WARNINGS Therapy with PROLEUKIN ® (aldesleukin) for injection should be restricted to patients with normal cardiac and pulmonary functions as defined by thallium stress testing and form al pulmonary function testing. Extreme caution should be used in patients with a normal thallium stress test and a normal pulmonary function test who have a history of cardiac or pulmonary disease. PROLEUKIN should be administered in a hospital setting under the supervision of a qualified physician experienced in the use of anticancer agents. An intensive care facility and specialists skilled in cardiopulmonary or intensive c are medicine must be available. PROLEUKIN administration has been associated with capillary leak syndrome (CLS) which is characterized by a loss of vascular tone and extravasation of plasma proteins and fluid into the extravascular space. CLS results in hypotension and reduced organ perfusion which may be s evere and can result in death. CLS may be associated with cardiac arrhythmias (supraventricular and ventricular), angina, myocardial infarction, respiratory insufficiency requiring intubation, gastrointestinal bleeding or infarction, renal insufficiency, edema, and mental status changes. PROLEUKIN treatment is associated with impaired neutrophil function (reduced chemotaxis) and with an increased risk of disseminated infection, including seps is and bacterial endocarditis. Consequently, preexisting bacterial infections should be adequately treated prior to in itiation of PROLEUKIN therapy. Patients with indwelling central lines are particularly at risk for infection with gram positive microorganisms. Antibiotic prophylaxis with oxacillin, nafcillin, ciprofloxacin, or vancomycin has been associated with a reduced incidence of staphylococcal infections. PROLEUKIN administration should be withheld in patients developing moderate to severe lethargy or somnolence; continued administration may result in coma.
openFDA text is shown for search and cross-checking; DailyMed SPL is canonical.
Warnings sections page 1 of 1 · 1 matching rows.
warnings
WARNINGS 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.
ADVERSE REACTIONS 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 III 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 IV 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%) Heart 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 <1% of the 525 patients: hypothermia; shock; bradycardia; ventricular extrasystoles; myocardial ischemia; syncope; hemorrhage; atrial arrhythmia; phlebitis; AV block second degree; endocarditis; pericardial effusion; peripheral gangrene; thrombosis; coronary artery disorder; stomatitis; nausea and vomiting; liver function tests abnormal; gastrointestinal hemorrhage; hematemesis; bloody diarrhea; gastrointestinal disorder; intestinal perforation; pancreatitis; anemia; leukopenia; leukocytosis; hypocalcemia; alkaline phosphatase increase; BUN increase; hyperuricemia; NPN increase; respiratory acidosis; somnolence; agitation; neuropathy; paranoid reaction; convulsion; grand mal convulsion; delirium; asthma, lung edema; hyperventilation; hypoxia; hemoptysis; hypoventilation; pneumothorax; mydriasis; pupillary disorder; kidney function abnormal; kidney failure; acute tubular necrosis. In an additional population of greater than 1,800 patients treated with PROLEUKIN-based regimens using a variety of doses and schedules (e.g., subcutaneous, continuous infusion, administration with LAK cells) the following serious adverse events were reported: duodenal ulceration; bowel necrosis; myocarditis; supraventricular tachycardia; permanent or transient blindness secondary to optic neuritis; transient ischemic attacks; meningitis; cerebral edema; pericarditis; allergic interstitial nephritis; tracheo-esophageal fistula. In the same clinical population, the following fatal events each occurred with a frequency of <1%: malignant hyperthermia; cardiac arrest; myocardial infarction; pulmonary emboli; stroke; intestinal perforation; liver or renal failure; severe depression leading to suicide; pulmonary edema; respiratory arrest; respiratory failure. In patients with both metastatic RCC and metastatic melanoma, those with ECOG PS of 1 or higher had a higher treatment-related mortality and serious adverse events. Most adverse reactions are self-limiting and, usually, but not invariably, reverse or improve within 2 or 3 days of discontinuation of therapy. Examples of adverse reactions with permanent sequelae include: myocardial infarction, bowel perforation/infarction, and gangrene. In post-marketing experience, the following serious adverse events have been reported in a variety of treatment regimens that include interleukin-2: anaphylaxis; cellulitis; injection site necrosis; retroperitoneal hemorrhage; cardiomyopathy; cerebral hemorrhage; fatal endocarditis ; hypertension; cholecystitis; colitis; gastritis; hepatitis; hepatosplenomegaly; intestinal obstruction; hyperthyroidism; neutropenia; myopathy; myositis; rhabdomyolysis; cerebral lesions; encephalopathy; extrapyramidal syndrome; insomnia; neuralgia; neuritis; neuropathy (demyelination); urticaria; pneumonia (bacterial, fungal, viral). Exacerbation or initial presentation of a number of autoimmune and inflammatory disorders have been reported (see “ WARNINGS ” section, “ PRECAUTIONS ” section, “ Drug Interactions ” subsection). Persistent but nonprogressive vitiligo has been observed in malignant melanoma patients treated with interleukin-2. Synergistic, additive and novel toxicities have been reported with PROLEUKIN used in combination with other drugs. Novel toxicities include delayed adverse reactions to iodinated contrast media and hypersensitivity reactions to antineoplastic agents (see “ PRECAUTIONS ” section, “ Drug Interactions ” subsection). Experience has shown the following concomitant medications to be useful in the management of patients on PROLEUKIN therapy: a) standard antipyretic therapy, including nonsteroidal anti-inflammatories (NSAIDs), started immediately prior to PROLEUKIN to reduce fever. Renal function should be monitored as some NSAIDs may cause synergistic nephrotoxicity; b) meperidine used to control the rigors associated with fever; c) H 2 antagonists given for prophylaxis of gastrointestinal irritation and bleeding; d) antiemetics and antidiarrheals used as needed to treat other gastrointestinal side effects. Generally these medications were discontinued 12 hours after the last dose of PROLEUKIN. Patients with indwelling central lines have a higher risk of infection with gram positive organisms. 9-11 A reduced incidence of staphylococcal infections in PROLEUKIN studies has been associated with the use of antibiotic prophylaxis which includes the use of oxacillin, nafcillin, ciprofloxacin, or vancomycin. Hydroxyzine or diphenhydramine has been used to control symptoms from pruritic rashes and continued until resolution of pruritus. Topical creams and ointments should be applied as needed for skin manifestations. Preparations containing a steroid (e.g., hydrocortisone) should be avoided. NOTE: Prior to the use of any product mentioned, the physician should refer to the package insert for the respective product.