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aldesleukin

( all-dess-LOO-kin )
Funding:
New Drug Funding Program
  • Aldesleukin (interleukin-2) - In-Transit Metastases from Melanoma
Other Name(s): Proleukin® (interleukin-2) (Novartis)
Appearance: Clear/colorless to slightly yellow solution mixed into larger bags of fluids
A - Drug Name

aldesleukin

SYNONYM(S):   interleukin-2; IL-2; lymphocyte mitogenic factor; T-cell growth factor; thymocyte stimulating factor

COMMON TRADE NAME(S):   Proleukin® (interleukin-2) (Novartis)

 
B - Mechanism of Action and Pharmacokinetics

Aldesleukin, a recombinant interleukin-2, has multiple immunologic effects, including activation of cellular immunity with lymphocytosis, eosinophilia, thrombocytopenia and production of lymphokines including TNF, IL-1 and gamma-interferon. Tumour growth inhibition has been reported in in vivo studies. Objective responses are seen in ± 16% of patients but no overall survival benefit in controlled studies has been demonstrated.

 
Absorption
Oral: no
Distribution

Pharmacokinetics appear to be dose proportional. Uptake into lung, liver, spleen and kidney is rapid.

Cross blood brain barrier?No information found
PPBNo information found
Metabolism

Aldesleukin is rapidly metabolized to its composite amino acids in the proximal tubules of the kidney.

Active metabolitesTrace
Inactive metabolitesYes (to its composite amino acids)
Elimination

2- compartmental disposition, cleared as inactive metabolites by glomerular filtration and peritubular extraction

Clearance268mL/minute
Half-life13-85 minutes
Urine80% via renal tubular and glomerular filtration
 
C - Indications and Status
Health Canada Approvals:
 
  • Carefully selected adults with metastatic renal cell carcinoma
  • Carefully selected adults with metastatic malignant melanoma

 
 
D - Adverse Effects

Emetogenic Potential:  

Low (≤ 12 MU/m2)
Moderate (>12-15 MU/m2)

 

Extravasation Potential:   None

ORGAN SITESIDE EFFECT* (%)ONSET**
CardiovascularArterial thromboembolism (rare)E
 Cardiotoxicity (<1%)E
 Venous thromboembolism (rare)E
 Ventricular arrhythmia (12%) (supraventricular)I
DermatologicalOther (persistent vitiligo; rare)E
 Rash (42%) (may be exfoliative)I  E
GastrointestinalAbdominal pain (11%)E
 Anorexia (20%)E
 Diarrhea (67%)E
 GI perforation (or obstruction, +/- bleeding; rare)E
 Mucositis (22%)E
 Nausea, vomiting (50%)I  E
GeneralFatigue (27%)E
 Flu-like symptoms (52%)I
 Hyperthermia (1%) (malignant hyper or hypothermia)E
HematologicalDisseminated intravascular coagulation (1%)I
 Myelosuppression ± infection, bleeding (37%) (severe 1%)E
Hepatobiliary↑ LFTs (40%) (may be severe)E
 Pancreatitis (rare)E
HypersensitivityDrug reaction (rare)E
ImmuneOther (risk of rejection in allograft recipients, exacerbation of autoimmune diseases)E  D
InfectionInfection (13%) (may be severe, including atypical)E
Metabolic / EndocrineAbnormal electrolyte(s) (12%) (decreased Ca, Mg)E
 Acidosis (12%)I  E
MusculoskeletalRhabdomyolysis (especially with interferon; rare)E
Nervous SystemConfusion (34%) (includes somnolence)E
 Depression (4%) (may be severe)E  D
 Dizziness (11%)E
 Leukoencephalopathy (rare)E
 Neuropathy (6%; optic neuritis, demyelination-rare)E
 Seizure (<1%)E
OphthalmicConjunctivitis (2%)E
 Eye disorders (1%)E
RenalCreatinine increased (33%) (may be severe)E
 Tumor lysis syndrome (with chemotherapy)E
RespiratoryAdult respiratory distress syndrome (ARDS) (3%)E
 Dyspnea (43%)E
VascularCapillary leak syndrome (71%)I  E
 Vasculitis (cutaneous; cerebral- rare)E


* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.
Dose-limiting side effects are underlined.

** I = immediate (onset in hours to days)     E = early (days to weeks)
D = delayed (weeks to months)      L = late (months to years)

Most adverse reactions usually reverse or improve within 2-3 days of discontinuing therapy, due to aldesleukin’s short half-life, but drug-related deaths occur in 2-4% of patients treated with aldesleukin.

The major dose-limiting side effect of aldesleukin is capillary leak syndrome. Aldesleukin administration induces decreased vascular tone and increased vascular permeability leading to hypotension, reduced organ perfusion and function (renal, cardiac, hepatic, etc.), ascites, effusions, cardiac arrhythmias/ischemia and respiratory insufficiency. The management of capillary leak syndrome involves careful monitoring of fluid and organ perfusion. Administration of intravenous dopamine or phenylephrine to increase blood pressure may help maintain organ perfusion, particularly renal perfusion and thereby preserve urine output. Administration of subsequent doses of aldesleukin should be delayed until recovery of organ perfusion is observed.

Renal dysfunction is reversible and also usually secondary to capillary leak syndrome. It is also correlated with the dose, duration of treatment and the patient’s baseline renal function. The administration of indomethacin for flu-like syndrome may potentiate renal dysfunction by decreasing intrarenal prostaglandins.

A flu-like syndrome (fever, rigors and chills) develops in most patients receiving aldesleukin. Treatment with acetaminophen or a NSAID (e.g. ibuprofen, indomethacin) may minimize the risk, but renal function should be monitored carefully. In clinical trials, meperidine was administered to control the rigors associated with fever.

The clinical significance of developing non-neutralizing anti-interleukin-2 antibodies to aldesleukin is unknown. The incidence of antibodies formation is less than 1%. Exacerbation of autoimmune disorders such as Crohns, myasthenia, vasculitis, hypo or hyperthyroidism and diabetes mellitus may also occur.

Hypersensitivity has been described and may be exacerbated when aldesleukin is administered with other drugs; delayed reactions may occur with contrast media.

CNS toxicity is dose-related and generally reversible, but it may be associated with demyelination and may be irreversible in some patients.

 
E - Dosing
 

Refer to protocol by which patient is being treated. Patients must be managed as an inpatient in a tertiary care setting with full ICU facilities. Consider the following pre-medications (generally discontinued 12 hours after the last dose of aldesleukin):

  • prophylactic antibiotics in patients with indwelling catheters
  • Antipyretics
  • H2 antagonists
  • Start meperidine and antidiarrheals early at the onset of symptoms.

Note: 1 MU = 1 million units = 1 million IU (international units) = 0.061 mg


 
Adults:
 

Optimal dosage and regimen for aldesleukin have not been established, but the following regimen has been approved by Health Canada.

Intravenous: 600,000 IU/kg (by a 15-minute infusion q8h; maximum 14 doses x 2)

 

Day

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

Dose

XXX

XXX

XXX

XXX

XX

 

 

 

 

 

 

 

 

 

XXX

XXX

XXX

XXX

XX

 

   (X refers to a single dose)

The course may be repeated 7 weeks after hospital discharge, if tolerable and there is evidence of anti-tumour response.

Dosage with Toxicity:
 

Aldesleukin should be held for toxicity rather than reducing the dose to be given. Consult the product monograph for detailed management recommendations.

 

Dose interruption:

Body system

 

Hold;

May Restart after Recovery

Discontinue permanently

Cardiovascular

 

Atrial fibrillation, SVT, bradycardia

X

 

Hypotension – pressors needed

X

 

EKG ischemia or myocarditis

X

 

Sustained VT, incontrollable arrhythmia

 

X

Angina, AMI, tamponade

 

X

Respiratory

O2 saturation < 94% on room air or

< 90% with 2 liters O2

X

 

Intubation for > 72hrs

 

X

CNS

Moderate-severe confusion, agitation, lethargy or somnolence

X

 

Coma, psychosis > 48 hrs

 

X

Uncontrollable seizures

 

X

Infection

Grade 4, unstable

X

 

Renal

Serum creatinine > 400 µmol/L

Oliguria -  < 10 mL/hour for 16-24 hours with ↑ creatinine

X

 

Dialysis required ≥ 72hrs

 

X

Hepatic

Hepatic failure**

X

 

Skin

Bullous dermatitis

X

 

GI

Ischemia, perforation

 

X

Bleed not requiring surgery

X

 

Bleed requiring surgery

 

X

**Abandon course. Do not start new course for at least 7 weeks after recovery.

Dosage in myelosuppression: No adjustment required


 
Dosage with Hepatic Impairment:
 

Hold until recovery if any signs of hepatic failure are present. See table above.


 
Dosage with Renal Impairment:
 

Do not start treatment if creatinine > 130 µmol/L. See table above.


 
Dosage in the elderly:
 

Limited data in elderly patients.  Monitor renal function closely as the elderly may have decreased renal function.


 
Children:
 

Safety and effectiveness in children under 18 years of age have not been established.


 
 
F - Administration Guidelines
  • Each vial (1.3 mg) should be reconstituted with 1.2 mL of SWI.
  • During reconstitution, USP should be directed at the side of the vial and the contents gently swirled to avoid excess foaming. Do not shake.
  • Addition of BSWI or NS may promote aggregation and these solutions should not be used
  • For IV administration, dilute further in 50 mL bag of D5W; infuse over 15 minutes
  • Final concentration of drug should be 30 - 70µg/mL
  • Drug delivery is more consistent when diluted in PVC container rather than non-PVC container
  • In-line filter should not be used when administering aldesleukin
  • Keep refrigerated; do not freeze. Avoid exposure to heat and light.
 
G - Special Precautions
Contraindications:

 

  • known allergic reaction to aldesleukin, interleukin-2 or any components of the product
  • abnormal thallium stress test
  • abnormal pulmonary function tests
  • organ allografts
  • significant cardiac, pulmonary, renal, hepatic or CNS impairment
  • concomitant use of cisplatin, vinblastine and dacarbazine as fatal tumour lysis syndrome has been reported

 

Other Warnings/Precautions:

 

  • use with extreme caution in patients with known cardiac, pulmonary or seizure disorders (even with normal thallium and pulmonary function tests)
  • use with extreme caution in patients with large fluid requirements (e.g., hypercalcemia)
  • use with caution in patients with inflammatory or autoimmune disorders
  • use with caution in combination with antihypertensives and psychotropic drugs as well as hepatotoxic, cardiotoxic or nephrotoxic drugs

 


Other Drug Properties:

 

  • Carcinogenicity: Unknown

 

Pregnancy and Lactation:
  • Embryotoxicity: Probable
    Aldesleukin is not recommended for use in pregnancy.  Adequate contraception should be used by both sexes during treatment, and for at least 6 months after the last dose.
  • Excretion into breast milk: Unknown
    Breastfeeding is not recommended.
Other:

Patients should have baseline pulmonary function tests with arterial blood gases, thallium stress tests to exclude the presence of significant coronary artery disease, and brain imaging to exclude metastases. Patients who have had a nephrectomy are still eligible for treatment if they have serum creatinine levels within normal range. Pre-existing infections must be treated prior to starting aldesleukin.

 
H - Interactions

 

AGENTEFFECTMECHANISMMANAGEMENT
Psychotropics (narcotics, sedatives, tranquilizers, antiemetics)Enhances CNS toxicitiesAdditiveCaution
AntihypertensivesPotentiate hypotensionAdditiveCaution; monitor blood pressure
Radiographic iodinated contrast medianon-anaphylactic hypersensitivityUnknownCaution
Glucocorticoids↓ anti-tumour effect of aldesleukinUnknownAvoid, but may be needed to manage side effects
cytotoxicsPotentiate myelosuppression, TLSAdditiveCaution
Nephrotoxic drugs (i.e. aminoglycosides, amphotericin B, methotrexate)potentiate renal toxicityAdditive (possibly)Caution
Hepatotoxic agents (e.g., methotrexate, asparaginase)potentiate hepatotoxicityAdditive (possibly)Caution
Cardiotoxic agents (e.g., doxorubicin)Potentiate cardiotoxicityAdditive (possibly)Caution
DTIC, cisplatin, interferon, tamoxifen↑ hypersensitivityAdditiveCaution
Interferon↑ hypersensitivity, cardiotoxicity and rhabdomyolysis, autoimmune diseaseUnknownCaution
Drug excreted via liver or kidney↓ excretion↓ renal, liver functionCaution
 
I - Recommended Clinical Monitoring

 

Recommended Clinical Monitoring
 
Monitor TypeMonitor Frequency
CBCBaseline and frequent
Electrolytes, blood glucoseBaseline and frequent
Liver function testsBaseline and frequent
Renal function tests, fluid intake and outputBaseline and frequent
Pulmonary function tests with arterial blood gases (FEV1 > 2L or ≥ 75% of predicted for age)Baseline
CT scan of brain to exclude CNS metastasesBaseline
Thallium stress tests to exclude significant coronary artery diseaseBaseline
Frequent weight, vital signs, EKG etc. during treatment 
Chest x-rayBaseline and regular
Clinical toxicity assessment for GI, hydration, cardiovascular, CNS, perfusion, autoimmune effectsregular

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
 
Suggested Clinical Monitoring
 
Monitor TypeMonitor Frequency

 

  • Repeat thallium testing if suspicion of ischemia or congestive cardiac failure
  • Constant cardiac rhythm monitoring and hourly vital signs in patients with hypotension, especially bp < 90 mmHg

 

 
 
J - Supplementary Public Funding

New Drug Funding Program (NDFP Website )

  • Aldesleukin (interleukin-2) - In-Transit Metastases from Melanoma

 

 
K - References

 

McEvoy GK, editor. AHFS Drug Information 2009. Bethesda: American Society of Health-System Pharmacists, p. 915-24.

Proleukin® (aldesleukin/interleukin-2) [product monograph]. Dorval, Quebec: Novartis Pharmaceuticals Canada Inc.; Sept 20, 2012.

 

 

 

October 2017 Modified synonyms and brand name section

 
L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.

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