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 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 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 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.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.
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