Proleukin (Aldesleukin)

PROLEUKIN®

Ligand

Aldesleukin

Antineoplastic Agent

Action And Clinical Pharmacology: The exact mechanism by which aldesleukin mediates its anitiumor activity is unknown. Aldesleukin has been shown to possess the biological activity of human native interleukin-2.

In vitro studies performed on human cell lines demonstrate the immunoregulatory properties of aldesleukin, including: 1) enhancement of lymphocyte mitogenesis and stimulation of long-term growth of human interleukin-2 dependent cell lines; 2) enhancement of lymphocyte cytotoxicity; 3) induction of killer cell [lymphokine-activated (LAK) and natural (NK)] activity; and 4) induction of interferon-gamma production.

The in vivo administration aldesleukin in murine tumor models and in the clinic 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 27 recombinant 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 to extravascular, extracellular space and elimination from the body by metabolism in the kidneys with little or no bioactive protein excreted in the urine.

The serum half-life (t 1/2) curves of aldesleukin remaining in the plasma are derived from studies done in 52 cancer patients following a 5-minute i.v. infusion. These patients were shown to have a distribution and elimination t 1/2 of 13 and 85 minutes, 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 described above, 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 renal cancer patients (74%) treated with the every 8-hour aldesleukin regimen developed low titres of non-neutralizing anti-interleukin-2 antibodies. Neutralizing antibodies were not detected in this group of patients, but have been detected in 1/106.
Clinical Experience: Two hundred and fifty-five patients with metastatic renal cell cancer were treated with single agent aldesleukin. Treatment was given by the every 8-hour regimen in 7 clinical studies conducted at 21 institutions. To be eligible for study, patients were required to have bidimensionally measurable disease; Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1 (see Table I); and normal organ function, including normal cardiac stress test and pulmonary function tests. Patients with brain metastases, active infections, organ allografts, and diseases requiring steroid treatment were excluded. In addition, it was noted that 218 of the 255 (85%) patients had undergone nephrectomy prior to treatment with aldesleukin.

Aldesleukin was given as either 600 000 or 720 000 IU/kg (0.037 mg/kg or 0.044 mg/kg respectively) by 15-minute i.v. infusion every 8 hours for up to 5 days (maximum of 14 doses). No treatment was given on days 6 to 14 and then dosing was repeated for up to 5 days on days 15 to 19 (maximum of 14 doses). These 2 cycles constituted 1 course of therapy. All patients were to be treated with 28 doses or until dose-limiting toxicity occurred requiring Intensive Care Unit (ICU)-level support. Patients received a median of 15 or 20 scheduled doses of aldesleukin for the higher and lower dosage regimens, respectively. Doses were held for specific toxicities (see Dosage, Dose Modification). A variety of serious adverse events were encountered including: hypotension; oliguria/anuria; mental status changes including coma; pulmonary congestion and dyspnea; gastrointestinal bleeding; respiratory failure leading to intubation; ventricular arrhythmias; myocardial ischemia and/or infarction; ileus or intestinal perforation; renal failure requiring dialysis; gangrene; seizures; sepsis and death (see Adverse Effects).

Due to the toxicities encountered during the clinical trials, investigators used the following concomitant medications. Acetaminophen and indomethacin were started immediately prior to aldesleukin to reduce fever. Renal function was particularly monitored because aldesleukin and indomethacin may both cause nephrotoxicity. Meperidine was added to control the rigors associated with fever. Ranitidine or cimetidine were given for prophylaxis of gastrointestinal irritation and bleeding. Antiemetics and antidiarrheals were used as needed to treat other gastrointestinal side effects. These medications were discontinued 12 hours after the last dose of aldesleukin. Hydroxyzine or diphenhydramine were used to control symptoms from pruritic rashes and continued until resolution of pruritus. Note: Prior to the use of any product mentioned in this paragraph, the physician should refer to the product monograph for the respective product.

For the 255 patients in the aldesleukin database, objective response was seen in 15% or 37 patients with 9 (4%) complete and 28 (11%) partial responders. The 95% confidence interval for response was 11 to 20%. Onset of tumor regression has been observed as early as 4 weeks after completion of the first course of treatment and tumor regression may continue for up to 12 months after the start of treatment. Durable responses were achieved with a median duration of objective (partial or complete) response by Kaplan-Meier projection of 23.2 months (1 to 50 months). The median duration of objective partial response was 18.8 months. The proportion of responding patients who will have response durations of 12 months or greater is projected to be 85% for all responders and 79% for patients with partial responses (Kaplan-Meier).

Complete Responders: 9 (4%); partial responders: 28 (11%); response rate: 15%; onset of response: 1 to 12 months; median duration of response: 23.2 months (range 1 to 50).

Response was observed in both lung and nonlung sites (e.g., liver, lymph node, renal bed recurrences, soft tissue). Patients with individual bulky lesions (>5´5 cm) as well as large cumulative tumor burden (>25 cmtumor area) achieved durable responses.

An analysis of prognostic factors showed that performance status as defined by the ECOG was a significant predictor of response. PS 0 patients had an 18% overall rate of objective response, which included all 9 complete response patients and 21 of 28 partial response patients. PS 1 patients had a lower rate of response (9%), all of which were partial responses. In this group it was notable that 6 of the 7 responders had resolution of tumor related symptoms and improved performance status to PS 0. All 7 patients were fully functional and 4 of the 7 returned to work, suggesting that responses among the PS 1 patients were clinically meaningful as well.

In addition, the frequency of toxicity was related to the performance status. As a group, PS 0 patients, when compared with PS 1 patients, had lower rates of adverse events with fewer on-study deaths (4% vs 6%), less frequent intubations (8% vs 25%), gangrene (0% vs 6%), coma (1% vs 6%), gastrointestinal bleeding (4% vs 8%), and sepsis (6% vs 18%). These differences in toxicity are reflected in the shorter mean time to hospital discharge for PS 0 patients (2 vs 3 days) as well as the smaller percentage of PS 0 patients experiencing a delayed (>7 days) discharge from the hospital (8% vs 19%).

Indications And Clinical Uses: The treatment of adults (18 years of age) with metastatic renal cell carcinoma.

Careful patient selection is mandatory prior to the administration of aldesleukin. See Contraindications, Warnings and Precautions regarding patient screening, including recommended cardiac and pulmonary function tests and laboratory tests.

Evaluation of clinical studies to date reveals that patients with more favorable ECOG performance status (ECOG PS 0) at treatment initiation respond better to aldesleukin, with a higher response rate and lower toxicity (see Pharmacology, Clinical Experience). Therefore, selection of patients for treatment should include assessment of performance status, as described in Table I.

Experience in patients with PS>1 is extremely limited.

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

Patients with an abnormal thallium stress test or pulmonary function tests are excluded from treatment with aldesleukin. Patients with organ allografts should be excluded as well. In addition, retreatment with aldesleukin is contraindicated in patients who experienced the following toxicities while receiving an earlier course of therapy: sustained ventricular tachycardia (³5 beats); cardiac rhythm disturbances not controlled or unresponsive to management; recurrent chest pain with ECG changes, consistent with angina or myocardial infarction; intubation required >72 hours; pericardial tamponade; renal dysfunction requiring dialysis >72 hours; coma or toxic psychosis lasting >48 hours; repetitive or difficult to control seizures; bowel ischemia/perforation; gastrointestinal bleeding requiring surgery.

Manufacturers’ Warnings In Clinical States: Intensive therapy with aldesleukin for injection 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 results from extravasation of plasma proteins and fluid into the extravascular space and loss of vascular tone. CLS results in hypotension and reduced organ perfusion which may be severe and can result in death. The CLS may be associated with cardiac arrhythmias (supraventicular and ventricular), angina, myocardial infarction, respiratory insufficiency requiring intubation, gastrointestinal bleeding or infarction, renal insufficiency, 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 exclude from treatment patients with significant cardiac, pulmonary, renal, hepatic, or CNS impairment.

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.

Aldesleukin may exacerbate pre-existing autoimmune disease. Because not all patients who develop interleukin-2-associated autoimmune phenomena have a pre-existing history of autoimmune disease, awareness and close monitoring for thyroid abnormalities or other potentially autoimmune phenomena is warranted. Two patients with quiescent Crohn’s disease had activation of their disease following treatment with aldesleukin, and both required surgical intervention.

Aldesleukin may exacerbate disease symptoms in patients with clinically unrecognized or untreated CNS metastases. All patients should have thorough evaluation and treatment of CNS metastases prior to receiving aldesleukin therapy. They should be neurologically stable with a negative computed tomography (CT) scan. In addition, extreme caution should be exercised in treating patients with a history of seizure disorder because 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, in treated patients. Consequently, pre-existing bacterial infection should be adequately treated prior to initiation of aldesleukin therapy. Additionally, all patients with indwelling central lines should receive antibiotic prophylaxis effective against S. aureus. Antibiotic prophylaxis which has been associated with a reduced incidence of staphylococcal infections in aldesleukin studies includes the use of oxacillin, nafcillin, ciprofloxacin, or vancomycin. 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. Patients who have had a nephrectomy are still eligible for treatment if they have serum creatinine levels £1.5 mg/dL.

Adverse events are predictable and frequent, often serious, and sometimes life-threatening.

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 2 to 12 hours after the start of treatment. With continued therapy, clinically significant hypotension (defined as systolic blood pressure below 90 mm Hg or a 20 mm Hg drop from baseline systolic pressure) and hypoperfusion will occur. In addition, extravasation of protein and fluids into the extravascular space will lead to edema and 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).

Patients with hypovolemia are managed by administering i.v. fluids, either colloids or crystalloids. I.V. fluids are usually given when the central venous pressure (CVP) is below 3 to 4 mm H2O. 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 some patients may develop ascites or pleural effusions. 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 (1 to 5 µg/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 6 to 10 µg/kg/min or have added phenylephrine HCl (1 to 5 µg/kg/min) to low dose dopamine (see Pharmacology, Clinical Experience). Prolonged use of pressors, either in combination or as individual agents, at relatively high doses, may be associated with cardiac rhythm disturbances. Note: Prior to the use of any product mentioned in this paragraph, the physician should refer to the product monograph for the respective product.

Failure to maintain organ perfusion, demonstrated by altered mental status, reduced urine output, a fall in the systolic blood pressure below 90 mm Hg or onset of cardiac arrhythmias, should lead to holding the subsequent doses until recovery of organ perfusion and a return of systolic blood pressure above 90 mm Hg are observed (see Dosage, Dose Modification).

Recovery from CLS begins soon after cessation of aldesleukin therapy. Usually, within a few hours, the blood pressure rises, organ perfusion is restored and resorption of extravasated fluid and protein begins. 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.

Oxygen is given to the patient if pulmonary function monitoring confirms that PaO2 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 Pharmacology, Clinical Experience.

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

Patients may experience mental status changes including irritability, confusion, or depression while receiving aldesleukin. These mental status changes may be indicators of bacteremia or early bacterial sepsis. Mental status changes due solely to aldesleukin are generally reversible when drug administration is discontinued. However, alterations in mental status may progress for several days before recovery begins.

Impairment of thyroid function has been reported following aldesleukin treatment. A small number of these patients required thyroid replacement therapy. This impairment of thyroid function may be a manifestation of autoimmunity.

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.

All patients should have baseline pulmonary function tests with arterial blood gases. Adequate pulmonary function should be documented (FEV1>2L or ³75% of value 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 of questionable significance, a stress echocardiogram to document normal wall motion may be useful to exclude significant coronary artery disease.

Daily monitoring during therapy with aldesleukin should include vital signs (temperature, pulse, blood pressure, and respiration rate) and weight. In a patient with a decreased blood pressure, especially less than 90 mm Hg, constant cardiac monitoring for rhythm 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 and central venous pressure (CVP) checked.

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 is 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 creatinine phosphokinase (CPK) evaluation. If there is evidence of cardiac ischemia or congestive heart failure, 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, 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 chemotherapies have not been established.

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 to 28%) of 501 patients 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 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.

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 sex not practising effective contraception.

Pregnancy : Animal reproduction studies have not been conducted with aldesleukin. It is also not known whether aldesleukin can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Aldesleukin should be given to a pregnant women only if clearly needed.

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 18 years of age have not been established.

Adverse Reactions: The rate of drug-related deaths in the 255 metastatic renal cell carcinoma patients on study who received single-agent aldesleukin was 4% (11/255).

Frequency and severity of adverse reactions to aldesleukin have generally been shown to be dose-related and schedule-dependent. Most adverse reactions are self-limiting and are usually, but not invariably, reversible within 2 or 3 days of discontinuation of therapy.

Examples of adverse reactions with permanent sequelae include: myocardial infarction, bowel perforation/infarction, and gangrene.

The most frequently reported serious adverse reactions include hypotension, renal dysfunction with oliguria/anuria, dyspnea or pulmonary congestion, and mental status changes (i.e., lethargy, somnolence, confusion, and agitation). Other serious toxicities have included myocardial ischemia, myocarditis, gangrene, respiratory failure leading to intubation, gastrointestinal bleeding requiring surgery, intestinal perforation/ileus, coma, seizure, sepsis, and renal impairment requiring dialysis. The incidence of these events has been higher in PS 1 patients than in PS 0 patients (see Pharmacology, Clinical Experience).

The following data on adverse reactions are based on 373 patients (255 with renal cell cancer and 118 with other tumors) treated with the recommended every 8-hour, 15-minute- infusion dosing regimen. These patients had metastatic or recurrent carcinoma and were enrolled in investigational trials in the United States and Canada.

Other serious adverse events were derived from trials involving more than 1 800 patients treated with aldesleukin-based regimens using a variety of doses and schedules. These events each occurred with a frequency of
Exacerbation of pre-existing autoimmune disease (Crohn’s Disease and Thyroid Disease, see Warnings) and delayed adverse reactions to iodinated contrast media (see Precautions) have also been reported. In clinical investigations, persistent but nonprogressive vitiligo has been observed in malignant melanoma patients treated with interleukin-2.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Side effects following the use of aldesleukin are dose-related. Administration of more than the recommended dose has been associated with a more rapid onset of expected dose-limiting toxicities. Adverse reactions generally will reverse when the drug is stopped, particularly because its serum half-life is short (see Pharmacology, Pharmacokinetics). Any continuing symptoms should be treated supportively. Life-threatening toxicities have been ameliorated by the i.v. administration of dexamethasone, which may result in loss of therapeutic effect from aldesleukin. Note: Prior to the use of dexamethasone, the physician should refer to the product monograph for this product. tag_DosageDosage

Dosage And Administration: 18 millions IU=1.1 mg of proteins. Aldesleukin for injection should be administered by a 15-minute i.v. infusion every 8 hours. Before initiating treatment, carefully review the Indications, Contraindications, Warnings, Precautions, and Adverse Effects sections, particularly regarding patient selection, possible serious adverse events, patient monitoring and withholding dosage.

The following schedules have been used to treat adult patients with metastatic renal cell carcinoma. Each course of treatment consists of two 5-day treatment cycles separated by a rest period.

1. 600 000 IU/kg (0.037 mg/kg) administered every 8 hours by a 15-minute i.v. infusion for a total of 14 doses. Following 9 days of rest, the schedule is repeated for another 14 doses, for a maximum of 28 doses per course.

2. 720 000 IU/kg (0.044 mg/kg) administered every 8 hours by a 15-minute i.v. infusion for a total of 14 doses. Following 9 days of rest, the schedule is repeated for another 14 doses, for a maximum of 28 doses per course.

3. During clinical trials, doses were frequently held for toxicity (see Dose Modifications). Patients treated with 600 000 IU/kg (0.037 mg/kg) received a median of 20 of the 28 doses during the first course of therapy, and patients treated with 720 000 IU/kg (0.044 mg/kg) received a median of 15 of the 28 doses during the first course of therapy.

Retreatment: Patients should be evaluated for response approximately 4 weeks after completion of a course of therapy and again immediately prior to the scheduled start of the next treatment course. Additional courses of treatment may 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. Tumors have continued to regress up to 12 months following the initiation of aldesleukin therapy.

Dose Modifications: Dose modification for toxicity should be accomplished by holding 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. With this in mind, the following guidelines should be used.

Stability and Storage Recommendations: Store vials of lyophilized aldesleukin in a refrigerator at 2 to 8°C.

Reconstituted or diluted aldesleukin is stable for up to 48 hours at refrigerated and room temperatures, 2 to 25°C. However, since this product contains no preservatives, the reconstituted and diluted solutions should be stored in the refrigerator.

Do not use beyond the expiration date printed on the vial. Note: This product contains no preservative.

Reconstitution: Reconstitution and dilution procedures other than those recommended may alter the delivery and/or pharmacology of aldesleukin and thus should be avoided.

1. Proleukin is a sterile, white to off-white, preservative-free, lyophilized powder suitable for i.v. infusion upon reconstitution and dilution. Each vial contains 22 million IU (1.3 mg) of aldesleukin and should be reconstituted aseptically with 1.2 mL of Sterile Water for Injection, USP. When reconstituted as directed, each mL contains 18 million IU (1.1 mg) of aldesleukin. The resulting solution should be a clear, colorless to slightly yellow liquid. The vial is for single-use only and any unused portion should be discarded.

2. During reconstitution the Sterile Water for Injection, USP should be directed at the side of the vial and the contents gently swirled to avoid excess foaming. Do not shake.

3. The dose of aldesleukin, reconstituted in Sterile Water for Injection, USP (without preservative) should be diluted aseptically in 50 mL of 5% Dextrose Injection, USP and infused over a 15-minute period. Although glass bottles and plastic (polyvinyl chloride) bags have been used in clinical trials with comparable results, it is recommended that plastic bags be used as the dilution container since experimental studies suggest that use of plastic containers results in more consistent drug delivery. In-line filters should not be used when administering aldesleukin.

4. Before and after reconstitution and dilution, store in a refrigerator at 2 to 8°C. Do not freeze. Administer aldesleukin within 48 hours of reconstitution. The solution should be brought to room temperature prior to infusion in the patient.

5. Reconstitution or dilution with Bacteriostatic Water for Injection, USP, or 0.9% Sodium Chloride Injection, USP should be avoided because of increased aggregation. Animal studies have shown that dilution with albumin can alter the pharmacology of aldesleukin. Aldesleukin should not be mixed with other drugs.

6. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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

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

PROLEUKIN® Ligand Aldesleukin Antineoplastic Agent

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