Aldesleukin
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Boxed warning
WARNING: CAPILLARY LEAK SYNDROME (CLS), NEUROLOGIC TOXICITIES and SERIOUS INFECTIONS Capillary leak syndrome (CLS), including life threatening or fatal reactions, has occurred in patients treated with Proleukin. Do not administer Proleukin to patients with significant cardiac, pulmonary, renal, and hepatic impairment. Administer Proleukin in a hospital setting with an intensive care facility. Withhold or discontinue Proleukin as recommended [see Dosage and Administration (2.4) , Contraindications (4) , Warnings and Precautions (5.1) ] . Neurologic toxicities, which may be life-threatening or result in coma or permanent neurological deficits, have occurred in patients treated with Proleukin.
Withhold or discontinue Proleukin as recommended [see Dosage and Administration (2.4) , Warnings and Precautions (5.2) ] . Serious Infections including sepsis and bacterial endocarditis have occurred in patients treated with Proleukin. Treat pre-existing bacterial infections prior to initiation of Proleukin therapy and withhold Proleukin as recommended [see Dosage and Administration (2.4) , Warnings and Precautions (5.3) ] . WARNING: CAPILLARY LEAK SYNDROME (CLS), NEUROLOGIC TOXICITY, AND SERIOUS INFECTIONS See full prescribing information for complete boxed warning. Capillary Leak Syndrome (CLS) including life-threatening or fatal reactions, has occurred in patients treated with Proleukin.
Administer Proleukin in a hospital setting with an intensive care unit. Withhold or discontinue Proleukin as recommended. ( 2.4 , 4 , 5.1 ) Neurologic toxicities, which may be life-threatening or result in coma or permanent neurological deficits, have occurred in patients treated with Proleukin. Withhold or discontinue Proleukin as recommended. ( 2.4 , 5.2 ) Serious infections including sepsis and bacterial endocarditis have occurred in patients treated with Proleukin. Treat preexisting bacterial infections prior to initiating Proleukin and withhold Proleukin as recommended. ( 2.4 , 5.3 )
Lymphocyte Growth Factor
Dosing in kidney impairment
Recommended Evaluation and Testing Before Initiating Proleukin 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 (5.1 , 5.2) ].
Verify pregnancy status of females of reproductive potential prior to initiating Proleukin [see Warnings and Precautions , Use in Specific Populations (8.1 , 8.3) ].
| Adverse Reaction | Severity | Dosage Modification |
|---|---|---|
| Cardiovascular [see Warnings and Precautions (5.1)] | Atrial fibrillation,Supraventricular tachycardia, orBradycardia that requires treatment or is recurrent or persistentDecrease in systolic blood pressure to <90 mmHg | Withhold until patient is asymptomatic with full recovery to normal sinus rhythm |
| Sustained ventricular tachycardia (≥5 beats)Cardiac rhythm disturbances not controlled or unresponsive to managementECG changes consistent with ischemia or myocardial infarction or angina/chest painCardiac tamponade | Permanently discontinue | |
| Respiratory [see Warnings and Precautions (5.1)] | O2 saturation <90% | Withhold until O2 saturation is >90% |
| Intubation for >72 hours | Permanently discontinue | |
| Neurologic [see Warnings and Precautions (5.2)] | Mental status changes, including moderate confusion or agitation | Withhold until completely resolved |
| Coma or toxic psychosis lasting >48 hoursRepetitive or difficult to control seizures | Permanently discontinue | |
| Gastrointestinal [see Warnings and Precautions (5.1)] | 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 (5.1)] | 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 (5.5, 5.7)] | Bullous dermatitis or marked worsening of pre-existing skin condition | Withhold until all signs of bullous dermatitis have resolved |
| Infectious [see Warnings and Precautions (5.3)] | 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 (5.1, 5.4)] | 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 | |
| Renal failure requiring dialysis >72 hours | Permanently discontinue |
Dosing in liver impairment
| Adverse Reaction | Severity | Dosage Modification |
|---|---|---|
| Cardiovascular [see Warnings and Precautions (5.1)] | Atrial fibrillation,Supraventricular tachycardia, orBradycardia that requires treatment or is recurrent or persistentDecrease in systolic blood pressure to <90 mmHg | Withhold until patient is asymptomatic with full recovery to normal sinus rhythm |
| Sustained ventricular tachycardia (≥5 beats)Cardiac rhythm disturbances not controlled or unresponsive to managementECG changes consistent with ischemia or myocardial infarction or angina/chest painCardiac tamponade | Permanently discontinue | |
| Respiratory [see Warnings and Precautions (5.1)] | O2 saturation <90% | Withhold until O2 saturation is >90% |
| Intubation for >72 hours | Permanently discontinue | |
| Neurologic [see Warnings and Precautions (5.2)] | Mental status changes, including moderate confusion or agitation | Withhold until completely resolved |
| Coma or toxic psychosis lasting >48 hoursRepetitive or difficult to control seizures | Permanently discontinue | |
| Gastrointestinal [see Warnings and Precautions (5.1)] | 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 (5.1)] | 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 (5.5, 5.7)] | Bullous dermatitis or marked worsening of pre-existing skin condition | Withhold until all signs of bullous dermatitis have resolved |
| Infectious [see Warnings and Precautions (5.3)] | 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 (5.1, 5.4)] | 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 | |
| Renal failure requiring dialysis >72 hours | Permanently discontinue |
Preparation and administration
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Preparation and Administration Preparation 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. Add 1.2 mL of Sterile Water for Injection, USP, by injecting the water along the walls of the vial and not directly on the lyophilized powder.
The resulting concentration is 18 million IU (1.1 mg)/mL of Proleukin. The prepared solution is a clear, colorless to slightly yellow liquid. Slowly swirl the vial; do not shake. Withdraw the required dose of Proleukin and discard the vial with any unused portion. Use polyvinyl chloride bags for dilution of Proleukin and dilute using 5% Dextrose Injection to a concentration between 0.03 mg/mL and 0.07 mg/mL based on the required dose as follows: [See table below.] Storage of Diluted Proleukin Infusion Solution Store under refrigeration at 2° to 8°C (36° to 46°F) for no more than 48 hours from the time of preparation to the end of the infusion.
Protect from light. Do not freeze. Allow the diluted solution to come to room temperature prior to administration. Administration Do not use in-line filters when administering Proleukin. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Do not co-administer Proleukin with other drugs through the same intravenous line. Administer by intravenous infusion over 15 minutes.
| Adverse Reaction | Severity | Dosage Modification |
|---|---|---|
| Cardiovascular [see Warnings and Precautions (5.1)] | Atrial fibrillation,Supraventricular tachycardia, orBradycardia that requires treatment or is recurrent or persistentDecrease in systolic blood pressure to <90 mmHg | Withhold until patient is asymptomatic with full recovery to normal sinus rhythm |
| Sustained ventricular tachycardia (≥5 beats)Cardiac rhythm disturbances not controlled or unresponsive to managementECG changes consistent with ischemia or myocardial infarction or angina/chest painCardiac tamponade | Permanently discontinue | |
| Respiratory [see Warnings and Precautions (5.1)] | O2 saturation <90% | Withhold until O2 saturation is >90% |
| Intubation for >72 hours | Permanently discontinue | |
| Neurologic [see Warnings and Precautions (5.2)] | Mental status changes, including moderate confusion or agitation | Withhold until completely resolved |
| Coma or toxic psychosis lasting >48 hoursRepetitive or difficult to control seizures | Permanently discontinue | |
| Gastrointestinal [see Warnings and Precautions (5.1)] | 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 (5.1)] | 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 (5.5, 5.7)] | Bullous dermatitis or marked worsening of pre-existing skin condition | Withhold until all signs of bullous dermatitis have resolved |
| Infectious [see Warnings and Precautions (5.3)] | 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 (5.1, 5.4)] | 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 | |
| Renal failure requiring dialysis >72 hours | Permanently discontinue |
| 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 |
Drug interactions
Check aldesleukin against a medication listLabel text (4 paragraphs)
Drug interaction studies with Proleukin have not been conducted. The drug interaction information described below have been observed post-marketing. See Full Prescribing Information for important drug interactions. ( 7 )
7.1 Effect of Other Drugs on Proleukin Glucocorticoids Avoid concomitant use of glucocorticoids. Coadministration with glucocorticoids may reduce aldesleukin antitumor effectiveness.
7.2 Effect of Proleukin on Other Drugs Radiographic Iodinated Contrast Media 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 (5.8) ] . Effect on Cytochrome P-450 Substrates 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 (12.2) ] that may suppress activity of CYP enzymes, resulting in increased exposure of CYP substrates.
Contraindications
Severe Hypersensitivity Reactions Proleukin is contraindicated in patients with a known history of severe hypersensitivity to aldesleukin or any component of the Proleukin formulation [see Adverse Reactions (6.2) ]. Organ Allografts Proleukin is contraindicated in patients with organ allografts [see Warnings and Precautions (5.5) ] .
Significant Organ Impairment 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 (5.1 , 5.2 , 5.4) ] . Hypersensitivity to aldesleukin. ( 4 ) Organ allografts. ( 4 ) Significant organ impairment. ( 4 )
Safety data
Reported adverse events (FAERS)
Liver injury (LiverTox)
C[HD]Likelihood score C[HD]: Probable cause of clinically apparent liver injury when given in high doses.
Aldesleukin is a recombinant form of human interleukin-2, a cytokine that stimulates the proliferation and maturation of T cells, which is used in immune therapy of renal cell cancer and malignant melanoma. When given in high doses, interleukin-2 regularly causes mild-to-moderate elevations in serum enzymes and bilirubin, but it rarely results in clinically significant acute liver injury.
ABCDEA: well known cause; E: unlikely cause. [HD]: high doses only.
Pregnancy and lactation
Pregnancy
8.1 Pregnancy Risk Summary 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 (12.1) ]. 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. Clinical Considerations 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. Data 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.
For breastfeeding, also see LactMed (National Library of Medicine), which summarizes milk levels and infant effects.
Supply and cost
Drug shortage status
Recalls (last 24 months)
Therapeutic equivalence (Orange Book)
Price ladder
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