Complete SPL Sections#
SPL UNCLASSIFIED SECTION
SPL UNCLASSIFIED SECTION
PROLEUKIN ® (aldesleukin) for injection, for intravenous infusion Rx Only
DESCRIPTION
DESCRIPTION SECTION
Aldesleukin, a human recombinant interleukin-2 product, is a highly purified protein with a molecular weight of approximately 15,300 daltons. The chemical name is des-alanyl-1, serine-125 human interleukin-2. Aldesleukin, a lymphokine, is produced by recombinant DNA technology using a genetically engineered E. coli strain containing an analog of the human interleukin-2 gene. Genetic engineering techniques were used to modify the human IL-2 gene, and the resulting expression clone encodes a modified human interleukin-2. This recombinant form differs from native interleukin-2 in the following ways: a) aldesleukin is not glycosylated because it is derived from E. coli ; b) the molecule has no N-terminal alanine; the codon for this amino acid was deleted during the genetic engineering procedure; c) the molecule has serine substituted for cysteine at amino acid position 125; this was accomplished by site specific manipulation during the genetic engineering procedure; and d) the aggregation state of aldesleukin is likely to be different from that of native interleukin-2. The manufacturing process for aldesleukin involves fermentation in a defined medium containing tetracycline hydrochloride. The presence of the antibiotic is not detectable in the final product. The in vitro biological activities of the native nonrecombinant molecule have been reproduced with aldesleukin. 1,2 Proleukin (aldesleukin) for injection is a sterile, preservative-free white to off-white, lyophilized powder, which has a cake-like appearance, supplied in single-dose vials for intravenous administration after reconstitution. When reconstituted with 1.2 mL Sterile Water for Injection, USP, each mL contains 18 million International Units (1.1 mg) aldesleukin, mannitol (50 mg), sodium dodecyl sulfate (0.19 mg), buffered with disodium hydrogen phosphate dihydrate (1.12 mg) and sodium dihydrogen phosphate dihydrate (0.19 mg) to a pH of 7.5 (range 7.2 to 7.8). Proleukin biological potency is determined by a lymphocyte proliferation bioassay and is expressed in International Units as established by the World Health Organization 1st International Standard for Interleukin-2 (human). The relationship between potency and protein mass is as follows: 18 million International Units Proleukin = 1.1 mg protein
CLINICAL PHARMACOLOGY
CLINICAL PHARMACOLOGY SECTION
Proleukin ® (aldesleukin) has been shown to possess the biological activities of human native interleukin-2. 1,2 In vitro studies performed on human cell lines demonstrate the immunoregulatory properties of Proleukin, including: a) enhancement of lymphocyte mitogenesis and stimulation of long-term growth of human interleukin-2 dependent cell lines; b) enhancement of lymphocyte cytotoxicity; c) induction of killer cell (lymphokine-activated (LAK) and natural (NK)) activity; and d) induction of interferon-gamma production. The in vivo administration of Proleukin in animals and humans produces multiple immunological effects in a dose dependent manner. These effects include activation of cellular immunity with profound lymphocytosis, eosinophilia, and thrombocytopenia, and the production of cytokines including tumor necrosis factor, IL-1 and gamma interferon. 3 In vivo experiments in murine tumor models have shown inhibition of tumor growth. 4 The exact mechanism by which Proleukin mediates its antitumor activity in animals and humans is unknown.
INDICATIONS AND USAGE
INDICATIONS & USAGE SECTION
Proleukin ® (aldesleukin) is indicated for the treatment of adults with metastatic renal cell carcinoma (metastatic RCC). Proleukin is indicated for the treatment of adults with metastatic melanoma. Careful patient selection is mandatory prior to the administration of Proleukin. See “ CONTRAINDICATIONS ”, “ WARNINGS ” and “ PRECAUTIONS ” sections regarding patient screening, including recommended cardiac and pulmonary function tests and laboratory tests. Evaluation of clinical studies to date reveals that patients with more favorable ECOG performance status (ECOG PS 0) at treatment initiation respond better to Proleukin, with a higher response rate and lower toxicity (See “ CLINICAL PHARMACOLOGY ” section, “ CLINICAL STUDIES ” section and “ ADVERSE REACTIONS ” section). Therefore, selection of patients for treatment should include assessment of performance status. Experience in patients with ECOG PS >1 is extremely limited.
CONTRAINDICATIONS
CONTRAINDICATIONS SECTION
Proleukin ® (aldesleukin) is contraindicated in patients with a known history of hypersensitivity to interleukin-2 or any component of the Proleukin formulation. Proleukin is contraindicated in patients with an abnormal thallium stress test or abnormal pulmonary function tests and those with organ allografts. Retreatment with Proleukin is contraindicated in patients who have experienced the following drug-related toxicities while receiving an earlier course of therapy: • Sustained ventricular tachycardia (≥5 beats) • Cardiac arrhythmias not controlled or unresponsive to management • Chest pain with ECG changes, consistent with angina or myocardial infarction • Cardiac tamponade • Intubation for >72 hours • Renal failure requiring dialysis >72 hours • Coma or toxic psychosis lasting >48 hours • Repetitive or difficult to control seizures • Bowel ischemia/perforation • GI bleeding requiring surgery
WARNINGS
WARNINGS SECTION
See boxed “ WARNINGS ” Because of the severe adverse events which generally accompany Proleukin ® (aldesleukin) therapy at the recommended dosages, thorough clinical evaluation should be performed to identify patients with significant cardiac, pulmonary, renal, hepatic, or CNS impairment in whom Proleukin is contraindicated. Patients with normal cardiovascular, pulmonary, hepatic, and CNS function may experience serious, life threatening or fatal adverse events. Adverse events are frequent, often serious, and sometimes fatal. Should adverse events, which require dose modification occur, dosage should be withheld rather than reduced (See “ DOSAGE AND ADMINISTRATION ” section, “ Dose Modifications ” subsection). Proleukin has been associated with exacerbation of pre-existing or initial presentation of autoimmune disease and inflammatory disorders. Exacerbation of Crohn’s disease, scleroderma, thyroiditis, inflammatory arthritis, diabetes mellitus, oculo-bulbar myasthenia gravis, crescentic IgA glomerulonephritis, cholecystitis, cerebral vasculitis, Stevens-Johnson syndrome and bullous pemphigoid, has been reported following treatment with IL-2. All patients should have thorough evaluation and treatment of CNS metastases and have a negative scan prior to receiving Proleukin therapy. New neurologic signs, symptoms, and anatomic lesions following Proleukin therapy have been reported in patients without evidence of CNS metastases. Clinical manifestations included changes in mental status, speech difficulties, cortical blindness, limb or gait ataxia, hallucinations, agitation, obtundation, and coma. Radiological findings included multiple and, less commonly, single cortical lesions on MRI and evidence of demyelination. Neurologic signs and symptoms associated with Proleukin therapy usually improve after discontinuation of Proleukin therapy; however, there are reports of permanent neurologic defects. One case of possible cerebral vasculitis, responsive to dexamethasone, has been reported. In patients with known seizure disorders, extreme caution should be exercised as Proleukin may cause seizures.
PRECAUTIONS
PRECAUTIONS SECTION
ADVERSE REACTIONS
ADVERSE REACTIONS SECTION
The rate of drug-related deaths in the 255 metastatic RCC patients who received single-agent Proleukin ® (aldesleukin) was 4% (11/255); the rate of drug-related deaths in the 270 metastatic melanoma patients who received single-agent Proleukin was 2% (6/270). The following data on common adverse events (reported in greater than 10% of patients, any grade), presented by body system, decreasing frequency and by preferred term (COSTART) are based on 525 patients (255 with renal cell cancer and 270 with metastatic melanoma) treated with the recommended infusion dosing regimen. TABLE 3: ADVERSE EVENTS OCCURRING IN ≥10% OF PATIENTS (n=525) Body System % Patients Body System % Patients Body as a Whole Metabolic and Nutritional Disorders Chills 52 Bilirubinemia 40 Fever 29 Creatinine increase 33 Malaise 27 Peripheral edema 28 Asthenia 23 SGOT increase 23 Infection 13 Weight gain 16 Pain 12 Edema 15 Abdominal pain 11 Acidosis 12 Abdomen enlarged 10 Hypomagnesemia 12 Cardiovascular Hypocalcemia 11 Hypotension 71 Alkaline phosphatase increase 10 Tachycardia 23 Nervous Vasodilation 13 Confusion 34 Supraventricular tachycardia 12 Somnolence 22 Cardiovascular disorder a 11 Anxiety 12 Arrhythmia 10 Dizziness 11 Digestive Respiratory Diarrhea 67 Dyspnea 43 Vomiting 50 Lung disorder b 24 Nausea 35 Respiratory disorder c 11 Stomatitis 22 Cough increase 11 Anorexia 20 Rhinitis 10 Nausea and vomiting 19 Skin and Appendages Hemic and Lymphatic Rash 42 Thrombocytopenia 37 Pruritus 24 Anemia 29 Exfoliative dermatitis 18 Leukopenia 16 Urogenital Oliguria 63 a Cardiovascular disorder: fluctuations in blood pressure, asymptomatic ECG changes, CHF. b Lung disorder: physical findings associated with pulmonary congestion, rales, rhonchi. c Respiratory disorder: ARDS, CXR infiltrates, unspecified pulmonary changes. The following data on life-threatening adverse events (reported in greater than 1% of patients, grade 4), presented by body system, and by preferred term (COSTART) are based on 525 patients (255 with renal cell cancer and 270 with metastatic melanoma) treated with the recommended infusion dosing regimen. TABLE 4: LIFE-THREATENING (GRADE 4) ADVERSE EVENTS (n= 525) Body System # (%) Patients Body System # (%) Patients Body as a Whole Metabolic and Nutritional Disorders Fever 5 (1%) Bilirubinemia 13 (2%) Infection 7 (1%) Creatinine increase 5 (1%) Sepsis 6 (1%) SGOT increase 3 (1%) Cardiovascular Acidosis 4 (1%) Hypotension 15 (3%) Nervous Supraventricular tachycardia 3 (1%) Confusion 5 (1%) Cardiovascular disorder a 7 (1%) Stupor 3 (1%) Myocardial infarct 7 (1%) Coma 8 (2%) Ventricular tachycardia 5 (1%) Psychosis 7 (1%) Cardiac arrest 4 (1%) Respiratory Digestive Dyspnea 5 (1%) Diarrhea 10 (2%) Respiratory disorder c 14 (3%) Vomiting 7 (1%) Apnea 5 (1%) Hemic and Lymphatic Urogenital Thrombocytopenia 5 (1%) Oliguria 33 (6%) Coagulation disorder b 4 (1%) Anuria 25 (5%) Acute kidney failure 3 (1%) a Cardiovascular disorder: fluctuations in blood pressure. b Coagulation disorder: intravascular coagulopathy. c Respiratory disorder: ARDS, respiratory failure, intubation. The following life-threatening (grade 4) events were reported by
OVERDOSAGE
OVERDOSAGE SECTION
Side effects following the use of Proleukin ® (aldesleukin) appear to be dose-related. Exceeding the recommended dose has been associated with a more rapid onset of expected dose-limiting toxicities. Symptoms which persist after cessation of Proleukin should be monitored and treated supportively. Life-threatening toxicities may be ameliorated by the intravenous administration of dexamethasone, which may also result in loss of the therapeutic effects of Proleukin. 12 NOTE: Prior to the use of dexamethasone, the physician should refer to the package insert for this product.
DOSAGE AND ADMINISTRATION
DOSAGE & ADMINISTRATION SECTION
The recommended Proleukin ® (aldesleukin) treatment regimen is administered by a 15-minute intravenous infusion every 8 hours. Before initiating treatment, carefully review the “ INDICATIONS AND USAGE ”, “ CONTRAINDICATIONS ”, “ WARNINGS ”, “ PRECAUTIONS ”, and “ ADVERSE REACTIONS ” sections, particularly regarding patient selection, possible serious adverse events, patient monitoring and withholding dosage. The following schedule has been used to treat adult patients with metastatic renal cell carcinoma (metastatic RCC) or metastatic melanoma. Each course of treatment consists of two 5-day treatment cycles separated by a rest period. 600,000 International Units/kg (0.037 mg/kg) dose administered every 8 hours by a 15-minute intravenous infusion for a maximum of 14 doses. Following 9 days of rest, the schedule is repeated for another 14 doses, for a maximum of 28 doses per course, as tolerated. During clinical trials, doses were frequently withheld for toxicity (See “ CLINICAL STUDIES ” section and “ Dose Modifications ” subsection). Metastatic RCC patients treated with this schedule received a median of 20 of the 28 doses during the first course of therapy. Metastatic melanoma patients received a median of 18 doses during the first course of therapy.
HOW SUPPLIED
HOW SUPPLIED SECTION
Proleukin ® (aldesleukin) is supplied in individually boxed single-dose vials. Each vial contains 22 million International Units of Proleukin. Discard unused portion. NDC 65483-116-07 Individually boxed single-dose vial Store vials of lyophilized Proleukin in a refrigerator at 2° to 8°C (36° to 46°F). PROTECT FROM LIGHT. Store in carton until time of use. Reconstituted or diluted Proleukin is stable for up to 48 hours at refrigerated and room temperatures, 2° to 25°C (36° to 77°F). However, since this product contains no preservative, the reconstituted and diluted solutions should be stored in the refrigerator. Do not use beyond the expiration date printed on the vial. NOTE: This product contains no preservative. Rx Only
REFERENCES
REFERENCES SECTION
Doyle MV, Lee MT, Fong S. Comparison of the biological activities of human recombinant interleukin-2 125 and native interleukin-2. J Biol Response Mod 1985; 4 :96-109. Ralph P, Nakoinz I, Doyle M, et al. Human B and T lymphocyte stimulating properties of interleukin-2 (IL-2) muteins. In: Immune Regulation By Characterized Polypeptides . Alan R. Liss, Inc. 1987; 453-62. Winkelhake JL and Gauny SS. Human recombinant interleukin-2 as an experimental therapeutic. Pharmacol Rev 1990; 42 :1-28. Rosenberg SA, Mule JJ, Spiess PJ, et al. Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high-dose recombinant interleukin-2. J Exp Med 1985; 161 :1169-88. Konrad MW, Hemstreet G, Hersh EM, et al. Pharmacokinetics of recombinant interleukin-2 in humans. Cancer Res 1990; 50 :2009-17. Donohue JH and Rosenberg SA. The fate of interleukin-2 after in vivo administration. J Immunol 1983; 130 :2203-8. Koths K, Halenbeck R. Pharmacokinetic studies on 35 S-labeled recombinant interleukin-2 in mice. In: Sorg C and Schimpl A, eds. Cellular and Molecular Biology of Lymphokines . Academic Press: Orlando, FL, 1985;779. Gibbons JA, Luo ZP, Hansen ER, et al. Quantitation of the renal clearance of interleukin-2 using nephrectomized and ureter ligated rats. J Pharmacol Exp Ther 1995; 272 : 119-125. Bock SN, Lee RE, Fisher B, et al. A prospective randomized trial evaluating prophylactic antibiotics to prevent triple-lumen catheter-related sepsis in patients treated with immunotherapy. J Clin Oncol 1990; 8:161-69. Hartman LC, Urba WJ, Steis RG, et al. Use of prophylactic antibiotics for prevention of intravascular catheter-related infections in interleukin-2-treated patients. J Natl Cancer Inst 1989; 81:1190-93. Snydman DR, Sullivan B, Gill M, et al. Nosocomial sepsis associated with interleukin-2. Ann Intern Med 1990; 112:102-07. Mier JW, Vachino G, Klempner MS, et al. Inhibition of interleukin-2-induced tumor necrosis factor release by dexamethasone: Prevention of an acquired neutrophil chemotaxis defect and differential suppression of interleukin-2 associated side effects. Blood 1990; 76:1933-40. Choyke PL, Miller DL, Lotze MT, et al. Delayed reactions to contrast media after interleukin-2 immunotherapy. Radiology 1992; 183:111-114. Manufactured by: Prometheus Laboratories Inc. San Diego, CA 92121 U.S. License No. 1848 At Boehringer Ingelheim Pharma Biberach/Riss, Germany For additional information, contact Prometheus Laboratories Inc. 1-877-PROLEUKIN (1-877-776-5385) PROLEUKIN is a registered trademark of Novartis Vaccines and Diagnostics, Inc. © 2010-2018 Prometheus Laboratories Inc. PROMETHEUS ® Therapeutics & Diagnostics REV: May 2019 PR001J
Principal Display Panel - Proleukin Label
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
NDC 65483-116-07 Rx only Proleukin ® (aldesleukin) for injection, for intravenous infusion 22 million International Units/Vial (1.3mg/vial) Single-Use Vial Discard Unused Portion
Principal Display Panel - Proleukin Carton
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
NDC 65483-116-07 Proleukin ® (aldesleukin) for injection, for intravenous infusion 22 million International Units/Vial (1.3 mg/vial) Single-Use Vial Discard Unused Portion For Intravenous Use Only Refrigerate Rx only
