Print This

Pharmacology
 Aldesleukin an analogue of human interleukin-2 produced by recombinant DNA technology, has been shown to possess the biological activities of human native interleukin-2. Aldesleukin exhibits antitumor activity; the exact mechanism by which aldesleukin mediates its antitumor activity in animals and humans is unknown.

 In vitro studies performed on human cell lines demonstrate the immunoregulatory properties of aldesleukin, including: a)enhance-ment of lymphocyte mitogenesis and stimulation of long-term growth of human interleukin-2 dependent cell lines; b)enhancement of lymphocyte cytotoxicity; c)induction of killer cell (lymphokine-activated (LAK) and natural (NK)) activity; and d) induction of interferon-gamma production.

 The in vivo administration of aldesleukin in animals and humans produces multiple immunological effects in a dose dependent manner. These effects include activation of cellular immunity with profound lymphocytosis, eosinophilia, and thrombocytopenia, and the production of cytokines including tumor necrosis factor, IL-1 and gamma interferon. In vivo experiments in murine tumor models have shown inhibition of tumor growth.

Pharmacokinetics:  Aldesleukin exists as biologically active, noncovalently bound microaggregates with an average size of 27recombinant interleukin-2 molecules. The solubilizing agent, sodium dodecyl sulfate, may have an effect on the kinetic properties of this product. The pharmacokinetic profile of aldesleukin is characterized by high plasma concentrations following a short i.v. infusion, rapid distribution into the extravascular space and elimination from the body by metabolism in the kidneys with little or no bioactive protein excreted in the urine.

Studies of i.v. aldesleukin in sheep and humans indicated that upon completion of infusion, approximately 30% of the administered dose is detectable in plasma. This finding is consistent with studies in rats using radiolabeled aldesleukin, which demonstrate a rapid (<1minute) uptake of the majority of the label into the lungs, liver, kidney, and spleen.

The serum half-life (t 1/2) curves of aldesleukin remaining in the plasma are derived from studies done in 52cancer patients follow-ing a 5-minute i.v. infusion. These patients were shown to have a distribution and elimination t 1/2 of 13 and 85minutes, respectively.

 The relatively rapid clearance rate of aldesleukin has led to dosage schedules characterized by frequent, short infusions. Observed serum levels are proportional to the dose of aldesleukin.

 Following the initial rapid organ distribution, the primary route of clearance of circulating aldesleukin is the kidney. In humans and animals, aldesleukin is cleared from the circulation by both glomerular filtration and peritubular extraction in the kidney. This dual mechanism for delivery of aldesleukin to the proximal tubule may account for the preservation of clearance in patients with rising serum creatinine values. Greater than 80% of the amount of aldesleukin distributed to plasma, cleared from the circulation and presented to the kidney is metabolized to amino acids in the cells lining the proximal convoluted tubules. In humans, the mean clearance rate in cancer patients is 268 mL/min.

Immunogenicity: Fifty-seven of 77 (74%) metastatic renal cell carcinoma patients treated with an every 8-hour aldesleukin regimen and 33of 50 (66%) metastatic malignant melanoma patients treated with a variety of i.v. regimens developed low titers of nonneutralizing anti-aldesleukin antibodies. Neutralizing antibodies were not detected in this group of patients, but have been detected in 1/106 (<1%) patients treated with i.v. aldesleukin using a wide variety of schedules and doses. The clinical significance of anti-aldesleukin antibodies is unknown.

Clinical Experience: Two hundred fifty-five patients with metastatic renal cell cancer (metastatic RCC) were treated with single agent aldesleukin in 7clinical studies conducted at 21institutions. Two hundred seventy patients with metastatic malignant melanoma were treated with single agent aldesleukin in 8clinical studies conducted at 22institutions. Patients enrolled in trials of single agent aldesleukin were required to have an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0or 1and normal organ function as determined by cardiac stress test, pulmonary function tests, and creatinine £1.5mg/dL. Patients with brain metastases, active infections, organ allografts and diseases requiring steroid treatment were excluded.

Aldesleukin was given by 15min i.v. infusion every 8hours for up to 5days (maximum of 14doses). No treatment was given on days 6to 14and then dosing was repeated for up to5 days on days 15to 19 (maximum of 14doses). These 2cycles constituted 1course of therapy. Patients could receive a maximum of 28doses during a course of therapy. In practice >90% of patients had doses withheld. Metastatic RCC patients received a median of 20of 28scheduled doses of aldesleukin. Metastatic malignant melanoma patients received a median of 18of 28scheduled doses of aldesleukin during the first course of therapy. Doses were withheld for specific toxicities (see Dosage, Dose Modifications and Adverse Effects).

In the renal cell cancer studies (n=255), objective response was seen in 37 (15%) patients, with 17 (7%) complete and 20 (8%) partial responders. The 95% confidence interval for objective response was 11to 20%. Onset of tumor regression was observed as early as 4weeks after completion of the first course of treatment, and in some cases, tumor regression continued for up to 12months after the start of treatment. The median duration of objective complete responses has not been observed and for partial response was 20months. Thirteen patients who achieved a complete response and 7patients who achieved a partial response had responses ongoing at the time of last contact. The median progression-free survival for all responding patients was 55months. Responses were observed in both lung and non-lung sites (e.g., liver, lymph node, renal bed occurrences, and soft tissue). Of the 37responding patients, 12patients with individual bulky lesions (largest lesion ³25cm 2) and 22patients with large cumulative tumor burden (total ³26cm 2) achieved responses.

In the metastatic malignant melanoma studies (n=270), objective response was seen in 43 (16%) patients, with 17 (6%) complete and 26 (10%) partial responders. The 95% confidence interval for objective response was 12to 21%. The median duration of objective (partial or complete) response was 9months (2to 106+months); the median duration of objective complete responses has not been observed and the median duration for partial response was 6months. Ten patients who achieved a complete response and 2patients who achieved a partial response had responses ongoing at the time of last contact. The median progression-free survival for the 43responding patients was 13months. Responses in metastatic malignant melanoma patients were observed in both visceral and nonvisceral sites (e.g., lung, liver, lymph node, soft tissue, adrenal, subcutaneous). Of the 43responding patients, 14patients with individual bulky lesions (largest lesion ³25cm 2) and 21patients with large cumulative tumor burden (total ³25cm 2) achieved responses.

Indications
 Aldesleukin An Analogue Of Human Interleukin-2 Produced By Recombinant DNA Technology, Has Been Shown To Possess The Biological Activities Of Human Native Interleukin-2. Aldesleukin Exhibits Antitumor Activity; The Exact Mechanism By Which Aldesleukin Mediates Its Antitumor Activity In Animals And Humans Is Unknown.

 In Vitro Studies Performed On Human Cell Lines Demonstrate The Immunoregulatory Properties Of Aldesleukin, Including: A)enhance-ment Of Lymphocyte Mitogenesis And Stimulation Of Long-term Growth Of Human Interleukin-2 Dependent Cell Lines; B)enhancement Of Lymphocyte Cytotoxicity; C)induction Of Killer Cell (lymphokine-activated (LAK) And Natural (NK)) Activity; And D) Induction Of Interferon-gamma Production.

 The In Vivo Administration Of Aldesleukin In Animals And Humans Produces Multiple Immunological Effects In A Dose Dependent Manner. These Effects Include Activation Of Cellular Immunity With Profound Lymphocytosis, Eosinophilia, And Thrombocytopenia, And The Production Of Cytokines Including Tumor Necrosis Factor, IL-1 And Gamma Interferon. In Vivo Experiments In Murine Tumor Models Have Shown Inhibition Of Tumor Growth.

Pharmacokinetics:  Aldesleukin Exists As Biologically Active, Noncovalently Bound Microaggregates With An Average Size Of 27recombinant Interleukin-2 Molecules. The Solubilizing Agent, Sodium Dodecyl Sulfate, May Have An Effect On The Kinetic Properties Of This Product. The Pharmacokinetic Profile Of Aldesleukin Is Characterized By High Plasma Concentrations Following A Short I.v. Infusion, Rapid Distribution Into The Extravascular Space And Elimination From The Body By Metabolism In The Kidneys With Little Or No Bioactive Protein Excreted In The Urine.

Studies Of I.v. Aldesleukin In Sheep And Humans Indicated That Upon Completion Of Infusion, Approximately 30% Of The Administered Dose Is Detectable In Plasma. This Finding Is Consistent With Studies In Rats Using Radiolabeled Aldesleukin, Which Demonstrate A Rapid (<1minute) Uptake Of The Majority Of The Label Into The Lungs, Liver, Kidney, And Spleen.

The Serum Half-life (t 1/2) Curves Of Aldesleukin Remaining In The Plasma Are Derived From Studies Done In 52cancer Patients Follow-ing A 5-minute I.v. Infusion. These Patients Were Shown To Have A Distribution And Elimination T 1/2 Of 13 And 85minutes, Respectively.

 The Relatively Rapid Clearance Rate Of Aldesleukin Has Led To Dosage Schedules Characterized By Frequent, Short Infusions. Observed Serum Levels Are Proportional To The Dose Of Aldesleukin.

 Following The Initial Rapid Organ Distribution, The Primary Route Of Clearance Of Circulating Aldesleukin Is The Kidney. In Humans And Animals, Aldesleukin Is Cleared From The Circulation By Both Glomerular Filtration And Peritubular Extraction In The Kidney. This Dual Mechanism For Delivery Of Aldesleukin To The Proximal Tubule May Account For The Preservation Of Clearance In Patients With Rising Serum Creatinine Values. Greater Than 80% Of The Amount Of Aldesleukin Distributed To Plasma, Cleared From The Circulation And Presented To The Kidney Is Metabolized To Amino Acids In The Cells Lining The Proximal Convoluted Tubules. In Humans, The Mean Clearance Rate In Cancer Patients Is 268 ML/min.

Immunogenicity: Fifty-seven Of 77 (74%) Metastatic Renal Cell Carcinoma Patients Treated With An Every 8-hour Aldesleukin Regimen And 33of 50 (66%) Metastatic Malignant Melanoma Patients Treated With A Variety Of I.v. Regimens Developed Low Titers Of Nonneutralizing Anti-aldesleukin Antibodies. Neutralizing Antibodies Were Not Detected In This Group Of Patients, But Have Been Detected In 1/106 (<1%) Patients Treated With I.v. Aldesleukin Using A Wide Variety Of Schedules And Doses. The Clinical Significance Of Anti-aldesleukin Antibodies Is Unknown.

Clinical Experience: Two Hundred Fifty-five Patients With Metastatic Renal Cell Cancer (metastatic RCC) Were Treated With Single Agent Aldesleukin In 7clinical Studies Conducted At 21institutions. Two Hundred Seventy Patients With Metastatic Malignant Melanoma Were Treated With Single Agent Aldesleukin In 8clinical Studies Conducted At 22institutions. Patients Enrolled In Trials Of Single Agent Aldesleukin Were Required To Have An Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Of 0or 1and Normal Organ Function As Determined By Cardiac Stress Test, Pulmonary Function Tests, And Creatinine £1.5mg/dL. Patients With Brain Metastases, Active Infections, Organ Allografts And Diseases Requiring Steroid Treatment Were Excluded.

Aldesleukin Was Given By 15min I.v. Infusion Every 8hours For Up To 5days (maximum Of 14doses). No Treatment Was Given On Days 6to 14and Then Dosing Was Repeated For Up To5 Days On Days 15to 19 (maximum Of 14doses). These 2cycles Constituted 1course Of Therapy. Patients Could Receive A Maximum Of 28doses During A Course Of Therapy. In Practice >90% Of Patients Had Doses Withheld. Metastatic RCC Patients Received A Median Of 20of 28scheduled Doses Of Aldesleukin. Metastatic Malignant Melanoma Patients Received A Median Of 18of 28scheduled Doses Of Aldesleukin During The First Course Of Therapy. Doses Were Withheld For Specific Toxicities (see Dosage, Dose Modifications And Adverse Effects).

In The Renal Cell Cancer Studies (n=255), Objective Response Was Seen In 37 (15%) Patients, With 17 (7%) Complete And 20 (8%) Partial Responders. The 95% Confidence Interval For Objective Response Was 11to 20%. Onset Of Tumor Regression Was Observed As Early As 4weeks After Completion Of The First Course Of Treatment, And In Some Cases, Tumor Regression Continued For Up To 12months After The Start Of Treatment. The Median Duration Of Objective Complete Responses Has Not Been Observed And For Partial Response Was 20months. Thirteen Patients Who Achieved A Complete Response And 7patients Who Achieved A Partial Response Had Responses Ongoing At The Time Of Last Contact. The Median Progression-free Survival For All Responding Patients Was 55months. Responses Were Observed In Both Lung And Non-lung Sites (e.g., Liver, Lymph Node, Renal Bed Occurrences, And Soft Tissue). Of The 37responding Patients, 12patients With Individual Bulky Lesions (largest Lesion ³25cm 2) And 22patients With Large Cumulative Tumor Burden (total ³26cm 2) Achieved Responses.

In The Metastatic Malignant Melanoma Studies (n=270), Objective Response Was Seen In 43 (16%) Patients, With 17 (6%) Complete And 26 (10%) Partial Responders. The 95% Confidence Interval For Objective Response Was 12to 21%. The Median Duration Of Objective (partial Or Complete) Response Was 9months (2to 106+months); The Median Duration Of Objective Complete Responses Has Not Been Observed And The Median Duration For Partial Response Was 6months. Ten Patients Who Achieved A Complete Response And 2patients Who Achieved A Partial Response Had Responses Ongoing At The Time Of Last Contact. The Median Progression-free Survival For The 43responding Patients Was 13months. Responses In Metastatic Malignant Melanoma Patients Were Observed In Both Visceral And Nonvisceral Sites (e.g., Lung, Liver, Lymph Node, Soft Tissue, Adrenal, Subcutaneous). Of The 43responding Patients, 14patients With Individual Bulky Lesions (largest Lesion ³25cm 2) And 21patients With Large Cumulative Tumor Burden (total ³25cm 2) Achieved Responses.

Contraindications
 In patients with a known history of hypersensitivity to interleukin-2 or any component of the aldesleukin formulation.

Aldesleukin is contraindicated in patients with an abnormal thallium stress test or abnormal pulmonary function tests and those with organ allografts. Retreatment with aldesleukin is contraindicated in patients who experienced the following drug related toxicities while receiving an earlier course of therapy: sustained ventricular tachycardia (³5beats); cardiac arrhythmias not controlled or unresponsive to management; chest pain with ECG changes, consistent with angina or myocardial infarction; cardiac tamponade; intubation required >72 hours; renal failure requiring dialysis >72 hours; coma or toxic psychosis lasting >48 hours; repetitive or difficult to control seizures; bowel ischemia/perforation; GI bleeding requiring surgery.

Safety Information / Warning
Aldesleukin should be administered only to well informed patients 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 care medicine must be available.

Aldesleukin 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 severe 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.

Because of the severe adverse events which generally accompany aldesleukin therapy at the recommended dosages, thorough clinical evaluation should be performed to identify patients with significant cardiac, pulmonary, renal, hepatic, or CNS impairment; aldesleukin is contraindicated in these patients.

Therapy with aldesleukin should be restricted to patients with normal cardiac and pulmonary functions as defined by thallium stress testing and formal pulmonary function testing. Extreme caution should be used in patients with normal thallium stress tests and pulmonary function tests who have a history of prior cardiac or pulmonary disease.

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, Dose Modifications).

Aldesleukin 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 aldesleukin therapy. New neurologic signs, symptoms, and anatomic lesions following aldesleukin 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 aldesleukin therapy usually improve after discontinuation of aldesleukin 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 aldesleukin may cause seizures.

 Aldesleukin administration should be held in patients developing moderate to severe lethargy or somnolence; continued administration may result in coma.

Aldesleukin treatment is associated with impaired neutrophil function (reduced chemotaxis) and with an increased risk of disseminated infection, including sepsis and bacterial endocarditis. Consequently, pre-existing bacterial infections should be adequately treated prior to initiation of aldesleukin 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. Disseminated infections acquired in the course of aldesleukin treatment are a major contributor to treatment morbidity, and use of antibiotic prophylaxis and aggressive treatment of suspected and documented infections may reduce the morbidity of aldesleukin treatment. Note: Prior to the use of any product mentioned in this paragraph, the physician should refer to the Product Monograph for the respective product.

Precautions
 General: Patients should have normal cardiac, pulmonary, hepatic, and CNS function at the start of therapy. Metastatic renal cell carcinoma patients who have had a nephrectomy are eligible for treatment if they have serum creatinine levels £1.5mg/dL.

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.

Capillary leak syndrome (CLS) begins immediately after aldesleukin treatment starts and is marked by increased capillary permeability to protein and fluids and reduced vascular tone. In most patients, this results in a concomitant drop in mean arterial blood pressure within 2to 12hours after the start of treatment. With continued therapy, clinically significant hypotension (defined as systolic blood pressure below 90mmHg or a 20mmHg drop from baseline systolic pressure) and hypoperfusion will occur. In addition, extravasation of protein and fluids into the extravascular space will lead to the formation of edema and creation of new effusions.

Medical management of CLS begins with careful monitoring of the patient's fluid and organ perfusion status. This is achieved by frequent determination of blood pressure and pulse, and by monitoring organ function, which includes assessment of mental status and urine output. Hypovolemia is assessed by catheterization and central pressure monitoring.

Flexibility in fluid and pressor management is essential for maintaining organ perfusion and blood pressure. Consequently, extreme caution should be used in treating patients with fixed requirements for large volumes of fluid (e.g., patients with hypercalcemia).

Administration of i.v. fluids, either colloids or crystalloids is recommended for treatment of hypovolemia. I.V. fluids are usually given when the central venous pressure (CVP) is below 3to 4mmH 2O. Correction of hypovolemia may require large volumes of i.v. fluids but caution is required because unrestrained fluid administration may exacerbate problems associated with edema formation or effusions.

With extravascular fluid accumulation, edema is common and ascites, pleural or pericardial effusions may develop. Management of these events depends on a careful balancing of the effects of fluid shifts so that neither the consequences of hypovolemia (e.g., impaired organ perfusion) nor the consequences of fluid accumulations (e.g., pulmonary edema) exceeds the patient's tolerance.

Clinical experience has shown that early administration of dopamine (1to 5µg/kg/min) to patients manifesting capillary leak syndrome, before the onset of hypotension, can help to maintain organ perfusion particularly to the kidney and thus preserve urine output. Weight and urine output should be carefully monitored. If organ perfusion and blood pressure are not sustained by dopamine therapy, clinical investigators have increased the dose of dopamine to 6to 10µg/kg/min or have added phenylephrine HCl (1to 5µg/kg/min) to low dose dopamine. Prolonged use of pressors, either in combination or as individual agents, at relatively high doses, may be associated with cardiac rhythm disturbances. If there has been excessive weight gain or edema formation, particularly if associated with shortness of breath from pulmonary congestion, use of diuretics, once blood pressure has normalized, has been shown to hasten recovery. Note: Prior to the use of any product mentioned, the physician should refer to the Product Monograph for the respective product.

 Aldesleukin treatment should be withheld for failure to maintain organ perfusion, as demonstrated by altered mental status, reduced urine output, a fall in the systolic blood pressure below 90mmHg or onset of cardiac arrhythmias (see Dosage, Dose Modifications). Recovery from CLS begins soon after cessation of aldesleukin therapy. Usually, within a few hours, the blood pressure rises, organ perfusion is restored and reabsorption of extravasated fluid and protein begins.

Oxygen is given to the patient if pulmonary function monitoring confirms that PaO 2 is decreased.

Aldesleukin administration may cause anemia and/or thrombocytopenia. Packed red blood cell transfusions have been given both for relief of anemia and to insure maximal oxygen carrying capacity. Platelet transfusions have been given to resolve absolute thrombocytopenia and to reduce the risk of gastrointestinal bleeding. In addition, leukopenia and neutropenia are observed.

Aldesleukin administration results in fever, chills, rigors, pruritus, and gastrointestinal side effects in most patients treated at recommended doses. These side effects have been aggressively managed as described in Adverse Effects.

Kidney and liver function are impaired during aldesleukin treatment. Use of concomitant nephrotoxic or hepatotoxic medications may further increase toxicity to the kidney or liver.

Mental status changes including irritability, confusion, or depression which occur while receiving aldesleukin may be indicators of bacteremia or early bacterial sepsis, hypoperfusion, occult CNS malignancy, or direct aldesleukin-induced CNS toxicity. Alterations in mental status due solely to aldesleukin may progress for several days before recovery begins. Rarely, patients have sustained permanent neurologic deficits (see Adverse Effects).

Exacerbation of preexisting autoimmune disease or initial presentation of autoimmune and inflammatory disorders has been reported following aldesleukin alone or in combination with interferon (see Adverse Effects). Impairment of thyroid function, sometimes preceded by hyperthyroidism, has been reported following aldesleukin treatment. Some of these patients required thyroid replacement therapy. Changes in thyroid function may be a manifestation of autoimmunity. Onset of symptomatic hyperglycemia and/or diabetes mellitus has been reported during aldesleukin therapy.

Aldesleukin enhancement of cellular immune function may increase the risk of allograft rejection in transplant patients.

Laboratory Tests: The following clinical evaluations are recommended for all patients, prior to beginning treatment and then daily during drug administration: standard hematologic tests--including complete blood count (CBC), differential and platelet counts; blood chemistries--including electrolytes, renal and hepatic function tests; and chest x-rays.

Serum creatinine should be £1.5mg/dL prior to initiation of aldesleukin treatment.

All patients should have baseline pulmonary function tests with arterial blood gases. Adequate pulmonary function should be documented (FEV 1 >2L or ³75% of predicted for height and age) prior to initiating therapy. All patients should be screened with a stress thallium study. Normal ejection fraction and unimpaired wall motion should be documented. If a thallium stress test suggests minor wall motion abnormalities, further testing is suggested to exclude significant coronary artery disease.

Daily monitoring during therapy with aldesleukin should include vital signs (temperature, pulse, blood pressure, and respiration rate), weight, and fluid intake and output. In a patient with a decreased systolic blood pressure, especially less than 90mmHg, constant cardiac rhythm monitoring should be conducted. If an abnormal complex or rhythm is seen, an ECG should be performed. Vital signs in these hypotensive patients should be taken hourly.

During treatment, pulmonary function should be monitored on a regular basis by clinical examination, assessment of vital signs and pulse oximetry. Patients with dyspnea or clinical signs of respiratory impairment (tachypnea or rales) should be further assessed with arterial blood gas determination. These tests are to be repeated as often as clinically indicated.

Cardiac function should be assessed daily by clinical examination and assessment of vital signs. Patients with signs or symptoms of chest pain, murmurs, gallops, irregular rhythm or palpitations should be further assessed with an ECG examination and cardiac enzyme evaluation. Evidence of myocardial injury, including findings compatible with myocardial infarction or myocarditis, has been reported. Ventricular hypokinesia due to myocarditis may be persistent for several months. If there is evidence of cardiac ischemia or congestive heart failure, aldesleukin therapy should be held, and a repeat thallium study should be done.

Drug Interactions : Aldesleukin may affect central nervous function. Therefore, interactions could occur following concomitant administration of psychotropic drugs (e.g., narcotics, analgesics, antiemetics, sedatives, and 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 aldesleukin may increase toxicity in these organ systems. The safety and efficacy of aldesleukin in combination with any antineoplastics have not been established.

In addition, reduced kidney and liver function secondary to aldesleukin 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 aldesleukin 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 aldesleukin and interferon-alfa concurrently.

Exacerbation or the initial presentation of a number of autoimmune and inflammatory disorders has been observed following concur-rent use of interferon-alfa and aldesleukin, including crescentic IgA glomerulonephritis, oculo-bulbar myasthenia gravis, inflammatory arthritis, thyroiditis, bullous pemphigoid, and Stevens-Johnson syndrome.

Although glucocorticoids have been shown to reduce aldesleukin-induced side effects including fever, renal insufficiency, hyperbilirubinemia, confusion, and dyspnea, concomitant administration of these agents with aldesleukin may reduce the antitumor effectiveness of aldesleukin and thus should be avoided.

Beta-blockers and other antihypertensives may potentiate the hypotension seen with aldesleukin.

Delayed adverse reactions to iodinated contrast media: A review of the literature revealed that 12.6% (range 11-28%) of 501patients treated with various interleukin-2 containing regimens who were then subsequently administered radiographic iodinated contrast media experienced acute, atypical adverse reactions. The onset of symptoms usually occurred within hours (most commonly 1to 4hours) 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 4weeks 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility: There have been no studies conducted assessing the carcinogenic or mutagenic potential of aldesleukin.

There have been no studies conducted assessing the effect of aldesleukin on fertility. It is recommended that this drug not be administered to fertile persons of either gender not practicing effective contraception.

Pregnancy:  Aldesleukin has been shown to have embryolethal effects in rats when given in doses at 27to 36times the human dose (scaled by body weight). Significant maternal toxicities were observed in pregnant rats administered aldesleukin by i.v. injection at doses 2.1to 36times higher than the human dose during critical period of organogenesis. No evidence of teratogenicity was observed other than that attributed to maternal toxicity. There are no adequate well-controlled studies of aldesleukin in pregnant women. Aldesleukin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lactation:  It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from aldesleukin, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Children: Safety and effectiveness in children under 18years of age have not been established.

Side Effects / Adverse Effects
The rate of drug-related deaths in the 255 metastatic RCC patients who received single-agent aldesleukin was 4% (11/255); the rate of drug-related deaths in the 270metastatic malignant melanoma patients who received single-agent aldesleukin 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 525patients (255with renal cell cancer and 270with metastatic malignant melanoma) treated with the recommended infusion dosing regimen.

Overdose
Symptoms and Treatment:  Side effects following the use of 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 aldesleukin should be monitored and treated supportively. Life-threatening toxicities may be ameliorated by the i.v. administration of dexamethasone, which may result in loss of the therapeutic effects of aldesleukin. Note: Prior to the use of dexamethasone, the physician should refer to the Product Monograph for this product.

Recommended Dosage
 18million IU aldesleukin=1.1mg protein. The recommended aldesleukin treatment regimen is administered by a 15-minute i.v. infusion every 8hours. Before initiating treatment, carefully review the indications, Contraindications, Warnings, Precautions and Adverse Effects, particularly regarding patient selection, possible serious adverse events, patient monitoring and withholding dosage.

The following schedule has been used to treat adult patients with metastatic renal cell carcinoma (metastatic RCC) or metastatic malignant melanoma. Each course of treatment consists of two 5-day treatment cycles separated by a rest period.

600000 IU/kg (0.037mg/kg) dose administered every 8hours by a 15-minute i.v. infusion for a maximum of 14doses. Following 9days of rest, the schedule is repeated for another 14doses, for a maximum of 28doses per course, as tolerated. During clinical trials, doses were frequently withheld for toxicity (see Pharmacology, Clinical Experience and Dose Modifications). Metastatic RCC patients treated with this schedule received a median of 20of the 28doses during the first course of therapy. Metastatic malignant melanoma patients received a median of 18 doses during the first course of therapy.

Retreatment: Patients should be evaluated for response approximately 4weeks after completion of a course of therapy and again immediately prior to the scheduled start of the next treatment course. Additional courses of treatment should be given to patients only if there is some tumor shrinkage following the last course and retreatment is not contraindicated (see Contraindications). Each treatment course should be separated by a rest period of at least 7 weeks from the date of hospital discharge.

Dose Modifications: Dose modification for toxicity should be accomplished by withholding or interrupting a dose rather than reducing the dose to be given. Decisions to stop, hold, or restart aldesleukin therapy must be made after a global assessment of the patient.

Supplied / Packaging
When reconstituted with 1.2mL Sterile Water for Injection, USP, eachmL contains: aldesleukin 18 million IU (1.1mg), mannitol 50mg and sodium dodecyl sulfate 0.18mg, buffered with approximately 0.17mg monobasic sodium phosphate and 0.89mg dibasic sodium phosphate to a pH of 7.5 (range 7.2 to 7.8). Preservative-free. Single-use vials of 22 millionIU (1.3mg).

Before and after reconstitution and dilution, store in a refrigerator at 2to 8°C.