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aldesleukin
aldesleukin
SYNONYM(S): interleukin-2; IL-2; lymphocyte mitogenic factor; T-cell growth factor; thymocyte stimulating factor
COMMON TRADE NAME(S): Proleukin® (interleukin-2)
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.
Pharmacokinetics appear to be dose proportional. Uptake into lung, liver, spleen and kidney is rapid.
| Cross blood brain barrier? | No information found |
| PPB | No information found |
Aldesleukin is rapidly metabolized to its composite amino acids in the proximal tubules of the kidney.
| Active metabolites | Trace |
| Inactive metabolites | Yes (to its composite amino acids) |
2- compartmental disposition, cleared as inactive metabolites by glomerular filtration and peritubular extraction
| Clearance | 268mL/minute |
| Half-life | 13-85 minutes |
| Urine | 80% via renal tubular and glomerular filtration |
- Carefully selected adults with metastatic renal cell carcinoma
- Carefully selected adults with metastatic malignant melanoma
Emetogenic Potential:
Low (IV doses ≤ 12 MU/m2)
Moderate (IV doses >12-15 MU/m2)
Extravasation Potential: None
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Arterial thromboembolism (rare) | E | |||
| Cardiotoxicity (<1%) | E | ||||
| Venous thromboembolism (rare) | E | ||||
| Ventricular arrhythmia (12%) (supraventricular) | I | ||||
| Dermatological | Other (persistent vitiligo; rare) | E | |||
| Rash (42%) (may be exfoliative) | I E | ||||
| Gastrointestinal | Abdominal pain (11%) | E | |||
| Anorexia (20%) | E | ||||
| Diarrhea (67%) | E | ||||
| GI perforation (or obstruction, +/- bleeding; rare) | E | ||||
| Mucositis (22%) | E | ||||
| Nausea, vomiting (50%) | I E | ||||
| General | Fatigue (27%) | E | |||
| Flu-like symptoms (52%) | I | ||||
| Hyperthermia (1%) (malignant hyper or hypothermia) | E | ||||
| Hematological | Disseminated intravascular coagulation (1%) | I | |||
| Myelosuppression ± infection, bleeding (37%) (severe 1%) | E | ||||
| Hepatobiliary | ↑ LFTs (40%) (may be severe) | E | |||
| Pancreatitis (rare) | E | ||||
| Hypersensitivity | Drug reaction (rare) | E | |||
| Immune | Other (risk of rejection in allograft recipients, exacerbation of autoimmune diseases) | E D | |||
| Infection | Infection (13%) (may be severe, including atypical) | E | |||
| Metabolic / Endocrine | Abnormal electrolyte(s) (12%) (decreased Ca, Mg) | E | |||
| Acidosis (12%) | I E | ||||
| Musculoskeletal | Rhabdomyolysis (especially with interferon; rare) | E | |||
| Nervous System | Confusion (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 | ||||
| Ophthalmic | Conjunctivitis (2%) | E | |||
| Eye disorders (1%) | E | ||||
| Renal | Creatinine increased (33%) (may be severe) | E | |||
| Tumor lysis syndrome (with chemotherapy) | E | ||||
| Respiratory | Adult respiratory distress syndrome (ARDS) (3%) | E | |||
| Dyspnea (43%) | E | ||||
| Vascular | Capillary 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.
** 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.
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
Optimal dosage and regimen for aldesleukin have not been established, but the following regimen has been approved by Health Canada.
|
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.
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
Hold until recovery if any signs of hepatic failure are present. See table above.
Do not start treatment if creatinine > 130 µmol/L. See table above.
Limited data in elderly patients. Monitor renal function closely as the elderly may have decreased renal function.
Safety and effectiveness in children under 18 years of age have not been established.
- 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.
- 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
- 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
-
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.
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.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Psychotropics (narcotics, sedatives, tranquilizers, antiemetics) | Enhances CNS toxicities | Additive | Caution |
| Antihypertensives | Potentiate hypotension | Additive | Caution; monitor blood pressure |
| Radiographic iodinated contrast media | non-anaphylactic hypersensitivity | Unknown | Caution |
| Glucocorticoids | ↓ anti-tumour effect of aldesleukin | Unknown | Avoid, but may be needed to manage side effects |
| cytotoxics | Potentiate myelosuppression, TLS | Additive | Caution |
| Nephrotoxic drugs (i.e. aminoglycosides, amphotericin B, methotrexate) | potentiate renal toxicity | Additive (possibly) | Caution |
| Hepatotoxic agents (e.g., methotrexate, asparaginase) | potentiate hepatotoxicity | Additive (possibly) | Caution |
| Cardiotoxic agents (e.g., doxorubicin) | Potentiate cardiotoxicity | Additive (possibly) | Caution |
| DTIC, cisplatin, interferon, tamoxifen | ↑ hypersensitivity | Additive | Caution |
| Interferon | ↑ hypersensitivity, cardiotoxicity and rhabdomyolysis, autoimmune disease | Unknown | Caution |
| Drug excreted via liver or kidney | ↓ excretion | ↓ renal, liver function | Caution |
| Monitor Type | Monitor Frequency |
|---|---|
| CBC | Baseline and frequent |
| Electrolytes, blood glucose | Baseline and frequent |
| Liver function tests | Baseline and frequent |
| Renal function tests, fluid intake and output | Baseline 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 metastases | Baseline |
| Thallium stress tests to exclude significant coronary artery disease | Baseline |
| Frequent weight, vital signs, EKG etc. during treatment | |
| Chest x-ray | Baseline and regular |
| Clinical toxicity assessment for GI, hydration, cardiovascular, CNS, perfusion, autoimmune effects | regular |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
| Monitor Type | Monitor Frequency |
|---|---|
|
New Drug Funding Program (NDFP Website )
- Aldesleukin (interleukin-2) - In-Transit Metastases from Melanoma
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.
June 2019 Updated emetic risk category
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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