYP substrates, minimal changes in the concentration may lead to serious adverse reactions. Monitor for toxicity or drug concentration changes of such CYP substrates when co-administered with PROLEUKIN. aldesleukin causes release of cytokines that may suppress activity of CYP enzymes, resulting in increased exposure of CYP substrates.

Use in Specific Populations

Pregnancy: Based on findings in an animal study and its mechanism of action, PROLEUKIN may cause fetal harm or loss of pregnancy when administered to a pregnant woman. Verify pregnancy status of females of reproductive potential prior to initiating PROLEUKIN. Advise females of reproductive potential to use effective contraception during treatment with PROLEUKIN.

Lactation: Because of the potential for serious adverse reactions from PROLEUKIN in a breastfed child, such as impaired immune function, advise women not to breastfeed during treatment.

Overdosage

Exceeding the recommended dose of PROLEUKIN has been associated with a more rapid onset of severe or lifethreatening toxicities. Treat toxicities supportively; life-threatening toxicities may be ameliorated by the intravenous administration of dexamethasone.

Most Common Adverse Reactions

The most common (≥30%) adverse reactions were hypotension, hyperbilirubinemia, dyspnea, rash, diarrhea, oliguria, chills, vomiting, thrombocytopenia, nausea, confusional state, and increased creatinine.

You may report side effects to Iovance at 1-844-845-4682, or to the FDA, at 1-800-FDA-1088 or at www.fda.gov/medwatch.

Please see accompanying Full Prescribing Information, including Boxed WARNINGS, for additional Important Safety Information.