Aldesleukin (3125)
[ al-des-loo'-kin ]
| Ingredients: |
Aldesleukin |
| Indications: |
Carcinoma, renal; Melanoma, malignant |
| Pregnancy Category: |
C |
| FDA Approved: |
1992- 05- 01 |
| Classes: |
Antineoplastics, biological response modifiers; Recombinant DNA Origin; WHO Formulary |
| HCFA Jcodes: |
J9015 |
| Brand Names: |
Proleukin
-
US; Argentina, Austria, Belgium, Brazil, Canada, Denmark, Ecuador, Egypt, England, Finland, France, Germany, Greece, Hong-kong, Hungary, Ireland, Israel, Italy, Korea, Mexico, Netherlands, New-zealand, Peru, Portugal, Singapore, Spain, Switzerland, Taiwan
;
|
| DEA schedules: |
(none)
|
| Cost of therapy: |
$48,615.28
(
Metastatic Melanoma ;
Proleukin Powder for Injection ;
22 million units/vial ;
44 million units/dose x 28 doses ;
19 day supply
)
$48,615.28
(
Metastatic Renal Cell Carcinoma ;
Proleukin Powder for Injection ;
22 million units/vial ;
44 million units/dose x 28 doses ;
19 day supply
)
|
BOXED WARNING
|
| |
- Therapy with aldesleukin should be restricted to patients with normal cardiac and pulmonary functions as defined by thallium
stress testing and formal pulmonary function testing. Extreme caution should be used in patients with normal thallium stress
tests and a normal pulmonary function test who have a history of prior cardiac or pulmonary disease.
- Aldesleukin for injection should be administered only in a hospital setting under the supervision of a qualified physician
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 capillary leak syndrome (CLS) which is characterized by a loss of vascular
tone and extravasation of plasma proteins and fluid into the extravascular space. 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, myocardial infarction, respiratory insufficiency requiring intubation, gastrointestinal bleeding or
infarction, renal insuffiency, 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. Consequently, preexisting bacterial infections should be adequately
treated prior to initiation of aldesleukin therapy. Patients with indwelling central lines are particularly at risk for infection
with gram positive microorganisms. Antibiotic prophylaxis with oxacillin, nafcillin, ciprofloxacin, or vancomycin has been
associated with a reduced incidence of staphylococcal infections.
- Aldesleukin administration should be withheld in patients developing moderate to severe lethargy or somnolence; continued
administration may result in coma.
|
|
DESCRIPTION
|
| |
Aldesleukin for injection, a human recombinant interleukin- 2 product, is a highly purified protein with a molecular weight
of approximately 15, 300 daltons. The chemical name is des- alanyl- 1, serine- 125 human interleukin- 2. Aldesleukin, a lymphokine,
is produced by recombinant DNA technology using a genetically engineered E. coli strain containing an analog of the human interleukin- 2 gene. Genetic engineering techniques were used to modify the human
IL- 2 gene, and the resulting expression clone encodes a modified human interleukin- 2. This recombinant form differs from
native interleukin- 2 in the following ways: a) aldesleukin is not glycosylated because it is derived from E. coli ; b) the molecule has no N- terminal alanine; the codon for this amino acid was deleted during the genetic engineering procedure;
c) the molecule has serine substituted for cysteine at amino acid position 125; this was accomplished by site specific manipulation
during the genetic engineering procedure; and d) the aggregation state of aldesleukin is likely to be different from that
of native interleukin- 2.
The in vitro biological activities of the native nonrecombinant molecule have been reproduced with aldesleukin. 1, 2
Aldesleukin is supplied as a sterile, white to off- white, lyophilized cake in single- use vials intended for intravenous
(IV) administration. When reconstituted with 1.2 ml sterile water for injection, each ml contains 18 million IU (1.1 mg) aldesleukin,
50 mg mannitol, and 0.18 mg sodium dodecyl sulfate, buffered with approximately 0.17 mg monobasic and 0.89 mg dibasic sodium
phosphate to a pH of 7.5 (range 7.2- 7.8). The manufacturing process for aldesleukin involves fermentation in a defined medium
containing tetracycline hydrochloride. The presence of the antibiotic is not detectable in the final product. Aldesleukin
contains no preservatives in the final product.
Aldesleukin biological potency is determined by a lymphocyte proliferation bioassay and is expressed in International Units
(IU) as established by the World Health Organization 1st International Standard for Interleukin- 2 (human). The relationship
between potency and protein mass is as follows:
- 18 million (18 × 106) IU aldesleukin=1.1 mg protein
|
CLINICAL PHARMACOLOGY
|
| |
Aldesleukin has been shown to possess the biological activity of human native interleukin- 2. 1, 2 In vitro studies performed on human cell lines demonstrate the immunoregulatory properties of aldesleukin, including: a) enhancement
of lymphocyte mitogenesis and stimulation of long- term growth of human interleukin- 2 dependent cell lines; b) enhancement
of lymphocyte cytotoxicity; c) induction of killer cell [lymphokine- activated (LAK) and natural (NK)] activity; and d) induction
of interferon- gamma production.
The in vivo administration of aldesleukin in animals and humans produces multiple immunological effects in a dose dependent manner. These
effects include activation of cellular immunity with profound lymphocytosis, eosinophilia, and thrombocytopenia, and the production
of cytokines including tumor necrosis factor, IL- 1 and gamma interferon. 3 In vivo experiments in murine tumor models have shown inhibition of tumor growth. 4 The exact mechanism by which aldesleukin mediates its antitumor activity in animals and humans is unknown.
Pharmacokinetics
|
| |
Aldesleukin exists as biologically active, non- covalently bound microaggregates with an average size of 27 recombinant interleukin-
2 molecules. The solubilizing agent, sodium dodecyl sulfate, may have an effect on the kinetic properties of this product.
The pharmacokinetic profile of aldesleukin is characterized by high plasma concentrations following a short IV infusion, rapid
distribution into the extravascular space and elimination from the body by metabolism in the kidneys with little or no bioactive
protein excreted in the urine. Studies of IV aldesleukin in sheep and humans indicate that upon completion of infusion, approximately
30% of the administered dose is detectable in plasma. This finding is consistent with studies in rats using radiolabeled aldesleukin,
which demonstrate a rapid (<1 minute) uptake of the majority of the label into the lungs, liver, kidney and spleen.
The serum half- life (T ½) curves of aldesleukin remaining in the plasma are derived from studies done in 52 cancer patients
following a 5 minute IV infusion. These patients were shown to have a distribution and elimination T½ of 13 and 85 minutes, respectively.
Following the initial rapid organ distribution, the primary route of clearance of circulating aldesleukin is the kidney. In
humans and animals, aldesleukin is cleared from the circulation by both glomerular filtration and peritubular extraction in
the kidney. 5- 8 This dual mechanism for delivery of aldesleukin to the proximal tubule may account for the preservation of clearance in patients
with rising serum creatinine values. Greater than 80% of the amount of aldesleukin distributed to plasma, cleared from the
circulation and presented to the kidney is metabolized to amino acids in the cells lining the proximal convoluted tubules.
In humans, the mean clearance rate in cancer patients is 268 ml/ min.
The relatively rapid clearance of aldesleukin has led to dosage schedules characterized by frequent, short infusions. Observed
serum levels are proportional to the dose of aldesleukin.
|
Immunogenicity
|
| |
Fifty- seven of 77 (74%) metastatic renal cell carcinoma patients treated with an every 8 hour aldesleukin regimen and 33
of 50 (66%) metastatic melanoma patients treated with a variety of IV regimens developed low titers of non- neutralizing anti-
aldesleukin antibodies. Neutralizing antibodies were not detected in this group of patients, but have been detected in 1/
106 (<1%) patients treated with IV aldesleukin using a wide variety of schedules and doses. The clinical significance of anti-
aldesleukin antibodies is unknown.
|
Clinical Experience
|
| |
Two hundred and fifty- five (255) patients with metastatic renal cell cancer (metastatic RCC) were treated with single agent
aldesleukin in 7 clinical studies conducted at 21 institutions. Two hundred seventy (270) patients with metastatic melanoma
were treated with single agent aldesleukin in 8 clinical studies conducted at 22 institutions. Patients enrolled in trials
of single agent aldesleukin were required to have an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of
0 or 1 and normal organ function as determined by cardiac stress test, pulmonary function tests, and creatinine ≤1.5 mg/ dl.
Patients with brain metastases, active infections, organ allografts and diseases requiring steroid treatment were excluded.
Aldesleukin was given by 15 minute IV infusion every 8 hours for up to 5 days (maximum of 14 doses). No treatment was given
on days 6- 14 and then dosing was repeated for up to 5 days on days 15- 19 (maximum of 14 doses). These 2 cycles constituted
1 course of therapy. Patients could receive a maximum of 28 doses during a course of therapy. In practice >90% of patients
had doses withheld. Metastatic RCC patients received a median of 20 of 28 scheduled doses of aldesleukin. Metastatic melanoma
patients received a median of 18- 28 scheduled doses of aldesleukin during the first course of therapy. Doses were held for
specific toxicities (see DOSAGE AND ADMINISTRATION, Dose Modification and ADVERSE REACTIONS ).
In the renal cell cancer studies (n=255), objective response was seen in 37 (15%) patients with 17 (7%) complete and 20 (8%)
partial responders. The 95% confidence interval for response was 11- 20%. Onset of tumor regression was observed as early
as 4 weeks after completion of the first course of treatment, and in some cases tumor regression continued for up to 12 months
after the start of treatment. The median duration of objective complete responses has not been observed and for parital response
was 20 months. Thirteen (13) patients who achieved a complete response and 7 patients who achieved a partial response had
responses ongoing at the time of last contact. The median progression- free survival for all responding patients was 55 months.
Responses were observed in both lung and non- lung sites ( e.g., liver, lymph node, renal bed occurrences, soft tissue). Some patients with individual bulky lesions and high tumor burden
achieved responses.
In the metastatic melanoma studies (n=270), objective response was seen in 43 (16%) patients, with 17 (6%) complete and 26
(10%) partial responders. The 95% confidence interval for objective response was 12- 21%. The median duration of objective
(partial or complete) response was 9 months (2- 106+ months); the median duration of objective complete responses has not
been observed and the median duration for partial response was 6 months. Ten (10) patients who achieved a complete response
and 2 patients who achieved a partial response had responses ongoing at the time of last contact. The median progression-
free survival for the 43 responding patients was 13 months. Responses in metastatic melanoma patients were observed in both
visceral and non- visceral sites ( e.g., lung, liver, lymph node, soft tissue, adrenal, subcutaneous). Some patients with individual bulky lesions and large cummulative
tumor burden achieved responses. (See TABLE 1 for a summary of response data.)
|
| TABLE 1
Proleukin Clinical Response Data
|
| |
Metastatic RCC |
Metastatic Melanoma |
| |
Number or Responding Patients (Response Rate) |
Median Response Duration in Months (Range) |
Number or Responding Patients (Response Rate) |
Median Response Duration in Months (Range) |
| CR's |
17 (7%) |
54+* (7- 107+) |
17 (6%) |
40+* (3- 106+) |
| PR's |
20 (8%) |
20 (3- 97+) |
26 (10%) |
6 (2- 92+) |
| PR's and CR's |
37 (15%) |
54 (3- 107+) |
43 (16%) |
9 (2- 106+) |
|
| +
|
Ongoing |
| *
|
Median duration not yet observed; a conservative value is presented which represents the minimum median duration of response. |
|
An analysis of prognostic factors showed that a better ECOG performance status (see TABLE 2 ) was significantly associated with response.
| TABLE 2
Proleukin Clinical REsponse by ECOG Performance Status
|
| Pre Treatment |
Metastatic RCC |
Metastatic Melanoma |
| ECOG PS |
CR |
PR |
CR |
PR |
| 0 |
14/ 166 (8%) |
16/ 166 (10%) |
14/ 191 (7%) |
22/ 191 (12%) |
| ≥1 |
3/ 89 (3%) |
4/ 89 (4%) |
3/ 79 (4%) |
4/ 79 (5%) |
|
|
INDICATIONS AND USAGE
|
| |
Aldesleukin is indicated for the treatment of adults with metastatic renal cell carcinoma (metastatic RCC).
Aldesleukin is indicated for the treatment of adults with metastatic melanoma.
Careful patient selection is mandatory prior to the administration of aldesleukin. See CONTRAINDICATIONS , WARNINGS and PRECAUTIONS regarding patient screening, including recommended cardiac and pulmonary function tests and laboratory tests.
Evaluation of clinical studies to date reveals that patients with more favorable ECOG performance status (ECOG PS O) at treatment
initiation respond better to aldesleukin, with a higher response rate and lower toxicity (see CLINICAL PHARMACOLOGY, Clinical Experience and ADVERSE REACTIONS ). Therefore, selection of patients for treatment should include assessment of performance status.
Experience in patients with PS >1 is extremely limited.
|
CONTRAINDICATIONS
|
| |
Aldesleukin is contraindicated in patients with a known history of hypersensitivity to interleukin- 2 or any component of
the aldesleukin formulation.
Aldesleukin is contraindicated in patients with an abnormal thallium stress test or abnormal pulmonary function tests and
those with organ allografts. Retreatment with aldesleukin is contraindicated in patients who have experienced the following
drug- related toxicities while receiving an earlier course of therapy:
| • |
Sustained ventricular tachycardia (≥5 beats).
|
| • |
Cardiac arrhythmias not controlled or unresponsive to management.
|
| • |
Chest pain with ECG changes, consistent with angina or myocardial infarction.
|
| • |
Cardiac tamponade.
|
| • |
Intubation required >72 hours.
|
| • |
Renal failure requiring dialysis >72 hours.
|
| • |
Coma or toxic psychosis lasting >48 hours.
|
| • |
Repetitive or difficult to control seizures.
|
| • |
Bowel ischemia/ perforation.
|
| • |
GI bleeding requiring surgery.
|
|
WARNINGS
|
| |
See BOXED WARNING .
Because of the severe adverse events which generally accompany aldesleukin therapy at the recommended dosages, thorough clinical
evaluation should be performed to identify patients with significant cardiac, pulmonary, renal, hepatic, or CNS impairment
in whom aldesleukin is contraindicated. Patients with normal cardiovascular, pulmonary, hepatic, and CNS function may experience
serious, life threatening or fatal adverse events. Adverse events are frequent, often serious, and sometimes fatal.
Should adverse events which require dose modification occur, dosage should be withheld rather than reduced (See DOSAGE AND ADMINISTRATION, Dose Modification .)
Aldesleukin has been associated with exacerbation of pre- existing or initial presentation of autoimmune disease and inflammatory
disorders. Exacerbation of Crohn's disease, scleroderma thyroiditis, inflammatory arthritis, diabetes mellitus, oculo- bulbar
myasthenia gravis, crescentic IgA glomerulonephritis, cholecystitis, cerebral vasculitis, Stevens- Johnson syndrome and bulbous
phemphigoid, has been reported following treatment with IL- 2.
All patients should have thorough evaluation and treatment of CNS metastases and have a negative scan prior to receiving aldesleukin
therapy. New neurologic signs, symptoms, and anatomic lesions following aldesleukin therapy have been reported in patients
without evidence of CNS metastases. Clinical manifestations included changes in mental status, speech difficulties, cortical
blindness, limb or gait ataxia, hallucinations, agitation, obtundation, and coma. Radiological findings included multiple
and, less commonly, single cortical lesions on MRI and evidence of demyelination. Neurologic signs and symptoms associated
with aldesleukin therapy usually improve after discontinuation of aldesleukin therapy; however, there are reports of permanent
neurologic defects. One case of possible cerebral vasculitis, responsive to dexamethasone, has been reported. In patients
with known seizure disorders, extreme caution should be exercised as aldesleukin may cause seizures.
|
PRECAUTIONS
|
| |
General
|
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Patients should have normal cardiac, pulmonary, hepatic, and CNS function at the start of therapy (see Laboratory Tests ). Capillary leak syndrome (CLS) begins immediately after aldesleukin treatment starts and is marked by increased capillary
permeability to protein and fluids and reduced vascular tone. In most patients, this results in a concomitant drop in mean
arterial blood pressure within 2- 12 hours after the start of treatment. With continued therapy, clinically significant hypotension
(defined as systolic blood pressure below 90 mm Hg or a 20 mm Hg drop from baseline systolic pressure) and hypoperfusion will
occur. In addition, extravasation of protein and fluids into the extravascular space will lead to the formation of edema and
creation of effusions.
Medical management of CLS begins with careful monitoring of the patient's fluid and organ perfusion status. This is achieved
by frequent determination of blood pressure and pulse, and by monitoring organ function, which includes assessment of mental
status and urine output. Hypovolemia is assessed by catheterization and central pressure monitoring.
Flexibility in fluid and pressor management is essential for maintaining organ perfusion and blood pressure. Consequently,
extreme caution should be used in treating patients with fixed requirements for large volumes of fluid ( e.g., patients with hypercalcemia). Administration of IV fluids, either colloids or crystalloids is recommended for treatment of
hypovolemia. Correction of hypovolemia may require large volumes of IV fluids but caution is required because unrestrained
fluid administration may exacerbate problems associated with edema formation or effusions. With extravascular fluid accumulation,
edema is common and ascites, pleural or pericardial effusions may develop. Management of these events depends on a careful
balancing of the effects of fluid shifts so that neither the consequences of hypovolemia ( e.g., impaired organ perfusion) nor the consequences of fluid accumulations ( e.g., pulmonary edema) exceeds the patient's tolerance.
Clinical experience has shown that early administration of dopamine (1- 5 μg/ kg/ min) to patients manifesting capillary leak
syndrome, before the onset of hypotension, can help to maintain organ perfusion particularly to the kidney and thus preserve
urine output. Weight and urine output should be carefully monitored. If organ perfusion and blood pressure are not sustained
by dopamine therapy, clinical investigators have increased the dose of dopamine to 6- 10 μg/ kg/ min or have added phenylephrine
hydrochloride (1- 5 μg/ kg/ min) to low dose dopamine. (See ADVERSE REACTIONS .) Prolonged use of pressors, either in combination or as individual agents, at relatively high doses, may be associated with
cardiac rhythm disturbances. If there has been excessive weight gain or edema formation, particularly if associated with shortness
of breath from pulmonary congestion, use of diuretics, once blood pressure has normalized, has been shown to hasten recovery. NOTE: Prior to the use of any product mentioned, the physician should refer to the monograph for the respective product.
Aldesleukin treatment should be withheld for failure to maintain organ perfusion, as demonstrated by altered mental status,
reduced urine output, a fall in the systolic blood pressure below 90 mm Hg or onset of cardiac arrhythmias. (See DOSAGE AND ADMINISTRATION, Dose Modification .) Recovery from CLS begins soon after cessation of aldesleukin therapy. Usually, within a few hours, the blood pressure rises,
organ perfusion is restored and resorption of extravasated fluid and protein begins.
Kidney and liver function are impaired during aldesleukin treatment. Use of concomitant nephrotoxic or hepatotoxic medications
may further increase toxicity to the kidney or liver.
Mental status changes including irritability, confusion, or depression which occur while receiving aldesleukin may be indicators
of bacteremia or early bacterial sepsis, hypoperfusion, occult CNS malignancy, or direct aldesleukin- induced CNS toxicity.
Alterations in mental status due solely to aldesleukin therapy may progress for several days before recovery begins. Rarely,
patients have sustained permanent neurologic deficits (see DRUG INTERACTIONS).
Exacerbation of preexisting autoimmune disease or initial presentation of autoimmune and inflammatory disorders has been reported
following aldesleukin alone or in combination with interferon (see PRECAUTIONS , DRUG INTERACTIONS and ADVERSE REACTIONS ). Impairment of thyroid function, sometimes preceded by hyperthyroidism, has been reported following aldesleukin treatment.
Some of these patients required thyroid replacement therapy. Changes in thyroid function may be a manifestation of autoimmunity.
Onset of symptomatic hyperglycemia and/ or diabetes mellitus has been reported during aldesleukin therapy.
Aldesleukin enhancement of cellular immune function may increase the risk of allograft rejection in transplant patients.
|
Laboratory Tests
|
| |
The following clinical evaluations are recommended for all patients, prior to beginning treatment and then daily during drug
administration.
| • |
Standard hematologic tests (including CBC, differential and platelet counts).
|
| • |
Blood chemistries (including electrolytes, renal and hepatic function tests).
|
| • |
Chest x- rays.
|
Serum cretinine should be ≤1.5 mg/ dl prior to initiation of aldesleukin treatment.
All patients should have baseline pulmonary function tests with arterial blood gases. Adequate pulmonary function should be
documented (FEV1 >2 liters or ≥75% of predicted for height and age) prior to initiating therapy.
All patients should be screened with a stress thallium study. Normal ejection fraction and unimpaired wall motion should be
documented. If a thallium stress test suggests minor wall motion abnormalities further testing is suggested to exclude significant
coronary artery disease.
Daily monitoring during therapy with aldesleukin should include vital signs (temperature, pulse, blood pressure, and respiration
rate) , weight, and fluid intake and weight output. In a patient with a decreased systolic blood pressure, especially less
than 90 mm Hg, constant cardiac rhythm monitoring should be conducted. If an abnormal complex or rhythm is seen, an ECG should
be performed. Vital signs in these hypotensive patients should be taken hourly.
During treatment, pulmonary function should be monitored on a regular basis by clinical examination, assessment of vital signs
and pulse oximetry. Patients with dyspnea or clinical signs of respiratory impairment (tachypnea or rales) should be further
assessed with arterial blood gas determination. These tests are to be repeated as often as clinically indicated.
Cardiac function is assessed daily by clinical examination and assessment of vital signs. Patients with signs or symptoms
of chest pain, murmurs, gallops, irregular rhythm or palpitations should be further assessed with an ECG examination and cardiac
enzyme evaluation. Evidence of myocardial injury including findings compatible with myocardial infarction or myocarditis,
has been reported. Ventricular hypokinesia due to myocarditis may be persistent for several months. If there is evidence of
cardiac ischemia or congestive heart failure, aldesleukin therapy should be held, and a repeat thallium study should be done.
|
Carcinogenesis, Mutagenesis, and Impairment of Fertility
|
| |
There have been no studies conducted assessing the carcinogenic or mutagenic potential of aldesleukin.
There have been no studies conducted assessing the effect of aldesleukin on fertility. It is recommended that this drug not
be administered to fertile persons of either gender not practicing effective contraception.
|
Pregnancy Category C
|
| |
Aldesleukin has been shown to have embryolethal effects in rats when given in doses at 27- 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. No evidence of teratogenicity was
observed other than that attributed to maternal toxicity. there are no adequate and well- controlled studies of aldesleukin
in pregnant women. Aldesleukin should be used during pregnancy only if the potential benefit justifies the potential risk
to the fetus.
|
Nursing Mothers
|
| |
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of
the potential for serious reactions in nursing infants from aldesleukin, a decision should be made whether to discontinue
nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
|
Pediatric Use
|
| |
Safety and effectiveness in children under 18 years of age have not been established.
|
|
DRUG INTERACTIONS
|
| |
Aldesleukin may affect central nervous function. Therefore, interactions could occur following concomitant administration
of psychotropic drugs ( e.g., narcotics, analgesics, antiemetics, sedatives, tranquilizers).
Concurrent administration of drugs possessing nephrotoxic ( e.g., aminoglycosides, indomethacin), myelotoxic ( e.g., cytotoxic chemotherapy), cardiotoxic ( e.g., doxorubicin) or hepatotoxic ( e.g., methotrexate, asparaginase) effects with aldesleukin may increase toxicity in these organ systems. The safety and efficacy
of aldesleukin in combination with any antineoplastic agents have not been established.
In addition, reduced kidney and liver function secondary to aldesleukin treatment may delay elimination of concomitant medications
and increase the risk of adverse events from those drugs.
Hypersensitivity reactions have been reported in patients receiving combination regimens containing sequential high dose aldesleukin
and antineoplastic agents, specifically, dacarbazine, cis- platinum, tamoxifen and interferon- alfa. These reactions consisted
of erythema, pruritus, and hypotension and occurred within hours of administration of chemotherapy. These events required
medical intervention in some patients.
Myocardial injury, including myocardial infarction, myocarditis, ventricular hypokinesia, and severe rhabdomyolysis appear
to be increased in patients receiving aldesleukin and interferon- alfa concurrently.
Exacerbation or the initial presentation of a number of autoimmune and inflammatory disorders has been observed following
concurrent use of interferon- alfa and aldesleukin, including crescentic IgA glomerulonephritis, oculo- bulbar myasthenia
gravis, inflammatory arthritis, thyroiditis, bullous pemphigoid, and Stevens- Johnson syndrome.
Although glucocorticoids have been shown to reduce aldesleukin- induced side effects including fever, renal insufficiency,
hyperbilirubinemia, confusion, and dyspnea, concomitant administration of these agents with aldesleukin may reduce the antitumor
effectiveness of aldesleukin and thus should be avoided. 12
Beta- blockers and other antihypertensives may potentiate the hypotension seen with aldesleukin.
Delayed Adverse Reactions to Iodinated Contrast Media
|
| |
A review of the literature revealed that 12.6% (range 11- 28%) of 501 patients treated with various interleukin- 2- containing
regimens who were subsequently administered radiographic iodinated contrast media experienced acute, atypical adverse reactions.
The onset of symptoms usually occurred within hours (most commonly 1- 4 hours) following the administration of contrast media.
These reactions include fever, chills, nausea, vomiting, pruritus, rash, diarrhea, hypotension, edema, and oliguria. Some
clinicians have noted that these reactions resemble the immediate side effects caused by interleukin- 2 administration, however
the cause of contrast reactions after interleukin- 2 therapy is unknown. Most events reported to occur when contrast media
was given within 4 weeks after the last dose of interleukin- 2. These events were also reported to occur when contrast media
was given several months after interleukin- 2 treatment. 13
|
|
ADVERSE REACTIONS
|
| |
The rate of drug- related deaths in the 255 metastatic RCC patients who received single- agent aldesleukin was 4% (11/ 255);
the rate of drug- related deaths in the 270 metastatic melanoma patients who received single- agent aldesleukin was 2% (6/
270).
TABLE 3 shows data on common adverse events (reported in greater than 10% of patients, any grade), presented by body system, decreasing
frequency and by preferred term (COSTART) are based on 525 patients (255 with renal cell cancer and 270 with metastatic melanoma)
treated with the recommended infusion dosing regimen.
| TABLE 3
Adverse Events Occurring in ≥10% of Patients
|
| Body System |
|
Body System |
|
| Body as a Whole
|
Metabolic & Nutritional Disorders
|
| |
Chills |
52% |
|
Bilirubinemia |
40% |
| |
Fever |
29% |
|
Creatinine increase |
33% |
| |
Malaise |
27% |
|
Peripheral edema |
28% |
| |
Asthenia |
23% |
|
SGOT increase |
23% |
| |
Infection |
13% |
|
Weight gain |
16% |
| |
Pain |
12% |
|
Edema |
15% |
| |
Abdominal pain |
11% |
|
Acidosis |
12% |
| |
Abdomen enlarged |
10% |
|
Hypomagnesemia |
12% |
| Cardiovascular
|
|
Hypocalcemia |
11% |
| |
Hypotension |
71% |
|
Alk. phos.increase |
10% |
| |
Tachycardia |
23% |
Nervous
|
| |
Vasodilation |
13% |
|
Confusion |
34% |
| |
Supraventricular tachycardia |
12% |
|
Somnolence |
22% |
| |
Cardiovascular disorder* |
11% |
|
Anxiety |
12% |
| |
Arrhythmia |
10% |
|
Dizziness |
11% |
| Digestive
|
Respiratory
|
| |
Diarrhea |
67% |
|
Dyspnea |
43% |
| |
Vomiting |
50% |
|
Lung disorder† |
24% |
| |
Nausea |
35% |
|
Respiratory disorder‡ |
11% |
| |
Stomatitis |
22% |
|
Cough increase |
11% |
| |
Anorexia |
20% |
|
Rhinitis |
10% |
| |
Nausea and vomiting |
19% |
Skin and Appendages
|
| Hemic and Lymphatic
|
|
Rash |
42% |
| |
Thrombocytopenia |
37% |
|
Pruritus |
24% |
| |
Anemia |
29% |
|
Exfoliative dermatitis |
18% |
| |
Leukopenia |
16% |
Urogenital
|
| |
|
|
|
Oliguria |
63% |
|
| *
|
Cardiovascular disorder: fluctuations in blood pressure, asymptomatic ECG changes, CHF. |
| †
|
Lung disorder: physical findings associated with pulmonary congestion, rales, rhonchi. |
| ‡
|
Respiratory disorder: ARDS, CXR infiltrates, unspecified pulmonary changes. |
|
TABLE 4 shows data on life- threatening adverse events (reported in greater than 1% of patients, grade 4), presented by body system,
and by preferred term (COSTART) are based on 525 patients (255 with renal cell cancer and 270 with metastatic melanoma) treated
with the recommended infusion dosing regimen.
| TABLE 4
Life- Threatening (Grade 4) Adverse Events (n=525)
|
| Body System |
|
Body System |
|
| Body as a Whole
|
Metabolic & Nutritional Disorders
|
| |
Fever |
5 (1%) |
|
Bilirubinemia |
13 (2%) |
| |
Infection |
7 (1%) |
|
Creatinine increase |
5 (1%) |
| |
Sepsis |
6 (1%) |
|
SGOT increase |
3 (1%) |
| Cardiovascular
|
|
Acidosis |
4 (1%) |
| |
Hypotension |
15 (3%) |
Nervous
|
| |
Supraventricular tachycardia |
3 (1%) |
|
Confusion |
5 (1%) |
| |
Cardiovascular disorder* |
7 (1%) |
|
Stupor |
3 (1%) |
| |
Myocardial infarct |
7(1%) |
|
Coma |
8 (2%) |
| |
Ventricular tachycardia |
5 (1%) |
|
Psychosis |
7 (1%) |
| |
Heart Arrest |
4 (1%) |
Respiratory
|
| Digestive
|
|
Dyspnea |
5 (1%) |
| |
Diarrhea |
10 (2%) |
|
Respiratory disorder‡ |
14 (3%) |
| |
Vomiting |
7 (1%) |
|
Apnea |
5 (1%) |
| Hemic and Lymphatic
|
Urogenital
|
| |
Thrombocytopenia |
5 (1%) |
|
Oliguria |
33 (6%) |
| |
Coagulation disorder† |
4 (1%) |
|
Anuria |
25 (5%) |
| |
|
|
|
Acute kidney failure |
3 (1%) |
|
| *
|
Cardiovascular disorder: fluctuations in blood pressure. |
| †
|
Coagulation disorder: intravascular coagulopathy. |
| ‡
|
Respiratory disorder: ARDS, respiratory failure, intubation. |
|
The following life- threatening (Grade 4) events were reported by <1% of the 525 patients: reaction unevaluable; hypothermia;
shock; bradycardia; ventricular extrasystoles; myocardial ischemia; syncope; hemorrhage; atrial arrhythmia; phlebitis; AV
block second degree; endocarditis; pericardial effusion; peripheral gangrene; thrombosis; coronary artery disorder; stomatitis;
nausea and vomiting; liver function tests abnormal; gastrointestinal hemorrhage; hematemesis; bloody diarrhea; gastrointestinal
disorder; intestinal perforation; pancreatitis; anemia; leukopenia; leukocytosis; hypocalcemia; alkaline phosphatase increase;
BUN increase; hyperuricemia; NPN increase; respiratory acidosis; somnolence; agitation; neuropathy; paranoid reaction; convulsion;
grand mal convulsion; delirium; lung edema; hyperventilation; hypoxia; hemoptysis; hypoventilation; pneumothorax; mydriasis;
pupillary disorder; kidney function abnormal; kidney failure; acute tubular necrosis.
In an additional population of greater than 1800 patients treated with aldesleukin- based regimens using a variety of doses
and schedules ( e.g., subcutaneous, continuous infusion, administration with lak cells) the following serious adverse events were reported: duodenal
ulceration; bowel necrosis; myocarditis; supraventricular tachycardia; permanent or transient blindness secondary to optic
neuritis; transient ischemic attacks; meningitis; cerebral edema; pericarditis; allergic interstitial nephritis; tracheo-
esophageal fistula.
In the same clinical population, the following events which were fatal or resulted in death each occurred with a frequency
of <1%: liver or renal failure; intestinal perforation; cardiac arrest; myocardial infarction; malignant hyperthermia; pulmonary
edema; respiratory arrest; respiratory failure; stroke; pulmonary emboli; severe depression leading to suicide.
In patients with both metastatic RCC and metastatic melanoma, those with ECOG PS of 1 or higher had a higher treatment- related
mortality, and serious adverse events.
Most adverse reactions are self- limiting and, usually, but not invariably, reverse or improve within 2 or 3 days of discontinuation
of therapy. Examples of adverse reactions with permanent sequelae include: myocardial infarction, bowel perforation/ infarction,
and gangrene.
In post marketing experience, the following serious adverse events have been reported in a variety of treatment regimens that
include interleukin- 2: hypertension; pneumonia (bacterial, fungal, viral); neutropenia; cholecystitis; colitis; gastritis;
hepatitis; hepatosplenomegaly; intestinal obstruction; retroperitoneal hemorrhage; cerbral lesions; cerebral hemorrhage; encephalopathy;
extrapyramidal syndrome; neuralgia; neuritis; neuropathy (demyelination); rhabdomyolysis; myopathy; myositis; hyperthyroidism;
anaphylaxis; cellulitis; injection site necrosis; insomnia.
Exacerbation or initial presentation of a number of autoimmune and inflammatory disorders have been reported (see WARNINGS , PRECAUTIONS , and DRUG INTERACTIONS ). Persistent but nonprogressive vitiligo has been observed in malignant melanoma patients treated with interleukin- 2. Synergistic,
additive and novel toxicities have been reported with aldesleukin used in combination with other drugs. Novel toxicities include
delayed adverse reactions to iodinated contrast media and hypersensitivity reactions to antineoplastic agents (see DRUG INTERACTIONS ).
Experience has shown the following concomitant medications to be useful in the management of patients on aldesleukin therapy:
a) standard antipyretic therapy, including nonsteroidal anti- inflammatories (NSAIDs), started immediately prior to aldesleukin
to reduce fever. Renal function should be monitored as some NSAIDs may cause synergistic nephrotoxicity; b) meperidine used
to control the rigors associated with fever; c) H2 antagonists given for prophylaxis of gastrointestinal irritation and bleeding; d) antiemetics and antidiarrheals used as needed
to treat other gastrointestinal side effects. Generally these medications were discontinued 12 hours after the last dose of
aldesleukin.
Patients with indwelling central lines have a higher risk of infection with gram positive organisms. 9 - 11 A reduced incidence of staphylococcal infections in aldesleukin studies has been associated with the use of antibiotic prophylaxis
which includes the use of oxacillin, nafcillin, ciprofloxacin, or vancomycin. Hydroxyzine or diphenhydramine has been used
to control symptoms from pruritic rashes and continued until resolution of pruritus. Topical creams and ointments should be
applied as needed for skin manifestations. Preparations containing a steroid ( e.g., hydrocortisone) should be avoided. NOTE: Prior to the use of any product mentioned, the physician should refer to the monograph for the respective product.
|
OVERDOSAGE
|
| |
Side effects following the use of aldesleukin appear to be dose- related. Exceeding the recommended dose has been associated
with a more rapid onset of expected dose- limiting toxicities. Symptoms which persist after cessation of aldesleukin should
be treated supportively. Life- threatening toxicities may be ameliorated by the intravenous administration of dexamethasone,
which may result in loss of therapeutic effect from aldesleukin. 12 NOTE: Prior to the use of dexamethasone, the physician should refer to the package insert for this product.
|
DOSAGE AND ADMINISTRATION
|
| |
The recommended aldesleukin for injection treatment regimen is administered by a 15 minute IV infusion every 8 hours. Before
initiating treatment, carefully review INDICATIONS AND USAGE , CONTRAINDICATIONS , WARNINGS , PRECAUTIONS , and ADVERSE REACTIONS , particularly regarding patient selection, possible serious adverse events, patient monitoring and withholding dosage. The
following schedule has been used to treat adult patients with renal cell carcinoma (metastatic RCC) or metastatic melanoma.
Each course of treatment consists of two 5 day treatment cycles separated by a rest period.
600, 000 IU/ kg (0.037 mg/ kg) dose administered every 8 hours by a 15 minute IV infusion for a maximum of 14 doses. Following
9 days of rest, the schedule is repeated for another 14 doses, for a maximum of 28 doses per course, as tolerated. During
clinical trials, doses were frequently held for toxicity (see CLINICAL PHARMACOLOGY, Clinical Experience and Dose Modification ). Metastatic RCC patients treated with this schedule received a median of 20 of the 28 doses during the first course of therapy.
Metastatic melanoma patients received a median of 18 doses during the first course of therapy.
Retreatment
|
| |
Patients should be evaluated for response approximately 4 weeks after completion of a course of therapy and again immediately
prior to the scheduled start of the next treatment course. Additional courses of treatment should be given to patients only
if there is some tumor shrinkage following the last course and retreatment is not contraindicated (see CONTRAINDICATIONS ). Each treatment course should be separated by a rest period of at least 7 weeks from the date of hospital discharge.
|
Dose Modification
|
| |
Dose modification for toxicity should be accomplished by withholding or interrupting a dose rather than reducing the dose
to be given. Decisions to stop, hold, or restart aldesleukin therapy must be made after a global assessment of the patient.
With this in mind, the guidelines in TABLE 5 and TABLE 6 should be used.
| TABLE 5
Retreatment With Aldesleukin is Contraindicated in Patients Who Have Experienced the Following Toxicities
|
| Body System |
|
| Cardiovascular |
Sustained ventricular tachycardia (≥5 beats) |
| |
Cardiac rhythm disturbances not controlled or unresponsive to management |
| |
Chest pain with ECG changes, consistent with angina or myocardial infarction |
| |
Cardiac tamponade |
| Respiratory |
Intubation required >72 hours |
| Urogenital |
Renal failure requiring dialysis >72 hours |
| Nervous |
Coma or toxic psychosis lasting >48 hours |
| |
Repetitive or difficult to control seizures |
| Gastrointestinal |
Bowel ischemia/ perforation |
| |
Gl bleeding requiring surgery |
|
| TABLE 6
Doses Should Be Held and Restarted According to the Following
|
| Organ System |
Hold Dose For |
Subsequent Doses May Be Given if |
| Cardiovascular |
Atrial fibrillation, supraventricular tachycardia, or bradycardia that requires treatment or is recurrent or persistent |
Patient is asymptomatic with full recovery to normal sinus rhythm |
| |
Systolic bp <90 mm Hg with increasing requirements for pressors |
Systolic bp ≥90 mm Hg and stable or improving requirements for pressors |
| |
Any ECG change consistent with MI, ischemia or myocarditis with or without chest pain; suspicion of cardiac ischemia |
Patient is asymptomatic, MI and myocarditis have been ruled out, clinical suspicion of angina is low; there is no evidence
of ventricular hypokinesa
|
| Respiratory |
O2 saturation <94% on room air or <90% with 2 liters O2 by nasal prongs
|
O2 saturation ≥94% on room air or ≥90% with 2 liters O2 by nasal prongs
|
| Nervous |
Mental status changes, including moderate confusion or agitation |
Mental status changes completely resolved |
| Body as a Whole |
Sepsis syndrome, patient is clinically unstable |
Sepsis syndrome has resolved, patient is clinically stable, infection is under treatment |
| Urogenital |
Serum creatinine >4.5 mg/ dl or a serum creatinine of ≥4 mg/ dl in the presence of severe volume overload, acidosis, or hyperkalemia |
Serum creatinine <4 mg/ dl and fluid and electrolyte status is stable |
| |
Persistent oliguria, urine output of <10 ml/ hour for 16 to 24 hours with rising serum creatinine |
Urine output >10 ml/ hour with a decrease of serum creatinine >1.5 mg/ dl or normalization of serum creatinine |
| Digestive |
Signs of hepatic failure including encephalopathy, increasing ascites, liver pain, hypoglycemia |
All signs of hepatic failure have resolved* |
| |
Stool guaiac repeatedly >3- 4+ |
Stool guaiac negative |
| Skin |
Bullous dermatitis or marked worsening of preexisting skin condition, avoid topical steroid therapy |
Resolution of all signs of bullous dermatitis |
|
| *
|
Discontinue all further treatment for that course. A new course of treatment, if warranted, should be initiated no sooner
than 7 weeks after cessation of adverse event and hospital discharge.
|
|
|
Reconstitution and Dilution Directions
|
| |
Reconstitution and dilution procedures other than those recommended may alter the delivery and/ or pharmacology of aldesleukin
and thus should be avoided.
- 1. Aldesleukin is a sterile, white to off- white, preservative- free, lyophilized powder suitable for IV infusion upon reconstitution
and dilution. EACH VIAL CONTAINS 22 MILLION IU (1.3 MG) OF ALDESLEUKIN AND SHOULD BE RECONSTITUTED ASEPTICALLY WITH 1.2 ML OF STERILE WATER
FOR INJECTION. WHEN RECONSTITUTED AS DIRECTED, EACH ML CONTAINS 18 MILLION IU (1.1 MG) OF ALDESLEUKIN. The resulting solution should be a clear, colorless to slightly yellow liquid. The vial is for single- use only and any unused
portion should be discarded.
- 2. During reconstitution, the sterile water for injection should be directed at the side of the vial and the contents gently
swirled to avoid excess foaming. DO NOT SHAKE.
- 3. The dose of aldesleukin, reconstituted in sterile water for injection (without preservative) should be diluted aseptically
in 50 ml of 5% dextrose injection (D5W) and infused over a 15 minute period.
In cases where the total dose of aldesleukin is 1.5 mg or less ( e.g., a patient with a body weight of less than 40 kilograms), the dose of aldesleukin should be diluted in a smaller volume of
D5W. Concentrations of aldesleukin below 30 μg/ ml and above 70 μg/ ml have shown increased variability in drug delivery.
Dilution and delivery of aldesleukin outside of this concentration range should be avoided.
- 4. Glass bottles and plastic (polyvinyl chloride) bags have been used in clinical trials with comparable results. It is recommended
that plastic bags be used as the dilution container since experimental studies suggest that use of plastic containers results
in more consistent drug delivery. In- line filters should not be used when administering aldesleukin.
- 5. Before and after reconstitution and dilution, store in a refrigerator at 2- 8°C (36- 46°F). Do not freeze. Administer aldesleukin
within 48 hours of reconstitution. The solution should be brought to room temperature prior to infusion in the patient.
- 6. Reconstitution or dilution with bacteriostatic water for injection or 0.9% sodium chloride injection should be avoided because
of increased aggregation. Aldesleukin should not be coadministered with other drugs in the same container.
- 7. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever
solution and container permit.
|
|
References
|
| |
1. Doyle MV, Lee MT, Fong S. Comparison of the biological activities of human recombinant interleukin- 2125 and native interleukin- 2. J Biol Response Mod 1985;4:96- 109.
2. Ralph P, Nakoinz I, Doyle M, et al. Human B and T lymphocyte stimulating properties of interleukin- 2 (IL- 2) muteins. In: Immune Regulation by Characterized Polypeptides . Alan R. Liss, Inc. 1987:453- 62.
3. Winkelhake JL and Gauny SS. Human recombinant interleukin- 2 as an experimental therapeutic. Pharmacol Rev 1990; 42:1- 28.
4. Rosenberg SA, Mule JJ, Spiess PJ, et al. Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high- dose
recombinant interleukin- 2. J Exp Med 1985;161:1169- 88.
5. Konrad MW, Hemstreet G, Hersh EM, et al. Pharmacokinetics of recombinant interleukin- 2 in humans. Cancer Res 1990; 50:2009- 17.
6. Donohue JH and Rosenberg SA. The fate of interleukin- 2 after invivo administration. J Immunol 1983; 130:2203- 8.
7. Koths K, Halenbeck R. Pharmacokinetic studies on35S- labeled recombinant interleukin- 2 in mice. In: Sorg C and Schimpl A, eds. Cellular and Molecular Biology of Lymphokines. Academic Press: Orlando, Fl, 1985:779.
8. Gibbons JA, Luo ZP, Hansen ER et al . Quantitation of the renal clearance of interleukin- 2 using nephrectomized and ureter ligated rats.. J Pharmacol Exp Ther 1995; 272:119- 125.
9. Bock SN, Lee RE, Fisher B, et al. A prospective randomized trial evaluating prophylactic antibiotics to prevent triple- lumen catheter- related sepsis in patients
treated with immunotherapy. J Clin Oncol 1990;8:161- 69.
10. Hartman LC, Urba, WJ, Steis RG, et al. Use of prophylactic antibiotics for prevention of intravascular catheter- related infections in interleukin- 2- treated patients. J Natl Cancer Inst 1989; 81:1190- 93.
11. Snydman DR, Sullivan B, Gill M, et al. Nosocomial sepsis associated with interleukin- 2. Ann Intern Med 1990; 112:102- 07.
12. Mier JW, Vachino G, Klempner MS, et al. Inhibition of interleukin- 2- induced tumor necrosis factor release by dexamethasone: Prevention of an acquired neutrophil
chemotaxis defect and differential suppression of interleukin- 2- associated side effects. Blood 1990; 76:1933- 40.
13. Choyke PL, Miller DL, Lotze MT, et al. Delayed reactions to contrast media after interleukin- 2 immunotherapy. Radiology 1992; 183:111- 114.
|
HOW SUPPLIED
|
| |
Proleukin for injection is supplied as 106IU of aldesleukin . Discard unused portion.
Store vials of lyophilized aldesleukin in a refrigerator at 2- 8°C (36- 46°F).
Reconstituted or diluted aldesleukin is stable for up to 48 hours at refrigerated and room temperatures, 2- 25°C (36- 77°F).
However, since this product contains no preservative, the reconstituted and diluted solutions should be stored in the refrigerator.
Do not use beyond the expiration date printed on the vial. Note: This product contains no preservative.
|
PRODUCT IDENTIFICATION
|
| |
None Available |
PRODUCT LISTING - RATED THERAPEUTICALLY EQUIVALENT
|
| |
| powder for injection - intravenous - 22000000 iu -
|
| 1.0 |
$811.88 |
Proleukin
Chiron Corporation
|
53905099101 |
|
|