Medication Guide App

Oprelvekin (Systemic)


VA CLASSIFICATION
Primary: BL400

Commonly used brand name(s): Neumega.

Other commonly used names are
interleukin-11, recombinant ; and rIL-11 .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Hematopoietic stimulant—

Indications

Accepted

Thrombocytopenia (prophylaxis)—Oprelvekin is indicated to prevent severe thrombocytopenia and reduce the need for platelet transfusions following myelosuppressive chemotherapy in patients with nonmyeloid malignancies who are at high risk of severe thrombocytopenia {01}.

Note: Oprelvekin is not indicated following myeloablative chemotherapy {01}.
Use of oprelvekin has not been evaluated in patients receiving chemotherapy regimens of greater than 5 days duration or regimens including medications associated with delayed myelosuppression (e.g., nitrosoureas, mitomycin) {01}.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Synthetic. Produced by a recombinant DNA process involving Escherichia coli . Oprelvekin differs from naturally occurring interleukin-11 (IL-11) in that it lacks the amino-terminal proline residue, so that the polypeptide is composed of 177 amino acids instead of 178 in the native chain. This variation has not been found to result in measurable differences in bioactivity either in vitro or in vivo. {01}

Chemical group—
    Related to naturally occurring interleukins. {01}
Molecular weight—
    Approximately 19,000 daltons {01}


pH
    Reconstituted injection: 7 {01}.

Mechanism of action/Effect:

Naturally occurring IL-11 is produced by bone marrow stromal cells and is part of the cytokine family that shares the gp130 signal transducer. Primary osteoblasts and mature osteoclasts express messenger RNAs (mRNAs) for both IL-11 receptor (IL-11R alpha) and gp130. Both bone-forming and bone-resorbing cells are potential targets of IL-11. {01}

Oprelvekin"s primary hematopoietic action is to stimulate megakaryocytopoiesis and thrombopoiesis. 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. {01}

No change in platelet reactivity as measured by platelet activation in response to adenosine diphosphate (ADP) has been reported {01}. Platelet aggregation in response to ADP, epinephrine, collagen, ristocetin, and arachidonic acid has not been reported in association with oprelvekin treatment {01}.


Other actions/effects:

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 {01}.

Mean 24-hour sodium excretion decreases during oprelvekin treatment {01}.

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 approximately 10% and hemoglobin decreases approximately 10%. {01}

Biotransformation:

Appears to be extensive (based on animal studies) {01}.

Half-life:


Elimination:

6.9 ± 1.7 hours {01}.


Onset of action:

Increased platelet count—5 to 9 days after initiation of therapy in non-myelosuppressed patients {01}.

Time to peak concentration:

3.2 ± 2.4 hours after a single 50 mcg per kg of body weight (mcg/kg) dose {01}.

Peak serum concentration:

17.4 ± 5.4 nanograms per mL after a single 50 mcg/kg dose {01}.

Note: No accumulation has been found to occur after multiple doses {01}.


Duration of action:

Platelet count—Continues to increase for up to 7 days after therapy is discontinued, then returns to baseline within 14 days in non-myelosuppressed patients {01}.

Elimination:
    Renal (largely metabolized) {01}.

Note: Pharmacokinetic studies suggest that clearance decreases with age; clearance in infants and children (8 months to 11 years of age) is approximately 1.2- to 1.6-fold higher than in adults and adolescents (12 years of age and older) {01}.



Precautions to Consider

Carcinogenicity

Studies have not been done. However, oprelvekin was not found to stimulate in vitro growth of tumor colony–forming cells harvested from patients with a variety of human malignancies. {01}

Mutagenicity

In vitro studies found no evidence of genotoxicity {01}.

Pregnancy/Reproduction
Fertility—
Studies in rats at doses of 2 to 20 times the human dose found prolonged estrus cycles, but no effect on fertility was found at doses of up to 1000 mcg per kg of body weight (mcg/kg) per day {01}.

Pregnancy—
Adequate and well-controlled studies in humans have not been done {01}.

Studies in rats and rabbits given doses of 0.2 to 20 times the human dose found embryocidal effects. Studies in rats given doses of 2 to 20 times the human dose (100 mcg/kg per day or more) and in rabbits given doses of 0.02 to 2 times the human dose (1 mcg/kg per day or more) found parental toxicity. In rats, findings included transient hypoactivity and dyspnea after administration, prolonged estrus cycle, increased early embryonic deaths, and decreased numbers of live fetuses. In addition, in rats given 20 times the human dose, studies found low fetal body weights and a reduced number of ossified sacral and caudal vertebrae (i.e., retarded fetal development); however, no long-term behavioral or developmental abnormalities were detected. In rabbits, findings included decreased (fecal and urine) eliminations (the only toxicity noted at a dosage of 1 mcg/kg per day), decreased food consumption, body weight loss, abortion, increased embryonic and fetal death, and decreased numbers of live fetuses; no teratogenic effects were observed. {01}

Risk-benefit should be considered before use of oprelvekin during pregnancy {01}.

FDA Pregnancy Category C {01}.

Breast-feeding

It is not known whether oprelvekin is distributed into breast milk {01}. Risk-benefit should be considered before breast-feeding during oprelvekin treatment {01}.

Pediatrics

Studies of efficacy have not been done in pediatric patients {01}. However, based on a pharmacokinetic study, a dose of 75 to 100 mcg/kg will produce plasma concentrations consistent with those obtained in adults at a dose of 50 mcg/kg {01}.

Incidence of adverse effects in children appears to be similar to or lower than that in adults, although the incidences of tachycardia and conjunctival injection were higher in the pediatric study than in studies in adults {01}.

Long-term studies of the effects of oprelvekin on growth and development have not been done. Studies in growing rodents given doses of 100, 300, or 1000 mcg/kg per day for a minimum of 28 days found thickening of femoral and tibial growth plates, which did not completely resolve after a 28-day nontreatment period. A nonhuman primate toxicology study at doses of 10 to 1000 mcg/kg for 2 to 13 weeks found partially reversible joint capsule and tendon fibrosis and periosteal hyperostosis. One patient in the pediatric studies was found to have an asymptomatic, laminated periosteal reaction in the diaphyses of the femur, tibia, and fibula. {01}


Geriatrics


Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of oprelvekin in the elderly.


Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Acute-phase proteins, such as
Alpha 1-acid glycoprotein
C-reactive protein
Fibrinogen
Serum amyloid A protein    (plasma concentrations may be increased; the increase in plasma fibrinogen may be two-fold; concentrations return to normal after treatment with oprelvekin is discontinued {01})


Albumin and
Gamma globulins and
Transferrin    (serum concentrations may be decreased as a result of the increase in plasma volume {01})


Calcium    (serum concentrations may be decreased in parallel to the decrease in albumin concentrations {01})


Hematocrit and
Hemoglobin and
Red blood cell count    (serum concentrations may be moderately decreased [approximately 10 to 15%], without a decrease in red blood cell mass, predominantly as a result of the increase in plasma volume [dilutional anemia] that is primarily related to renal sodium and water retention; the decrease in hemoglobin concentrations typically begins within 3 to 5 days after initiation of oprelvekin therapy and reverses over approximately 1 week following discontinuation of oprelvekin {01})


Von Willebrand factor    (concentrations may be increased with a normal multimer pattern {01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Arrhythmias, atrial, history of    (transient atrial arrhythmias have occurred during oprelvekin treatment; risk-benefit should be considered before use of oprelvekin in patients with a history of atrial arrhythmia {01})


» Congestive heart failure    (oprelvekin may cause fluid retention; caution is recommended in patients with existing, or a predisposition to, congestive heart failure, as well as in those with a history of congestive heart failure who are well-compensated and receiving appropriate medical therapy {01})


» Fluid collections, pre-existing, including
Ascites or
Pleural effusions    (may be increased as a result of fluid retention caused by oprelvekin; monitoring is recommended and drainage considered if clinically indicated {01})


Medical conditions associated with fluid retention or
Medical conditions exacerbated by fluid retention    (oprelvekin may cause fluid retention {01})


Papilledema, existing or
Tumors involving the central nervous system    (risk of worsening or development of papilledema during oprelvekin treatment {01})


Sensitivity to oprelvekin{01}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Complete blood count and
» Platelet count    (a complete blood count should be obtained prior to chemotherapy and at regular intervals during oprelvekin treatment; platelet counts should be monitored during the time of the expected nadir and until adequate recovery of platelets has occurred [post-nadir counts ³ 50,000 cells per microliter] {01})


» Electrolyte concentrations, serum and
» Fluid balance monitoring    (recommended during treatment, with appropriate medical management for fluid retention; if a diuretic is used, it is recommended that fluid and electrolyte balance be carefully monitored; sudden deaths associated with severe hypokalemia have occurred in patients receiving chronic diuretic therapy and ifosfamide during oprelvekin treatment {01})




Side/Adverse Effects

Note: Most side/adverse effects are mild to moderate and reversible when oprelvekin is discontinued {01}.
Two cases of sudden death have been reported; both cases involved patients with severe hypokalemia (< 3 mEq per liter) who had received high doses of ifosfamide and daily doses of a diuretic {01}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Arrhythmias, atrial (irregular heartbeat)—may be asymptomatic; transient{01}
    
fluid retention (shortness of breath; swelling of feet or lower legs)—mild to moderate{01}
    
moniliasis, oral{01} (sore mouth or tongue; white patches in mouth and/or on tongue)
    
tachycardia{01} (fast heartbeat)

Note: Transient atrial arrhythmias, including atrial fibrillation or atrial flutter, have occurred in approximately 10% of patients treated with oprelvekin. In some patients, this effect may be related to increased plasma volume associated with fluid retention; oprelvekin is not directly arrhythmogenic. Arrhythmias are usually brief in duration, with conversion to sinus rhythm usually occurring either spontaneously or with rate-control medication therapy, and without clinical sequelae. Recurrence is unusual, even with continued oprelvekin treatment. Retrospective studies indicate a possible correlation between advancing age and other conditions associated with an increased risk of atrial arrhythmias (e.g., use of cardiac medications and a history of doxorubicin exposure) and the risk of development of atrial arrhythmias during oprelvekin therapy. {01}
Weight gain is not commonly associated with fluid retention {01}. In some patients, pre-existing pleural effusions increase during oprelvekin treatment {01}. Capillary leak syndrome has not been observed {01}.
Fluid retention is reversible within several days following withdrawal of oprelvekin {01}.


Incidence less frequent
    
Blurred vision{01}
    
conjunctival hemorrhage{01} (bloody eye)
    
dehydration{01} —may be asymptomatic
    
exfoliative dermatitis{01} (severe redness and peeling of skin)

Note: Blurred vision is usually transient and mild. However, papilledema has been reported in approximately 1.5% of patients following repeated treatment cycles. Papilledema not associated with inflammation or any other histologic abnormality has also been reported in nonhuman primates given doses of 1000 mcg per kg of body weight (mcg/kg) subcutaneously once a day for 4 to 13 weeks; it was reversible on discontinuation of oprelvekin. {01}




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Asthenia, severe{01} (weakness)
    
conjunctival injection{01} (red eyes)

Incidence less frequent
    
Paresthesia{01} (numbness or tingling of hands or feet)
    
skin discoloration{01}
    
skin rash at injection site

Note: Transient skin rashes at the injection site have occurred, as well as development of antibodies to oprelvekin (in about 1% of patients). However, presence of these antibodies or occurrence of the injection site reaction has not been associated with anaphylactoid reactions or loss of clinical response. No anaphylactoid or other severe allergic reactions have been reported with oprelvekin therapy. {01}






Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
While doses higher than 100 mcg per kg of body weight (mcg/kg) have not been administered to humans and clinical experience is limited, doses above 50 mcg/kg may be associated with an increased incidence of cardiovascular effects in adults {01}.

Treatment of overdose
Discontinue oprelvekin therapy and observe patient for signs of toxicity {01}. Decisions about possible reinstitution of oprelvekin should be based on individual patient factors (e.g., evidence of toxicity, continued need for therapy) {01}.




Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Oprelvekin (Systemic) .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to oprelvekin

Pregnancy—Embryocidal and toxic to parents in animal studies; risk-benefit should be considered





Use in children—Possible joint capsule and tendon fibrosis and periosteal hyperostosis with continuous dosing

Other medical problems, especially history of atrial arrhythmias, congestive heart failure, and pre-existing fluid retention states such as ascites or pleural effusions

Proper use of this medication
» Reading and following patient directions carefully with regard to:

• Preparation of the injection


• Use of disposable syringes; safe handling and disposal of syringe and needle


• Proper administration technique


• Stability of the injection


Giving each dose at about the same time each day {01}

» Proper dosing
Missed dose: Skip the missed dose and continue with the next scheduled dose {01}

» Proper storage

Precautions while using this medication
» Importance of close monitoring by physician


Side/adverse effects
Signs of potential side effects, especially atrial arrhythmias, fluid retention, oral moniliasis, tachycardia, blurred vision, conjunctival hemorrhage, dehydration, and exfoliative dermatitis


General Dosing Information
It is recommended that appropriate precautions be taken in the event that an allergic reaction occurs {01}.

Oprelvekin therapy should be initiated 6 to 24 hours after the completion of chemotherapy and discontinued at least 2 days before starting the next planned cycle of chemotherapy {01}. Safety and efficacy of administration of oprelvekin prior to or concurrently with cytotoxic chemotherapy have not been established {01}.


Parenteral Dosage Forms

OPRELVEKIN FOR INJECTION

Usual adult dose
Thrombocytopenia (prophylaxis)
Subcutaneous, 50 mcg per kg of body weight once a day {01}.

Note: It is recommended that oprelvekin be administered as a single subcutaneous injection into either the abdomen, thigh, or hip (or upper arm if the patient is not self-injecting) {01}.
It is recommended that dosing be initiated six to twenty-four hours after the completion of chemotherapy, and continued until the post-nadir platelet count is 50,000 cells per microliter or more. In clinical studies, doses were administered in courses of ten to twenty-one days. {01}
It is recommended that a single treatment course not exceed twenty-one days {01}.
It is recommended that treatment with oprelvekin be discontinued at least two days before the next planned cycle of chemotherapy {01}.



Usual pediatric dose
Thrombocytopenia (prophylaxis)
Efficacy has not been established {01}. However, a pharmacokinetic study has shown that a dose of 75 to 100 mcg per kg of body weight will produce a plasma concentration consistent with a dose of 50 mcg per kg of body weight in adults {01}.


Strength(s) usually available
U.S.—


5 mg (Rx) [Neumega (lyophilized powder)]

Note: The specific activity is approximately 8 x 10 6 Units per mg {01}.


Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F) {01}. Protect from freezing {01}.

Preparation of dosage form:
Oprelvekin for injection is prepared for subcutaneous administration by adding 1 mL of sterile water for injection (without preservative), provided by the manufacturer, to the vial using aseptic technique, producing a solution containing 5 mg of oprelvekin per mL. The vial should be gently swirled until the powder is dissolved. The vial should not be shaken. {01}

Stability:
Any unused portion of a vial should be discarded {01}. The single-use vial should not be re-entered {01}.

The reconstituted solution can be stored for up to 3 hours either at 2 to 8 °C (36 to 46 °F) or at room temperature up to 25 °C (77 °F) before use {01}. Reconstituted solution should not be stored in a syringe {01}.

Auxiliary labeling:
   • Do not shake {01}.
   • Do not freeze.



Developed: 04/23/1998



References
  1. Neumega package insert (Genetics Institute—US), Rev 12/97, Rec 12/97.
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