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boxed warning
WARNING: CAPILLARY LEAK SYNDROME (CLS), NEUROLOGIC TOXICITIES and SERIOUS INFECTIONS Capillary leak syndrome (CLS), including life threatening or fatal reactions, has occurred in patients treated with Proleukin. Do not administer Proleukin to patients with significant cardiac, pulmonary, renal, and hepatic impairment. Administer Proleukin in a hospital setting with an intensive care facility. Withhold or discontinue Proleukin as recommended [see Dosage and Administration (2.4) , Contraindications (4) , Warnings and Precautions (5.1) ] . Neurologic toxicities, which may be life-threatening or result in coma or permanent neurological deficits, have occurred in patients treated with Proleukin. Withhold or discontinue Proleukin as recommended [see Dosage and Administration (2.4) , Warnings and Precautions (5.2) ] . Serious Infections including sepsis and bacterial endocarditis have occurred in patients treated with Proleukin. Treat pre-existing bacterial infections prior to initiation of Proleukin therapy and withhold Proleukin as recommended [see Dosage and Administration (2.4) , Warnings and Precautions (5.3) ] . WARNING: CAPILLARY LEAK SYNDROME (CLS), NEUROLOGIC TOXICITY, AND SERIOUS INFECTIONS See full prescribing information for complete boxed warning. Capillary Leak Syndrome (CLS) including life-threatening or fatal reactions, has occurred in patients treated with Proleukin. Administer Proleukin in a hospital setting with an intensive care unit. Withhold or discontinue Proleukin as recommended. ( 2.4 , 4 , 5.1 ) Neurologic toxicities, which may be life-threatening or result in coma or permanent neurological deficits, have occurred in patients treated with Proleukin. Withhold or discontinue Proleukin as recommended. ( 2.4 , 5.2 ) Serious infections including sepsis and bacterial endocarditis have occurred in patients treated with Proleukin. Treat preexisting bacterial infections prior to initiating Proleukin and withhold Proleukin as recommended. ( 2.4 , 5.3 )
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warnings and cautions
5 WARNINGS AND PRECAUTIONS 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. ( 5.5 ) 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 ) 5.1 Capillary 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 48 hours or for repetitive or difficult to control seizures [see Dosage and Administration (2.4) ]. 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 [see Contraindications (4) , Adverse Reactions (6.1 , 6.2) ] . Concomitant use of Proleukin with other products that cause neurotoxicity may result in a greater risk of severe neurotoxicity. 5.3 Serious Infections Including Sepsis Proleukin can cause impaired neutrophil function (reduced chemotaxis) and an increased risk of di...
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adverse reactions
6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Capillary Leak Syndrome [see Warnings and Precautions (5.1) ]. Neurotoxicity [see Warnings and Precautions (5.2) ]. Serious Infections Including Sepsis [see Warnings and Precautions (5.3) ]. Renal Toxicity [see Warnings and Precautions (5.4) ]. Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.5) ]. Serious Manifestations of Eosinophilia [see Warnings and Precautions (5.7) ]. Severe Hypersensitivity Reactions [see Warnings and Precautions (5.9) ]. Infusion-Related Reactions [see Warnings and Precautions (5.10) ] . Most common (≥ 30%) adverse reactions including laboratory abnormalities are hypotension, hyperbilirubinemia, dyspnea, rash, diarrhea, oliguria, chills, vomiting, thrombocytopenia, nausea, confusional state and increased creatinine. ( 6.1 ) 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. 6.1 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) [see Clinical Studies (14.1 , 14.2) ] . 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 [see Dosage and Administration (2.4) ]. 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 = 5...
adverse reactions table
Table 4: Adverse Reactions (≥10% all grades or ≥1% Grade 4) in Patients with Metastatic Renal Cell Carcinoma or Metastatic Melanoma (n=525) receiving ProleukinAdverse ReactionProleukin N = 525 All Grades (%)Grade 4 (%)General disordersChills520Pyrexia291Edema peripheral280Malaise270Asthenia230Edema150Pain120Cardiac disordersHypotension713Blood pressure fluctuationNot documented1Tachycardia230Dilated veins130Supraventricular tachycardia121Ventricular tachycardia<101Cardiovascular disorder Cardiovascular disorder: Electrocardiogram abnormal, cardiac failure congestive.110Myocardial infarction<101Arrhythmia100Cardiac arrest<101Gastrointestinal disordersDiarrhea672Vomiting500Nausea350Stomatitis22<1Decreased appetite200Abdominal pain110Abdominal distention100Blood and lymphatic system disordersThrombocytopenia371Anemia290Leukopenia160Disseminated intravascular coagulation<101InfectionsInfections131Sepsis<101Hepatobiliary disordersHyperbilirubinemia402Aspartate aminotransferase increased231Metabolic and nutritional disordersWeight increased160Acidosis121Hypomagnesemia120Hypocalcemia11<1Blood alkaline phosphatase increased100Nervous system disordersConfusional state341Stupor<101Coma<102Psychotic disorder<101Somnolence220Anxiety120Dizziness110Respiratory, thoracic, and mediastinal disordersDyspnea431Lung disorder Lung disorder: Pulmonary congestion, rales, rhonchi.240Respiratory disorder Respiratory disorder: Acute respiratory distress syndrome, lung infiltration, lung disorder, respiratory failure, endotracheal intubation.113Apnea<101Cough110Rhinitis100Skin and subcutaneous tissue disordersRash420Pruritis240Dermatitis exfoliative180Renal and urinary disordersOliguria636Blood creatinine increased331Anuria<105Acute kidney injury<101