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ALDESLEUKIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Aldesleukin is a human recombinant interleukin-2 agent, and is produced by recombinant DNA technology using an Escherichia coli strain containing an analogue of the human interleukin-2 gene.

Specific Substances

    1) Aldesleukina
    2) Des-alanyl-1
    3) Serine-125 Human Interleukin-2
    4) Recombinant interleukin 2
    5) 125-L-Serine-2-133-interleukin 2 (human reduced)
    6) Macrolin(FM) (DI)
    7) Proleukin(R)

Available Forms Sources

    A) FORMS
    1) Aldesleukin is available for injection and is supplied in individually boxed single-use vials; a vial contains 22 X 10(6) International Units of aldesleukin (Prod Info PROLEUKIN(R) intravenous injection, 2012).
    B) SOURCES
    1) Aldesleukin is a human recombinant interleukin-2 agent, and is produced by recombinant DNA technology using an Escherichia coli strain containing an analogue of the human interleukin-2 gene (Prod Info PROLEUKIN(R) intravenous injection, 2012; Sweetman, 2005).
    C) USES
    1) Aldesleukin is indicated for the treatment of metastatic renal cell carcinoma and the treatment of metastatic melanoma in adults (Prod Info PROLEUKIN(R) intravenous injection, 2012).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Aldesleukin is indicated for the treatment of metastatic renal cell carcinoma and the treatment of metastatic melanoma in adults.
    B) PHARMACOLOGY: Aldesleukin is a human recombinant interleukin-2 agent, and is produced by recombinant DNA technology using an Escherichia coli strain containing an analogue of the human interleukin-2 gene. In vitro, aldesleukin enhances lymphocyte mitogenesis and cytotoxicity, induces killer cell activity, and induces interferon-gamma production, and stimulated long term growth of human interleukin-2 dependent cell lines. In vivo, aldesleukin activates cellular immunity, induces lymphocytosis, eosinophilia and thrombocytopenia, and induces the production of cytokines, including tumor necrosis factor, interleukin 1 and gamma interferon. It also inhibits tumor growth in murine models.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Capillary leak syndrome (hypotension, tachycardia, oliguria, generalized edema, weight gain, pleural effusions, pulmonary edema, ascites, renal insufficiency and confusion) develops within a few hours of the start of therapy and resolves within a few hours of its discontinuation; OTHER EFFECTS: Nausea, vomiting, diarrhea (may be severe), anemia, neutropenia, leukopenia, thrombocytopenia, fever, chills, increased serum bilirubin, increased aminotransferase levels, and electrolyte disturbances (hypomagnesemia, hypocalcemia, hypokalemia, and hypophosphatemia).
    E) WITH POISONING/EXPOSURE
    1) Overdose information is limited. Higher doses have been associated with a more rapid onset of typical adverse effects.
    0.2.20) REPRODUCTIVE
    A) Aldesleukin is classified as Pregnancy Category C. In rats, embryolethal effects and maternal toxicities were observed.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs, mental status, CBC with differential, renal function, hepatic enzymes, and coagulation studies (INR, PTT) following a significant overdose.
    C) Monitor fluid intake and output and daily weights. Monitor serum electrolytes.
    D) Obtain an ECG, and institute continuous cardiac monitoring.
    E) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with respiratory symptoms.
    F) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    G) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Treat persistent nausea and vomiting with several antiemetics of different classes. Treat diarrhea with antidiarrheal agents. Treat rash with emollients and antihistamines. Avoid corticosteroids. Treat fever with acetaminophen. Non-steroidal anti-inflammatory agents have been recommended by some, but they may worsen nephrotoxicity or gastritis. Meperidine and diphenhydramine have been used for chills and rigors.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. For hypotension, administer IV 0.9% saline (1 to 1.5 L in adults). Avoid large volumes of IV fluids (more than 1.5 L/day above maintenance requirements) as they may worsen capillary leak syndrome. If hypotension persists, administer phenylephrine. In patients with tachycardia, evaluate for fever, hypoxia, anemia, and infection and treat accordingly. Persistent supraventricular tachycardia greater than 150 beats/min may warrant rate control. Life threatening toxicity may be improved by intravenous dexamethasone, but it may reduce the therapeutic effect of the drug. Optimal dose is not known.
    C) INTRATHECAL INJECTION
    1) No clinical reports available, information derived from experience with other antineoplastics. Immediately drain at least 20 mL CSF; drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative free normal saline or lactated ringers). For large overdoses, consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline through ventricular catheter, drain fluid from lumbar catheter; typical volumes 80 to 150 mL/hr). Dexamethasone 4 mg intravenously every 6 hours to prevent arachnoiditis.
    D) DECONTAMINATION
    1) Gastrointestinal decontamination is not recommended; administered via the parenteral route.
    E) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with life-threatening cardiac dysrhythmias, significant CNS depression, severe allergic reactions, pulmonary toxicity, or hemodynamic instability.
    F) ANTIDOTE
    1) None.
    G) VENTRICULAR DYSRHYTHMIAS
    1) Institute continuous cardiac monitoring, obtain an ECG, and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders. Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Unstable rhythms require cardioversion.
    H) ACUTE LUNG INJURY
    1) Oxygen; may require endotracheal intubation and mechanical ventilation, but pulmonary toxicity usually resolves rapidly once aldesleukin is discontinued.
    I) OLIGURIA
    1) Administer IV 0.9% saline judiciously (limit to 1 to 1.5 liters/day above maintenance needs) to increase urine output. Low dose dopamine (2 to 5 mcg/kg/min) if patient does not respond to IV fluids.
    J) MYELOSUPPRESSION
    1) Administer colony stimulating factors if patients develop severe neutropenia. Filgrastim: 5 mcg/kg/day IV or subQ. Sargramostim: 250 mcg/m(2)/day IV over 4 hours OR 250 mcg/m(2)/day SubQ once daily. Monitor CBC with differential and platelet count daily for evidence of bone marrow suppression until recovery has occurred. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage. Patients with severe neutropenia should be in protective isolation. Transfer to a bone marrow transplant center should be considered.
    K) NEUTROPENIA
    1) Prophylactic therapy with a fluoroquinolone should be considered in high risk patients with expected prolonged (more than 7 days), and profound neutropenia (ANC 100 cells/mm(3) or less).
    L) FEBRILE NEUTROPENIA
    1) If fever (38.3 C) develops during neutropenic phase (ANC 500 cells/mm(3) or less), cultures should be obtained and empiric antibiotics started. HIGH RISK PATIENT (anticipated neutropenia of 7 days or more; unstable; significant comorbidities): IV monotherapy with either piperacillin-tazobactam; a carbapenem (meropenem or imipenem-cilastatin); or an antipseudomonal beta-lactam agent (eg, ceftazidime or cefepime). LOW RISK PATIENT (anticipated neutropenia of less than 7 days; clinically stable; no comorbidities): oral ciprofloxacin and amoxicillin/clavulanate.
    M) NAUSEA AND VOMITING
    1) Treat severe nausea and vomiting with agents from several different classes. Agents to consider: dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, prochlorperazine, promethazine), 5-HT3 serotonin antagonists (eg, dolasetron, granisetron, ondansetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and antipsychotics (eg, haloperidol, olanzapine).
    N) STOMATITIS
    1) Treat mild mucositis with bland oral rinses with 0.9% saline, sodium bicarbonate, and water. For moderate cases with pain, consider adding a topical anesthetic (eg, lidocaine, benzocaine, dyclonine, diphenhydramine, or doxepin). Treat moderate to severe mucositis with topical anesthetics and systemic analgesics. Patients with mucositis and moderate xerostomia may receive sialagogues (eg, sugarless candy/mints, pilocarpine/cevimeline, or bethanechol) and topical fluorides to stimulate salivary gland function. Consider prophylactic antiviral and antifungal agents to prevent infections. Topical oral antimicrobial mouthwashes, rinses, pastilles, or lozenges may be used to decrease the risk of infection.
    O) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no data to support home management.
    2) OBSERVATION CRITERIA: Symptomatic patients need to be monitored until they are clearly improving and clinically stable.
    3) ADMISSION CRITERIA: Patients with severe symptoms despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with an overdose.
    5) TRANSFER CRITERIA: Patients with large overdoses or severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.
    P) PITFALLS
    1) When managing a suspected overdose, the possibility of multidrug involvement should be considered. Symptoms of overdose are similar to reported side effects of the medication. Patients who are receiving aldesleukin may have severe co-morbidities and may be receiving other drugs that may produce synergistic effects (ie, myelosuppression).
    Q) PHARMACOKINETICS
    1) Absorption: Intramuscular absorption is slow and incomplete. Distribution: Widely distributed; only about 30% of an administered dose is detected in plasma after intravenous administration. Radiolabeled aldesleukin is detected in lungs, liver, kidney and spleen. Distribution half life: 13 minutes. Metabolism: More than 80% of an administered dose is metabolized into amino acids by the cells lining the proximal convoluted tubules of the kidney. Renal clearance: 268 mL/min. Elimination half-life: 85 minutes.
    R) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause myelosuppression or hepatotoxicity.

Range Of Toxicity

    A) TOXICITY: Doses up to 720,000 international units every 8 hours have been administered to adults in clinical trials.
    B) THERAPEUTIC DOSE: ADULT: METASTATIC RENAL CELL CARCINOMA OR METASTATIC MELANOMA: 600,000 international units/kg (0.037 mg/kg) IV every 8 hours for 14 doses, repeat after a rest period of 9 days for a maximum of 28 doses per course. PEDIATRIC: According to the manufacturer, safety and efficacy have not been established in children. In children with refractory malignancies (aged 3.5 to 18 years) aldesleukin doses of 3 to 30 million international units/square meter/day as a 5 day continuous infusion have been used. Most adverse effects were associated with doses of 18 million international units/square meter/day or more. Doses of 10,000 to 50,000 international units/kilogram intravenously every 8 hours for 12 days have been used for treatment of rheumatoid arthritis and atopic dermatitis.

Clinical Effects

Summary Of Exposure

    A) USES: Aldesleukin is indicated for the treatment of metastatic renal cell carcinoma and the treatment of metastatic melanoma in adults.
    B) PHARMACOLOGY: Aldesleukin is a human recombinant interleukin-2 agent, and is produced by recombinant DNA technology using an Escherichia coli strain containing an analogue of the human interleukin-2 gene. In vitro, aldesleukin enhances lymphocyte mitogenesis and cytotoxicity, induces killer cell activity, and induces interferon-gamma production, and stimulated long term growth of human interleukin-2 dependent cell lines. In vivo, aldesleukin activates cellular immunity, induces lymphocytosis, eosinophilia and thrombocytopenia, and induces the production of cytokines, including tumor necrosis factor, interleukin 1 and gamma interferon. It also inhibits tumor growth in murine models.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Capillary leak syndrome (hypotension, tachycardia, oliguria, generalized edema, weight gain, pleural effusions, pulmonary edema, ascites, renal insufficiency and confusion) develops within a few hours of the start of therapy and resolves within a few hours of its discontinuation; OTHER EFFECTS: Nausea, vomiting, diarrhea (may be severe), anemia, neutropenia, leukopenia, thrombocytopenia, fever, chills, increased serum bilirubin, increased aminotransferase levels, and electrolyte disturbances (hypomagnesemia, hypocalcemia, hypokalemia, and hypophosphatemia).
    E) WITH POISONING/EXPOSURE
    1) Overdose information is limited. Higher doses have been associated with a more rapid onset of typical adverse effects.

Vital Signs

    3.3.2) RESPIRATIONS
    A) WITH THERAPEUTIC USE
    1) Dyspnea is a common complaint, reported in 43% of 525 patients in clinical trials (Prod Info PROLEUKIN(R) intravenous injection lyophilized powder, 2015).
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Fever is common, developing in 29% of 525 patients in clinical trials. It usually develops within 2 to 4 hours of the first or second dose and may reach 40.5 degrees centigrade(Schwartz et al, 2002). Other common systemic manifestations are chills (52% of patients), and malaise (27%) (Prod Info PROLEUKIN(R) intravenous injection lyophilized powder, 2015).
    3.3.4) BLOOD PRESSURE
    A) WITH THERAPEUTIC USE
    1) Hypotension is common, developing in 71% of patients in clinical trials (n=525) (Prod Info PROLEUKIN(R) intravenous injection lyophilized powder, 2015).
    3.3.5) PULSE
    A) WITH THERAPEUTIC USE
    1) Tachycardia was reported in 23% of patients treated with aldesleukin during clinical trials (Prod Info PROLEUKIN(R) intravenous injection lyophilized powder, 2015).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CAPILLARY LEAK SYNDROME
    1) WITH THERAPEUTIC USE
    a) Capillary leak syndrome is common in patients receiving therapeutic aldesleukin. Increased capillary permeability and decreased vascular resistance causes a shift of fluid from the intravascular to the extravascular space. Common manifestations include generalized edema, weight gain, pleural effusions, pulmonary edema and ascites. Hypotension is common and decreased perfusion may cause oliguria and confusion (Schwartz et al, 2002).
    B) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Based on clinical trials (n=525), approximately 71% of treated patients developed hypotension secondary to capillary leak syndrome. The incidence of life threatening hypotension was 3%. Vasodilation also developed in 13% of patients (Prod Info PROLEUKIN(R) intravenous injection lyophilized powder, 2015).
    b) During therapeutic use, hypotension is a predicted and known outcome of parenteral therapy(Atkins et al, 1999; Rosenberg et al, 1985). Many patients (31% of those receiving high-dose therapy in recent studies) require pressor therapy to maintain adequate blood pressure and urine output (Schwartz et al, 2002).
    C) SINUS TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) In clinical trials (n=525), sinus tachycardia developed in 23% of patients (Prod Info PROLEUKIN(R) intravenous injection lyophilized powder, 2015).
    D) SUPRAVENTRICULAR TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) Supraventricular tachycardia is common(Atkins et al, 1999). Based on clinical trials (n=525), supraventricular tachycardia was reported in 12% of patients receiving aldesleukin therapy. The event was considered life threatening in 1% (n=3) of patients treated (Prod Info PROLEUKIN(R) intravenous injection lyophilized powder, 2015).
    E) VENTRICULAR TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 49-year-old man receiving high-dose bolus interleukin-2 therapy developed frequent premature ventricular complexes and then recurrent wide complex tachycardia along with near syncope. The dysrhythmia was suppressed initially with lidocaine and then sotalol (80 mg twice daily) (Oleksowica et al, 2000).
    b) Ventricular tachycardia developed in less than 1% of 270 patients receiving aldesleukin in one study(Atkins et al, 1999).
    F) CARDIOVASCULAR FINDING
    1) WITH THERAPEUTIC USE
    a) Cardiovascular dysfunction described as fluctuations in blood pressure, asymptomatic ECG changes and congestive heart failure occurred in 11% of patients (n=525) treated with aldesleukin. Life threatening cardiovascular disorders were reported in 1% of patients (Prod Info PROLEUKIN(R) intravenous injection lyophilized powder, 2015).
    G) MYOCARDITIS
    1) WITH THERAPEUTIC USE
    a) Myocarditis develops in 2.5% to 5% of patients. It is usually asymptomatic, and associated with transient left ventricular dysfunction(Schwartz et al, 2002).
    H) MYOCARDIAL INFARCTION
    1) WITH THERAPEUTIC USE
    a) In early studies of high dose IL-2, myocardial infarction was reported in 2% to 4% of patients. Underlying cardiac disease is now considered a contraindication to IL-2 therapy, and myocardial infarction has not been reported in more recent studies(Schwartz et al, 2002).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) ACUTE LUNG INJURY
    1) WITH THERAPEUTIC USE
    a) Capillary leak syndrome may cause pleural effusions and pulmonary edema. In clinical trials (n=525), acute lung injury and/or infiltrates on chest radiograph developed in 11% of patients (Prod Info PROLEUKIN(R) intravenous injection lyophilized powder, 2015). About 3% of patients require endotracheal intubation (Schwartz et al, 2002).
    B) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) Dyspnea was common in clinical trials, developing in 43% of 525 patients (Prod Info PROLEUKIN(R) intravenous injection lyophilized powder, 2015).
    C) PLEURAL EFFUSION
    1) WITH THERAPEUTIC USE
    a) Pleural effusions are the most common abnormality on chest radiographs in patients receiving aldesleukin, occurring in about 50% of patients. Effusions generally resolve when therapy is discontinued, but about 17% of patients have persistent effusion 4 weeks after therapy is discontinued(Huggins & Sahn, 2004).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CLOUDED CONSCIOUSNESS
    1) WITH THERAPEUTIC USE
    a) Confusion (34%) and somnolence (22%) were common in clinical trials (n=525) (Prod Info PROLEUKIN(R) intravenous injection lyophilized powder, 2015). Anxiety (12%) and dizziness (11%) were reported less often. Mental status changes may be exacerbated by concomitant drug therapies (eg meperidine for chills or phenothiazines for nausea), sleep disturbances, and "ICU psychosis"(Schwartz et al, 2002).
    B) COMA
    1) WITH THERAPEUTIC USE
    a) Coma can develop but is rare (2% of patients in early clinical trials, less common in more recent studies)(Schwartz et al, 2002).(Atkins et al, 1999)

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea was reported in 67% of patients (n=525) treated with aldesleukin (Prod Info PROLEUKIN(R) intravenous injection lyophilized powder, 2015).
    B) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea (35%) and vomiting (50%) were reported in aldesleukin treated patients (n=525), and appear to be dose-related (Prod Info PROLEUKIN(R) intravenous injection lyophilized powder, 2015).
    C) GASTROINTESTINAL TRACT FINDING
    1) WITH THERAPEUTIC USE
    a) Other effects frequently reported with therapy include stomatitis (22%) and anorexia (20%). Gastrointestinal hemorrhage, constipation, esophagitis, sialorrhea, pancreatitis, and tracheoesophageal fistulas are rare complications (Prod Info PROLEUKIN(R) intravenous injection lyophilized powder, 2015; Schwartz et al, 2002).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) INJURY OF LIVER
    1) WITH THERAPEUTIC USE
    a) Transient increases in serum bilirubin are the most common manifestation of hepatotoxicity and develop in about 40% of patients. Increased SGOT developed in about 23% of patients and increased alkaline phosphatase in 10% of 525 patients in clinical trials (Prod Info PROLEUKIN(R) intravenous injection lyophilized powder, 2015). Hypoalbuminemia and prolonged prothrombin time develop rarely. Laboratory evidence of hepatic injury generally resolves within 5 to 6 days of discontinuation of therapy(Schwartz et al, 2002).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) OLIGURIA
    1) WITH THERAPEUTIC USE
    a) Oliguria is common, occurring in 63% of patients in clinical trials (n=525) (Prod Info PROLEUKIN(R) intravenous injection lyophilized powder, 2015).
    B) ACUTE RENAL IMPAIRMENT
    1) WITH THERAPEUTIC USE
    a) Elevations in serum creatinine are common; in one study of patients receiving high dose aldesleukin the mean peak serum creatinine level after the second dose was 2.7 mg/dL (Schwartz et al, 2002). Renal dysfunction typically resolves within 7 to 14 days of discontinuing therapy, and hemodialysis is rarely needed (Schwartz et al, 2002).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Thrombocytopenia was reported in 37% of 525 patients in early clinical trials (Prod Info PROLEUKIN(R) intravenous injection lyophilized powder, 2015). Severe thrombocytopenia is unusual. In one study platelet counts of less than 50,000/microliter and less than 25,000/microliter developed in 12% and 1% of treatment courses, respectively. Only 3% of patients required platelet transfusion. Platelet counts usually continue to drop for 1 to 2 days after therapy is discontinued and then return to baseline(Schwartz et al, 2002).
    B) ANEMIA
    1) WITH THERAPEUTIC USE
    a) Anemia developed in 29% of 525 patients in early clinical trials (Prod Info PROLEUKIN(R) intravenous injection lyophilized powder, 2015). In one study 14% of patients treated with high dose aldesleukin required red cell transfusion(Schwartz et al, 2002).
    C) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Leukopenia developed in 16% of 525 patients in early clinical trials (Prod Info PROLEUKIN(R) intravenous injection lyophilized powder, 2015). Severe leukopenia develops in only about 1.5% of patients and does not seem to be associated with an increased risk of infection (Schwartz et al, 2002).
    D) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) In the post-marketing period, neutropenia and febrile neutropenia were observed in patients receiving aldesleukin (Prod Info PROLEUKIN(R) intravenous injection lyophilized powder, 2015).
    E) LYMPHOCYTOPENIA
    1) WITH THERAPEUTIC USE
    a) Profound lymphocytopenia occurs rapidly and persists during therapy. It appears to be secondary to lymphocyte sequestration. When therapy is discontinued lymphocyte levels rebound to nearly twice baseline, and slowly return to normal(Schwartz et al, 2002).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERYTHEMA
    1) WITH THERAPEUTIC USE
    a) Rash is common with therapeutic use of aldesleukin. It usually begins as erythema and may progress to pruritus followed by mild desquamation(Schwartz et al, 2002). In early clinical trials (n=525), rash developed in 42%, pruritus in 24% and exfoliative dermatitis in 18% (Prod Info PROLEUKIN(R) intravenous injection lyophilized powder, 2015).
    B) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) Hair loss or thinning has been reported, but is usually mild(Schwartz et al, 2002).
    C) VITILIGO
    1) WITH THERAPEUTIC USE
    a) Depigmented skin, patches of white hair, and/or halo depigmentation around nevi or cutaneous tumors have been reported in up to 45% of patients with metastatic melanoma treated with aldesleukin (Schwartz et al, 2002).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) AUTOIMMUNE DISEASE
    1) WITH THERAPEUTIC USE
    a) Treatment with aldesleukin has been associated with exacerbation of pre-existing or initial presentation of autoimmune and inflammatory disorders such as: Crohn's disease, scleroderma, thyroiditis, arthritis, diabetes mellitus, oculo-bulbar myasthenia gravis, IgA glomerulonephritis, cholecystitis, cerebral vasculitis, Stevens-Johnson syndrome, and bullous pemphigoid (Prod Info PROLEUKIN(R) intravenous injection lyophilized powder, 2015).
    B) IMMUNOSUPPRESSION
    1) WITH THERAPEUTIC USE
    a) Infections are fairly common in patients receiving IL-2 therapy(Atkins et al, 1999). Early studies reported infection rates up to 38%, but more recent studies indicated a rate of about 13%. The most common sources are the urinary tract and the site of venous catheters(Schwartz et al, 2002). In a study of 270 patients receiving aldesleukin for metastatic melanoma 6 patients (2%) died from adverse events, all related to sepsis(Atkins et al, 1999).

Reproductive

    3.20.1) SUMMARY
    A) Aldesleukin is classified as Pregnancy Category C. In rats, embryolethal effects and maternal toxicities were observed.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) RATS: No teratogenic effects were observed when pregnant rats were administered IV doses 2.1 to 36 times higher than the human dose during organogenesis (Prod Info Proleukin(R) intravenous injection, 2014).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Aldesleukin is classified as Pregnancy Category C (Prod Info Proleukin(R) intravenous injection, 2014).
    B) ANIMAL STUDIES
    1) RATS: Embryolethal effects were observed when rats were administered doses 27 to 36 times the human dose. Maternal toxicities were observed in pregnant rats administered IV doses 2.1 to 36 times higher than the human dose during organogenesis (Prod Info Proleukin(R) intravenous injection, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is not known if aldesleukin is excreted in human milk (Prod Info Proleukin(R) intravenous injection, 2014).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS110942-02-4 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs, mental status, CBC with differential, renal function, hepatic enzymes, and coagulation studies (INR, PTT) following a significant overdose.
    C) Monitor fluid intake and output and daily weights. Monitor serum electrolytes.
    D) Obtain an ECG, and institute continuous cardiac monitoring.
    E) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with respiratory symptoms.
    F) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    G) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    4.1.2) SERUM/BLOOD
    A) FLUID AND ELECTROLYTES
    1) Monitor fluid intake and output and daily weights. Monitor serum electrolytes.
    2) Capillary leak syndrome is common with aldesleukin therapy, and can cause intravascular volume depletion and peripheral edema. Nausea, vomiting and diarrhea develop in about 35%, 50% and 67%, respectively, of treated patients (Prod Info PROLEUKIN(R) intravenous injection lyophilized powder, 2015). Hypokalemia, hypomagnesemia, hypocalcemia and hypophosphatemia are fairly common(Schwartz et al, 2002).
    B) COMPLETE BLOOD COUNT
    1) Monitor complete blood count with differential.
    2) Anemia develops in about 30% of patient after therapeutic use, leukopenia in 16%, and thrombocytopenia in about 37%, although severe toxicity is rare (Prod Info PROLEUKIN(R) intravenous injection lyophilized powder, 2015).
    C) RENAL FUNCTION
    1) Monitor serum BUN and creatinine, and urine output.
    2) Oliguria develops in up to 63% of patients after therapeutic use, and increases in serum creatinine are common (about one third of patients), although hemodialysis is rarely needed(Schwartz et al, 2002).
    D) HEPATIC ENZYMES
    1) Monitor liver enzymes and serum bilirubin.
    2) Hyperbilirubinemia develops in about 40% of patients after therapeutic use, increases in SGOT in 23%, and increases alkaline phosphatase in 10% (Prod Info PROLEUKIN(R) intravenous injection lyophilized powder, 2015).
    E) COAGULATION STUDIES
    1) Monitor INR and PTT after overdose.
    2) Coagulopathies are fairly common after therapeutic use, but clinical bleeding is unusual(Schwartz et al, 2002).
    F) CARDIAC ENZYMES
    1) Obtain cardiac enzymes (troponin or CK-MB) in patients with chest pain, hypoxia, ECG changes or dysrhythmias.
    4.1.3) URINE
    A) Urinalysis may show protein, bilirubin, red or white blood cells and granular casts during therapy(Schwartz et al, 2002). Urinalysis usually returns to normal after aldesleukin therapy is discontinued.
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Obtain an ECG and institute continuous cardiac monitoring. Obtain cardiac enzymes in patient with chest pain, hypoxia, dysrhythmias or ischemic ECG changes.
    b) Supraventricular tachycardia is fairly common after therapeutic use (12%) and other dysrhythmias have been reported less often. Myocardial infarction is a rare complication. Myocarditis occurs in 2.5% to 5% of patients after therapeutic use(Schwartz et al, 2002).

Radiographic Studies

    A) Obtain a chest radiograph in patients with hypoxia, or pulmonary signs or symptoms.
    B) Capillary leak syndrome is very common with therapeutic use of aldesleukin, and acute lung injury develops in up to 11% of patients (Prod Info PROLEUKIN(R) intravenous injection lyophilized powder, 2015). Roentgenographic findings are not specific, and may include perihilar alveolar or interstitial infiltrates, focal infiltrates and/or pleural effusions(Huggins & Sahn, 2004).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients with severe symptoms despite treatment should be admitted.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) There is no data to support home management.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with an overdose.
    6.3.2.4) PATIENT TRANSFER/PARENTERAL
    A) Patients with large overdoses or severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) Symptomatic patients need to be monitored until they are clearly improving and clinically stable.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs, mental status, CBC with differential, renal function, hepatic enzymes, and coagulation studies (INR, PTT) following a significant overdose.
    C) Monitor fluid intake and output and daily weights. Monitor serum electrolytes.
    D) Obtain an ECG, and institute continuous cardiac monitoring.
    E) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with respiratory symptoms.
    F) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    G) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Gastrointestinal decontamination is not recommended; administered via the parenteral route.

Range Of Toxicity

Summary

    A) TOXICITY: Doses up to 720,000 international units every 8 hours have been administered to adults in clinical trials.
    B) THERAPEUTIC DOSE: ADULT: METASTATIC RENAL CELL CARCINOMA OR METASTATIC MELANOMA: 600,000 international units/kg (0.037 mg/kg) IV every 8 hours for 14 doses, repeat after a rest period of 9 days for a maximum of 28 doses per course. PEDIATRIC: According to the manufacturer, safety and efficacy have not been established in children. In children with refractory malignancies (aged 3.5 to 18 years) aldesleukin doses of 3 to 30 million international units/square meter/day as a 5 day continuous infusion have been used. Most adverse effects were associated with doses of 18 million international units/square meter/day or more. Doses of 10,000 to 50,000 international units/kilogram intravenously every 8 hours for 12 days have been used for treatment of rheumatoid arthritis and atopic dermatitis.

Therapeutic Dose

    7.2.1) ADULT
    A) METASTATIC RENAL CELL CARCINOMA OR METASTATIC MELANOMA - 600,000 international units/kg (0.037 mg/kg) IV every 8 hours for 14 doses, repeat after a rest period of 9 days for a maximum of 28 doses per course (Prod Info PROLEUKIN(R) intravenous injection, 2012).
    7.2.2) PEDIATRIC
    A) According to the manufacturer, safety and efficacy have not been established in children(Prod Info PROLEUKIN(R) intravenous injection, 2012).
    B) In children with refractory malignancies (aged 3.5 to 18 years) aldesleukin doses of 3 to 30 million international units/square meter/day as a 5 day continuous infusion have been used. Most adverse effects were associated with doses of 18 million international units/square meter/day or more(Ribeiro et al, 1993).
    C) Doses of 10,000 to 50,000 international units/kilogram intravenously every 8 hours for 12 days have been used for treatment of rheumatoid arthritis and atopic dermatitis(Chien & Hsieh, 1990).

Maximum Tolerated Exposure

    A) Doses up to 720,000 international units every 8 hours have been administered to adults in clinical trials(Atkins et al, 1999). Severe toxic effects are very common in patients receiving these doses. Exceeding the recommended dose has resulted in a more rapid onset of the expected dose-limiting toxicity (Prod Info PROLEUKIN(R) intravenous injection lyophilized powder, 2015).
    B) PEDIATRIC
    1) In children with refractory malignancies (aged 3.5 to 18 years) aldesleukin doses of 3 to 30 million international units/square meter/day as a 5 day continuous infusion have been used. Most adverse effects were associated with doses of 18 million international units/square meter/day or more (Ribeiro et al, 1993).

Workplace Standards

    A) ACGIH TLV Values for CAS110942-02-4 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS110942-02-4 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS110942-02-4 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS110942-02-4 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Pharmacology Toxicology

Pharmacologic Mechanism

    A) In vitro, aldesleukin enhances lymphocyte mitogenesis and cytotoxicity, induces killer cell activity, and induces interferon-gamma production, and stimulated long term growth of human interleukin-2 dependent cell lines(Prod Info Proleukin(R), 2000).
    B) In vivo, aldesleukin activates cellular immunity, induces lymphocytosis, eosinophilia and thrombocytopenia, and induces the production of cytokines, including tumor necrosis factor, interleukin 1 and gamma interferon. It also inhibits tumor growth in murine models(Prod Info Proleukin(R), 2000).

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