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Aldesleukin

Pronunciation: al-dess-LOO-kin
Class: Biologic response modifier

Trade Names

Proleukin
- Preservative-free lyophilized powder for reconstitution 22 million units (1.3 mg) vials (18 million units [1.1 mg] per mL when reconstituted)

Pharmacology

Enhancement of lymphocyte mitogenesis and stimulation of long-term growth of human IL-2 dependent cell lines. Enhancement of lymphocyte cytotoxicity. Induction of killer cell (lymphokine-activated [LAK] and natural [NK]) activity. Induction of interferon-gamma production.

Slideshow: Flashback: FDA Drug Approvals 2013

Pharmacokinetics

Distribution

Rapidly distributed into extravascular space; about 30% detectable in plasma. Distribution t ½ is 13 min.

Elimination

Elimination t ½ is 85 min. Eliminated by kidneys with little or no bioactive protein excreted in urine. Cl is 268 mL/min.

Indications and Usage

Metastatic renal cell carcinoma, metastatic melanoma.

Contraindications

Hypersensitivity to interleukin-2 or any component of the formulation; abnormal thallium stress test or pulmonary function tests; organ allografts; re-treatment in patients experiencing CLS toxicities during initial therapy.

Dosage and Administration

Metastatic Renal Cell Carcinoma, Metastatic Melanoma
Adults

IV 600,000 units/kg every 8 h by a 15 min IV infusion for 14 doses. Repeat regimen after 9 days recovery for a total of 28 doses/course. Evaluate tumor response 4 wk after therapy. If tumor shrinkage is evident and further treatment is not contraindicated, another course of aldesleukin may be given using the same regimen. Allow at least 7 wk between treatment courses (from date of hospital discharge). If toxicity occurs, hold or interrupt doses rather than decrease them. If hepatic failure occurs, discontinue further treatment for that course. Further courses may be given at least 7 wk after resolution of hepatic failure or hospital discharge, whichever is most recent.

Required Dosage Modification Because of Adverse Reactions
CV

Permanently discontinue therapy if sustained ventricular tachycardia (at least 5 beats), uncontrolled or unresponsive arrhythmias, recurrent chest pain with ECG changes, documented angina, MI, or pericardial tamponade occur. Delay subsequent doses if atrial fibrillation, supraventricular tachycardia, or bradycardia that requires therapy, recurs or persists. If systolic BP under 90 mm Hg with increasing pressor requirements occurs. If ECG changes consistent with MI, myocarditis, or ischemia with or without chest pain, or suspected cardiac ischemia occur. Continue with subsequent doses if asymptomatic with full recovery to normal sinus rhythm, or if MI is ruled out, there is a low suspicion of angina, systolic BP is at least 90 mm Hg and stable, and patient asymptomatic, or if no ventricular hypokinesia is present.

CNS

Permanently discontinue therapy if coma or toxic psychoses lasting more than 48 h or if repetitive or refractory seizures occur. Delay subsequent doses if mental status changes occur (eg, moderate confusion, agitation). Continue with subsequent doses if complete resolution of mental status changes occurs.

DERM

Delay subsequent doses if bullous dermatitis or if marked worsening of preexisting skin condition occur. Continue with subsequent doses if complete resolution of bullous dermatitis occurs.

GI

Permanently discontinue therapy if bowel ischemia, perforation, or bleeding requiring surgery occur. Delay subsequent doses if stool guaiac is more than 3 to 4+, repeatedly. Continue with subsequent doses if negative stool guaiac occurs.

HEPA

Delay subsequent doses if signs of hepatic failure (eg, encephalopathy, increased ascites, liver pain, hypoglycemia) occur. Continue with subsequent doses if resolution of hepatic failure occurs.

RESP

Permanently discontinue therapy if intubation is required for more than 72 h. Delay subsequent doses if oxygen saturation is below 90%. Continue with subsequent doses if oxygen saturation above 90%.

RENAL

Permanently discontinue therapy if dysfunction requiring dialysis for more than 72 h occurs. Delay subsequent doses if serum creatinine above 4.5 mg/dL or serum creatinine of above 4 mg/dL with severe volume overload, acidosis, or hyperkalemia. Persistent oliguria or urine output less than 10 mL/h for 16 to 24 h with increasing serum creatinine. Continue with subsequent doses if serum creatinine is below 4 mg/dL with stable fluid and electrolytes, or if urine output is above 10 mL/h with normalization or decrease (over 1.5 mg/dL) in creatinine.

SYST

Delay subsequent doses if sepsis syndrome occurs. Continue with subsequent doses if resolution of sepsis syndrome occurs, patient is clinically stable, or if infection is under treatment.

General Advice

  • Follow institutional procedures for handling, administration, and disposal of anticancer drugs.
  • Reconstitute powder for injection with 1.2 mL sterile water for injection following manufacturer's guidelines. Swirl to mix; do not shake vial. Dilute prescribed amount of reconstituted solution with appropriate volume of dextrose 5% injection following manufacturer's guidelines.
  • Do not reconstitute or dilute with bacteriostatic water for injection or sodium chloride 0.9% injection or mix with any other medications.
  • Do not administer if particulate matter or cloudiness is noted. A slight yellow coloration is normal and of no concern.
  • Administer premedications (eg, NSAIDs, meperidine, H 2 antagonists) as ordered before beginning infusion and for 12 h after the final aldesleukin dose.
  • Administer prescribed dose by IV infusion over 15 min. Do not use in-line filters.
  • For single use only. Discard unused portions of vial. Do not save any unused portions for future use.

Storage/Stability

Store unopened vials, reconstituted and diluted solutions in refrigerator (36° to 46°F). Do not freeze. Administer within 48 h of reconstitution. Bring refrigerated solution to room temperature prior to infusion. Discard solution if not used within 48 h.

Drug Interactions

Beta-blockers and other antihypertensives

May exacerbate aldesleukin-induced hypotension.

Cardiotoxic drugs (eg, doxorubicin)

May exacerbate aldesleukin cardiotoxicity.

CNS depressants (eg, narcotics, analgesics, alcohol, antiemetics, benzodiazepines, sedatives, tranquilizers)

May exacerbate aldesleukin CNS adverse reactions.

Corticosteroids

May reduce the antineoplastic effect of aldesleukin.

Hepatotoxic drugs (eg, methotrexate, asparaginase)

May exacerbate aldesleukin hepatotoxicity.

Myelotoxic drugs (eg, cytotoxic chemotherapy)

May exacerbate aldesleukin myelotoxicity.

Nephrotoxic drugs (eg, aminoglycosides, NSAIDs)

May exacerbate aldesleukin nephrotoxicity.

Protease inhibitors (eg, indinavir)

Protease inhibitor levels may be elevated, increasing risk of toxicity.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Hypotension (71%); tachycardia (23%); supraventricular tachycardia (12%); CV disorder (eg, asymptomatic ECG changes, CHF, BP fluctuations [11%]); arrhythmia (10%); MI, ventricular tachycardia; heart arrest (1%); myocarditis, pericarditis, transient ischemic attacks, atrial arrhythmia, second-degree AV block, bradycardia, coronary artery disorders, endocarditis, myocardial ischemia, pericardial effusion, syncope, thrombosis, ventricular extrasystoles, stroke, peripheral gangrene, phlebitis (less than 1%); cardiomyopathy, cerebral hemorrhage, fatal endocarditis, hypertension (postmarketing).

CNS

Confusion (34%); somnolence (22%); anxiety (12%); dizziness (11%); coma (2%); psychosis, stupor (1%); cerebral edema, meningitis, agitation, convulsion, delirium, grand mal convulsion, hyperthermia, neuropathy, paranoid reaction, shock somnolence, malignant hyperthermia, severe depression leading to suicide (less than 1%); cerebral lesions, encephalopathy, extrapyramidal syndrome, insomnia, neuralgia, neuropathy (demyelination), neuritis (postmarketing).

Dermatologic

Rash (42%); pruritus (24%); exfoliative dermatitis (18%); cellulitis, injection-site necrosis, urticaria (postmarketing).

EENT

Mydriasis, papillary disorder (less than 1%).

GI

Diarrhea (67%); vomiting (50%); nausea (35%); stomatitis (22%); anorexia (20%); abdominal pain (11%); enlarged abdomen (10%); bowel necrosis, duodenal ulceration, tracheo-esophageal fistula, bloody diarrhea, GI hemorrhage, hematemesis, intestinal perforation, nausea, stomatitis, vomiting, pancreatitis (less than 1%); cholecystitis, colitis, gastritis, intestinal obstruction (postmarketing).

Genitourinary

Oliguria (63%); anuria (5%); acute kidney failure (1%); abnormal kidney function, acute tubular necrosis, increased BUN, kidney failure, hyperuricemia (less than 1%).

Hepatic

Increased AST (23%); abnormal LFTs, liver failure (less than 1%); hepatitis, hepatosplenomegaly (postmarketing).

Hematologic-Lymphatic

Thrombocytopenia (37%); anemia (29%); leukopenia (16%); coagulation disorders (including, intravascular coagulopathy [1%]); leukocytosis, hemorrhage (less than 1%); neutropenia (postmarketing).

Lab Tests

Increased nonprotein nitrogen (less than 1%).

Metabolic-Nutritional

Bilirubinemia (40%); increased creatinine (33%); peripheral edema (28%); weight gain (16%); edema (15%); acidosis, hypomagnesemia, (12%); hypocalcemia (11%); increased alkaline phosphatase (10%).

Musculoskeletal

Myopathy, myositis, rhabdomyolysis (postmarketing).

Renal

Renal failure (less than 1%).

Respiratory

Dyspnea (43%); lung disorder (including, pulmonary congestion, rales, rhonchi [24%]); respiratory disorder (including, ARDS, chest x-ray infiltrates, unspecified pulmonary changes), increased cough (11%); rhinitis (10%); apnea (1%); pulmonary edema, pulmonary emboli, asthma, hemoptysis, hyperventilation, hypoventilation, hypoxia, pneumothorax, respiratory acidosis, respiratory arrest, respiratory failure (less than 1%); pneumonia (bacterial, fungal, viral [postmarketing]).

Miscellaneous

Chills (52%); fever (29%); malaise (27%); asthenia (23%); infection (13%); pain (12%); sepsis (1%); anaphylaxis, hyperthyroidism, retroperitoneal hemorrhage (postmarketing).

Precautions

Warnings

Therapy with aldesleukin for injection should be restricted to patients with normal cardiac and pulmonary functions.

Aldesleukin should be administered in a hospital setting under the supervision of a qualified health care provider 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 CLS. 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, MI, respiratory insufficiency requiring intubation, GI bleeding or infarction, renal insufficiency, edema, and mental status changes.

Aldesleukin treatment is associated with impaired neutrophil function (reduced chemotaxis) and with an increased risk of disseminated infection, including sepsis and bacterial endocarditis. Treat pre-existing infections prior to initiation of therapy.

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


Monitor

Cardiac function

Assess vital signs, weight, and fluid intake and output daily during treatment. If patient develops a decreased systolic BP (below 90 mm Hg), conduct constant cardiac rhythm monitoring and take vital signs hourly. Monitor cardiac function (clinical examination, vital signs) daily during therapy. Further assess patient with new signs or symptoms of cardiac dysfunction (eg, chest pain, irregular rhythm) with an ECG and cardiac enzyme evaluation. Hold aldesleukin therapy and perform a repeat thallium studies if there is evidence of cardiac ischemia or CHF.

CLS

Monitor patient for signs and symptoms of CLS (eg, hypotension, tachycardia, edema). Inform health care provider immediately and be prepared to treat appropriately with close monitoring (eg, BP, pulse, weight, urine output), IV fluids (eg, colloids, crystalloids), and vasopressors (eg, dopamine). Discontinue aldesleukin therapy if evidence of failure to maintain organ perfusion (eg, altered mental status, reduced urine output, cardiac arrhythmias, or systolic BP less than 90 mm Hg) develop.

CNS toxicity

Monitor patient for signs and symptoms of CNS toxicity (eg, change in mental status, speech difficulties, hallucinations, agitation, cortical blindness, limb or gait ataxia, obtundation, coma). Immediately notify health care provider and be prepared to discontinue therapy.

Ensure testing

Ensure that pulmonary function tests, arterial blood gasses, and stress thallium study are performed, and the results documented before initiating therapy.

Pulmonary function

Monitor pulmonary function (clinical examination, pulse oximetry, vital signs) on regular basis during therapy. Further assess patient with dyspnea or clinical signs of respiratory impairment (eg, tachypnea, rales) with arterial blood gas determinations.

Serum creatinine

Do not administer to patient with serum creatinine greater than 1.5 mg/dL.


Pregnancy

Category C .

Lactation

Undetermined. Because of the potential for serious adverse reactions in breast-feeding infants, decide whether to discontinue breast-feeding or to discontinue the drug, taking into account the importance of the drug to the mother.

Children

Safety and efficacy not established.

Hypersensitivity

Reactions have been reported in patients receiving combination regimens containing sequential high-dose aldesleukin and antineoplastic agents.

Renal Function

Impairment of renal function occurs during treatment.

Hepatic Function

Impairment of hepatic function occurs during treatment.

Fertility

It is recommended that this drug not be administered to fertile people of either sex not practicing effective contraception.

Allograft rejection

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

Autoimmune diseases

Aldesleukin may exacerbate autoimmune disease.

CLS

Begins immediately after initiation of treatment and results from extravasation of plasma proteins and fluid into the extravascular space and loss of vascular tone. Watch for a drop in mean arterial BP within 2 to 12 h after the start of treatment and reduced organ perfusion, which may be severe and result in death.

CNS effects

New neurologic signs, symptoms, and anatomic lesions have been reported in patients without evidence of CNS metastases.

CNS metastases

May exacerbate disease symptoms in patients with clinically unrecognized or untreated CNS metastases.

Iodinated contrast media

Acute, atypical adverse reactions (eg, fever, chills, nausea, vomiting, pruritus, rash, diarrhea, hypotension, edema) have been reported in patients administered iodine contrast media subsequent to IL-2 treatment.

Mental status changes

Mental status changes including irritability, confusion, or depression may occur and may be indicators of bacteremia or early bacterial sepsis.

Re-treatment

Contraindicated in patients who experienced the following toxicities while receiving an earlier course of therapy: sustained ventricular tachycardia (at least 5 beats); cardiac rhythm disturbances uncontrolled or unresponsive; recurrent chest pain with ECG changes, consistent with angina or MI; intubation required more than 72 h; pericardial tamponade, renal function impairment requiring dialysis more than 72 h; coma or toxic psychosis lasting more than 48 h; repetitive or difficult to control seizures; bowel ischemia/perforation; GI bleeding requiring surgery.

Thyroid function impairment

Impairment has occurred following treatment.

Overdosage

Symptoms

Dose-related adverse reactions.

Patient Information

  • Advise patient, family, or caregiver that medication will be prepared and administered by health care provider in a health care setting.
  • Review dosing schedule with patient, family, or caregiver.
  • Advise patient, family, or caregiver to immediately report any of the following to health care provider: fever, mental status changes, hallucinations, agitation, speech difficulties, vision changes, incoordination, swelling, difficulty breathing, shortness of breath or unexplained rapid breathing, chest pain, pounding in chest, changes in heart rhythm.
  • Caution women of childbearing potential to avoid becoming pregnant during therapy.

Copyright © 2009 Wolters Kluwer Health.

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