Aldesleukin

Proleukin is a lymphocyte growth factor indicated for: The treatment of adults with metastatic renal cell carcinoma. The treatment of adults with metastatic melanoma.

1.1Metastatic Renal Cell Carcinoma Proleukin

is indicated for the treatment of adults with metastatic renal cell carcinoma (RCC).

1.2Metastatic Melanoma Proleukin

is indicated for the treatment of adults with metastatic melanoma.

Administer Proleukin in an inpatient hospital setting with an intensive care facility. Evaluate cardiovascular, pulmonary, neurologic and renal function before beginning Proleukin. See Full Prescribing Information for Premedication and Supportive medications. 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). Evaluate patients approximately 4 weeks after completion of a course of therapy and again immediately prior to the start of the next course. Dose modification for toxicity should be accomplished by withholding or interrupting a dose. Follow reconstitution and dilution procedures.

2.1Recommended 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 . Verify pregnancy status of females of reproductive potential prior to initiating Proleukin .

2.2Recommended Dosage Administer Proleukin in an

inpatient hospital setting. An intensive care facility with specialists skilled in cardiopulmonary or intensive care medicine must be available . 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 . Administer pre-infusion medications and supportive treatment, as appropriate, prior to and during each infusion . Discontinue Proleukin for unacceptable toxicity . 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 . Separate each treatment course by a rest period of at least 7 weeks from the date of hospital discharge.

2.3Premedication and Supportive Medications Premedicate

patients with an antipyretic immediately prior to beginning Proleukin. Continue antipyretics during treatment as needed for fever . Administer prophylactic antibiotics per institutional guidelines prior to beginning Proleukin and throughout the treatment course for patients with indwelling central catheters . Administer prophylactic medication for gastrointestinal irritation and bleeding during each Proleukin treatment course . Additional medications may be needed if patients experience hypotension, dyspnea, rigors, nausea, diarrhea, pruritis, or dermatitis .

2.4Dosage Modifications for Adverse Reactions No

dose reduction for Proleukin is recommended for adverse reactions. In general, withhold or interrupt a dose or permanently discontinue Proleukin based on the severity of the adverse reaction as described in Table 2. Table 2: Recommended Dosage Modifications for Adverse Reactions Adverse Reaction Severity Dosage Modification Cardiovascular Atrial fibrillation, Supraventricular tachycardia, or Bradycardia that requires treatment or is recurrent or persistent Decrease in systolic blood pressure to <90 mmHg Withhold until patient is asymptomatic with full recovery to normal sinus rhythm Sustained ventricular tachycardia (≥5 beats) Cardiac rhythm disturbances not controlled or unresponsive to management ECG changes consistent with ischemia or myocardial infarction or angina/chest pain Cardiac tamponade Permanently discontinue Respiratory O2 saturation <90% Withhold until O2 saturation is >90% Intubation for >72 hours Permanently discontinue Neurologic Mental status changes, including moderate confusion or agitation Withhold until completely resolved Coma or toxic psychosis lasting >48 hours Repetitive or difficult to control seizures Permanently discontinue Gastrointestinal Fecal immunochemical test (FIT) or fecal occult blood test (FOBT) positive Withhold until FIT or FOBT negative Bowel ischemia/perforation or GI bleeding requiring surgery Permanently discontinue Hepatic Signs of hepatic toxicity including liver pain or ≥ Grade 3 AST or ALT elevation Withhold all further treatment for that course.

Initiate a new course of treatment no sooner than 7 weeks after signs of hepatic toxicity have resolved and hospital discharge Hepatic failure Permanently discontinue Dermatologic Bullous dermatitis or marked worsening of pre-existing skin condition Withhold until all signs of bullous dermatitis have resolved Infectious Sepsis syndrome, patient is clinically unstable Withhold until sepsis syndrome has resolved, patient is clinically stable, infection is under treatment Renal Serum creatinine >4.5 mg/dL or a serum creatinine of ≥4 mg/dL in the presence of severe volume overload, acidosis, or hyperkalemia Withhold until serum creatinine levels return to normal (<1.5 mg/dL) or baseline and fluid and electrolyte status are stable Persistent oliguria, urine output of <10 mL/hr for 16-24 hours with rising SCr Withhold until urine output >10 mL/hour with a decrease of serum creatinine >1.5 mg/dL or normalization of serum creatinine Renal failure requiring dialysis >72 hours Permanently discontinue

2.5Preparation and Administration Preparation Reconstitute Proleukin

using Sterile Water for Injection, USP. Do not reconstitute or dilute Proleukin with Bacteriostatic Water for Injection, or 0.9% Sodium Chloride Injection. Add 1.2 mL of Sterile Water for Injection, USP, by injecting the water along the walls of the vial and not directly on the lyophilized powder. The resulting concentration is 18 million IU (1.1 mg)/mL of Proleukin.

The prepared solution is a clear, colorless to slightly yellow liquid. Slowly swirl the vial; do not shake. Withdraw the required dose of Proleukin and discard the vial with any unused portion. Use polyvinyl chloride bags for dilution of Proleukin and dilute using 5% Dextrose Injection to a concentration between 0.03 mg/mL and 0.07 mg/mL based on the required dose as follows: Table 3: Recommended Proleukin Dilution Dose 5% Dextrose Volume ≤25.4 million IU (≤1.5 mg) 25 mL >25.4 million IU-60 million IU (>1.5 mg-3.5 mg) 50 mL >60 million IU (>3.5 mg) 100 mL Storage of Diluted Proleukin Infusion Solution Store under refrigeration at 2° to 8°C (36° to 46°F) for no more than 48 hours from the time of preparation to the end of the infusion.

Protect from light. Do not freeze. Allow the diluted solution to come to room temperature prior to administration. Administration Do not use in-line filters when administering Proleukin. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Do not co-administer Proleukin with other drugs through the same intravenous line. Administer by intravenous infusion over 15 minutes.

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. 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 )

5.1Capillary 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 .

5.2Neurologic 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.

5.3Serious 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 .

5.4Renal 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 .

5.5Immune-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.

5.6Embryo-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 .

5.7Serious Manifestations of Eosinophilia Serious

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

5.8Delayed 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 .

5.9Severe Hypersensitivity Reactions Proleukin

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

5.10Infusion-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 .

Severe Hypersensitivity Reactions Proleukin is contraindicated in patients with a known history of severe hypersensitivity to aldesleukin or any component of the Proleukin formulation . Organ Allografts Proleukin is contraindicated in patients with organ allografts . 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 . Hypersensitivity to aldesleukin. Organ allografts. Significant organ impairment.

8.1Pregnancy 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 . 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 . 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 . 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.

The following clinically significant adverse reactions are described elsewhere in the labeling: Capillary Leak Syndrome . Neurotoxicity . Serious Infections Including Sepsis . Renal Toxicity . Immune-Mediated Adverse Reactions . Serious Manifestations of Eosinophilia . Severe Hypersensitivity Reactions . Infusion-Related Reactions . Most common (≥ 30%) adverse reactions including laboratory abnormalities are hypotension, hyperbilirubinemia, dyspnea, rash, diarrhea, oliguria, chills, vomiting, thrombocytopenia, nausea, confusional state and increased creatinine. 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.

6.1Clinical 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) . 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 . 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 0 Dermatitis exfoliative 18 0 Renal and urinary disorders Oliguria 63 6 Blood creatinine increased 33 1 Anuria <10 5 Acute kidney injury <10 1 Additional life-threatening adverse reactions (Grade 4) were reported by <1% of the 525 patients: Cardiac disorders: bradycardia, pericardial effusion, ventricular extrasystoles, myocardial ischemia, arrhythmia supraventricular, coronary artery disease, atrioventricular block second degree, endocarditis Eye disorders: mydriasis, pupillary disorder Gastrointestinal disorders: intestinal perforation, gastrointestinal hemorrhage, hematemesis, pancreatitis, diarrhea hemorrhagic General disorders and administration site conditions: hypothermia Infections and infestations: gangrene Metabolism and nutrition disorders: hyperuricemia Nervous system disorders: syncope, neuropathy peripheral, seizure, generalized tonic-clonic seizure Investigations: liver function tests abnormal, blood urea increased Psychiatric disorders: agitation, paranoia Renal and urinary disorders: renal failure, renal tubular necrosis Respiratory, thoracic and mediastinal disorders: respiratory acidosis, asthma, pulmonary edema, hyperventilation, hypoxia, hemoptysis, hypoventilation, pneumothorax Vascular disorders: shock, hemorrhage, phlebitis, thrombosis Other Clinical Trial Experience The following serious adverse reactions were reported in patients with RCC, melanoma, or other cancers treated with Proleukin-based regimens (n >1800 patients) using dosages other than the recommended dosage: Cardiovascular disorders: transient ischemic attacks, pericarditis Gastrointestinal disorders: duodenal ulcer; gastrointestinal necrosis, tracheo-esophageal fistula Nervous system disorders: meningitis, brain edema Renal and urinary disorders: nephritis (allergic) In the same clinical population, the following fatal events each occurred with a frequency of <1%: hyperthermia malignant; cardiac arrest; myocardial infarction; pulmonary embolism; cerebrovascular accident; intestinal perforation; hepatic failure or renal failure; severe depression leading to suicide; pulmonary edema; respiratory arrest; respiratory failure. Patients with ECOG PS of 1 or higher had a higher treatment-related mortality and serious adverse events.

6.2Postmarketing Experience The

following adverse reactions have been identified during post-approval use of Proleukin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders: neutropenia, febrile neutropenia, eosinophilia, lymphopenia Cardiac disorders: cardiomyopathy, cardiac tamponade Endocrine disorders: hyperthyroidism Gastrointestinal disorders: gastritis, intestinal obstruction General disorders and administration site conditions: injection site necrosis Hepatobiliary disorders: hepatitis, hepatosplenomegaly, cholecystitis Immune system disorders: anaphylactic reaction, angioedema, urticaria Infections and infestations: pneumonia (bacterial, fungal, viral), endocarditis, cellulitis Metabolism and nutrition disorders: hyponatremia, hypophosphatemia Musculoskeletal and connective tissue disorders: myopathy, rhabdomyolysis Nervous system disorders: encephalopathy, extrapyramidal disorder, neuralgia Psychiatric disorders: insomnia Vascular disorders: hypertension, subdural hemorrhage, subarachnoid hemorrhage, cerebral hemorrhage, retroperitoneal hemorrhage