Proleukin (Aldesleukin) - Indications and Dosage

INDICATIONS AND USAGE

PROLEUKIN^® (aldesleukin) is indicated for the treatment of adults with metastatic renal cell carcinoma (metastatic RCC).

PROLEUKIN is indicated for the treatment of adults with metastatic melanoma.

Careful patient selection is mandatory prior to the administration of PROLEUKIN. See “CONTRAINDICATIONS”, “WARNINGS” and “PRECAUTIONS” sections 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 PROLEUKIN, with a higher response rate and lower toxicity (see “CLINICAL PHARMACOLOGY” section, “Clinical Experience” subsection and “ADVERSE REACTIONS” section). Therefore, selection of patients for treatment should include assessment of performance status.

Experience in patients with ECOG PS >1 is extremely limited.

DOSAGE AND ADMINISTRATION

The recommended PROLEUKIN^® (aldesleukin) for injection treatment regimen is administered by a 15-minute IV 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 IU/kg (0.037 mg/kg) dose administered every 8 hours by a 15-minute IV
      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
      Experience” and “Dose Modifications” subsections). 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 experi enced 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.

Reconstit ution and Dilution Directions: Reconstitution and dilution procedures other than those recommended may alter the delivery and/or pharmacology of PROLEUK IN 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 IU (1.3 MG) OF PROLEUKIN AND SHOULD BE RECONSTITUTED ASEPTICALLY WITH 1.2 ML OF STE RILE WATER FOR INJECTION, USP. WHEN RECONSTITUTED AS DIRECTED, EACH ML CONTAINS 18 MILLION IU (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 30 µg/mL and above 70 µg/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) for injection is supplied in individually boxed single-use vials. Each vial contains 22 x 10⁶ IU of PROLEUKIN. Discard unused portion.

NDC 0078-0495-61       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:

Bayer HealthCare Pharmaceuticals, Inc.

Emeryville, CA 94608

For

Novartis Vaccines and Diagnostics, Inc.

Emeryville, CA 94608

U.S. License No. 1751

Distributed by:

Novartis Pharmaceuticals Corporation

East Hanover, NJ 07936

For additional information, contact Novartis Pharmaceuticals Corporation 1-888-669-6682.

U.S. Patent Nos. RE 33653; 4,530,787; 4,569,790; 4,604,377; 4,748,234; 4,572,798; 4,853,332; 4,959,314; 5,464,939

REV: October 2008       5001913

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