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DENILEUKIN DIFTITOX

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Denileukin diftitox is a recombinant DNA-derived interleukin fusion protein that directs the cytotoxic action of diptheria toxin to cells that express the high affinity (CD25/CD122/CD132) form of the IL-2 receptor. Certain leukemias and lymphomas, including cutaneous T-cell lymphoma, contain malignant cells that express at least one subunit of the IL-2 receptor.

Specific Substances

    1) DAB(389)IL2
    2) Denileucina diftitox
    3) Denileukin Diftitox
    4) Denileukine Diftitox
    5) Denileukinum Diftitoxum
    6) LY-335348
    7) CAS 173146-27-5

Available Forms Sources

    A) FORMS
    1) Denileukin diftitox is available in US as 150 mcg/mL sterile, frozen solution (300 mcg in 2 mL) in a sterile, single-use vial (Prod Info ONTAK(R) intravenous injection, 2006).
    B) USES
    1) Denileukin diftitox is used to treat patients with persistent or recurrent cutaneous T-cell lymphoma whose malignant cells express the CD25 component of the IL-2 receptor (Prod Info ONTAK(R) intravenous injection, 2006).

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: Used for treatment of persistent or recurrent cutaneous T-cell lymphoma whose malignant cells express the CD25 component of the IL-2 receptor.
    B) PHARMACOLOGY: A recombinant DNA-derived interleukin fusion protein that directs the cytotoxic action of diphtheria toxin to cells that express the high affinity (CD25/CD122/CD132) form of the IL-2 receptor. Certain leukemias and lymphomas, including cutaneous T-cell lymphoma, contain malignant cells that express at least one subunit of the IL-2 receptor.
    C) EPIDEMIOLOGY: Overdose is rarely reported.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most commonly reported adverse reactions, with an incidence of at least 20% during clinical trials, were nausea, vomiting, diarrhea, pyrexia, fatigue, rigors, headache, peripheral edema, elevated liver enzymes, cough, and pruritus.
    2) INFREQUENT: Other adverse effects that have been reported less frequently with denileukin diftitox therapy include tachycardia, hypotension, chest pain, anorexia, myalgia, arthralgia, back pain, upper respiratory tract infection, hypersensitivity reactions, thrombotic disorder, hypertension, dysrhythmias, rash, sweating, hypocalcemia, hypokalemia, constipation, dyspepsia, dysphagia, oral ulcers, pancreatitis, proteinuria, pyuria, hematuria, elevated serum creatinine, lymphocytopenia, anemia, thrombocytopenia, leukopenia, hypoalbuminemia, dizziness, asthenia, paresthesia, nervousness, confusion, insomnia, dyspnea, pharyngitis, rhinitis, thyroiditis, thyrotoxicosis, hypothyroidism, dysgeusia, and injection site reaction.
    3) SERIOUS EFFECTS: Capillary leak syndrome, characterized by hypotension, edema, and hypoalbuminemia, has occurred, with reports of fatalities, with denileukin diftitox therapy. Other serious adverse effects with therapeutic administration of denileukin diftitox include infusion reactions with reported fatalities, and loss of visual acuity and color vision, with reports of persistent visual impairment in some patients.
    E) WITH POISONING/EXPOSURE
    1) Nausea, vomiting, fever, chills, and persistent asthenia were reported at doses of 31 mcg/kg/day (approximately twice the recommended dose). In general, clinical events in overdose are anticipated to be an extension of adverse effects.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Fever and chills have been reported with denileukin diftitox therapy.
    B) WITH POISONING/EXPOSURE
    1) Fever and chills were reported at doses of 31 mcg/kg/day (approximately twice the recommended dose).
    0.2.20) REPRODUCTIVE
    A) Denileukin diftitox does not have an FDA pregnancy category rating. No studies examining the use of denileukin diftitox during pregnancy are available at this time.
    0.2.21) CARCINOGENICITY
    A) Studies have not been done to evaluate the carcinogenic potential of denileukin diftitox.

Laboratory Monitoring

    A) Monitor vital signs including temperature and blood pressure.
    B) Obtain baseline CBC and complete chemistry panel, including renal function, liver enzymes and serum albumin levels.
    C) Monitor fluid status, as dehydration is possible with therapy.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    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) Plasma concentrations are not readily available or clinically useful in the management of overdose.

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.
    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. Myelosuppression has been reported. Monitor serial CBC with differential. For severe neutropenia, administer colony stimulating factor (eg; filgrastim, sargramostim). Transfusions as needed for severe thrombocytopenia, bleeding. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required.
    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 severe allergic reactions, pulmonary toxicity, or hemodynamic instability.
    F) ANTIDOTE
    1) None
    G) MYELOSUPPRESSION
    1) Administer colony stimulating factors following a significant overdose as these patients are at risk for 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.
    H) 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).
    I) 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.
    J) 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 denileukin diftitox may have severe co-morbidities and may be receiving other drugs that may produce synergistic effects (ie, myelosuppression).
    K) PHARMACOKINETICS
    1) Volume of distribution is 0.06 to 0.09 L/kg. Clearance is approximately 0.6 to 2 mL/min/kg and terminal half-life is 70 to 80 minutes.
    L) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause myelosuppression.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established. Doses of 31 mcg/kg/day caused moderate to severe nausea, vomiting, fever, chills and/or persistent asthenia.
    B) THERAPEUTIC DOSE: ADULT: The recommended dosage regimen is 9 or 18 mcg/kg/day infused intravenously over 30 to 60 minutes, administered for 5 consecutive days every 3 weeks for 8 cycles. PEDIATRIC: Safety and efficacy have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Used for treatment of persistent or recurrent cutaneous T-cell lymphoma whose malignant cells express the CD25 component of the IL-2 receptor.
    B) PHARMACOLOGY: A recombinant DNA-derived interleukin fusion protein that directs the cytotoxic action of diphtheria toxin to cells that express the high affinity (CD25/CD122/CD132) form of the IL-2 receptor. Certain leukemias and lymphomas, including cutaneous T-cell lymphoma, contain malignant cells that express at least one subunit of the IL-2 receptor.
    C) EPIDEMIOLOGY: Overdose is rarely reported.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most commonly reported adverse reactions, with an incidence of at least 20% during clinical trials, were nausea, vomiting, diarrhea, pyrexia, fatigue, rigors, headache, peripheral edema, elevated liver enzymes, cough, and pruritus.
    2) INFREQUENT: Other adverse effects that have been reported less frequently with denileukin diftitox therapy include tachycardia, hypotension, chest pain, anorexia, myalgia, arthralgia, back pain, upper respiratory tract infection, hypersensitivity reactions, thrombotic disorder, hypertension, dysrhythmias, rash, sweating, hypocalcemia, hypokalemia, constipation, dyspepsia, dysphagia, oral ulcers, pancreatitis, proteinuria, pyuria, hematuria, elevated serum creatinine, lymphocytopenia, anemia, thrombocytopenia, leukopenia, hypoalbuminemia, dizziness, asthenia, paresthesia, nervousness, confusion, insomnia, dyspnea, pharyngitis, rhinitis, thyroiditis, thyrotoxicosis, hypothyroidism, dysgeusia, and injection site reaction.
    3) SERIOUS EFFECTS: Capillary leak syndrome, characterized by hypotension, edema, and hypoalbuminemia, has occurred, with reports of fatalities, with denileukin diftitox therapy. Other serious adverse effects with therapeutic administration of denileukin diftitox include infusion reactions with reported fatalities, and loss of visual acuity and color vision, with reports of persistent visual impairment in some patients.
    E) WITH POISONING/EXPOSURE
    1) Nausea, vomiting, fever, chills, and persistent asthenia were reported at doses of 31 mcg/kg/day (approximately twice the recommended dose). In general, clinical events in overdose are anticipated to be an extension of adverse effects.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Fever and chills have been reported with denileukin diftitox therapy.
    B) WITH POISONING/EXPOSURE
    1) Fever and chills were reported at doses of 31 mcg/kg/day (approximately twice the recommended dose).
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) FEVER: During a randomized placebo-controlled trial, fever was reported in 22 (48.9%) and 35 (63.6%) patients who received denileukin diftitox as a single agent at doses of 9 mcg/kg (n=45) and 18 mcg/kg (n=55), respectively, compared to 7 (15.9%) patients who received a placebo (n=44) (Prod Info ONTAK(R) IV solution, 2010).
    2) CHILLS: During a randomized placebo-controlled trial, rigors was reported in 19 (42.2%) and 26 (47.3%) patients who received denileukin diftitox as a single agent at doses of 9 mcg/kg (n=45) and 18 mcg/kg (n=55), respectively, compared to 9 (20.5%) patients who received a placebo (n=44) (Prod Info ONTAK(R) IV solution, 2010).
    B) WITH POISONING/EXPOSURE
    1) Fever and chills were reported at doses of 31 mcg/kg/day (approximately twice the recommended dose) (Prod Info ONTAK(R) IV solution, 2010).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Loss of visual acuity, usually with loss of color vision after administration of denileukin diftitox has been reported with denileukin therapy. Some cases also experienced retinal pigment mottling. Most patients reported persistent visual impairment (Prod Info ONTAK(R) IV solution, 2010).
    2) TOXIC RETINOPATHY: Two patients with hematological malignancies experienced visual symptoms (loss of central and color vision, coarse pigmentary macular changes, and decreased electroretinographic amplitudes) during denileukin diftitox therapy. One patient continued to have visual symptoms after receiving plasmapheresis, pooled human immunoglobulin and high-dose prednisolone (Ruddle et al, 2006).
    3) POSTERIOR ISCHEMIC OPTIC NEUROPATHY: A 69-year-old woman with skin-limited cutaneous T-cell lymphoma developed hypotension and decreased visual acuity and impaired color perception possibly due to posterior ischemic optic neuropathy during the first 5-day cycle of denileukin diftitox therapy (9 mcg/kg/day). Her exam revealed no edema of the optic disc, a normal cup-to-disc ratio, no fundus changes, central scotomas on visual field testing, and temporal pallor. Denileukin diftitox was discontinued and her vision improved slowly over the next 2 years (Park et al, 2007).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) In two clinical studies of 143 patients with lymphoma (including 105 patients with cutaneous T-cell lymphoma [CTCL]), tachycardia (all grades) was reported in 17 (12%) patients receiving denileukin diftitox doses ranging from 3 to 31 mcg/kg/day; 2 (1%) patients experienced grade 3 and 4 tachycardia (Prod Info ONTAK(R) intravenous injection, 2006).
    B) CHEST PAIN
    1) WITH THERAPEUTIC USE
    a) During a randomized placebo-controlled trial, chest pain was reported in 2 (4.4%) and 7 (12.7%) patients who received denileukin diftitox as a single agent at doses of 9 mcg/kg (n=45) and 18 mcg/kg (n=55), respectively, compared to 1 patient who received a placebo (n=44) (Prod Info ONTAK(R) IV solution, 2010).
    C) THROMBOSIS
    1) WITH THERAPEUTIC USE
    a) In two clinical studies of 143 patients with lymphoma (including 105 patients with cutaneous T-cell lymphoma [CTCL]), thrombotic disorder (all grades) was reported in 10 (7%) patients receiving denileukin diftitox doses ranging from 3 to 31 mcg/kg/day; 6 (4%) patients experienced grade 3 and 4 thrombotic disorder (Prod Info ONTAK(R) intravenous injection, 2006).
    b) Thrombotic events occurred in 11% of patients with cutaneous T-cell lymphoma (n=71). An acute myocardial infarction occurred 10 days after the last dose of denileukin diftitox in a single patient with preexisting cardiopulmonary disease. Deep vein thrombosis occurred in 2 patients, one of whom developed a pulmonary embolus. Superficial thrombophlebitis not requiring treatment occurred in 4 patients (Olsen et al, 2001a).
    D) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) In two clinical studies of 143 patients with lymphoma (including 105 patients with cutaneous T-cell lymphoma [CTCL]), hypertension (all grades) was reported in 9 (6%) patients receiving denileukin diftitox doses ranging from 3 to 31 mcg/kg/day (Prod Info ONTAK(R) intravenous injection, 2006).
    E) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) In two clinical studies of 143 patients with lymphoma (including 105 patients with cutaneous T-cell lymphoma [CTCL]), dysrhythmias (all grades) was reported in 8 (6%) patients receiving denileukin diftitox doses ranging from 3 to 31 mcg/kg/day; 5 (3%) patients experienced grade 3 and 4 dysrhythmias (Prod Info ONTAK(R) intravenous injection, 2006).
    F) CAPILLARY LEAK SYNDROME
    1) WITH THERAPEUTIC USE
    a) Capillary leak syndrome, defined as the occurrence of at least 2 of the 3 symptoms (hypotension, edema, serum albumin less than 3 g/dL) at any time during therapy, was reported in 76 of 234 patients (32.5%) treated with denileukin diftitox during clinical trials. Capillary leak syndrome with fatalities has also been reported during post-marketing surveillance of denileukin diftitox (Prod Info ONTAK(R) IV solution, 2010).
    1) Onset of symptoms may occur up to 2 weeks following denileukin diftitox infusion and may persist or worsen following discontinuation of therapy (Prod Info ONTAK(R) IV solution, 2010).
    b) In a phase III trial of patients with cutaneous T-cell lymphoma (n=71), 25% of patients experienced vascular leak syndrome (VLS). VLS was defined as the simultaneous occurrence of at least two of the following: edema, hypoalbuminemia (2.8 g/dL or less), and/or hypotension during days 1 to 14 of the beginning of a cycle. Hypoalbuminemia (2.3 g/dL or less) occurred in 15% of patients. VLS was usually self-limited. Preexisting edema and/or hypoalbuminemia were risk factors for VLS (Olsen et al, 2001a).
    c) In a phase I trial involving patients with cutaneous T-cell lymphoma, other non-Hodgkin's lymphomas, and Hodgkin's disease, evidence of a vascular leak syndrome was observed only in those with cutaneous T-cell lymphoma (8% incidence). Serum albumin was decreased in 86% of all patients treated (degree unspecified). There was a correlation between preexisting antibody titers to denileukin diftitox/diphtheria toxin and hypoalbuminemia (LeMaistre et al, 1998a).
    d) CASE REPORT: A 53-year-old man with cutaneous gamma/delta T-cell lymphoma and occult cirrhosis developed profound vascular leak syndrome after receiving high-dose denileukin diftitox (18 mcg/kg/day infused over 30 minutes) for 4 days. He presented with dizziness, orthostatic hypotension and hypoalbuminemia (2.1 g/dL; normal, 3.5 to 5.8 g/dL). His condition deteriorated and he experienced severe generalized myalgia and hypoxemic respiratory failure. On hospital day 3, he experienced refractory hypotension, generalized edema, a profound acidosis, and rhabdomyolysis (CK, 29,160 units/L). Despite supportive treatment, he died on hospital day 4 (Avarbock et al, 2008).
    G) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) During a randomized placebo-controlled trial, hypotension was reported in 3 (6.7%) and 9 (16.4%) patients who received denileukin diftitox as a single agent at doses of 9 mcg/kg (n=45) and 18 mcg/kg (n=55), respectively, compared to 1 patient who received a placebo (n=44) (Prod Info ONTAK(R) IV solution, 2010).
    b) In one study, hypotension was common during or shortly after infusion, occurring in over 50% of patients (LeMaistre et al, 1998a).
    c) Edema and hypoalbuminemia have accompanied reductions in blood pressure, highly suggestive of a vascular leak syndrome, which has been observed in about 27% of patients (Prod Info ONTAK(R) intravenous injection, 2006; LeMaistre et al, 1998a; Anon, 1998).
    d) CASE REPORT: A 69-year-old woman with skin-limited cutaneous T-cell lymphoma developed mild asymptomatic hypotension (80/35 mm Hg), fatigue, and leg edema during the first 5-day cycle of denileukin diftitox therapy (9 mcg/kg/day) (Park et al, 2007).
    H) PERIPHERAL EDEMA
    1) WITH THERAPEUTIC USE
    a) During a randomized placebo-controlled trial, peripheral edema was reported in 9 (20%) and 14 (25.5%) patients who received denileukin diftitox as a single agent at doses of 9 mcg/kg (n=45) and 18 mcg/kg (n=55), respectively, compared to 10 (22.7%) patients who received a placebo (n=44) (Prod Info ONTAK(R) IV solution, 2010).
    b) CASE REPORT: A 69-year-old woman with skin-limited cutaneous T-cell lymphoma developed mild asymptomatic hypotension (80/35 mm Hg), fatigue, and leg edema during the first 5-day cycle of denileukin diftitox therapy (9 mcg/kg/day) (Park et al, 2007).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) During a randomized placebo-controlled trial, dyspnea was reported in 6 (13.3%) and 6 (10.9%) patients who received denileukin diftitox as a single agent at doses of 9 mcg/kg (n=45) and 18 mcg/kg (n=55), respectively, compared to 2 (4.5%) patients who received a placebo (n=44) (Prod Info ONTAK(R) IV solution, 2010).
    B) COUGH
    1) WITH THERAPEUTIC USE
    a) During a randomized placebo-controlled trial, cough was reported in 9 (20%) and 10 (18.2%) patients who received denileukin diftitox as a single agent at doses of 9 mcg/kg (n=45) and 18 mcg/kg (n=55), respectively, compared to 3 (6.8%) patients who received a placebo (n=44) (Prod Info ONTAK(R) IV solution, 2010).
    C) PHARYNGITIS
    1) WITH THERAPEUTIC USE
    a) In two clinical studies of 143 patients with lymphoma (including 105 patients with cutaneous T-cell lymphoma [CTCL]), pharyngitis (all grades) was reported in 25 (17%) patients receiving denileukin diftitox doses ranging from 3 to 31 mcg/kg/day (Prod Info ONTAK(R) intravenous injection, 2006).
    D) RHINITIS
    1) WITH THERAPEUTIC USE
    a) In two clinical studies of 143 patients with lymphoma (including 105 patients with cutaneous T-cell lymphoma [CTCL]), rhinitis (all grades) was reported in 19 (13%) patients receiving denileukin diftitox doses ranging from 3 to 31 mcg/kg/day; 2 (1%) patients experienced grade 3 and 4 rhinitis (Prod Info ONTAK(R) intravenous injection, 2006).
    E) DISORDER OF LUNG
    1) WITH THERAPEUTIC USE
    a) In two clinical studies of 143 patients with lymphoma (including 105 patients with cutaneous T-cell lymphoma [CTCL]), lung disorder (all grades) was reported in 11 (8%) patients receiving denileukin diftitox doses ranging from 3 to 31 mcg/kg/day (Prod Info ONTAK(R) intravenous injection, 2006).
    F) UPPER RESPIRATORY INFECTION
    1) WITH THERAPEUTIC USE
    a) During a randomized placebo-controlled trial, upper respiratory tract infection was reported in 6 (13.3%) and 7 (12.7%) patients who received denileukin diftitox as a single agent at doses of 9 mcg/kg (n=45) and 18 mcg/kg (n=55), respectively, compared to 5 (11.4%) patients who received a placebo (n=44) (Prod Info ONTAK(R) IV solution, 2010).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) During a randomized placebo-controlled trial, dizziness was reported in 5 (11.1%) and 7 (12.7%) patients who received denileukin diftitox as a single agent at doses of 9 mcg/kg (n=45) and 18 mcg/kg (n=55), respectively, compared to 5 (11.4%) patients who received a placebo (n=44) (Prod Info ONTAK(R) IV solution, 2010).
    B) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) During a randomized placebo-controlled trial, asthenia was reported in 8 (17.8%) and 10 (18.2%) patients who received denileukin diftitox as a single agent at doses of 9 mcg/kg (n=45) and 18 mcg/kg (n=55), respectively, compared to 2 (4.5%) patients who received a placebo (n=44) (Prod Info ONTAK(R) IV solution, 2010).
    2) WITH POISONING/EXPOSURE
    a) Persistent asthenia was reported at doses of 31 mcg/kg/day (approximately twice the recommended dose) (Prod Info ONTAK(R) IV solution, 2010).
    C) PARESTHESIA
    1) WITH THERAPEUTIC USE
    a) In two clinical studies of 143 patients with lymphoma (including 105 patients with cutaneous T-cell lymphoma [CTCL]), paresthesia (all grades) was reported in 19 (13%) patients receiving denileukin diftitox doses ranging from 3 to 31 mcg/kg/day; 2 (1%) patients experienced grade 3 and 4 paresthesia (Prod Info ONTAK(R) intravenous injection, 2006).
    D) FEELING NERVOUS
    1) WITH THERAPEUTIC USE
    a) In two clinical studies of 143 patients with lymphoma (including 105 patients with cutaneous T-cell lymphoma [CTCL]), nervousness (all grades) was reported in 16 (11%) patients receiving denileukin diftitox doses ranging from 3 to 31 mcg/kg/day; 2 (1%) patients experienced grade 3 and 4 nervousness (Prod Info ONTAK(R) intravenous injection, 2006).
    E) CLOUDED CONSCIOUSNESS
    1) WITH THERAPEUTIC USE
    a) In two clinical studies of 143 patients with lymphoma (including 105 patients with cutaneous T-cell lymphoma [CTCL]), confusion (all grades) was reported in 11 (8%) patients receiving denileukin diftitox doses ranging from 3 to 31 mcg/kg/day; 8 (6%) patients experienced grade 3 and 4 confusion (Prod Info ONTAK(R) intravenous injection, 2006).
    F) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) In two clinical studies of 143 patients with lymphoma (including 105 patients with cutaneous T-cell lymphoma [CTCL]), insomnia (all grades) was reported in 13 (9%) patients receiving denileukin diftitox doses ranging from 3 to 31 mcg/kg/day; 4 (3%) patients experienced grade 3 and 4 insomnia (Prod Info ONTAK(R) intravenous injection, 2006).
    G) HEADACHE
    1) WITH THERAPEUTIC USE
    a) During a randomized placebo-controlled trial, headache was reported in 13 (28.9%) and 14 (25.5%) patients who received denileukin diftitox as a single agent at doses of 9 mcg/kg (n=45) and 18 mcg/kg (n=55), respectively, compared to 8 (18.2%) patients who received a placebo (n=44) (Prod Info ONTAK(R) IV solution, 2010).
    H) FATIGUE
    1) WITH THERAPEUTIC USE
    a) During a randomized placebo-controlled trial, fatigue was reported in 21 (46.7%) and 24 (43.6%) patients who received denileukin diftitox as a single agent at doses of 9 mcg/kg (n=45) and 18 mcg/kg (n=55), respectively, compared to 14 (31.8%) patients who received a placebo (n=44) (Prod Info ONTAK(R) IV solution, 2010).
    b) CASE REPORT: A 69-year-old woman with skin-limited cutaneous T-cell lymphoma developed mild asymptomatic hypotension (80/35 mm Hg), fatigue, and leg edema during the first 5-day cycle of denileukin diftitox therapy (9 mcg/kg/day) (Park et al, 2007).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROINTESTINAL TRACT FINDING
    1) WITH THERAPEUTIC USE
    a) Gastrointestinal effects including diarrhea, anorexia, nausea, and vomiting occurred in approximately 75% of patients in a phase III trial of patients with cutaneous T-cell lymphoma (n=71). Grade 3/4 gastrointestinal effects occurred in 20% of patients who received 9 mcg/kg/day and 36% of patients who received 18 mcg/kg/day. Anorexia occurred in 44% of patients. Gastrointestinal adverse effects are most common and severe early in therapy (first or second course) and tend to subside thereafter (Olsen et al, 2001a; LeMaistre et al, 1998a; Sewell et al, 1994).
    B) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) During a randomized placebo-controlled trial, nausea and vomiting were reported in 21 (46.7%) and 6 (13.3%) patients, respectively who received denileukin diftitox as a single agent at a dose of 9 mcg/kg (n=45) and in 33 (60%) and 19 (34.5%) patients, respectively, who received denileukin diftitox as a single agent at a dose of 18 mcg/kg (n=55), compared to 10 (22.7%) and 3 (6.8%) patients, respectively, who received a placebo (n=44) (Prod Info ONTAK(R) IV solution, 2010).
    b) Grade 3 or 4 nausea and vomiting were infrequent (2%) with doses of up to 19 mcg/kg/day in a phase I trial involving lymphoma patients; at higher doses it was common and dose-limiting (LeMaistre et al, 1998a).
    2) WITH POISONING/EXPOSURE
    a) Moderate to severe nausea and vomiting were reported at doses of 31 mcg/kg/day (approximately twice the recommended dose) (Prod Info ONTAK(R) IV solution, 2010).
    C) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) During a randomized placebo-controlled trial, anorexia was reported in 4 (8.9%) and 11(20%) patients who received denileukin diftitox as a single agent at doses of 9 mcg/kg (n=45) and 18 mcg/kg (n=55), respectively, compared to 2 (4.5%) patients who received a placebo (n=44) (Prod Info ONTAK(R) IV solution, 2010).
    D) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) During a randomized placebo-controlled trial, diarrhea was reported in 10 (22.2%) and 12 (21.8%) patients who received denileukin diftitox as a single agent at doses of 9 mcg/kg (n=45) and 18 mcg/kg (n=55), respectively, compared to 4 (9.1%) patients who received a placebo (n=44) (Prod Info ONTAK(R) IV solution, 2010).
    b) Persistent diarrhea has led to dehydration (Anon, 1998). Dehydration (all grades) was reported in 13 (9%) patients receiving denileukin diftitox doses ranging from 3 to 31 mcg/kg/day; 10 (7%) patients experienced grade 3 and 4 dehydration (Prod Info ONTAK(R) intravenous injection, 2006).
    E) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) In two clinical studies of 143 patients with lymphoma (including 105 patients with cutaneous T-cell lymphoma [CTCL]), constipation (all grades) was reported in 13 (9%) patients receiving denileukin diftitox doses ranging from 3 to 31 mcg/kg/day; 2 (1%) patients experienced grade 3 and 4 constipation (Prod Info ONTAK(R) intravenous injection, 2006).
    F) INDIGESTION
    1) WITH THERAPEUTIC USE
    a) In two clinical studies of 143 patients with lymphoma (including 105 patients with cutaneous T-cell lymphoma [CTCL]), dyspepsia (all grades) was reported in 10 (7%) patients receiving denileukin diftitox doses ranging from 3 to 31 mcg/kg/day (Prod Info ONTAK(R) intravenous injection, 2006).
    G) DYSPHAGIA
    1) WITH THERAPEUTIC USE
    a) In two clinical studies of 143 patients with lymphoma (including 105 patients with cutaneous T-cell lymphoma [CTCL]), dysphagia (all grades) was reported in 9 (6%) patients receiving denileukin diftitox doses ranging from 3 to 31 mcg/kg/day; 2 (1%) patients experienced grade 3 and 4 dysphagia (Prod Info ONTAK(R) intravenous injection, 2006).
    H) TASTE SENSE ALTERED
    1) WITH THERAPEUTIC USE
    a) During a randomized placebo-controlled trial, dysgeusia was reported in 6 (10.9%) patients who received denileukin diftitox as a single agent at a dose of 18 mcg/kg (n=55) compared to 1 patient who received a placebo (n=44) (Prod Info ONTAK(R) IV solution, 2010).
    I) PANCREATITIS
    1) WITH THERAPEUTIC USE
    a) Pancreatitis has been reported infrequently (less than 5%) with denileukin diftitox use (Prod Info ONTAK(R) intravenous injection, 2006).
    J) ULCER OF MOUTH
    1) WITH THERAPEUTIC USE
    a) Oral ulcer has been reported infrequently (less than 5%) with denileukin diftitox use (Prod Info ONTAK(R) intravenous injection, 2006).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) INJURY OF LIVER
    1) WITH THERAPEUTIC USE
    a) Reversible transaminase elevations are seen in 61% of patients, and reach grade 3 or 4 in up to 17% (Olsen et al, 2001a; LeMaistre et al, 1998a; Nichols et al, 1997). These changes are most often observed during the first course of treatment, and decrease in frequency and severity with subsequent courses. In phase I studies, grade 3 or 4 transaminase elevations (5 times normal) were observed in 15% of lymphoma patients (LeMaistre et al, 1998a).
    b) Elevated transaminase levels were reported in 84% of patients treated with denileukin diftitox (n=234). The hepatic enzyme elevations primarily occurred during the first or second chemotherapy cycle and resolved without discontinuation of denileukin diftitox or medical intervention (Prod Info ONTAK(R) IV solution, 2010).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ACUTE RENAL IMPAIRMENT
    1) WITH THERAPEUTIC USE
    a) Acute renal insufficiency has been reported infrequently (less than 5%) with denileukin diftitox use (Prod Info ONTAK(R) intravenous injection, 2006).
    B) BLOOD IN URINE
    1) WITH THERAPEUTIC USE
    a) Microscopic hematuria has been reported infrequently (less than 5%) with denileukin diftitox use (Prod Info ONTAK(R) intravenous injection, 2006).
    b) In two clinical studies of 143 patients with lymphoma (including 105 patients with cutaneous T-cell lymphoma [CTCL]), hematuria (all grades) was reported in 15 (10%) patients receiving denileukin diftitox doses ranging from 3 to 31 mcg/kg/day; 5 (3%) patients experienced grade 3 and 4 hematuria (Prod Info ONTAK(R) intravenous injection, 2006).
    C) PROTEINURIA
    1) WITH THERAPEUTIC USE
    a) In two clinical studies of 143 patients with lymphoma (including 105 patients with cutaneous T-cell lymphoma [CTCL]), albuminuria (all grades) was reported in 14 (10%) patients receiving denileukin diftitox doses ranging from 3 to 31 mcg/kg/day; one (1%) patient experienced grade 3 and 4 albuminuria (Prod Info ONTAK(R) intravenous injection, 2006).
    D) PYURIA
    1) WITH THERAPEUTIC USE
    a) In two clinical studies of 143 patients with lymphoma (including 105 patients with cutaneous T-cell lymphoma [CTCL]), pyuria (all grades) was reported in 14 (10%) patients receiving denileukin diftitox doses ranging from 3 to 31 mcg/kg/day; one (1%) patient experienced grade 3 and 4 pyuria (Prod Info ONTAK(R) intravenous injection, 2006).
    E) SERUM CREATININE RAISED
    1) WITH THERAPEUTIC USE
    a) In two clinical studies of 143 patients with lymphoma (including 105 patients with cutaneous T-cell lymphoma [CTCL]), elevated serum creatinine (all grades) was reported in 10 (7%) patients receiving denileukin diftitox doses ranging from 3 to 31 mcg/kg/day; one (1%) patient experienced grade 3 and 4 elevated serum creatinine (Prod Info ONTAK(R) intravenous injection, 2006).
    b) In a phase III trial of patients with cutaneous T-cell lymphoma (n=71), 10% of patients had more than 50% increase in serum creatinine over baseline. The increase in serum creatinine was most likely related to dehydration and/or vascular leak syndrome and generally responded quickly to fluids and/or diuretics. Most renal changes first occurred during the initial course and normalized off drug (Olsen et al, 2001a).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LYMPHOCYTOPENIA
    1) WITH THERAPEUTIC USE
    a) In two clinical studies of 143 patients with lymphoma (including 105 patients with cutaneous T-cell lymphoma [CTCL]), decreased lymphocyte counts (less than 900 cells/mcL) occurred in 34% of lymphoma patients, mainly during dosing days 1 to 5 and returning to normal by day 15 (Prod Info ONTAK(R) intravenous injection, 2006).
    b) Lymphopenia (less than 1000/microliter) occurred in 70% of patients in a phase III trial (n=71); 24% of patients had lymphopenia prior to receiving denileukin diftitox. Four patients who received 18 mcg/kg/day developed an absolute lymphocyte count of less than 200/microliter (Olsen et al, 2001a). However, in a phase I study, no change in peripheral blood lymphocytes was observed with varying doses (3 to 31 mcg/kg/day) (LeMaistre et al, 1998a).
    B) ANEMIA
    1) WITH THERAPEUTIC USE
    a) In two clinical studies of 143 patients with lymphoma (including 105 patients with cutaneous T-cell lymphoma [CTCL]), anemia (all grades) was reported in 26 (18%) patients receiving denileukin diftitox doses ranging from 3 to 31 mcg/kg/day; 9 (6%) patients experienced grade 3 and 4 anemia (Prod Info ONTAK(R) intravenous injection, 2006).
    C) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) In two clinical studies of 143 patients with lymphoma (including 105 patients with cutaneous T-cell lymphoma [CTCL]), thrombocytopenia (all grades) was reported in 12 (8%) patients receiving denileukin diftitox doses ranging from 3 to 31 mcg/kg/day; 3 (2%) patients experienced grade 3 and 4 thrombocytopenia (Prod Info ONTAK(R) intravenous injection, 2006).
    D) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) In two clinical studies of 143 patients with lymphoma (including 105 patients with cutaneous T-cell lymphoma [CTCL]), leukopenia (all grades) was reported in 9 (6%) patients receiving denileukin diftitox doses ranging from 3 to 31 mcg/kg/day; 4 (3%) patients experienced grade 3 and 4 leukopenia (Prod Info ONTAK(R) intravenous injection, 2006).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) During a randomized placebo-controlled trial, pruritus was reported in 7 (15.6%) and 10 (18.2%) patients who received denileukin diftitox as a single agent at doses of 9 mcg/kg (n=45) and 18 mcg/kg (n=55), respectively, compared to 4 (9.1%) patients who received a placebo (n=44) (Prod Info ONTAK(R) IV solution, 2010).
    b) Pruritus was reported by 21% of patients with cutaneous T-cell lymphoma in a phase III trial (n=71). The relationship of denileukin diftitox to pruritus was difficult to assess as 75% of patients had clinically significant pruritus upon entering the trial (Olsen et al, 2001a).
    B) ERUPTION
    1) WITH THERAPEUTIC USE
    a) During a randomized placebo-controlled trial, rash was reported in 11 (24.4%) and 11 (20%) patients who received denileukin diftitox as a single agent at doses of 9 mcg/kg (n=45) and 18 mcg/kg (n=55), respectively, compared to 2 (4.5%) patients who received a placebo (n=44) (Prod Info ONTAK(R) IV solution, 2010).
    b) Rashes (maculopapular, petechial, vesicular-bullous, urticarial, and/or eczematous) occurred in 35% of patients in a phase III trial of patients with cutaneous T-cell lymphoma (n=71). Grade 3/4 rash occurred in 23% of patients who received 9 mcg/kg/day and 19% of patients who received 18 mcg/kg/day. Rashes occurred during dosing days in 15% of patients. Noninfusion related rashes occurred in 25% of patients. Most rashes were treated with antihistamines, oral/topical corticosteroids, and/emollients. The relationship of denileukin diftitox infusion to rashes was difficult to assess (Olsen et al, 2001a).
    C) SWEATING
    1) WITH THERAPEUTIC USE
    a) In two clinical studies of 143 patients with lymphoma (including 105 patients with cutaneous T-cell lymphoma [CTCL]), sweating (all grades) was reported in 15 (10%) patients receiving denileukin diftitox doses ranging from 3 to 31 mcg/kg/day; one (1%) patient experienced grade 3 and 4 pruritus (Prod Info ONTAK(R) intravenous injection, 2006).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) During a randomized placebo-controlled trial, myalgia was reported in 8 (17.8%) and 11 (20%) patients who received denileukin diftitox as a single agent at doses of 9 mcg/kg (n=45) and 18 mcg/kg (n=55), respectively, compared to 2 (4.5%) patients who received a placebo (n=44) (Prod Info ONTAK(R) IV solution, 2010).
    B) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) During a randomized placebo-controlled trial, arthralgia was reported in 7 (15.6%) and 7 (12.7%) patients who received denileukin diftitox as a single agent at doses of 9 mcg/kg (n=45) and 18 mcg/kg (n=55), respectively, compared to 5 (11.4%) patients who received a placebo (n=44) (Prod Info ONTAK(R) IV solution, 2010).
    C) BACKACHE
    1) WITH THERAPEUTIC USE
    a) During a randomized placebo-controlled trial, back pain was reported in 7 (15.6%) and 10 (18.2%) patients who received denileukin diftitox as a single agent at doses of 9 mcg/kg (n=45) and 18 mcg/kg (n=55), respectively, compared to 1 patient who received a placebo (n=44) (Prod Info ONTAK(R) IV solution, 2010).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERTHYROIDISM
    1) WITH THERAPEUTIC USE
    a) Hyperthyroidism including thyroiditis and thyrotoxicosis have been reported infrequently (less than 5%) with denileukin diftitox use (Prod Info ONTAK(R) intravenous injection, 2006; Ghori et al, 2006).
    b) Eight patients with mycosis fungoides developed transient thyrotoxicosis within days of the first cycle of denileukin diftitox therapy (9 or 18 mcg/kg/day IV for 5 days every 3 weeks) or after the second cycle (n=4). Patients experienced tremors, nervousness, tachycardia, diarrhea, and weight loss. All symptoms resolved after the discontinuation of denileukin diftitox. Five patients developed hypothyroidism requiring levothyroxine therapy and two patients became euthyroid (Ghori et al, 2006).
    B) HYPOTHYROIDISM
    1) WITH THERAPEUTIC USE
    a) Hypothyroidism has been reported infrequently (less than 5%) with denileukin diftitox use (Prod Info ONTAK(R) intravenous injection, 2006; Ghori et al, 2006).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) Acute hypersensitivity reactions (eg, hypotension, back pain, chest pain or tightness, vasodilation, rash, dyspnea, tachycardia, dysphagia or laryngismus, syncope, other allergic responses) have occurred in as many as 69% (98 of 143) of patients during or within 24 hours of denileukin diftitox treatment; anaphylaxis is rare as have interrupting or decreasing the rate of infusion (Prod Info ONTAK(R) intravenous injection, 2006; LeMaistre et al, 1998a; Anon, 1998).
    b) In a phase III trial of patients with cutaneous T-cell lymphoma (n=71), a group of acute hypersensitivity-type events occurred in 60% of patients during or within 24 hours of infusion and included dyspnea (20%), hypotension (17%), back pain (17%), chest pain/tightness (13%), pruritus (13%), and flushing of face/upper body (13%). Treatment consisted of temporarily interrupting or decreasing the rate of infusion and the administration of antihistamines or corticosteroids as necessary (Olsen et al, 2001a).

Reproductive

    3.20.1) SUMMARY
    A) Denileukin diftitox does not have an FDA pregnancy category rating. No studies examining the use of denileukin diftitox during pregnancy are available at this time.
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) There is no data on the use of denileukin diftitox in pregnant women. The effects, if any, on the developing fetus are unknown. Until more information is available, denileukin diftitox should only be used during pregnancy if the maternal condition justifies the potential risk to the fetus (Prod Info ONTAK(R) IV solution , 2008).
    B) PREGNANCY CATEGORY
    1) The manufacturer had previously classified denileukin diftitox as FDA pregnancy category C, although the pregnancy category rating has been withdrawn and is currently unassigned (Prod Info ONTAK(R) IV solution , 2008).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) No reports describing the use of denileukin diftitox during human lactation are available and the effects on the nursing infant from exposure to the drug in milk are unknown. Until more data are available, use caution when considering the use of denileukin diftitox in lactating women (Prod Info ONTAK(R) IV solution , 2008).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) Fertility studies have not been conducted in humans or animals (Prod Info ONTAK(R) IV solution , 2008).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS173146-27-5 (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
    3.21.2) SUMMARY/HUMAN
    A) Studies have not been done to evaluate the carcinogenic potential of denileukin diftitox.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) Studies have not been done to evaluate the carcinogenic potential of denileukin diftitox (Prod Info ONTAK(R) intravenous injection, 2006).

Genotoxicity

    A) Denileukin diftitox was not mutagenic in the Ames test or the chromosomal aberration assay (Prod Info ONTAK(R) intravenous injection, 2006).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs including temperature and blood pressure.
    B) Obtain baseline CBC and complete chemistry panel, including renal function, liver enzymes and serum albumin levels.
    C) Monitor fluid status, as dehydration is possible with therapy.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    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) Plasma concentrations are not readily available or clinically useful in the management of overdose.

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) Monitor vital signs including temperature and blood pressure.
    B) Obtain baseline CBC and complete chemistry panel, including renal function, liver enzymes and serum albumin levels.
    C) Monitor fluid status, as dehydration is possible with therapy.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    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) Plasma concentrations are not readily available or clinically useful in the management of overdose.

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: A specific toxic dose has not been established. Doses of 31 mcg/kg/day caused moderate to severe nausea, vomiting, fever, chills and/or persistent asthenia.
    B) THERAPEUTIC DOSE: ADULT: The recommended dosage regimen is 9 or 18 mcg/kg/day infused intravenously over 30 to 60 minutes, administered for 5 consecutive days every 3 weeks for 8 cycles. PEDIATRIC: Safety and efficacy have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) 9 or 18 mcg/kg/day administered intravenously, infused over 30 to 60 minutes for 5 consecutive days every 3 weeks for 8 cycles (Prod Info ONTAK(R) IV solution, 2010)
    7.2.2) PEDIATRIC
    A) Safety and efficacy in the pediatric or adolescent population have not been established (Prod Info ONTAK(R) IV solution, 2010).

Maximum Tolerated Exposure

    A) A specific toxic dose has not been established. Doses of 31 mcg/kg/day caused moderate to severe nausea, vomiting, fever, chills and/or persistent asthenia (Prod Info ONTAK(R) IV solution, 2010).

Workplace Standards

    A) ACGIH TLV Values for CAS173146-27-5 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS173146-27-5 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS173146-27-5 :
    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 CAS173146-27-5 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Denileukin diftitox is a fusion protein that directs the cytotoxic action of diptheria toxin to cells that express the high affinity (CD25/CD122/CD132) form of the IL-2 receptor. Certain leukemias and lymphomas, including cutaneous T-cell lymphoma, contain malignant cells that express at least one subunit of the IL-2 receptor. By interacting with the high affinity IL-2 receptor on the cell surface (seen ex vivo), denileukin diftitox inhibits cellular protein synthesis, resulting in cell death (Prod Info ONTAK(R) intravenous injection, 2006).

Physicochemical

Molecular Weight

    A) 58 kD (Prod Info ONTAK(R) intravenous injection, 2006)

References

General Bibliography

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