Proleukin

• 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 Dosage Modifications for Adverse Reactions

  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 ]	Atrial fibrillation, Supraventricular tachycardia, or Bradycardia that requires treatment or is recurrent or persistent Decrease 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 management ECG changes consistent with ischemia or myocardial infarction or angina/chest pain Cardiac tamponade	Permanently discontinue
  Respiratory [see Warnings and Precautions ]	O2 saturation <90%	Withhold until O2 saturation is >90%
  	Intubation for >72 hours	Permanently discontinue
  Neurologic [see Warnings and Precautions ]	Mental status changes, including moderate confusion or agitation	Withhold until completely resolved
  	Coma or toxic psychosis lasting >48 hours Repetitive or difficult to control seizures	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
  	Renal failure requiring dialysis >72 hours	Permanently discontinue

  ), Contraindications (

  4 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 ].

  • Organ Allografts

  Proleukin is contraindicated in patients with organ allografts

  [see Warnings and Precautions ]

  .

  • 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 ]

  .

  • Hypersensitivity to aldesleukin.
  • Organ allografts.
  • Significant organ impairment.

  ), Warnings and Precautions (

  5.1 Capillary Leak Syndrome

  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 ]

  .

  )]

  .
• 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 Dosage Modifications for Adverse Reactions

  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 ]	Atrial fibrillation, Supraventricular tachycardia, or Bradycardia that requires treatment or is recurrent or persistent Decrease 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 management ECG changes consistent with ischemia or myocardial infarction or angina/chest pain Cardiac tamponade	Permanently discontinue
  Respiratory [see Warnings and Precautions ]	O2 saturation <90%	Withhold until O2 saturation is >90%
  	Intubation for >72 hours	Permanently discontinue
  Neurologic [see Warnings and Precautions ]	Mental status changes, including moderate confusion or agitation	Withhold until completely resolved
  	Coma or toxic psychosis lasting >48 hours Repetitive or difficult to control seizures	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
  	Renal failure requiring dialysis >72 hours	Permanently discontinue

  ), Warnings and Precautions (

  5.2 Neurologic Toxicity

  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.

  )]

  .
• 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 Dosage Modifications for Adverse Reactions

  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 ]	Atrial fibrillation, Supraventricular tachycardia, or Bradycardia that requires treatment or is recurrent or persistent Decrease 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 management ECG changes consistent with ischemia or myocardial infarction or angina/chest pain Cardiac tamponade	Permanently discontinue
  Respiratory [see Warnings and Precautions ]	O2 saturation <90%	Withhold until O2 saturation is >90%
  	Intubation for >72 hours	Permanently discontinue
  Neurologic [see Warnings and Precautions ]	Mental status changes, including moderate confusion or agitation	Withhold until completely resolved
  	Coma or toxic psychosis lasting >48 hours Repetitive or difficult to control seizures	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
  	Renal failure requiring dialysis >72 hours	Permanently discontinue

  ), Warnings and Precautions (

  5.3 Serious Infections Including Sepsis

  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 ].

  )]

  .

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.

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Capillary Leak Syndrome
  [see Warnings and Precautions (

  5.1 Capillary Leak Syndrome

  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 ]

  .

  )].
• Neurotoxicity
  [see Warnings and Precautions (

  5.2 Neurologic Toxicity

  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.

  )].
• Serious Infections Including Sepsis
  [see Warnings and Precautions (

  5.3 Serious Infections Including Sepsis

  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 ].

  )].
• Renal Toxicity
  [see Warnings and Precautions (

  5.4 Renal Toxicity

  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 ]

  .

  )].
• Immune-Mediated Adverse Reactions
  [see Warnings and Precautions (

  5.5 Immune-mediated Adverse Reactions

  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 ]

  .

  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.

  )].
• Serious Manifestations of Eosinophilia
  [see Warnings and Precautions (

  5.7 Serious Manifestations of Eosinophilia

  Serious manifestations of eosinophilia involving eosinophilic infiltration of cardiac and pulmonary tissues can occur following Proleukin.

  )].
• Severe Hypersensitivity Reactions
  [see Warnings and Precautions (

  5.9 Severe Hypersensitivity 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 ].

  )].
• Infusion-Related Reactions
  [see Warnings and Precautions (

  5.10 Infusion-Related 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 ].

  )]
  .

Drug interaction studies with Proleukin have not been conducted. The drug interaction information described below have been observed post-marketing.

Aldesleukin is a human interleukin-2 lymphocyte growth factor produced by recombinant DNA technology using a genetically engineered

The manufacturing process for aldesleukin involves fermentation in a defined medium containing tetracycline hydrochloride. The presence of tetracycline hydrochloride is not detectable in the final product.

Proleukin (aldesleukin) for injection is a sterile, preservative-free white to off-white, lyophilized powder, which has a cake-like appearance, supplied in single-dose vials for intravenous administration after reconstitution and dilution. When reconstituted with 1.2 mL Sterile Water for Injection, USP, each mL contains 18 million International Units (1.1 mg) aldesleukin, mannitol (50 mg), sodium dodecyl sulfate (0.19 mg), buffered with disodium hydrogen phosphate dihydrate (1.12 mg) and sodium dihydrogen phosphate dihydrate (0.19 mg) to a pH of 7.5 (range 7.2 to 7.8).