PROLEUKIN: Safety Information

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ADVERSE REACTIONS

The rate of drug-related deaths in the 255 metastatic RCC patients who received single-agent PROLEUKIN® (aldesleukin) for injection 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 phophatase increase	10
Tachycardia	23	Nervous
Vasodilation	13	Confusion	34
Supraventricular tachycardia	12	Somnolence	22
Cardiovascular disordera	11	Anxiety	12
Arrhythmia	10	Dizziness	11
Digestive		Respiratory
Diarrhea	67	Dyspnea	43
Vomiting	50	Lung disorderb	24
Nausea	35	Respiratory disorderc	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 disordera	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 disorderc	14 (3%)
Vomiting	7 (1%)	Apnea	5 (1%)
Hemic and Lymphatic		Urogenital
Thrombocytopenia	5 (1%)	Oliguria	33 (6%)
Coagulation disorderb	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) H2 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. 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.

OVERDOSAGE

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. NOTE: Prior to the use of dexamethasone, the physician should refer to the package insert for this product.