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WARNING
Therapy with Proleukin® (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 a normal thallium stress test and a normal pulmonary function test who have a history of cardiac or pulmonary disease.
Proleukin should be administered 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.
Proleukin 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.
Proleukin treatment is associated with impaired neutrophil function (reduced chemotaxis) and with an increased risk of disseminated infection, including sepsis and bacterial endocarditis. Consequently, preexisting bacterial infections should be adequately treated prior to initiation of Proleukin 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.
Proleukin administration should be withheld in patients developing moderate to severe lethargy or somnolence; continued administration may result in coma.
Proleukin® (aldesleukin), a human recombinant interleukin-2 product, is a highly purified protein with a molecular weight of approximately 15,300 daltons. The chemical name is desalanyl-1, serine-125 human interleukin-2. Proleukin, a lymphokine, is produced by recombinant DNA technology using a genetically engineered E. coli strain containing an analog of the human interleukin-2 gene. Genetic engineering techniques were used to modify the human IL-2 gene, and the resulting expression clone encodes a modified human interleukin-2. This recombinant form differs from native interleukin-2 in the following ways: a) Proleukin is not glycosylated because it is derived from E. coli ; b) the molecule has no N-terminal alanine; the codon for this amino acid was deleted during the genetic engineering procedure; c) the molecule has serine substituted for cysteine at amino acid position 125; this was accomplished by site specific manipulation during the genetic engineering procedure; and d) the aggregation state of Proleukin is likely to be different from that of native interleukin-2.
The in vitro biological activities of the native nonrecombinant molecule have been reproduced with Proleukin.1,2
Proleukin is supplied as a sterile, white to off-white, lyophilized cake in single-use vials intended for intravenous administration. When reconstituted with 1.2 mL Sterile Water for Injection, USP, each mL contains 18 million International Units (1.1 mg) Proleukin, 50 mg mannitol, and 0.18 mg sodium dodecyl sulfate, buffered with approximately 0.17 mg monobasic and 0.89 mg dibasic sodium phosphate to a pH of 7.5 (range 7.2 to 7.8). The manufacturing process for Proleukin involves fermentation in a defined medium containing tetracycline hydrochloride. The presence of the antibiotic is not detectable in the final product. Proleukin contains no preservatives in the final product.
Proleukin biological potency is determined by a lymphocyte proliferation bioassay and is expressed in International Units as established by the World Health Organization 1st International Standard for Interleukin-2 (human). The relationship between potency and protein mass is as follows:
18 million International Units Proleukin = 1.1 mg protein
REFERENCES
1. Doyle MV, Lee MT, Fong S. Comparison of the biological activities of human recombinant interleukin-2125 and native interleukin-2. J Biol Response Mod 1985; 4:96 -109.
2. Ralph P, Nakoinz I, Doyle M, et al. Human B and T lymphocyte stimulating properties of interleukin-2 (IL-2) muteins. In: Immune Regulation By Characterized Polypeptides. Alan R. Liss, Inc. 1987; 453-62.
3. Winkelhake JL and Gauny SS. Human recombinant interleukin-2 as an experimental therapeutic. Pharmacol Rev 1990; 42:1-28.
Proleukin is indicated for the treatment of adults with metastatic renal cell carcinoma (RCC).
Proleukin is indicated for the treatment of adults with metastatic melanoma.
Conduct baseline hematologic, chemistry, renal and hepatic function tests. Additionally, evaluate cardiac ejection fraction, coronary artery disease as appropriate, pulmonary function with PFTs, and evaluate for renal, hepatic, and CNS impairment prior to initiating treatment with Proleukin [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS].
Verify pregnancy status of females of reproductive potential prior to initiating Proleukin [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].
Administer Proleukin in an inpatient hospital setting. An intensive care facility with specialists skilled in cardiopulmonary or intensive care medicine must be available [see WARNINGS AND PRECAUTIONS].
The recommended dosage of Proleukin for metastatic renal cell carcinoma and metastatic melanoma is described in Table 1.
Administer Proleukin as an intravenous infusion after dilution [see Preparation And Administration].
Administer pre-infusion medications and supportive treatment, as appropriate, prior to and during each infusion [see Premedication And Supportive Medications]. Discontinue Proleukin for unacceptable toxicity [see Dosage Modifications For Adverse Reactions].
Table 1: Recommended Dosage of Proleukin
| Each course of therapy consists of the following: | ||
| Cycle 1 | Days 1-5 | 600,000 IU/kg (0.037 mg/kg) every 8 hours; maximum of 14 doses1 |
| Rest period | Days 6-14 | |
| Cycle 2 | Days 15-19 | 600,000 IU/kg (0.037 mg/kg) every 8 hours; maximum of 14 doses1 |
| 1 A maximum of 28 doses (2 cycles) per treatment course | ||
Evaluate patients 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 administered to patients if there is a treatment response following the last course, and the patient did not experience any adverse reactions in previous course(s) that led to permanent discontinuation [see Dosage Modifications For Adverse Reactions].
Separate each treatment course by a rest period of at least 7 weeks from the date of hospital discharge.
Premedicate patients with an antipyretic immediately prior to beginning Proleukin. Continue antipyretics during treatment as needed for fever [see WARNINGS AND PRECAUTIONS].
Administer prophylactic antibiotics per institutional guidelines prior to beginning Proleukin and throughout the treatment course for patients with indwelling central catheters [see WARNINGS AND PRECAUTIONS].
Administer prophylactic medication for gastrointestinal irritation and bleeding during each Proleukin treatment course [see ADVERSE REACTIONS].
Additional medications may be needed if patients experience hypotension, dyspnea, rigors, nausea, diarrhea, pruritis, or dermatitis [see WARNINGS AND PRECAUTIONS].
No dose reduction for Proleukin is recommended for adverse reactions. In general, withhold or interrupt a dose or permanently discontinue Proleukin based on the severity of the adverse reaction as described in Table 2.
Table 2: Recommended Dosage Modifications for Adverse Reactions
| Adverse Reaction | Severity | Dosage Modification |
| Cardiovascular [see WARNINGS AND PRECAUTIONS] |
|
Withhold until patient is asymptomatic with full recovery to normal sinus rhythm |
|
Permanently discontinue | |
| Respiratory [see WARNINGS AND PRECAUTIONS] |
|
Withhold until O2 saturation is >90% |
|
Permanently discontinue | |
| Neurologic [see WARNINGS AND PRECAUTIONS] |
|
Withhold until completely resolved |
|
Permanently discontinue | |
| Gastrointestinal [see WARNINGS AND PRECAUTIONS] | Fecal immunochemical test (FIT) or fecal occult blood test (FOBT) positive | Withhold until FIT or FOBT negative |
| Bowel ischemia/perforation or GI bleeding requiring surgery | Permanently discontinue | |
| Hepatic [see WARNINGS AND PRECAUTIONS] | Signs of hepatic toxicity including liver pain or ≥ Grade 3 AST or ALT elevation | Withhold all further treatment for that course. Initiate a new course of treatment no sooner than 7 weeks after signs of hepatic toxicity have resolved and hospital discharge |
| Hepatic failure | Permanently discontinue | |
| Dermatologic [see WARNINGS AND PRECAUTIONS] | Bullous dermatitis or marked worsening of pre-existing skin condition | Withhold until all signs of bullous dermatitis have resolved |
| Infectious [see WARNINGS AND PRECAUTIONS] | Sepsis syndrome, patient is clinically unstable | Withhold until sepsis syndrome has resolved, patient is clinically stable, infection is under treatment |
| Renal [see WARNINGS AND PRECAUTIONS] | Serum creatinine >4.5 mg/dL or a serum creatinine of ≥4 mg/dL in the presence of severe volume overload, acidosis, or hyperkalemia | Withhold until serum creatinine levels return to normal (<1.5 mg/dL) or baseline and fluid and electrolyte status are stable |
| Persistent oliguria, urine output of <10 mL/hr for 16-24 hours with rising SCr | Withhold until urine output >10 mL/hour with a decrease of serum creatinine >1.5 mg/dL or normalization of serum creatinine | |
| rising SCr Withhold until urine output >10 mL/hour with a decrease of serum creatinine >1.5 mg/dL or normalization of serum creatinine Renal failure requiring dialysis >72 hours | Permanently discontinue |
Reconstitute Proleukin using Sterile Water for Injection, USP. Do not reconstitute or dilute Proleukin with Bacteriostatic Water for Injection, or 0.9% Sodium Chloride Injection.
Table 3: Recommended Proleukin Dilution
| Dose | 5% Dextrose Volume |
| ≤25.4 million IU (≤1.5 mg) | 25 mL |
| >25.4 million IU-60 million IU (>1.5 mg-3.5 mg) | 50 mL |
| >60 million IU (>3.5 mg) | 100 mL |
For Injection: 22 million International Units (1.3 mg) of aldesleukin available as a white to off-white, lyophilized powder in a single-dose vial for reconstitution. When reconstituted, each mL contains 18 million International Units (1.1 mg) aldesleukin.
Proleukin® (aldesleukin) for injection is supplied in single-dose vials. Each vial contains 22 million International Units (1.3 mg) of Proleukin.
NDC 76310-022-01 - Individually boxed single-dose vial
Store unopened vials refrigerated at 2° to 8°C (36° to 46°F) in the original carton to protect from light.
Do not use beyond the expiration date printed on the vial. NOTE: This product contains no preservative.
Manufactured by: Clinigen, Inc. Malvern, PA 19355. Revised: Sep 2023.
The following clinically significant adverse reactions are described elsewhere in the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of Proleukin was evaluated in a series of single and multicenter, controlled studies enrolling a total of 525 patients with metastatic renal cell carcinoma (mRCC studies) or metastatic melanoma (metastatic melanoma studies) [see Clinical Studies].
In patients who received Proleukin in these studies, fatal adverse reactions occurred in 4% (11/255) of the patients with metastatic RCC, and 2% (6/270) of the patients with metastatic melanoma.
In these studies, >90% of patients had doses withheld for adverse reactions [see DOSAGE AND ADMINISTRATION].
The most common (≥30%) adverse reactions were hypotension, hyperbilirubinemia, dyspnea, rash, diarrhea, oliguria, chills, vomiting, thrombocytopenia, nausea, confusional state, and increased creatinine.
Table 4 summarizes adverse reactions that occurred in these studies.
Table 4: Adverse Reactions (≥10% all grades or ≥1% Grade 4) in Patients with Metastatic Renal Cell Carcinoma or Metastatic Melanoma (n=525) receiving Proleukin
| Adverse Reaction | Proleukin N = 525 |
|
| All Grades (%) | Grade 4 (%) | |
| General disorders | ||
| Chills | 52 | 0 |
| Pyrexia | 29 | 1 |
| Edema peripheral | 28 | 0 |
| Malaise | 27 | 0 |
| Asthenia | 23 | 0 |
| Edema | 15 | 0 |
| Pain | 12 | 0 |
| Cardiac disorders | ||
| Hypotension | 71 | 3 |
| Blood pressure fluctuation | Not documented | 1 |
| Tachycardia | 23 | 0 |
| Dilated veins | 13 | 0 |
| Supraventricular tachycardia | 12 | 1 |
| Ventricular tachycardia | <10 | 1 |
| Cardiovascular disordera | 11 | 0 |
| Myocardial infarction | <10 | 1 |
| Arrhythmia | 10 | 0 |
| Cardiac arrest | <10 | 1 |
| Gastrointestinal disorders | ||
| Diarrhea | 67 | 2 |
| Vomiting | 50 | 0 |
| Nausea | 35 | 0 |
| Stomatitis | 22 | <1 |
| Decreased appetite | 20 | 0 |
| Abdominal pain | 11 | 0 |
| Abdominal distention | 10 | 0 |
| Blood and lymphatic system disorders | ||
| Thrombocytopenia | 37 | 1 |
| Anemia | 29 | 0 |
| Leukopenia | 16 | 0 |
| Disseminated intravascular coagulation | <10 | 1 |
| Infections | ||
| Infections | 13 | 1 |
| Sepsis | <10 | 1 |
| Hepatobiliary disorders | ||
| Hyperbilirubinemia | 40 | 2 |
| Aspartate aminotransferase increased | 23 | 1 |
| Metabolic and nutritional disorders | ||
| Weight increased | 16 | 0 |
| Acidosis | 12 | 1 |
| Hypomagnesemia | 12 | 0 |
| Hypocalcemia | 11 | <1 |
| Blood alkaline phosphatase increased | 10 | 0 |
| Nervous system disorders | ||
| Confusional state | 34 | 1 |
| Stupor | <10 | 1 |
| Coma | <10 | 2 |
| Psychotic disorder | <10 | 1 |
| Somnolence | 22 | 0 |
| Anxiety | 12 | 0 |
| Dizziness | 11 | 0 |
| Respiratory, thoracic, and mediastinal disorders | ||
| Dyspnea | 43 | 1 |
| Lung disorderb | 24 | 0 |
| Respiratory disorderc | 11 | 3 |
| Apnea | <10 | 1 |
| Cough | 11 | 0 |
| Rhinitis | 10 | 0 |
| Skin and subcutaneous tissue disorders | ||
| Rash | 42 | 0 |
| Pruritis | 24 | 0 |
| Dermatitis exfoliative | 18 | 0 |
| Renal and urinary disorders | ||
| Oliguria | 63 | 6 |
| Blood creatinine increased | 33 | 1 |
| Anuria | <10 | 5 |
| Acute kidney injury | <10 | 1 |
| a Cardiovascular disorder: Electrocardiogram abnormal, cardiac failure congestive. b Lung disorder: Pulmonary congestion, rales, rhonchi. c Respiratory disorder: Acute respiratory distress syndrome, lung infiltration, lung disorder, respiratory failure, endotracheal intubation. |
||
Additional life-threatening adverse reactions (Grade 4) were reported by <1% of the 525 patients:
The following serious adverse reactions were reported in patients with RCC, melanoma, or other cancers treated with Proleukin-based regimens (n >1800 patients) using dosages other than the recommended dosage:
In the same clinical population, the following fatal events each occurred with a frequency of <1%: hyperthermia malignant; cardiac arrest; myocardial infarction; pulmonary embolism; cerebrovascular accident; intestinal perforation; hepatic failure or renal failure; severe depression leading to suicide; pulmonary edema; respiratory arrest; respiratory failure. Patients with ECOG PS of 1 or higher had a higher treatment-related mortality and serious adverse events.
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.
Drug interaction studies with Proleukin have not been conducted. The drug interaction information described below have been observed post-marketing.
Avoid concomitant use of glucocorticoids. Coadministration with glucocorticoids may reduce aldesleukin antitumor effectiveness.
Monitor for delayed adverse reactions in patients receiving iodinated contrast media following Proleukin. Administration of radiographic iodinated contrast media following administration of interleukin-2 resulted in acute, atypical adverse reactions that resemble the immediate side effects caused by Proleukin in some patients [see WARNINGS AND PRECAUTIONS].
For certain CYP substrates, minimal changes in the concentration may lead to serious adverse reactions. Monitor for toxicity or drug concentration changes of such CYP substrates when co-administered with Proleukin.
Aldesleukin causes release of cytokines [see CLINICAL PHARMACOLOGY] that may suppress activity of CYP enzymes, resulting in increased exposure of CYP substrates.
Included as part of the "PRECAUTIONS" Section
Severe and life-threatening capillary leak syndrome (CLS) characterized by hypotension, dyspnea, edema, and hypoalbuminemia can occur with Proleukin, and can result in end organ toxicity including cardiac, respiratory, renal, hepatic toxicity, or death. Do not administer Proleukin to patients with significant cardiac, pulmonary, renal, or hepatic impairment. Avoid concomitant use of Proleukin with other products known to cause hypotension including antihypertensive drugs, those that cause renal toxicity, or hepatotoxicity.
CLS may begin immediately after Proleukin treatment is initiated. Monitor for signs and symptoms of CLS including assessments of vital signs, weight, fluid intake, albumin levels and urine output.
Withhold or discontinue Proleukin for failure to maintain organ perfusion as demonstrated by altered mental status, reduced urine output, oxygen saturation <90%, a fall in the systolic blood pressure below 90 mm Hg, or onset of cardiac arrhythmias. Initiate standard management for CLS, which may include intensive care [see DOSAGE AND ADMINISTRATION, Use In Specific Populations].
Proleukin can cause neurologic toxicities including mental status changes, speech difficulties, cortical blindness, limb or gait ataxia, hallucinations, agitation, obtundation, demyelinating polyneuropathy, and coma. Alterations in mental status may progress for several days before recovery begins. Permanent neurologic deficits have occurred. Radiological findings included multiple and, less commonly, single cortical lesions on MRI and evidence of demyelination. One case of possible cerebral vasculitis has been reported.
Monitor patients for signs and symptoms of neurological toxicity during Proleukin treatment. Withhold Proleukin in patients developing moderate to severe lethargy or somnolence; continued administration may result in coma. Permanently discontinue Proleukin for coma or toxic psychosis lasting >48 hours or for repetitive or difficult to control seizures [see DOSAGE AND ADMINISTRATION].
Evaluate and treat CNS metastases prior to initiation of Proleukin. If possible, avoid concomitant use of Proleukin with other product(s) with a known potential to cause neurotoxicity, and avoid Proleukin in patients with seizure disorders or abnormal intracranial imaging [see CONTRAINDICATIONS, ADVERSE REACTIONS]. Concomitant use of Proleukin with other products that cause neurotoxicity may result in a greater risk of severe neurotoxicity.
Proleukin can cause impaired neutrophil function (reduced chemotaxis) and an increased risk of disseminated infection, including sepsis and bacterial endocarditis. Treat pre-existing bacterial infections prior to initiating Proleukin. Consider antibiotic prophylaxis in patients with indwelling central lines. Monitor patients for the development of signs and symptoms of infection during treatment and withhold Proleukin based on severity [see DOSAGE AND ADMINISTRATION].
Serious renal toxicity, including oliguria and renal failure can occur with Proleukin [see ADVERSE REACTIONS]. Pre-existing renal impairment or coadministration of Proleukin with other products known to cause renal toxicity may increase this risk. If possible, avoid concomitant use of Proleukin with other product(s) with a known potential to cause renal toxicity. Serum creatinine should be ≤1.5 mg/dL before beginning Proleukin.
Monitor serum creatinine at baseline and daily throughout each course of therapy. Withhold Proleukin, or permanently discontinue, based on severity [see DOSAGE AND ADMINISTRATION].
Exacerbation of pre-existing autoimmune disease or initial presentation of autoimmune and inflammatory disorders has been reported following treatment with Proleukin. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. These have included exacerbation of Crohn’s disease, colitis, scleroderma, thyroiditis, inflammatory arthritis, diabetes mellitus, oculo-bulbar myasthenia gravis, crescentic IgA glomerulonephritis, cholecystitis, cerebral vasculitis, Stevens-Johnson syndrome, bullous pemphigoid, myocarditis, myositis, and neuritis including optic neuritis resulting in blindness [see ADVERSE REACTIONS (6.2)].
Proleukin may increase the risk of allograft rejection in transplant patients [see CONTRAINDICATIONS].
Hypothyroidism, sometimes preceded by hyperthyroidism, has been reported following Proleukin treatment. Evaluate thyroid function at baseline and periodically during treatment and initiate thyroid replacement therapy as clinically indicated.
Hyperglycemia and/or diabetes mellitus has been reported during Proleukin therapy. Monitor patients for hyperglycemia and initiate treatment with insulin as clinically indicated.
Based on findings in an animal study and its mechanism of action, Proleukin may cause fetal harm or loss of pregnancy when administered to a pregnant woman. In pregnant rats, aldesleukin has been shown to have embryolethal effects at doses 27 times and maternal toxicities at doses 2.1 times the human exposure at the recommended clinical dose. Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to use effective contraception during treatment with Proleukin [see Use In Specific Populations].
Serious manifestations of eosinophilia involving eosinophilic infiltration of cardiac and pulmonary tissues can occur following Proleukin.
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. These reactions may resemble the immediate side effects caused by interleukin-2 administration. 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 [see ADVERSE REACTIONS].
Proleukin can cause severe hypersensitivity reactions, including anaphylactic reactions. Permanently discontinue Proleukin in patients who experience a severe hypersensitivity reaction [see CONTRAINDICATIONS, ADVERSE REACTIONS].
Proleukin can cause fevers, chills, or rigors. Premedicate patients with an antipyretic prior to beginning Proleukin and continue during treatment as needed for fever [see ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION].
The carcinogenic and genotoxic potential of aldesleukin have not been evaluated.
Animal fertility studies have not been conducted with aldesleukin.
Based on findings in an animal study and its mechanism of action, Proleukin may cause fetal harm or loss of pregnancy when administered to a pregnant woman [see CLINICAL PHARMACOLOGY]. Data on the use of Proleukin in pregnant women are limited and insufficient to assess the drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes; however, development of capillary leak syndrome during pregnancy can lead to adverse fetal outcomes (see Clinical Considerations).
Intravenous administration of aldesleukin to pregnant rats during the period of organogenesis resulted in embryo lethality at doses 27 times and maternal toxicities at doses 2.1 times the human exposure at the recommended clinical dose (see Data). Advise pregnant women of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15–20%, respectively.
Fetal/Neonatal Adverse Reactions
Capillary leak syndrome in women who are exposed to Proleukin during pregnancy may result in maternal hypotension and decreased placental perfusion. Severe or prolonged maternal hypotension and decreased placental perfusion can lead to intrauterine growth restriction, perinatal asphyxia, or fetal/neonatal demise. Monitor fetal and neonatal status in pregnant women who develop capillary leak syndrome associated with Proleukin.
Animal Data
Aldesleukin has been shown to have embryolethal effects in rats when given in doses at 27 to 36 times the human dose (scaled by body weight). Significant maternal toxicities were observed in pregnant rats administered aldesleukin by IV injection at doses 2.1 to 36 times higher than the human dose during critical period of organogenesis.
There are no data on the presence of aldesleukin in either human or animal milk, the effects on the breastfed child, or the effects on milk production. Maternal cytokines are known to be present in human breast milk. Because of the potential for serious adverse reactions from Proleukin in a breastfed child, such as impaired immune function, advise women not to breastfeed during treatment.
Based on animal data and mechanism of action, Proleukin may cause embryo-fetal harm [see Pregnancy].
Verify pregnancy status of females of reproductive potential prior to initiating Proleukin [see Pregnancy].
Females
Advise females of reproductive potential to use effective contraception during treatment with Proleukin.
The safety and effectiveness of Proleukin have not been established in pediatric patients.
Clinical studies of Proleukin did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.
Exceeding the recommended dose of Proleukin has been associated with a more rapid onset of severe or life-threatening toxicities. Treat toxicities supportively; life-threatening toxicities may be ameliorated by the intravenous administration of dexamethasone.
Proleukin is contraindicated in patients with a known history of severe hypersensitivity to aldesleukin or any component of the Proleukin formulation [see ADVERSE REACTIONS].
Proleukin is contraindicated in patients with organ allografts [see WARNINGS AND PRECAUTIONS].
Proleukin is contraindicated in patients with significant cardiac (including those with an abnormal cardiac ejection fraction, impaired wall motion, or significant coronary artery disease), pulmonary (including those with an FEV1 ≤ 2 liters or < 75% predicted for height and age), renal, hepatic, or CNS impairment [see WARNINGS AND PRECAUTIONS].
Aldesleukin is an interleukin-2 lymphocyte growth factor. The antitumor activity of aldesleukin has not been fully characterized. In vitro studies performed on human cell lines show enhancement of lymphocyte mitogenesis and cytotoxicity, induction of killer cell activity [lymphokine-activated killer (LAK) and natural killer (NK) cells] and interferon gamma production, and proliferation of human interleukin-2-dependent cell lines.
Administration of aldesleukin in animals and humans produces multiple immunological effects in a dose-dependent manner. These effects include activation of cellular immunity and the production of cytokines including tumor necrosis factor, IL-1, and interferon gamma. In vivo experiments in murine melanoma and sarcoma tumor models have shown inhibition of tumor growth.
Dose-dependent immunological effects including activation of cellular immunity with lymphocytosis, eosinophilia, and thrombocytopenia, and the production of cytokines including tumor necrosis factor, IL-1, and gamma interferon were observed following administration of aldesleukin in animals and humans.
Aldesleukin exposure-response relationships and the time course of pharmacodynamic response are unknown.
Aldesleukin serum concentrations change proportionally with the Proleukin dosage.
Aldesleukin is rapidly distributed (distribution half-life of 13 minutes) into the extravascular space following a Proleukin intravenous infusion.
The serum elimination half-life aldesleukin is 85 minutes in patients with cancer following a 5-minute intravenous infusion of Proleukin. The mean clearance rate of aldesleukin is 268 mL/min.
Metabolism
Aldesleukin is metabolized to amino acids in the proximal convoluted tubules of the kidney.
Excretion
Aldesleukin is primarily excreted in the kidney by both glomerular filtration and peritubular extraction. In the kidney it is metabolized and excreted into urine with little or no aldesleukin present.
The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies.
In clinical studies, using an enzyme-linked immunosorbent assay (ELISA), low titers of anti-aldesleukin antibodies were observed in 74% (57 of 77) of patients with metastatic renal cell carcinoma treated with an every 8-hour Proleukin regimen and in 66% (33 of 50) of patients with metastatic melanoma treated with a variety of intravenous regimens. In a separate study in 13 patients, following the first cycle of therapy, the geometric mean aldesleukin exposure (AUC) on Day 15 compared to Day 1 increased by 68% in 11 patients who developed anti-aldesleukin antibodies while no change was observed in the 2 antibody-negative patients. Overall, neutralizing antibodies were detected in 1 patient. Based on these data, the clinical relevance of antialdesleukin antibodies could not be assessed.
Repeated doses of aldesleukin administered to animals intravenously resulted in dose-dependent extramedullary hematopoiesis and lymphoid hyperplasia.
The efficacy of Proleukin was evaluated in two hundred fifty-five patients with metastatic renal cell carcinoma (mRCC) in 7 clinical studies conducted at 21 institutions (mRCC studies). Eligible patients had an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1 and normal organ function as determined by cardiac stress test, pulmonary function tests, and creatinine ≤1.5 mg/dL. Studies excluded patients with brain metastases, active infections, organ allografts, and diseases requiring steroid treatment. Not all patients in these studies received the recommended Proleukin dosing regimen.
The major efficacy outcome measure was objective response rate (ORR) determined by investigator assessment per ECOG response criteria for solid tumors (1982).
Efficacy results are summarized in Table 5.
Table 5: Proleukin Efficacy Results in mRCC Studies
| Proleukin (n=255) |
|
| Objective Response Rate | |
| ORR (95% CI), % | 15% (11, 20) |
| Complete Response (CR), % | 7% |
| Partial Response (PR), % | 8% |
| Duration of response (months) | |
| Number of Patients Who Responded | n= 37 |
| Median (months) | 54 |
| Range (months) | 3, 131+ |
| + Denotes ongoing responses | |
The efficacy of Proleukin was evaluated in two hundred seventy patients with metastatic melanoma in 8 clinical studies conducted at 22 institutions (metastatic melanoma studies). Eligible patients had an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1 and normal organ function as determined by cardiac stress test, pulmonary function tests, and creatinine ≤1.5 mg/dL. Studies excluded patients with brain metastases, active infections, organ allografts, and diseases requiring steroid treatment. Not all patients in these studies received the recommended Proleukin dosing regimen.
Patients with metastatic melanoma received a median of 18 of the 28 scheduled doses of Proleukin during the first course of therapy.
The major efficacy outcome measure was objective response rate (ORR) determined by investigator assessment per ECOG response criteria for solid tumors (1982).
Efficacy results are summarized in Table 6.
Table 6: Proleukin Efficacy Results in Metastatic Melanoma Studies
| Proleukin (n=270) |
|
| Objective Response Rate | |
| ORR (95% CI), % | 16% (12, 21) |
| Complete Response (CR), % | 6% |
| Partial Response (PR), % | 10% |
| Duration of response (months) | |
| Number of Patients Who Responded | n=43 |
| Median (months) | 9 |
| Range (months) | 1, 122+ |
| + Denotes ongoing responses | |
Inform patients or caregivers of the following risks of Proleukin:
Advise patients about the risk of capillary leak syndrome and to inform their healthcare provider immediately if they develop new or worsening symptoms of hypotension, dyspnea, or edema [see WARNINGS AND PRECAUTIONS].
Advise the patient to inform their healthcare provider immediately if they develop mental status changes, speech difficulties, blindness, ataxia, hallucinations, agitation, or experienced a seizure [see WARNINGS AND PRECAUTIONS].
Advise patients to inform their healthcare provider immediately if they develop signs of infection or sepsis including fever, chills, weakness, dyspnea [see WARNINGS AND PRECAUTIONS].
Advise patients that Proleukin can cause immune-mediated adverse reactions and can exacerbate pre-existing autoimmune disease. These immune-mediated adverse reactions can occur in any organ system or tissue. Proleukin may also increase the risk of allograft rejection in transplant patients. Advise patients to contact their healthcare provider for any new or worsening signs or symptoms [see WARNINGS AND PRECAUTIONS].
Hypothyroidism, sometimes preceded by hyperthyroidism, has been reported following Proleukin treatment. Evaluate thyroid function at baseline and periodically during treatment and initiate thyroid replacement therapy as clinically indicated.
Hyperglycemia and/or diabetes mellitus has been reported during Proleukin therapy. Monitor patients for hyperglycemia and initiate treatment with insulin as clinically indicated.
Advise patients to inform their healthcare provider immediately if they develop serious symptoms of eosinophilia including new severe rash or dyspnea [see WARNINGS AND PRECAUTIONS].
Advise patients to inform their health care provider that they received Proleukin prior to undergoing imaging that requires iodinated contrast material [see WARNINGS AND PRECAUTIONS].
Advise females of reproductive potential to use effective contraception during treatment with Proleukin [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].
Proleukin may cause fetal harm. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].
Advise females not to breastfeed during treatment with Proleukin [see Use In Specific Populations].
Advise patients to inform their healthcare provider if they develop signs and symptoms of hypersensitivity reactions [see WARNINGS AND PRECAUTIONS].
