Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity,
assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying
disease. For these reasons, comparison of incidence of antibodies to PROLEUKIN with the incidence of
antibodies to other products may be misleading.
Post Marketing Experience
The following adverse reactions have been identified during post-approval use of Proleukin. Because these
reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate
their frequency or establish a causal relationship to drug exposure.
• Blood and lymphatic system: neutropenia, febrile neutropenia, eosinophilia, lymphocytopenia
• Cardiac: cardiomyopathy, cardiac tamponade
• Endocrine: hyperthyroidism
• Gastrointestinal: gastritis, intestinal obstruction, colitis
• General and administration site conditions: injection site necrosis
• Hepatobiliary: hepatitis, hepatosplenomegaly, cholecystitis
• Immune system: anaphylaxis, angioedema, urticaria
• Infections and infestations: pneumonia (bacterial, fungal, viral), fatal endocarditis, cellulitis
• Musculoskeletal and connective tissue: myopathy, myositis, rhabdomyolysis
• Nervous system: cerebral lesions, encephalopathy, extrapyramidal syndrome, neuralgia, neuritis,
demyelinating neuropathy
• Psychiatric: insomnia
• Vascular: hypertension, fatal subdural and subarachnoid hemorrhage, cerebral hemorrhage,
retroperitoneal hemorrhage
Exacerbation or initial presentation of a number of autoimmune and inflammatory disorders have been reported (See
“WARNINGS” section, “PRECAUTIONS” section, “Drug Interactions” subsection). Persistent but nonprogressive
vitiligo has been observed in malignant melanoma patients treated with interleukin-2. Synergistic, additive and
novel toxicities have been reported with Proleukin used in combination with other drugs. Novel toxicities include
delayed adverse reactions to iodinated contrast media and hypersensitivity reactions to antineoplastic agents (See
“PRECAUTIONS” section, “Drug Interactions” subsection).
Experience has shown the following concomitant medications to be useful in the management of patients on
Proleukin therapy: a) standard antipyretic therapy, including nonsteroidal anti-inflammatories (NSAIDs), started
immediately prior to Proleukin to reduce fever. Renal function should be monitored as some NSAIDs may cause
synergistic nephrotoxicity; b) meperidine used to control the rigors associated with fever; c) H2 antagonists given
for prophylaxis of gastrointestinal irritation and bleeding; d) antiemetics and antidiarrheals used as needed to
treat other gastrointestinal side effects. Generally these medications were discontinued 12 hours after the last
dose of Proleukin.
Patients with indwelling central lines have a higher risk of infection with gram positive organisms.9-11 A reduced
incidence of staphylococcal infections in Proleukin studies has been associated with the use of antibiotic
prophylaxis which includes the use of oxacillin, nafcillin, ciprofloxacin, or vancomycin. Hydroxyzine or
diphenhydramine has been used to control symptoms from pruritic rashes and continued until resolution of
pruritus. Topical creams and ointments should be applied as needed for skin manifestations. Preparations
containing a steroid (e.g., hydrocortisone) should be avoided. NOTE: Prior to the use of any product
mentioned, the physician should refer to the package insert for the respective product.
OVERDOSAGE
Side effects following the use of Proleukin® (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 Proleukin should be monitored and treated supportively. Life-threatening toxicities may be
ameliorated by the intravenous administration of dexamethasone, which may also result in loss of the therapeutic
effects of Proleukin.12 NOTE: Prior to the use of dexamethasone, the physician should refer to the package
insert for this product.
DOSAGE AND ADMINISTRATION
The recommended Proleukin® (aldesleukin) treatment regimen is administered by a 15-minute intravenous
infusion every 8 hours. Before initiating treatment, carefully review the “INDICATIONS AND USAGE”,
“CONTRAINDICATIONS”, “WARNINGS”, “PRECAUTIONS”, and “ADVERSE REACTIONS” sections, 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 melanoma. Each course of treatment consists of two 5-day treatment cycles separated by a rest period.
600,000 International Units/kg (0.037 mg/kg) dose administered every 8 hours by a 15-minute intravenous
infusion for a maximum of 14 doses. Following 9 days of rest, the schedule is repeated for another 14 doses, for a
maximum of 28 doses per course, as tolerated. During clinical trials, doses were frequently withheld for toxicity
(See “CLINICAL STUDIES” section and “Dose Modifications” subsection). Metastatic RCC
patients treated with this schedule received a median of 20 of the 28 doses during the first course of therapy.
Metastatic melanoma patients received a median of 18 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
should be given to patients only if there is some tumor shrinkage following the last course and retreatment is
not contraindicated (See “CONTRAINDICATIONS” section). 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 Proleukin therapy must be made after a global assessment
of the patient. With this in mind, the following guidelines should be used:
Retreatment with Proleukin is contraindicated in patients who have experienced the following toxicities:
Body System
Cardiovascular Sustained ventricular tachycardia (≥5 beats)
Cardiac rhythm disturbances not controlled or unresponsive to management
Chest pain with ECG changes, consistent with angina or myocardial infarction
Cardiac tamponade
Respiratory Intubation for >72 hours
Urogenital Renal failure requiring dialysis >72 hours
Nervous Coma or toxic psychosis lasting >48 hours
Repetitive or difficult to control seizures
Digestive Bowel ischemia/perforation
GI bleeding requiring surgery
Doses should be held and restarted according to the following:
Body System Hold dose for Subsequent doses may be given if
Cardiovascular Atrial fibrillation, supraventricular
tachycardia or bradycardia that requires
treatment or is recurrent or persistent
Patient is asymptomatic with full recovery to
normal sinus rhythm
Systolic bp <90 mm Hg with increasing
requirements for pressors
Systolic bp ≥90 mm Hg and stable or improving
requirements for pressors
Any ECG change consistent with MI,
ischemia or myocarditis with or without
chest pain; suspicion of cardiac ischemia
Patient is asymptomatic, MI and myocarditis
have been ruled out, clinical suspicion of angina
is low; there is no evidence of ventricular
hypokinesia
Respiratory O2 saturation <90% O2 saturation >90%
Nervous Mental status changes, including
moderate confusion or agitation
Mental status changes completely resolved
Body as a Whole Sepsis syndrome, patient is clinically
unstable
Sepsis syndrome has resolved, patient is
clinically stable, infection is under treatment
Urogenital Serum creatinine >4.5 mg/dL or a serum
creatinine of ≥4 mg/dL in the presence of
severe volume overload, acidosis, or
hyperkalemia
Serum creatinine <4 mg/dL and fluid and
electrolyte status is stable
Persistent oliguria, urine output of <10
mL/hour for 16 to 24 hours with rising
serum creatinine
Urine output >10 mL/hour with a decrease of
serum creatinine >1.5 mg/dL or normalization
of serum creatinine
Digestive Signs of hepatic failure including
encephalopathy, increasing ascites, liver
pain, hypoglycemia
All signs of hepatic failure have resolved*
Stool guaiac repeatedly >3-4+ Stool guaiac negative
Skin Bullous dermatitis or marked worsening
of pre-existing skin condition, avoid
topical steroid therapy
Resolution of all signs of bullous dermatitis
* Discontinue all further treatment for that course. A new course of treatment, if warranted, should be initiated no sooner than 7 weeks after
cessation of adverse event and hospital discharge.
Reconstitution and Dilution Directions: Reconstitution and dilution procedures other than those recommended
may alter the delivery and/or pharmacology of Proleukin and thus should be avoided.
1. Proleukin® (aldesleukin) is a sterile, white to off-white, preservative-free, lyophilized powder suitable for
IV infusion upon reconstitution and dilution. EACH VIAL CONTAINS 22 MILLION International Units
(1.3 mg) OF PROLEUKIN AND SHOULD BE RECONSTITUTED ASEPTICALLY WITH 1.2 mL OF STERILE
WATER FOR INJECTION, USP. WHEN RECONSTITUTED AS DIRECTED, EACH mL CONTAINS 18
MILLION International Units (1.1 mg) OF PROLEUKIN. 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 Proleukin, reconstituted with Sterile Water for Injection, USP (without preservative) should be
diluted aseptically in 50 mL of 5% Dextrose Injection, USP (D5W) and infused over a 15-minute period.
In cases where the total dose of Proleukin is 1.5 mg or less (e.g., a patient with a body weight of less
than 40 kilograms), the dose of Proleukin should be diluted in a smaller volume of D5W. Concentrations
of Proleukin below 0.03 mg/mL and above 0.07 mg/mL have shown increased variability in drug
delivery. Dilution and delivery of Proleukin outside of this concentration range should be avoided.
4. 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 Proleukin.
5. Before and after reconstitution and dilution, store in a refrigerator at 2° to 8°C (36° to 46°F). Do not
freeze. Administer Proleukin within 48 hours of reconstitution. The solution should be brought to room
temperature prior to infusion in the patient.
6. Reconstitution or dilution with Bacteriostatic Water for Injection, USP, or 0.9% Sodium Chloride Injection,
USP should be avoided because of increased aggregation. Proleukin should not be coadministered with
other drugs in the same container.
7. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration, whenever solution and container permit.
HOW SUPPLIED
Proleukin® (aldesleukin) is supplied in individually boxed single-use vials. Each vial contains 22 million
International Units of Proleukin. Discard unused portion.
NDC 65483-116-07 Individually boxed single-use vial
Store vials of lyophilized Proleukin in a refrigerator at 2° to 8°C (36° to 46°F). PROTECT FROM LIGHT. Store in carton
until time of use.
Reconstituted or diluted Proleukin is stable for up to 48 hours at refrigerated and room temperatures, 2° to 25°C
(36° to 77°F). However, since this product contains no preservative, 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.
Rx Only
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.
4. Rosenberg SA, Mule JJ, Spiess PJ, et al. Regression of established pulmonary metastases
and subcutaneous tumor mediated by the systemic administration of high-dose recombinant
interleukin-2. J Exp Med 1985; 161:1169-88.
5. Konrad MW, Hemstreet G, Hersh EM, et al. Pharmacokinetics of recombinant interleukin-2 in
humans. Cancer Res 1990; 50:2009-17.
6. Donohue JH and Rosenberg SA. The fate of interleukin-2 after in vivo administration. J Immunol 1983;
130:2203-8.
7. Koths K, Halenbeck R. Pharmacokinetic studies on 35S-labeled recombinant interleukin-2 in mice. In:
Sorg C and Schimpl A, eds. Cellular and Molecular Biology of Lymphokines. Academic Press: Orlando,
FL, 1985;779.
8. Gibbons JA, Luo ZP, Hansen ER, et al. Quantitation of the renal clearance of interleukin-2 using
nephrectomized and ureter ligated rats. J Pharmacol Exp Ther 1995; 272: 119-125.
9. Bock SN, Lee RE, Fisher B, et al. A prospective randomized trial evaluating prophylactic antibiotics to
prevent triple-lumen catheter-related sepsis in patients treated with immunotherapy. J Clin Oncol 1990;
8:161-69.
10. Hartman LC, Urba WJ, Steis RG, et al. Use of prophylactic antibiotics for prevention of intravascular
catheter-related infections in interleukin-2-treated patients. J Natl Cancer Inst 1989; 81:1190-93.
11. Snydman DR, Sullivan B, Gill M, et al. Nosocomial sepsis associated with interleukin-2. Ann Intern Med
1990; 112:102-07.
12. Mier JW, Vachino G, Klempner MS, et al. Inhibition of interleukin-2-induced tumor necrosis factor
release by dexamethasone: Prevention of an acquired neutrophil chemotaxis defect and differential
suppression of interleukin-2 associated side effects. Blood 1990; 76:1933-40.
13. Choyke PL, Miller DL, Lotze MT, et al. Delayed reactions to contrast media after interleukin-2
immunotherapy. Radiology 1992; 183:111-114.
Manufactured by:
Prometheus Laboratories Inc.
San Diego, CA 92121
U.S. License No. 1848
At
Boehringer Ingelheim Pharma
Biberach/Riss, Germany
For additional information, contact Prometheus Laboratories Inc. 1-877-PROLEUKIN (1-877-776-5385)
PROLEUKIN is a registered trademark of Novartis Vaccines and Diagnostics, Inc.
© 2010-2015 Prometheus Laboratories Inc.
REV: January 2015 PR001H