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|
|Hypotension||71||Alkaline phosphatase increase||10|
|Nausea and vomiting||19||Skin and Appendages|
|Hemic and Lymphatic||Rash||42|
| aCardiovascular disorder: fluctuations in blood pressure, asymptomatic ECG changes, CHF. |
bLung disorder: physical findings associated with pulmonary congestion, rales, rhonchi.
cRespiratory 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%)|
|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%)|
|Cardiac arrest||4 (1%)||Respiratory|
|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%)|
| aCardiovascular disorder: fluctuations in blood pressure. |
bCoagulation disorder: intravascular coagulopathy.
cRespiratory 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; intravenous 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.
Serum samples from patients in the clinical studies were tested by enzyme-linked immunosorbent assay (ELISA) for anti-aldesleukin antibodies. Low titers of anti-aldesleukin antibodies were detected in 57 of 77 (74%) patients with metastatic renal cell carcinoma treated with an every 8-hour PROLEUKIN regimen and in 33 of 50 (66%) patients with metastatic melanoma treated with a variety of intravenous regimens. In a separate study, the effect of immunogenicity on the pharmacokinetics of aldesleukin was evaluated in 13 patients. Following the first cycle of therapy, comparing the geometric mean aldesleukin exposure (AUC) Day 15 to Day 1, there was an average 68% increase in 11 patients who developed anti-aldesleukin antibodies and no change was observed in the antibody-negative patients (n=2). Overall, neutralizing antibodies were detected in 1 patient. The impact of antialdesleukin antibody formation on clinical efficacy and safety of PROLEUKIN is unknown.
Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to PROLEUKIN with the incidence of antibodies to other products may be misleading.
Post Marketing Experience
The following adverse reactions have been identified during post-approval use of Proleukin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Blood and lymphatic system: neutropenia, febrile neutropenia, eosinophilia, lymphocytopenia
- Cardiac: cardiomyopathy, cardiac tamponade
- Endocrine: hyperthyroidism
- Gastrointestinal: gastritis, intestinal obstruction, colitis
- General and administration site conditions: injection site necrosis
- Hepatobiliary: hepatitis, hepatosplenomegaly, cholecystitis
- Immune system: anaphylaxis, angioedema, urticaria
- Infections and infestations: pneumonia (bacterial, fungal, viral), fatal endocarditis, cellulitis
- Musculoskeletal and connective tissue: myopathy, myositis, rhabdomyolysis
- Nervous system: cerebral lesions, encephalopathy, extrapyramidal syndrome, neuralgia, neuritis, demyelinating neuropathy
- Psychiatric: insomnia
- Vascular: hypertension, fatal subdural and subarachnoid hemorrhage, cerebral hemorrhage, retroperitoneal hemorrhage
Exacerbation or initial presentation of a number of autoimmune and inflammatory disorders have been reported (See “WARNINGS” section, “PRECAUTIONS” section, “DRUG INTERACTIONS” section). 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” section).
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.
Proleukin may affect central nervous function. Therefore, interactions could occur following concomitant administration of psychotropic drugs (e.g., narcotics, analgesics, antiemetics, sedatives, tranquilizers).
Concurrent administration of drugs possessing nephrotoxic (e.g., aminoglycosides, indomethacin), myelotoxic (e.g., cytotoxic chemotherapy), cardiotoxic (e.g., doxorubicin) or hepatotoxic (e.g., methotrexate, asparaginase) effects with Proleukin may increase toxicity in these organ systems. The safety and efficacy of Proleukin in combination with any antineoplastic agents have not been established.
In addition, reduced kidney and liver function secondary to Proleukin treatment may delay elimination of concomitant medications and increase the risk of adverse events from those drugs.
Hypersensitivity reactions have been reported in patients receiving combination regimens containing sequential high dose Proleukin and antineoplastic agents, specifically, dacarbazine, cis-platinum, tamoxifen and interferon-alfa. These reactions consisted of erythema, pruritus, and hypotension and occurred within hours of administration of chemotherapy. These events required medical intervention in some patients.
Myocardial injury, including myocardial infarction, myocarditis, ventricular hypokinesia, and severe rhabdomyolysis appear to be increased in patients receiving Proleukin and interferonalfa concurrently.
Exacerbation or the initial presentation of a number of autoimmune and inflammatory disorders has been observed following concurrent use of interferon-alfa and Proleukin, including crescentic IgA glomerulonephritis, oculo-bulbar myasthenia gravis, inflammatory arthritis, thyroiditis, bullous pemphigoid, and Stevens-Johnson syndrome.
Although glucocorticoids have been shown to reduce Proleukin-induced side effects including fever, renal insufficiency, hyperbilirubinemia, confusion, and dyspnea, concomitant administration of these agents with Proleukin may reduce the antitumor effectiveness of Proleukin and thus should be avoided.12
Beta-blockers and other antihypertensives may potentiate the hypotension seen with Proleukin.
Delayed Adverse Reactions to Iodinated Contrast Media
A review of the literature revealed that 12.6% (range 11-28%) of 501 patients treated with various interleukin-2 containing regimens who were subsequently administered radiographic iodinated contrast media experienced acute, atypical adverse reactions. The onset of symptoms usually occurred within hours (most commonly 1 to 4 hours) following the administration of contrast media. These reactions include fever, chills, nausea, vomiting, pruritus, rash, diarrhea, hypotension, edema, and oliguria. Some clinicians have noted that these reactions resemble the immediate side effects caused by interleukin-2 administration, however the cause of contrast reactions after interleukin-2 therapy is unknown. Most events were reported to occur when contrast media was given within 4 weeks after the last dose of interleukin-2. These events were also reported to occur when contrast media was given several months after interleukin-2 treatment.13
9. 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.
10.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.
11.Snydman DR, Sullivan B, Gill M, et al. Nosocomial sepsis associated with interleukin-2. Ann Intern Med 1990; 112:102-07.
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