PROLEUKIN

1 INDICATIONS AND USAGE Proleukin is a lymphocyte growth factor indicated for: The treatment of adults with metastatic renal cell carcinoma. ( 1.1 ) The treatment of adults with metastatic melanoma. ( 1.2 ) 1.1 Metastatic Renal Cell Carcinoma Proleukin is indicated for the treatment of adults with metastatic renal cell carcinoma (RCC). 1.2 Metastatic Melanoma Proleukin is indicated for the treatment of adults with metastatic melanoma.

2 DOSAGE AND ADMINISTRATION Administer Proleukin in an inpatient hospital setting with an intensive care facility. Evaluate cardiovascular, pulmonary, neurologic and renal function before beginning Proleukin. ( 2.1 ) See Full Prescribing Information for Premedication and Supportive medications. ( 2.3 ) Recommended dosage: 600,000 IU/kg (0.037 mg/kg) every 8 hours by a 15-minute intravenous infusion for a maximum of 14 doses. Following 9 days of rest, repeat the schedule for a maximum of another 14 doses (total of 28 doses per course, as tolerated). ( 2.2 ) Evaluate patients approximately 4 weeks after completion of a course of therapy and again immediately prior to the start of the next course. ( 2.2 ) Dose modification for toxicity should be accomplished by withholding or interrupting a dose. ( 2.4 ) Follow reconstitution and dilution procedures. ( 2.5 ) 2.1 Recommended Evaluation and Testing Before Initiating Proleukin Conduct baseline hematologic, chemistry, renal and hepatic function tests. Additionally, evaluate cardiac ejection fraction, coronary artery disease as appropriate, pulmonary function with PFTs, and evaluate for renal, hepatic, and CNS impairment prior to initiating treatment with Proleukin [see Contraindications (4) , Warnings and Precautions (5.1 , 5.2) ]. Verify pregnancy status of females of reproductive potential prior to initiating Proleukin [see Warnings and Precautions (5.6) , Use in Specific Populations (8.1 , 8.3) ]. 2.2 Recommended Dosage Administer Proleukin in an inpatient hospital setting. An intensive care facility with specialists skilled in cardiopulmonary or intensive care medicine must be available [see Warnings and Precautions (5.1) ] . The recommended dosage of Proleukin for metastatic renal cell carcinoma and metastatic melanoma is described in Table 1. Administer Proleukin as an intravenous infusion after dilution [see Dosage and Administration (2.5) ] . Administer pre-infusion medications and supportive treatment, as appropriate, prior to and during each infusion [see Dosage and Administration (2.3) ]. Discontinue Proleukin for unacceptable toxicity [see Dosage and Administration (2.4) ]. Table 1: Recommended Dosage of Proleukin Each course of therapy consists of the following: Cycle 1 Days 1-5 600,000 IU/kg (0.037 mg/kg) every 8 hours; maximum of 14 doses A maximum of 28 doses (2 cycles) per treatment course Rest period Days 6-14 Cycle 2 Days 15-19 600,000 IU/kg (0.037 mg/kg) every 8 hours; maximum of 14 doses Evaluate patients for response approximately 4 weeks after completion of a course of therapy and again immediately prior to the scheduled start of the next treatment course. Additional courses of treatment may be administered to patients if there is a treatment response following the last course, and the patient did not experience any adverse reactions in previous course(s) that led to permanent discontinuation [see Dosage and Administration (2.4) ]. Separate each treatment course by a rest period of at least 7 weeks from the date of hospital discharge. 2.3 Premedication and Supportive Medications Premedicate patients with an antipyretic immediately prior to beginning Proleukin. Continue antipyretics during treatment as needed for fever [see Warnings and Precautions (5.1 , 5.10) ]. Administer prophylactic antibiotics per institutional guidelines prior to beginning Proleukin and throughout the treatment course for patients with indwelling central catheters [see Warnings and Precautions (5.3) ]. Administer prophylactic medication for gastrointestinal irritation and bleeding during each Proleukin treatment course [see Adverse Reactions (6.1) ]. Additional medications may be needed if patients experience hypotension, dyspnea, rigors, nausea, diarrhea, pruritis, or dermatitis [see Warnings and Precautions (5.1 , 5.8 , 5.9) ]. 2.4 Dosage Modifications for Adverse Reactions No dose reduction for Proleukin is recommended for adverse reactions. In general, withhold or interrupt a dose or …

5 WARNINGS AND PRECAUTIONS Renal Toxicity: Monitor renal function at baseline and throughout treatment. Withhold Proleukin or permanently discontinue, based on severity. ( 2.4 , 5.4 ) Immune-mediated Adverse Reactions: Exacerbation of pre-existing autoimmune disease or initial presentation of autoimmune and inflammatory disorders can occur in any system or tissue. Proleukin may increase the risk of allograft rejection in transplant patients. Monitor patients and treat as indicated. ( 5.5 ) Severe Hypersensitivity Reaction: Permanently discontinue Proleukin for severe hypersensitivity reactions. ( 4 , 5.9 ) Embryo-Fetal Toxicity : May cause fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use effective contraception. ( 5.6 , 8.1 , 8.3 ) 5.1 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 [see Dosage and Administration (2.4) , Use in Specific Populations (8.1) ] . 5.2 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 [see Dosage and Administration (2.4) ]. 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 [see Contraindications (4) , Adverse Reactions (6.1 , 6.2) ] . Concomitant use of Proleukin with other products that cause neurotoxicity may result in a greater risk of severe neurotoxicity. 5.3 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 [see Dosage and Administration (2.4) ]. 5.4 Renal Toxicity Serious renal toxicity, including oliguria and renal failure can occur with Proleukin [see Adverse Reactions (6.1 ,…

4 CONTRAINDICATIONS Severe Hypersensitivity Reactions Proleukin is contraindicated in patients with a known history of severe hypersensitivity to aldesleukin or any component of the Proleukin formulation [see Adverse Reactions (6.2) ]. Organ Allografts Proleukin is contraindicated in patients with organ allografts [see Warnings and Precautions (5.5) ] . Significant Organ Impairment Proleukin is contraindicated in patients with significant cardiac (including those with an abnormal cardiac ejection fraction, impaired wall motion, or significant coronary artery disease), pulmonary (including those with an FEV1 ≤ 2 liters or < 75% predicted for height and age), renal, hepatic, or CNS impairment [see Warnings and Precautions (5.1 , 5.2 , 5.4) ] . Hypersensitivity to aldesleukin. ( 4 ) Organ allografts. ( 4 ) Significant organ impairment. ( 4 )

7 DRUG INTERACTIONS Drug interaction studies with Proleukin have not been conducted. The drug interaction information described below have been observed post-marketing. See Full Prescribing Information for important drug interactions. ( 7 ) 7.1 Effect of Other Drugs on Proleukin Glucocorticoids Avoid concomitant use of glucocorticoids. Coadministration with glucocorticoids may reduce aldesleukin antitumor effectiveness. 7.2 Effect of Proleukin on Other Drugs Radiographic Iodinated Contrast Media 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 [see Warnings and Precautions (5.8) ] . Effect on Cytochrome P-450 Substrates 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 [see Clinical Pharmacology (12.2) ] that may suppress activity of CYP enzymes, resulting in increased exposure of CYP substrates.

8.1 Pregnancy Risk Summary 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 [see Clinical Pharmacology (12.1) ]. Data on the use of Proleukin in pregnant women are limited and insufficient to assess the drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes; however, development of capillary leak syndrome during pregnancy can lead to adverse fetal outcomes (see Clinical Considerations ) . Intravenous administration of aldesleukin to pregnant rats during the period of organogenesis resulted in embryo lethality at doses 27 times and maternal toxicities at doses 2.1 times the human exposure at the recommended clinical dose (see Data ) . Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15–20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Capillary leak syndrome in women who are exposed to Proleukin during pregnancy may result in maternal hypotension and decreased placental perfusion. Severe or prolonged maternal hypotension and decreased placental perfusion can lead to intrauterine growth restriction, perinatal asphyxia, or fetal/neonatal demise. Monitor fetal and neonatal status in pregnant women who develop capillary leak syndrome associated with Proleukin. Data Animal Data Aldesleukin has been shown to have embryolethal effects in rats when given in doses at 27 to 36 times the human dose (scaled by body weight). Significant maternal toxicities were observed in pregnant rats administered aldesleukin by IV injection at doses 2.1 to 36 times higher than the human dose during critical period of organogenesis.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Capillary Leak Syndrome [see Warnings and Precautions (5.1) ]. Neurotoxicity [see Warnings and Precautions (5.2) ]. Serious Infections Including Sepsis [see Warnings and Precautions (5.3) ]. Renal Toxicity [see Warnings and Precautions (5.4) ]. Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.5) ]. Serious Manifestations of Eosinophilia [see Warnings and Precautions (5.7) ]. Severe Hypersensitivity Reactions [see Warnings and Precautions (5.9) ]. Infusion-Related Reactions [see Warnings and Precautions (5.10) ] . Most common (≥ 30%) adverse reactions including laboratory abnormalities are hypotension, hyperbilirubinemia, dyspnea, rash, diarrhea, oliguria, chills, vomiting, thrombocytopenia, nausea, confusional state and increased creatinine. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Iovance Biotherapeutics Manufacturing LLC. at 1 844-845-IOVA or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of Proleukin was evaluated in a series of single and multicenter, controlled studies enrolling a total of 525 patients with metastatic renal cell carcinoma (mRCC studies) or metastatic melanoma (metastatic melanoma studies) [see Clinical Studies (14.1 , 14.2) ] . In patients who received Proleukin in these studies, fatal adverse reactions occurred in 4% (11/255) of the patients with metastatic RCC, and 2% (6/270) of the patients with metastatic melanoma. In these studies, >90% of patients had doses withheld for adverse reactions [see Dosage and Administration (2.4) ]. The most common (≥30%) adverse reactions were hypotension, hyperbilirubinemia, dyspnea, rash, diarrhea, oliguria, chills, vomiting, thrombocytopenia, nausea, confusional state, and increased creatinine. Table 4 summarizes adverse reactions that occurred in these studies. Table 4: Adverse Reactions (≥10% all grades or ≥1% Grade 4) in Patients with Metastatic Renal Cell Carcinoma or Metastatic Melanoma (n=525) receiving Proleukin Adverse Reaction Proleukin N = 525 All Grades (%) Grade 4 (%) General disorders Chills 52 0 Pyrexia 29 1 Edema peripheral 28 0 Malaise 27 0 Asthenia 23 0 Edema 15 0 Pain 12 0 Cardiac disorders Hypotension 71 3 Blood pressure fluctuation Not documented 1 Tachycardia 23 0 Dilated veins 13 0 Supraventricular tachycardia 12 1 Ventricular tachycardia <10 1 Cardiovascular disorder Cardiovascular disorder: Electrocardiogram abnormal, cardiac failure congestive. 11 0 Myocardial infarction <10 1 Arrhythmia 10 0 Cardiac arrest <10 1 Gastrointestinal disorders Diarrhea 67 2 Vomiting 50 0 Nausea 35 0 Stomatitis 22 <1 Decreased appetite 20 0 Abdominal pain 11 0 Abdominal distention 10 0 Blood and lymphatic system disorders Thrombocytopenia 37 1 Anemia 29 0 Leukopenia 16 0 Disseminated intravascular coagulation <10 1 Infections Infections 13 1 Sepsis <10 1 Hepatobiliary disorders Hyperbilirubinemia 40 2 Aspartate aminotransferase increased 23 1 Metabolic and nutritional disorders Weight increased 16 0 Acidosis 12 1 Hypomagnesemia 12 0 Hypocalcemia 11 <1 Blood alkaline phosphatase increased 10 0 Nervous system disorders Confusional state 34 1 Stupor <10 1 Coma <10 2 Psychotic disorder <10 1 Somnolence 22 0 Anxiety 12 0 Dizziness 11 0 Respiratory, thoracic, and mediastinal disorders Dyspnea 43 1 Lung disorder Lung disorder: Pulmonary congestion, rales, rhonchi. 24 0 Respiratory disorder Respiratory disorder: Acute respiratory distress syndrome, lung infiltration, lung disorder, respiratory failure, endotracheal intubation. 11 3 Apnea <10 1 Cough 11 0 Rhinitis 10 0 Skin and subcutaneous tissue disorders Rash 42 0 Pruritis 24…