Proleukin Drug Information

Metastatic Renal Cell Carcinoma Proleukin is indicated for the treatment of adults with metastatic renal cell carcinoma (RCC).

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

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. 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 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.

Premedication 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.

Dosage 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

Preparation 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 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.

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 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= 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.