Proleukin Drug Information

Metastatic Renal Cell Carcinoma Proleukin is indicated for the treatment of adults

with metastatic renal cell carcinoma (RCC).

Metastatic Melanoma Proleukin is indicated for the treatment of adults with metastatic

melanoma.

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) . 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.

Postmarketing 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

Effect of Other Drugs on Proleukin Glucocorticoids

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

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 . 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 that may suppress activity of CYP enzymes, resulting in increased exposure of CYP substrates.

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. 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.

Pediatric Use The safety and effectiveness of Proleukin have not been established in pediatric patients.

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.

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