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OPRELVEKIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Oprelvekin, a recombinant human interleukin-11, is a platelet growth factor that can stimulate the proliferation and maturation of megakaryocytes thereby increasing the production of platelets.

Specific Substances

    1) Oprelvekina
    2) Oprelvekine
    3) Oprelvekinum
    4) Molecular Formula: C85-H1411-N253-O235-S2
    5) CAS 145941-26-0

Available Forms Sources

    A) FORMS
    1) Oprelvekin is available in single use vials containing 5 mg of oprelvekin as a sterile, lyophilized powder with 23 mg glycine, 1.6 mg dibasic sodium phosphate heptahydrate, and 0.55 mg monobasic sodium phosphate monohydrate (Prod Info NEUMEGA(R) subcutaneous injection, 2012).
    B) USES
    1) Oprelvekin is used for the prevention of severe thrombocytopenia and to reduce the need for platelet transfusions following myelosuppressive therapy in adults with nonmyeloid malignancies (Prod Info NEUMEGA(R) subcutaneous injection, 2012). It stimulates hematopoietic stem cells and megakaryocytes which result in an increase in platelet production (Borbolla et al, 2001).

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: Oprelvekin is used for the prevention of severe thrombocytopenia and to reduce the need for platelet transfusions following myelosuppressive therapy in adults with nonmyeloid malignancies.
    B) PHARMACOLOGY: Oprelvekin, a recombinant human interleukin-11, is a thrombopoietic growth factor that stimulates the proliferation of hematopoietic stem cells and megakaryocyte progenitor cells and induces megakaryocyte maturation, thereby increasing the production of platelets.
    C) TOXICOLOGY: Oprelvekin is capable of inducing plasma volume expansion with hemodilution as a result of stimulation of renal sodium reabsorption. Serious fluid retention has resulted in peripheral edema, dyspnea on exertion, pulmonary edema, capillary leak syndrome, atrial arrhythmias, and exacerbation of preexisting pleural effusions.
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH THERAPEUTIC USE
    1) COMMON: Edema, dyspnea, tachycardia, conjunctival injection, palpitations, atrial arrhythmias and pleural effusions have been reported. Other reported effects include rash, nausea, vomiting, abdominal pain, diarrhea, oral moniliasis, blurred vision, rhinitis, neutropenic fever, anemia, headache, dizziness, and fatigue. SERIOUS: Allergic reaction including anaphylaxis may occur. Syncope, fluid retention (ie, peripheral edema, dyspnea, pulmonary edema, capillary leak syndrome and exacerbation of preexisting pleural effusions), atrial fibrillation, fever, and pneumonia have also been reported.
    F) WITH POISONING/EXPOSURE
    1) No reports of overdose. Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses. Based on limited experience, oprelvekin doses of greater than 50 mcg/kg may increase the risk of cardiovascular effects (ie, dysrhythmias, fluid retention).
    0.2.20) REPRODUCTIVE
    A) Oprelvekin is classified as FDA pregnancy category C.
    B) Embryocidal effects have been observed in pregnant rats and rabbits receiving doses of 0.2 to 20 times the human dose.
    0.2.21) CARCINOGENICITY
    A) Carcinogenic studies involving oprelvekin have not been performed. Based on in vitro studies oprelvekin is not mutagenic.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Obtain an ECG following a significant overdose, and institute continuous cardiac monitoring.
    C) Monitor fluid balance and electrolytes as indicated.
    D) Assess for evidence of fluid retention (eg, peripheral edema, dyspnea, pleural effusion).
    E) Obtain a chest x-ray in patient's with evidence of fluid retention to evaluate for pulmonary edema, and/or pleural effusion.
    F) Monitor CBC with differential and platelet count in symptomatic patients.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Assess cardiovascular function. Monitor for fluid retention following a significant exposure; monitor fluid and electrolyte balance frequently. Evaluate and monitor airway patency and adequacy of respiration and oxygenation. Treatment may consist of diuretic therapy to manage fluid retention and an increase in plasma volume. If symptoms are severe, endotracheal intubation and assisted ventilation may be indicated. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required.
    C) DECONTAMINATION
    1) Gastrointestinal decontamination is not recommended; oprelvekin is only available parenterally.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with life-threatening cardiac dysrhythmias, respiratory distress, severe allergic reactions, or hemodynamic instability.
    E) ANTIDOTE
    1) None.
    F) TACHYARRHYTHMIAS
    1) Monitor ECG and consider continuous cardiac monitoring following a significant overdose. Sinus tachycardia does not generally require treatment unless hemodynamic compromise develops. Atrial fibrillation or flutter generally respond to discontinuing oprelvekin, occasionally rate control is required.
    G) ENHANCED ELIMINATION
    1) It is unknown if hemodialysis would be effective in overdose.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients who are symptomatic and patients with deliberate overdose should be observed with frequent monitoring of vital signs. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients who remain symptomatic despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    I) PITFALLS
    1) When managing a suspected oprelvekin overdose, the possibility of multidrug involvement should be considered. Symptoms of overdose are similar to reported side effects of the medication.
    J) PHARMACOKINETICS
    1) Tmax and Cmax: Following a single 50 mcg/kg subQ dose, the peak serum concentration of 17.4 +/- 5.4 ng/mL was reached at 3.2 +/- 2.4 hours. Absolute bioavailability: Greater than 80%. Vd: 112 to 152 mL/kg. Metabolism: Extensively metabolized. Excretion: The kidney is the primary route of elimination. Elimination half-life: Single subQ infusion: 6.9 +/- 1.7 hours.
    K) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause fluid retention or dysrhythmias.

Range Of Toxicity

    A) TOXICITY: The minimum acute oral toxic dose for humans is unknown. Oprelvekin doses of greater than 50 mcg/kg may increase the risk of cardiovascular effects (ie, dysrhythmias, fluid retention). The maximum dose given to humans has not exceeded 125 mcg/kg.
    B) THERAPEUTIC DOSE: ADULT: 50 mcg/kg subQ once daily until post-nadir platelet count is 50,000/mcL or greater, up to 21 days of dosing. Dosing should not to exceed beyond 21 days per treatment course. CHILD: Safety and efficacy have not been established in children.

Clinical Effects

Summary Of Exposure

    A) USES: Oprelvekin is used for the prevention of severe thrombocytopenia and to reduce the need for platelet transfusions following myelosuppressive therapy in adults with nonmyeloid malignancies.
    B) PHARMACOLOGY: Oprelvekin, a recombinant human interleukin-11, is a thrombopoietic growth factor that stimulates the proliferation of hematopoietic stem cells and megakaryocyte progenitor cells and induces megakaryocyte maturation, thereby increasing the production of platelets.
    C) TOXICOLOGY: Oprelvekin is capable of inducing plasma volume expansion with hemodilution as a result of stimulation of renal sodium reabsorption. Serious fluid retention has resulted in peripheral edema, dyspnea on exertion, pulmonary edema, capillary leak syndrome, atrial arrhythmias, and exacerbation of preexisting pleural effusions.
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH THERAPEUTIC USE
    1) COMMON: Edema, dyspnea, tachycardia, conjunctival injection, palpitations, atrial arrhythmias and pleural effusions have been reported. Other reported effects include rash, nausea, vomiting, abdominal pain, diarrhea, oral moniliasis, blurred vision, rhinitis, neutropenic fever, anemia, headache, dizziness, and fatigue. SERIOUS: Allergic reaction including anaphylaxis may occur. Syncope, fluid retention (ie, peripheral edema, dyspnea, pulmonary edema, capillary leak syndrome and exacerbation of preexisting pleural effusions), atrial fibrillation, fever, and pneumonia have also been reported.
    F) WITH POISONING/EXPOSURE
    1) No reports of overdose. Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses. Based on limited experience, oprelvekin doses of greater than 50 mcg/kg may increase the risk of cardiovascular effects (ie, dysrhythmias, fluid retention).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Papilledema
    a) After repeated cycles of exposure in clinical trials, the incidence of papilledema was 16% (7/43) in children and 1% (3/362) in adults. In nonhuman primates treated with an oprelvekin dose of 1000 micrograms/kilogram subcutaneously once daily for 4 to 13 weeks, papilledema was not associated with inflammation or histologic abnormality, and was reversible when dosing was discontinued. Oprelvekin should not be administered to children, especially those under the age of 12 years (Prod Info NEUMEGA(R) subcutaneous injection, 2012).
    b) According to postmarketing reports, changes in visual acuity and/or visual field defects, including blurred vision and blindness, can occur in patients with papilledema (Prod Info NEUMEGA(R) subcutaneous injection, 2012).
    2) Blurred Vision
    a) Transient, mild visual blurring has been reported by patients receiving oprelvekin (Prod Info NEUMEGA(R) subcutaneous injection, 2012).
    b) CASE REPORT: A 38-year-old male with a recurrence of stage IIIA follicular mixed non-Hodgkins lymphoma was started on oprelvekin for thrombocytopenia and developed bilateral blurred vision. Ocular exam showed bilateral optic disc edema with exudate near the right optic nerve. Self-reported visual improvement occurred shortly after oprelvekin was discontinued, and follow-up exam showed resolution of bilateral edema (Peterson et al, 2005).
    3) Disorder of Optic Nerve
    a) There have been postmarketing reports of optic neuropathy occurring during the use of oprelvekin. A causal relationship to drug exposure has not been established (Prod Info NEUMEGA(R) subcutaneous injection, 2012).
    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) In a multiple-dose study of healthy volunteers (n=42) receiving oral oprelvekin, rhinitis was reported following a 10 mg dose (Cotreau et al, 2004).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) RISK FACTORS: Advanced age, a history of more than moderate alcohol consumption, cardiac disorder, doxorubicin therapy, diabetes, or hypertension may increase the risk of developing atrial dysrhythmias during therapy with oprelvekin (Smith, 2000).
    b) In adults, atrial fibrillation/flutter developed in approximately 12% of patients treated with oprelvekin compared with 1% of patients given placebo (Prod Info NEUMEGA(R) subcutaneous injection, 2012).
    2) WITH POISONING/EXPOSURE
    a) Based on limited experience, oprelvekin doses of greater than 50 mcg/kg may increase the risk of cardiovascular effects (ie, dysrhythmias, fluid retention) (Prod Info NEUMEGA(R) subcutaneous injection, 2012).
    B) PERIPHERAL EDEMA
    1) WITH THERAPEUTIC USE
    a) In a pilot study to improve liver histology with oprelvekin in patients with chronic hepatitis C and advanced liver disease nonresponsive to antiviral therapy, lower extremity edema was the most common adverse event reported. The edema was managed by low dose hydrochlorothiazide (25 to 50 mg/day). Only one patient stopped treatment early because of edema (Lawitz et al, 2004).
    2) WITH POISONING/EXPOSURE
    a) Based on limited experience, oprelvekin doses of greater than 50 mcg/kg may increase the risk of cardiovascular effects (ie, dysrhythmias, fluid retention) (Prod Info NEUMEGA(R) subcutaneous injection, 2012).
    C) TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) In adults, tachycardia has occurred in approximately 20% of patients treated with oprelvekin compared with 3% of patients given placebo. The incidence of tachycardia in pediatric patients during clinical trials has been as high as 84% (Prod Info NEUMEGA(R) subcutaneous injection, 2012).
    D) PALPITATIONS
    1) WITH THERAPEUTIC USE
    a) Palpitations have occurred in approximately 14% of patients treated with oprelvekin compared with 3% of patients given placebo (Prod Info NEUMEGA(R) subcutaneous injection, 2012).
    E) SYNCOPE
    1) WITH THERAPEUTIC USE
    a) Syncope has occurred in approximately 13% of patients treated with oprelvekin compared with 6% of patients given placebo (Prod Info NEUMEGA(R) subcutaneous injection, 2012).
    F) CARDIOMEGALY
    1) WITH THERAPEUTIC USE
    a) Radiographic and echocardiographic evidence of cardiomegaly (21%) has been reported during clinical trials involving pediatric patients (Prod Info NEUMEGA(R) subcutaneous injection, 2012).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) Dyspnea, possibly attributed to plasma volume-expanding effects, has been a frequent complication of oprelvekin in cancer patients receiving chemotherapy (Tepler et al, 1996). In two phase II placebo-controlled chemotherapy studies, most cases of dyspnea were mild to moderate and symptoms were self-limiting or responded well to diuretic therapy (Smith, 2000).
    b) In clinical trials, dyspnea was reported in 48% of patients who received oprelvekin 50 mcg/kg (n=69) compared with 22% of patients who received placebo (n=67) (Prod Info NEUMEGA(R) subcutaneous injection, 2012).
    B) PLEURAL EFFUSION
    1) WITH THERAPEUTIC USE
    a) In clinical trials, pleural effusions were reported in 10% of patients who received oprelvekin 50 mcg/kg (n=69) compared with 0% of patients who received placebo (n=67) (Prod Info NEUMEGA(R) subcutaneous injection, 2012).
    b) RISK FACTOR: One pilot study of patients with breast cancer suggested that patients with a past or current history of pleural effusion may be more at risk for fluid accumulation, as well as patients with preexisting ascites. Of the 7 patients that developed pleural effusion, 4 patients with existing pleural effusion developed worsening symptoms during oprelvekin therapy; all patients responded to furosemide therapy (Smith, 2000).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache is a relatively common adverse effect of subcutaneous oprelvekin, occurring in more than 30% of patients (Prod Info NEUMEGA(R) subcutaneous injection, 2012; Tepler et al, 1996; Gordon et al, 1996). Headache may be a complication of the plasma volume expansion induced by oprelvekin.
    b) In a multiple-dose study of healthy volunteers (n=42) receiving oral oprelvekin, headache was reported following a 10 mg dose (Cotreau et al, 2004).
    B) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness is a relatively common adverse effect of subcutaneous oprelvekin, occurring in more than 30% of patients (Prod Info NEUMEGA(R) subcutaneous injection, 2012; Tepler et al, 1996; Gordon et al, 1996).
    C) FATIGUE
    1) WITH THERAPEUTIC USE
    a) Fatigue is a relatively common adverse effect of subcutaneous oprelvekin, occurring in more than 30% of patients (Tepler et al, 1996; Gordon et al, 1996).
    D) CEREBRAL HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) A small intracerebral hemorrhage was described in one patient in a phase I trial of subcutaneous oprelvekin (at the time of blood count nadirs), although a causal relationship is doubtful (Gordon et al, 1996).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting were reported in 77% of patients receiving oprelvekin 50 micrograms/kilogram during clinical trials (Prod Info NEUMEGA(R) subcutaneous injection, 2012).
    B) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) In a multiple-dose study of healthy volunteers (n=42) receiving oral oprelvekin, abdominal pain was reported (Cotreau et al, 2004).
    C) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) In a multiple-dose study of healthy volunteers (n=42) receiving oral oprelvekin, diarrhea was reported in one subject (Cotreau et al, 2004).
    b) In clinical trials, diarrhea was reported in 43% of patients who received oprelvekin 50 mcg/kg (n=69) compared with 33% of patients who received placebo (n=67) (Prod Info NEUMEGA(R) subcutaneous injection, 2012).
    D) CANDIDIASIS
    1) WITH THERAPEUTIC USE
    a) In clinical trials, oral moniliasis was reported in 14% of patients who received oprelvekin 50 mcg/kg (n=69) compared with 1% of patients who received placebo (n=67) (Prod Info NEUMEGA(R) subcutaneous injection, 2012).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) In a multiple-dose study of healthy volunteers (n=42) receiving oral oprelvekin, a subject developed a Grade 3 alanine aminotransferase elevation of 142 International Units/L (3.2 the upper limit of normal) on day 5 of therapy, which peaked at 235 International Units/L on day 9. No other clinically significant signs or symptoms developed and the level returned to normal within 5 weeks following discontinuation of oprelvekin (Cotreau et al, 2004).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) RENAL FAILURE SYNDROME
    1) WITH THERAPEUTIC USE
    a) There have been postmarketing reports of renal failure occurring during the use of oprelvekin. A causal relationship to drug exposure has not been established (Prod Info NEUMEGA(R) subcutaneous injection, 2012).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) In clinical trials of patients with malignancies, neutropenic fever was experienced by 48% of patients who had received 50 micrograms/kilogram of oprelvekin as compared to 42% of patients receiving placebo. A 2-fold increase in plasma fibrinogen after daily subcutaneous injections of oprelvekin was also reported (Prod Info NEUMEGA(R) subcutaneous injection, 2012).
    B) ANEMIA
    1) WITH THERAPEUTIC USE
    a) Anemia was reported in all cancer patients treated with subcutaneous oprelvekin alone in a phase I study. This was not associated with occult blood loss or hemolysis and appears to be related to plasma volume expansion induced by cytokine (producing dilutional anemia). Anemia became evident on day 2 to 3 of treatment and resolved within 2 weeks after discontinuation (Gordon et al, 1996).
    b) INCIDENCE: In two phase II placebo-controlled chemotherapy studies, anemia was reported in approximately 10% of oprelvekin patients as compared with 6% of placebo-treated patients (Smith, 2000).
    c) Oprelvekin does not appear to worsen the anemia induced by chemotherapy (Gordon et al, 1996).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Skin rashes were described in 25% of cancer patients treated with oprelvekin in one study (Prod Info NEUMEGA(R) subcutaneous injection, 2012; Tepler et al, 1996).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLAXIS
    1) WITH THERAPEUTIC USE
    a) Anaphylaxis has been reported during post marketing experience with the use of oprelvekin. Administration of oprelvekin should be permanently discontinued in any patient who develops an allergic or hypersensitivity reaction (Prod Info NEUMEGA(R) subcutaneous injection, 2012).

Reproductive

    3.20.1) SUMMARY
    A) Oprelvekin is classified as FDA pregnancy category C.
    B) Embryocidal effects have been observed in pregnant rats and rabbits receiving doses of 0.2 to 20 times the human dose.
    3.20.2) TERATOGENICITY
    A) PREGNANCY CATEGORY
    1) Oprelvekin is classified by the manufacturer as US FDA pregnancy category C (Prod Info NEUMEGA(R) subcutaneous injection, 2006).
    B) ANIMAL STUDIES
    1) In rabbits receiving oprelvekin at doses up to 0.6 times the human dose (30 mcg/kg/da), no teratogenic effects were produced (Prod Info NEUMEGA(R) subcutaneous injection, 2006).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is not known if oprelvekin is excreted in human milk. Women taking oprelvekin should consider stopping treatment or not breast feed (Prod Info NEUMEGA(R) subcutaneous injection, 2006).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) Transient hypoactivity and dyspnea occurred in pregnant rats at doses of two to 20 times the human dose (>/= 100 mcg/kg/day). Other effects included prolonged estrus cycle, increased early embryonic deaths and a decreased number of live fetuses (Prod Info NEUMEGA(R) subcutaneous injection, 2006).
    2) In animal studies, pregnant rabbits developed a decrease in fecal/urine elimination (the only toxicity noted at 1 mcg/kg/day in dams), as well as a decrease in food consumption, body weight loss, abortion, increased embryonic and fetal deaths, and a decrease in the number of live fetuses (Prod Info NEUMEGA(R) subcutaneous injection, 2006).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) Carcinogenic studies involving oprelvekin have not been performed. Based on in vitro studies oprelvekin is not mutagenic.
    3.21.4) ANIMAL STUDIES
    A) LACK OF INFORMATION
    1) Carcinogenic studies involving oprelvekin have not been performed (Prod Info NEUMEGA(R) subcutaneous injection, 2006).

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) Obtain an ECG following a significant overdose, and institute continuous cardiac monitoring.
    C) Monitor fluid balance and electrolytes as indicated.
    D) Assess for evidence of fluid retention (eg, peripheral edema, dyspnea, pleural effusion).
    E) Obtain a chest x-ray in patient's with evidence of fluid retention to evaluate for pulmonary edema, and/or pleural effusion.
    F) Monitor CBC with differential and platelet count in symptomatic patients.

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 who remain symptomatic despite treatment should be admitted.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) Patients who are symptomatic and patients with deliberate overdose should be observed with frequent monitoring of vital signs. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Obtain an ECG following a significant overdose, and institute continuous cardiac monitoring.
    C) Monitor fluid balance and electrolytes as indicated.
    D) Assess for evidence of fluid retention (eg, peripheral edema, dyspnea, pleural effusion).
    E) Obtain a chest x-ray in patient's with evidence of fluid retention to evaluate for pulmonary edema, and/or pleural effusion.
    F) Monitor CBC with differential and platelet count in symptomatic patients.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Gastrointestinal decontamination is not recommended; oprelvekin is only available parenterally.

Range Of Toxicity

Summary

    A) TOXICITY: The minimum acute oral toxic dose for humans is unknown. Oprelvekin doses of greater than 50 mcg/kg may increase the risk of cardiovascular effects (ie, dysrhythmias, fluid retention). The maximum dose given to humans has not exceeded 125 mcg/kg.
    B) THERAPEUTIC DOSE: ADULT: 50 mcg/kg subQ once daily until post-nadir platelet count is 50,000/mcL or greater, up to 21 days of dosing. Dosing should not to exceed beyond 21 days per treatment course. CHILD: Safety and efficacy have not been established in children.

Therapeutic Dose

    7.2.1) ADULT
    A) THROMBOCYTOPENIA
    1) The recommended dose is 50 mcg/kg subQ once daily as a single injection. Dosing beyond 21 days per treatment course is not recommended (Prod Info NEUMEGA(R) subcutaneous injection, 2012)
    7.2.2) PEDIATRIC
    A) The safety and efficacy of oprelvekin have not been established in children (Prod Info NEUMEGA(R) subcutaneous injection, 2012).

Maximum Tolerated Exposure

    A) Oprelvekin doses of greater than 50 mcg/kg may increase the risk of cardiovascular effects (ie, dysrhythmias, fluid retention). The maximum dose given to humans has not exceeded 125 mcg/kg (Prod Info NEUMEGA(R) subcutaneous injection, 2012).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) Following a single 50 mcg/kg subcutaneous dose, the peak serum concentration was of 17.4 +/- 5.4 ng/mL was reached at 3.2 +/- 2.4 hours (Tmax) (Sitaraman & Gewirtz, 2001).
    2) Clearance of IL-11 decreases with an increase in age, and clearance in infants and children (8 months to 11 years) is between 1.2 and 1.6 fold higher than in adults and adolescents 12 years of age and older (Prod Info NEUMEGA(R) subcutaneous injection, 2006).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) SYSTEMIC - Naturally occurring IL-11 is part of the cytokine family that shares the gp 130 signal transducer and is produced by bone marrow stromal cells. Primary osteoblasts and mature osteoclasts express messenger RNAs (mRNAs) for both IL-11 receptor (IL-11R alpha) and gp130. Potential targets of IL-11 are both bone-forming and bone-resorbing cells (Prod Info NEUMEGA(R) subcutaneous injection, 2006).
    B) The primary hematopoietic action of oprelvekin is to stimulate megakaryocytopoiesis and thrombopoiesis. It has potent thrombopoietic activity in animal models of compromised hematopoiesis. Preclinical studies have shown that mature megakaryocytes developed during in vivo treatment with oprelvekin are ultrastructurally normal and that platelets developed during treatment are morphologically and functionally normal with a normal life span (Prod Info NEUMEGA(R) subcutaneous injection, 2006).
    C) No change in platelet reactivity as measured by platelet activation in response to adenosine diphosphate (ADP) has been associated with therapy (Prod Info NEUMEGA(R) subcutaneous injection, 2006).
    D) Nonhematopoietic actions in animals include regulation of intestinal epithelium growth (enhanced healing of gastrointestinal lesions), inhibition of adipogenesis, induction of acute phase protein synthesis, inhibition of pro-inflammatory cytokine production by macrophages, and stimulation of osteoclastogenesis and neurogenesis (Prod Info NEUMEGA(R) subcutaneous injection, 2006).
    E) Mean 24-hour sodium excretion decreased during oprelvekin treatment; no effect on potassium was observed (Prod Info NEUMEGA(R) subcutaneous injection, 2006).
    F) Oprelvekin produces a mean increase in plasma volume of more than 20% (with all subjects having at least a 10% increase); red blood cell volume decreases similarly (as a result of repeated phlebotomy). As a result, whole blood volume increases by approximately 10%, and hemoglobin decreases by approximately 10% (Prod Info NEUMEGA(R) subcutaneous injection, 2006).

Toxicologic Mechanism

    A) Inadvertent exposure can result in an increase in plasma volume and may result in clinical symptoms characteristic of fluid retention (ie, edema, hemodilution, dyspnea, pleural effusion, cardiac complications).
    B) HUMAN
    1) Because oprelvekin may produce an increase in plasma volume during therapeutic use, inadvertent exposure may result in clinical symptoms in a patient with pre-existing pleural effusion or history of cardiac disease (eg, congestive heart failure). Dilutional anemia defined as a reduction in hemoglobin concentration (10% to 15% decrease in hematocrit and red blood cell count) is associated with an increase in plasma volume secondary to renal sodium and water retention; treatment is usually not indicated (Prod Info NEUMEGA(R) subcutaneous injection, 2006).

References

General Bibliography

    1) Aoyama K, Uchida T, Takanuki F, et al: Pharmacokinetics of recombinant interleukin-11 (rhIL-11) in healthy male subjects. Br J Clin Pharmacol 1997; 43:571-578.
    2) Borbolla JR, Lopez-Hernandez MA, DeDiego J, et al: Use of interleukin-11 after autologous stem cell transplant: report of three cases and a very brief review of the literature. Haematologica 2001; 86(8):891-892.
    3) Cotreau MM, Stonis L, Strahs A, et al: A multiple-dose, safety, tolerability, pharmacokinetics and pharmacodynamic study of oral recombinant human interleukin-11 (oprelvekin). Biopharm Drug Dispos 2004; 25(7):291-296.
    4) Gordon MS, McCaskill-Stevens WJ, Battiato LA, et al: A phase I trial of recombinant human interleukin-11 (Neumega rhIL-11 growth factor) in women with breast cancer receiving chemotherapy. Blood 1996; 87:3615-3624.
    5) Lawitz EJ, Hepburn MJ, & Casey TJ: A pilot study of interleukin-11 in subjects with chronic hepatitis C and advanced liver disease nonresponsive to antiviral therapy. Am J Gastroenterol 2004; 99(12):2359-2364.
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