Oprelvekin

Oprelvekin
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]

Disclaimer

WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.

Black Box Warning

Allergic Reactions Including Anaphylaxis See full prescribing information for complete Boxed Warning. Condition Name:Neumega has caused allergic or hypersensitivity reactions, including anaphylaxis. Administration of Neumega should be permanently discontinued in any patient who develops an allergic or hypersensitivity reaction

Overview

Oprelvekin is a thrombopoietic growth factor that is FDA approved for the prophylaxis of severe thrombocytopenia and the reduction of the need for platelet transfusions following myelosuppressive chemotherapy in adult patients with nonmyeloid malignancies who are at high risk of severe thrombocytopenia. There is a Black Box Warning for this drug as shown here. Common adverse reactions include rash, candidiasis, nausea, oral candidiasis, vomiting, dizziness, fatigue, headache, blurred vision, conjunctival hyperemia and dyspnea.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

There is limited information regarding Oprelvekin FDA-Labeled Indications and Dosage (Adult) in the drug label.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Oprelvekin in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Oprelvekin in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Oprelvekin FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Oprelvekin in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Oprelvekin in pediatric patients.

Contraindications

• Neumega is contraindicated in patients with a history of hypersensitivity to Neumega or any component of the product.

Warnings

Allergic Reactions Including Anaphylaxis See full prescribing information for complete Boxed Warning. Condition Name:Neumega has caused allergic or hypersensitivity reactions, including anaphylaxis. Administration of Neumega should be permanently discontinued in any patient who develops an allergic or hypersensitivity reaction

Allergic Reactions Including Anaphylaxis

• In the post-marketing setting, Neumega has caused allergic or hypersensitivity reactions, including anaphylaxis. The administration of Neumega should be attended by appropriate precautions in case allergic reactions occur. In addition, patients should be counseled about the symptoms for which they should seek medical attention. Signs and symptoms reported included edema of the face, tongue, or larynx; shortness of breath; wheezing; chest pain; hypotension (including shock); dysarthria; loss of consciousness; mental status changes; rash; urticaria; flushing and fever. Reactions occurred after the first dose or subsequent doses of Neumega. Administration of Neumega should be permanently discontinued in any patient who develops an allergic or hypersensitivity reaction.

Increased Toxicity Following Myeloablative Therapy

• Neumega is not indicated following myeloablative chemotherapy. In a randomized, placebo-controlled Phase 2 study, the effectiveness of Neumega was not demonstrated. In this study, a statistically significant increased incidence in edema, conjunctival bleeding, hypotension, and tachycardia was observed in patients receiving Neumega as compared to placebo.
• The following severe or fatal adverse reactions have been reported in post-marketing use in patients who received Neumega following bone marrow transplantation: fluid retention or overload (eg, facial edema, pulmonary edema), capillary leak syndrome, pleural and pericardial effusion, papilledema and renal failure.

Fluid Retention

• Neumega is known to cause serious fluid retention that can result in peripheral edema, dyspnea on exertion, pulmonary edema, capillary leak syndrome, atrial arrhythmias, and exacerbation of pre-existing pleural effusions. Severe fluid retention, some cases resulting in death, was reported following recent bone marrow transplantation in patients who have received Neumega. Neumega is not indicated following myeloablative chemotherapy. It should be used with caution in patients with clinically evident congestive heart failure, patients who may be susceptible to developing congestive heart failure, patients receiving aggressive hydration, patients with a history of heart failure who are well-compensated and receiving appropriate medical therapy, and patients who may develop fluid retention as a result of associated medical conditions or whose medical condition may be exacerbated by fluid retention.
• Fluid retention is reversible within several days following discontinuation of Neumega. During dosing with Neumega, fluid balance should be monitored and appropriate medical management is advised.
• Close monitoring of fluid and electrolyte status should be performed in patients receiving chronic diuretic therapy. Sudden deaths have occurred in oprelvekin-treated patients receiving chronic diuretic therapy and ifosfamide who developed severe hypokalemia.
• Pre-existing fluid collections, including pericardial effusions or ascites, should be monitored. Drainage should be considered if medically indicated.

Dilutional Anemia

• Moderate decreases in hemoglobin concentration, hematocrit, and red blood cell count (~10% to 15%) without a decrease in red blood cell mass have been observed. These changes are predominantly due to an increase in plasma volume (dilutional anemia) that is primarily related to renal sodium and water retention. The decrease in hemoglobin concentration typically begins within three to five days of the initiation of Neumega, and is reversible over approximately a week following discontinuation of Neumega.

Cardiovascular Events

• Neumega use is associated with cardiovascular events including arrhythmias and pulmonary edema. Cardiac arrest has been reported, but the causal relationship to Neumega is uncertain. Use with caution in patients with a history of atrial arrhythmias, and only after consideration of the potential risks in relation to anticipated benefit. In clinical trials, cardiac events including atrial arrhythmias (atrial fibrillation or atrial flutter) occurred in 15% (23/157) of patients treated with Neumega at doses of 50 mcg/kg. Arrhythmias were usually brief in duration; conversion to sinus rhythm typically occurred spontaneously or after rate-control drug therapy. Approximately one-half (11/24) of the patients who were rechallenged had recurrent atrial arrhythmias. Clinical sequelae, including stroke, have been reported in patients who experienced atrial arrhythmias while receiving Neumega.
• The mechanism for induction of arrhythmias is not known. Neumega was not directly arrhythmogenic in animal models. In some patients, development of atrial arrhythmias may be due to increased plasma volume associated with fluid retention.
• In the post-marketing setting, ventricular arrhythmias have been reported, generally occurring within two to seven days of initiation of treatment.

Nervous System Events

• Stroke has been reported in the setting of patients who develop atrial fibrillation/flutter while receiving Neumega. Patients with a history of stroke or transient ischemic attack may also be at increased risk for these events.

Papilledema

• Papilledema has been reported in 2% (10/405) of patients receiving Neumega in clinical trials following repeated cycles of exposure. The incidence was higher, 16% (7/43) in children than in adults, 1% (3/362). Nonhuman primates treated with Neumega at a dose of 1,000 mcg/kg SC once daily for four to 13 weeks developed papilledema that was not associated with inflammation or any other histologic abnormality and was reversible after dosing was discontinued. Neumega should be used with caution in patients with pre-existing papilledema, or with tumors involving the central nervous system since it is possible that papilledema could worsen or develop during treatment. Changes in visual acuity and/or visual field defects ranging from blurred vision to blindness can occur in patients with papilledema taking Neumega.

Adverse Reactions

Clinical Trials Experience

• Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.
• Three hundred twenty-four subjects, with ages ranging from eight months to 75 years, have been exposed to Neumega treatment in clinical studies. Subjects have received up to six (eight in pediatric patients) sequential courses of Neumega treatment, with each course lasting from one to 28 days. Apart from the sequelae of the underlying malignancy or cytotoxic chemotherapy, most adverse events were mild or moderate in severity and reversible after discontinuation of Neumega dosing.
• In general, the incidence and type of adverse events were similar between Neumega 50 mcg/kg and placebo groups. The most frequently reported serious adverse events were neutropenic fever, syncope, atrial fibrillation, fever and pneumonia. The most commonly reported adverse events were edema, dyspnea, tachycardia, conjunctival injection, palpitations, atrial arrhythmias, and pleural effusions. The most frequently reported adverse reactions resulting in clinical intervention (eg, discontinuation of Neumega, adjustment in dosage, or the need for concomitant medication to treat an adverse reaction symptom) were atrial arrhythmias, syncope, dyspnea, congestive heart failure, and pulmonary edema. Selected adverse events that occurred in ≥10% of Neumega-treated patients are listed in TABLE 3.

• The following adverse events also occurred more frequently in cancer patients receiving Neumega than in those receiving placebo: blurred vision, paresthesia, dehydration, skin discoloration, exfoliative dermatitis, and eye hemorrhage. Other than a higher incidence of severe asthenia in Neumega treated patients (10 [14%] in Neumega patients versus two [3%] in placebo patients), the incidence of severe or life-threatening adverse events was comparable in the Neumega and placebo treatment groups.
• Two patients with cancer treated with Neumega experienced sudden death that the investigator considered possibly or probably related to Neumega. Both deaths occurred in patients with severe hypokalemia (<3.0 mEq/L) who had received high doses of ifosfamide and were receiving daily doses of a diuretic.
• Other serious events associated with Neumega were papilledema and cardiovascular events including atrial arrhythmias and stroke. In addition, cardiomegaly was reported in children.
• The following adverse events, occurring in ≥10% of patients, were observed at equal or greater frequency in placebo-treated patients: asthenia, pain, chills, abdominal pain, infection, anorexia, constipation, dyspepsia, ecchymosis, myalgia, bone pain, nervousness, and alopecia. The incidence of fever, neutropenic fever, flu-like symptoms, thrombocytosis, thrombotic events, the average number of units of red blood cells transfused per patient, and the duration of neutropenia <500 cells/μL were similar in the Neumega 50 mcg/kg and placebo groups.

Immunogenicity

• In clinical studies that evaluated the immunogenicity of Neumega, two of 181 patients (1%) developed antibodies to Neumega. In one of these two patients, neutralizing antibodies to Neumega were detected in an unvalidated assay. The clinical relevance of the presence of these antibodies is unknown. In the post-marketing setting, cases of allergic reactions, including anaphylaxis have been reported. The presence of antibodies to Neumega was not assessed in these patients.
• The data reflect the percentage of patients whose test results were considered positive for antibodies to Neumega and are highly dependent on the sensitivity and specificity of the assay. Additionally the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, concomitant medications, and underlying disease. For these reasons, comparisons of the incidence of antibodies to Neumega with incidence of antibodies to other products may be misleading.

Abnormal Laboratory Values

• The most common laboratory abnormality reported in patients in clinical trials was a decrease in hemoglobin concentration predominantly as a result of expansion of the plasma volume. The increase in plasma volume is also associated with a decrease in the serum concentration of albumin and several other proteins (eg, transferrin and gamma globulins). A parallel decrease in calcium without clinical effects has been documented.
• After daily SC injections, treatment with Neumega resulted in a two-fold increase in plasma fibrinogen. Other acute-phase proteins also increased. These protein levels returned to normal after dosing with Neumega was discontinued. Von Willebrand factor (vWF) concentrations increased with a normal multimer pattern in healthy subjects receiving Neumega.

Postmarketing Experience

• Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reactions, (2) frequency of reporting, or (3) strength of causal connection to Neumega.
• The following adverse reactions have been reported during the post-marketing use of Neumega:
  • allergic reactions and anaphylaxis/anaphylactoid reactions
  • papilledema
  • visual disturbances ranging from blurred vision to blindness
  • optic neuropathy
  • ventricular arrhythmias
  • capillary leak syndrome
  • renal failure
  • injection site reactions (dermatitis, pain, and discoloration)

Drug Interactions

• Most patients in trials evaluating Neumega were treated concomitantly with filgrastim (G-CSF) with no adverse effect of Neumega on the activity of G-CSF. No information is available on the clinical use of sargramostim (GM-CSF) with Neumega in human subjects. However, in a study in nonhuman primates in which Neumega and GM-CSF were coadministered, there were no adverse interactions between Neumega and GM-CSF and no apparent difference in the pharmacokinetic profile of Neumega.
• Drug interactions between Neumega and other drugs have not been fully evaluated. Based on in vitro and nonclinical in vivo evaluations of Neumega, drug-drug interactions with known substrates of P450 enzymes would not be predicted.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): C

• Neumega has been shown to have embryocidal effects in pregnant rats and rabbits when given in doses of 0.2 to 20 times the human dose. There are no adequate and well-controlled studies of Neumega in pregnant women. Neumega should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
• Neumega has been tested in studies of fertility, early embryonic development, and pre- and postnatal development in rats and in studies of organogenesis (teratogenicity) in rats and rabbits. Parental toxicity has been observed when Neumega is given at doses of two to 20 times the human dose (≥100 mcg/kg/day) in the rat and at 0.02 to 2.0 times the human dose (≥1 mcg/kg/day) in the rabbit. Findings in pregnant rats consisted of transient hypoactivity and dyspnea after administration (maternal toxicity), as well as prolonged estrus cycle, increased early embryonic deaths and decreased numbers of live fetuses. In addition, low fetal body weights and a reduced number of ossified sacral and caudal vertebrae (ie, retarded fetal development) occurred in rats at 20 times the human dose. Findings in pregnant rabbits consisted of decreased fecal/urine eliminations (the only toxicity noted at 1 mcg/kg/day in dams) as well as decreased food consumption, body weight loss, abortion, increased embryonic and fetal deaths, and decreased numbers of live fetuses. No teratogenic effects of Neumega were observed in rabbits at doses up to 0.6 times the human dose (30 mcg/kg/day).
• Adverse effects in the first generation offspring of rats given Neumega at maternally toxic doses ≥2 times the human dose (≥100 mcg/kg/day) during both gestation and lactation included increased newborn mortality, decreased viability index on day 4 of lactation, and decreased body weights during lactation. In rats given 20 times the human dose (1000 mcg/kg/day) during both gestation and lactation, maternal toxicity and growth retardation of the first generation offspring resulted in an increased rate of fetal death of the second generation offspring.

Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Oprelvekin in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Oprelvekin during labor and delivery.

Nursing Mothers

It is not known if Neumega is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Neumega, a decision should be made whether to discontinue nursing or to discontinue Neumega, taking into account the importance of the drug to the mother.

Pediatric Use

A safe and effective dose of Neumega has not been established in children. In a Phase 1, single arm, dose-escalation study, 43 pediatric patients were treated with Neumega at doses ranging from 25 to 125 mcg/kg/day following ICE chemotherapy. All patients required platelet transfusions and the lack of a comparator arm made the study design inadequate to assess efficacy. The projected effective dose (based on comparable AUC observed for the effective dose in healthy adults) in children appears to exceed the maximum tolerated pediatric dose of 50 mcg/kg/day. Papilledema was dose-limiting and occurred in 16% of children.

• The most common adverse events seen in pediatric studies included tachycardia (84%), conjunctival injection (57%), radiographic and echocardiographic evidence of cardiomegaly (21%) and periosteal changes (11%). These events occurred at a higher frequency in children than adults. The incidence of other adverse events was generally similar to those observed using Neumega at a dose of 50 mcg/kg in the randomized studies in adults receiving chemotherapy.
• Studies in animals were predictive of the effect of Neumega on developing bone in children. In growing rodents treated with 100, 300, or 1000 mcg/kg/day for a minimum of 28 days, thickening of femoral and tibial growth plates was noted, which did not completely resolve after a 28-day non-treatment period. In a nonhuman primate toxicology study of Neumega, animals treated for two to 13 weeks at doses of 10 to 1000 mcg/kg showed partially reversible joint capsule and tendon fibrosis and periosteal hyperostosis. An asymptomatic, laminated periosteal reaction in the diaphyses of the femur, tibia, and fibula has been observed in one patient during pediatric studies involving multiple courses of Neumega treatment. The relationship of these findings to treatment with Neumega is unclear. No studies have been performed to assess the long-term effects of Neumega on growth and development.

Geriatic Use

• Clinical studies of Neumega did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger subjects. In a controlled study, 141 adult patients with various nonmyeloid malignancies were randomized (2:1) to Neumega 50 mcg/kg/day or placebo administered subcutaneously for 14 days after chemotherapy was completed. Among 106 patients less than 65 years of age, the proportion who did not require platelet transfusions was higher among Neumega-treated patients (36.5% vs. 14.3%). Among 35 patients greater than or equal to 65 years of age, the proportion who did not require platelet transfusions was similar between treatment groups (32% vs. 30%, Neumega and placebo, respectively).

Gender

There is no FDA guidance on the use of Oprelvekin with respect to specific gender populations.

Race

There is no FDA guidance on the use of Oprelvekin with respect to specific racial populations.

Renal Impairment

• Neumega is eliminated primarily by the kidneys. The pharmacokinetics of Neumega were studied in subjects with varying degrees of renal dysfunction. AUC0-∞, Cmax, and absolute bioavailability were significantly increased in subjects with severe renal impairment (creatinine clearance < 30 mL/min). There were no significant changes in the pharmacokinetic parameters in subjects with mild or moderate impairment. A significant decrease in the hemoglobin concentration was noted on Day 2 after a single dose of Neumega in subjects with all degrees of renal impairment. By Day 14, the hemoglobin was decreased only in patients with severe renal impairment. Fluid retention associated with Neumega treatment has not been studied in patients with renal impairment, but fluid balance should be carefully monitored in these patients

Hepatic Impairment

There is no FDA guidance on the use of Oprelvekin in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Oprelvekin in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Oprelvekin in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Oprelvekin Administration in the drug label.

Monitoring

There is limited information regarding Oprelvekin Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Oprelvekin and IV administrations.

Overdosage

• Doses of Neumega above 125 mcg/kg have not been administered to humans. While clinical experience is limited, doses of Neumega greater than 50 mcg/kg may be associated with an increased incidence of cardiovascular events in adult patients. If an overdose of Neumega is administered, Neumega should be discontinued, and the patient should be closely observed for signs of toxicity. Reinstitution of Neumega therapy should be based upon individual patient factors (eg, evidence of toxicity, continued need for therapy).

Pharmacology

Oprelvekin

Clinical data
AHFS/Drugs.com	Monograph
Pregnancy category	C
Routes of administration	s.c. injection
ATC code	L03AC02 (WHO)
Legal status
Legal status	Rx only. Not a controlled substance.
Pharmacokinetic data
Bioavailability	>80% (s.c. application)
Metabolism	mainly renal
Elimination half-life	6.9 ± 1.7h
Identifiers
IUPAC name ?
CAS Number	145941-26-0 Y
DrugBank	DB00038 N
ChemSpider	NA N
UNII	HM5641GA6F
ChEMBL	ChEMBL1201573 N
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}
Chemical and physical data
Formula	C854H1411N253O235S2
Molar mass	approx. 19,000 daltons
NY (what is this?)  (verify)

Mechanism of Action

• The primary hematopoietic activity of Neumega is stimulation of megakaryocytopoiesis and thrombopoiesis. Neumega has shown potent thrombopoietic activity in animal models of compromised hematopoiesis, including moderately to severely myelosuppressed mice and nonhuman primates. In these models, Neumega improved platelet nadirs and accelerated platelet recoveries compared to controls.
• IL-11 has also been shown to have non-hematopoietic activities in animals including the regulation of intestinal epithelium growth (enhanced healing of gastrointestinal lesions), the inhibition of adipogenesis, the induction of acute phase protein synthesis, inhibition of pro-inflammatory cytokine production by macrophages, and the stimulation of osteoclastogenesis and neurogenesis. Non-hematopoietic pathologic changes observed in animals include fibrosis of tendons and joint capsules, periosteal thickening, papilledema, and embryotoxicity.
• 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 mRNAs for both IL-11 receptor (IL-11R alpha) and gp130. Both bone-forming and bone-resorbing cells are potential targets of IL-11. (1)

Structure

There is limited information regarding Oprelvekin Structure in the drug label.

Pharmacodynamics

• In a study in which Neumega was administered to non-myelosuppressed cancer patients, daily subcutaneous dosing for 14 days with Neumega increased the platelet count in a dose-dependent manner. Platelet counts began to increase relative to baseline between five and nine days after the start of dosing with Neumega. After cessation of treatment, platelet counts continued to increase for up to seven days then returned toward baseline within 14 days. No change in platelet reactivity as measured by platelet activation in response to ADP, and platelet aggregation in response to ADP, epinephrine, collagen, ristocetin and arachidonic acid has been observed in association with Neumega treatment.
• In a randomized, double-blind, placebo-controlled study in normal volunteers, subjects receiving Neumega had a mean increase in plasma volume of >20%, and all subjects receiving Neumega had at least a 10% increase in plasma volume. Red blood cell volume decreased similarly (due to repeated phlebotomy) in the Neumega and placebo groups. As a result, whole blood volume increased approximately 10% and hemoglobin concentration decreased approximately 10% in subjects receiving Neumega compared with subjects receiving placebo. Mean 24 hour sodium excretion decreased, and potassium excretion did not increase, in subjects receiving Neumega compared with subjects receiving placebo.

Pharmacokinetics

• The pharmacokinetics of Neumega have been evaluated in studies of healthy, adult subjects and cancer patients receiving chemotherapy. In a study in which a single 50 mcg/kg subcutaneous dose was administered to eighteen healthy men, the peak serum concentration (Cmax) of 17.4 ± 5.4 ng/mL (mean ± S.D.) was reached at 3.2 ± 2.4 hrs (Tmax) following dosing. The terminal half-life was 6.9 ± 1.7 hrs. In a second study in which single 75 mcg/kg subcutaneous and intravenous doses were administered to twenty-four healthy subjects, the pharmacokinetic profiles were similar between men and women. The absolute bioavailability of Neumega was >80%. In a study in which multiple, subcutaneous doses of both 25 and 50 mcg/kg were administered to cancer patients receiving chemotherapy, Neumega did not accumulate and clearance of Neumega was not impaired following multiple doses.
• Neumega was administered at doses ranging from 25 to 125 mcg/kg/day to 43 pediatric patients (ages 8 months to 18 years) and 1 adult patient receiving ICE (ifosfamide, carboplatin, etoposide) chemotherapy. Analysis of data from 40 pediatric patients showed that Cmax, Tmax, and terminal half-life were comparable to that in adults. The mean area under the concentration-time curve (AUC) for pediatric patients (8 months to 18 years), receiving 50 mcg/kg was approximately half that achieved in healthy adults receiving 50 mcg/kg. Available data suggest that clearance of Neumega decreases with increasing age in children.
• Neumega was administered as a single 50 mcg/kg dose subcutaneously to 48 healthy male and female adults aged 20 to 79 years; 18 subjects were aged 65 or older. The pharmacokinetic profile of Neumega was similar between those 65 years of age or older and those younger than 65 years.
• In preclinical trials in rats, radiolabeled Neumega was rapidly cleared from the serum and distributed to highly perfused organs. The kidney was the primary route of elimination. The amount of intact Neumega in urine was low, indicating that the molecule was metabolized before excretion. In a clinical study, a single dose of Neumega was administered to subjects with severely impaired renal function (creatinine clearance <30 mL/min). The mean ± S.D. values for Cmax and AUC were 30.8 ± 8.6 ng/mL and 373 ± 106 ng*hr/mL, respectively. When compared with control subjects in this study with normal renal function, the mean Cmax was 2.2 fold higher and the mean AUC was 2.6 fold (95% confidence interval, 1.7%-3.8%) higher in the subjects with severe renal impairment. In the subjects with severe renal impairment, clearance was approximately 40% of the value seen in subjects with normal renal function. The average terminal half-life was similar in subjects with severe renal impairment and those with normal renal function.
• A second clinical study of 24 subjects with varying degrees of renal function was also performed and confirmed the results observed in the first study. Single 50 mcg/kg subcutaneous and intravenous doses were administered in a randomized fashion. As the degree of renal impairment increased, the Neumega AUC increased, although half-life remained unchanged. In the six patients with severe impairment, the mean ± S.D. Cmax and AUC were 23.6 ± 6.7 ng/mL and 373 ± 55.2 ng*hr/mL, respectively, compared with 13.1 ± 3.8 ng/mL and 195 ± 49.3 ng*hr/mL, respectively, in the six subjects with normal renal function. A comparable increase in exposure was observed after intravenous administration of Neumega.
• The pharmacokinetic studies suggest that overall exposure to oprelvekin increases as renal function decreases, indicating that a 50% dose reduction of Neumega is warranted for patients with severe renal impairment. No dosage reduction is required for smaller changes in renal function.

Nonclinical Toxicology

There is limited information regarding Oprelvekin Nonclinical Toxicology in the drug label.

Clinical Studies

Two randomized, double-blind, placebo-controlled trials in adults studied Neumega for the prevention of severe thrombocytopenia following single or repeated sequential cycles of various myelosuppressive chemotherapy regimens.

Study in Patients with Prior Chemotherapy-Induced Thrombocytopenia

• One study evaluated the effectiveness of Neumega in eliminating the need for platelet transfusions in patients who had recovered from an episode of severe chemotherapy-induced thrombocytopenia (defined as a platelet count ≤20,000/μL), and were to receive one additional cycle of the same chemotherapy without dose reduction. Patients had various underlying non-myeloid malignancies, and were undergoing dose-intensive chemotherapy with a variety of regimens. Patients were randomized to receive Neumega at a dose of 25 mcg/kg or 50 mcg/kg, or placebo. The primary endpoint was whether the patient required one or more platelet transfusions in the subsequent chemotherapy cycle. Ninety-three patients were randomized. Five patients withdrew from the study prior to receiving the study drug. As a result, eighty-eight patients were included in a modified intent-to-treat analysis. The results for the Neumega 50 mcg/kg and placebo groups are summarized in TABLE 1. The placebo group includes one patient who underwent chemotherapy dose reduction and who avoided platelet transfusions.

• In the primary efficacy analysis, more patients avoided platelet transfusion in the Neumega 50 mcg/kg arm than in the placebo arm (p = 0.04, Fisher's Exact test, 2-tailed). The difference in the proportion of patients avoiding platelet transfusions in the Neumega 50 mcg/kg and placebo groups was 21% (95% confidence interval, 2%-40%). The results observed in patients receiving 25 mcg/kg of Neumega were intermediate between those of the placebo and the 50 mcg/kg groups.

Study in Patients Receiving Dose-Intensive Chemotherapy

• A second study evaluated the effectiveness of Neumega in eliminating platelet transfusions over two dose-intensive chemotherapy cycles in breast cancer patients who had not previously experienced severe chemotherapy-induced thrombocytopenia. All patients received the same chemotherapy regimen (cyclophosphamide 3,200 mg/m2 and doxorubicin 75 mg/m2). All patients received concomitant filgrastim (G-CSF) in all cycles. The patients were stratified by whether or not they had received prior chemotherapy, and randomized to receive Neumega 50 mcg/kg or placebo. The primary endpoint was whether or not a patient required one or more platelet transfusions in the two study cycles. Seventy-seven patients were randomized. Thirteen patients failed to complete both study cycles—eight of these had insufficient data to be evaluated for the primary endpoint. The results of this trial are summarized in TABLE 2.

• This study showed a trend in favor of Neumega, particularly in the subgroup of patients with prior chemotherapy. Open-label treatment with Neumega has been continued for up to four consecutive chemotherapy cycles without evidence of any adverse effect on the rate of neutrophil recovery or red blood cell transfusion requirements. Some patients continued to maintain platelet nadirs >20,000/μL for at least four sequential cycles of chemotherapy without the need for transfusions, chemotherapy dose reduction, or changes in treatment schedules.
• Platelet activation studies done on a limited number of patients showed no evidence of abnormal spontaneous platelet activation, or an abnormal response to ADP. In an unblinded, retrospective analysis of the two placebo-controlled studies, 19 of 69 patients (28%) receiving Neumega 50 mcg/kg and 34 of 67 patients (51%) receiving placebo reported at least one hemorrhagic adverse event which involved bleeding.

How Supplied

There is limited information regarding Oprelvekin How Supplied in the drug label.

Storage

There is limited information regarding Oprelvekin Storage in the drug label.

Images

Drug Images

{{#ask: Page Name::Oprelvekin |?Pill Name |?Drug Name |?Pill Ingred |?Pill Imprint |?Pill Dosage |?Pill Color |?Pill Shape |?Pill Size (mm) |?Pill Scoring |?NDC |?Drug Author |format=template |template=DrugPageImages |mainlabel=- |sort=Pill Name }}

Package and Label Display Panel

{{#ask: Label Page::Oprelvekin |?Label Name |format=template |template=DrugLabelImages |mainlabel=- |sort=Label Page }}

Patient Counseling Information

There is limited information regarding Oprelvekin Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Oprelvekin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Oprelvekin Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Oprelvekin Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

Oprelvekin

Clinical data
Pregnancy category	C
Routes of administration	s.c. injection
ATC code	L03AC02 (WHO)
Legal status
Legal status	Rx only. Not a controlled substance.
Pharmacokinetic data
Bioavailability	>80% (s.c. application)
Metabolism	mainly renal
Elimination half-life	6.9 +- 1.7h
Identifiers
IUPAC name ?
CAS Number	145941-26-0
DrugBank	BTD00021
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}
Chemical and physical data
Formula	C854H1411N253O235S2
Molar mass	approx. 19,000 daltons

Basic Chemical, Pharmacological and Marketing Data

Interleukin eleven (IL-11) is a thrombopoietic growth factor that directly stimulates the proliferation of hematopoietic stem cells and megakaryocyte progenitor cells and induces megakaryocyte maturation resulting in increased platelet production. IL-11 is a member of a family of human growth factors and is being produced in the bone marrow of healthy adults. Synonyms are:

• AGIF
• Adipogenesis inhibitory factor
• Interleukin-11 precursor.

Oprelvekin, the active ingredient in Neumega® is recombinant Interleukin eleven, which is produced in Escherichia coli (E. coli) by recombinant DNA technology. The protein has a molecular mass of approximately 19,000 daltons, and is non-glycosylated. The polypeptide is 177 amino acids in length (the natural IL-11 has 178). This alteration has not resulted in measurable differences in bioactivity either in vitro or in vivo.

The primary hematopoietic activity of Neumega® is stimulation of megakaryocytopoiesis and thrombopoiesis. In mice and nonhuman primate studies Neumega® has shown potent thrombopoietic activity in compromised hematopoiesis, including moderately to severely myelosuppressed animals. In these studies, Neumega® improved platelet nadirs and accelerated platelet recoveries compared to controls.

In animal studies Oprelvekin also has non-hematopoetic activities. This includes the regulation of intestinal epithelium growth (enhanced healing of gastrointestinal lesions), the inhibition of adipogenesis, the induction of acute phase protein synthesis (e.g., fibrinogen), and inhibition of macrophageal released pro-inflammatory cytokines. However, pathologic changes, some also seen in humans, have been noticed:

• papilledema
• fibrosis of tendons and joint capsules
• periostal thickening and
• embryotoxicity (see under pregnancy).

In preclinical human trials mature megakaryocytes which develop during in vivo treatment with Neumega® were ultrastructurally, morphologically, and functionally normal. They also showed a normal life span.

In a study in which a single 50 µg/kg subcutaneous dose was administered to eighteen healthy men, the peak serum concentration (Cmax) of 17.4 +- 5.4 ng/mL was reached at 3.2 +-2.4 h (Tmax) following dosing. The terminal half-life was 6.9 +- 1.7 h. In a second study in which single 75 µg/kg subcutaneous and intravenous doses were administered to twenty-four healthy subjects, the pharmacokinetic profiles were similar between men and women. The absolute bioavailability of Neumega® was >80%. In a study in which multiple, subcutaneous doses of both 25 and 50 µg/kg were administered to cancer patients receiving chemotherapy, Neumega® did not accumulate and clearance of Neumega® was not altered following multiple doses. Pediatric cancer patients treated with aggressive chemotherapy showed similar pharmakinetic characteristics.

In humans treated with Oprelvekin on a daily base a twofold increase in fibrinogen levels occurred. Healthy volunteers displayed an increase in von-Willebrand-factor (vWf) activity. Isolated molecules formed under Oprelvekin were found to have exact the same multimere structure as the 'normal' factor and were therefore fully functioning. These increases in coagulation factors may contribute to the development of stroke (see under side-effects), but a precise association cannot be made at this stage.

In a variety of clinical studies upon which FDA approval is based, Neumega® showed effectivity in reducing thrombocytopenia in oncologic patients treated with myelosuppressant chemotherapeutic drugs as measured by significantly decreased need of platelet transfusions.

Neumega® is manufactured and sold by Wyeth. The drug is formulated in single-use vials containing 5 mg of oprelvekin (specific activity approximately 8 x 106 Units/mg) as a sterile, lyophilized powder. The FDA has approved the drug very recently, in 2006.

Indications

Neumega® is indicated for the prevention of severe thrombocytopenia and the reduction of the need for platelet transfusions following myelosuppressive chemotherapy in adult patients with nonmyeloid malignancies who are at high risk of severe thrombocytopenia. Efficiacy was demonstrated in patients who had experienced severe thrombocytopenia following the previous chemotherapy cycle.

Contraindications and Precautions

• Patients with known hypersensitivity to Oprelvekin itself or any other ingredient.

• Patients with severe or decompensated heart failure should not be treated, because Oprelvekin may cause excessive fluid retention with edema and cardiac decompensation. Patients with compensated heart disease should be treated with caution and under permanent clinical supervision.

• Neumega® is not indicated following myeloablative chemotherapy (increased likelihood of severe side-effects) and in pediatric patients.

• Renal impairment : Neumega® is excreted renally. No differences of pharmakinetic parameters and clinical differences have been seen in mild to moderate impairment. Severe impairment has led to an increased number of patients with reduced hemoglobin due to dilutional anemia. Patients with severely disturbed renal function should be monitored very closely.

• The efficacy of Oprelvekin has not been systematically studied in patients receiving chemotherapy regimes of more than 5 days duration/each cycle or in those regimes containing agents that induce delayed thrombocytopenia (e.g. nitrosoureas, mitomycin C. Neumega® should not be given in these cases.

Pregnancy

Pregnanc Category C:

In studies with rats and rabbits treated chronically, Oprelvekin showed embryo- and fetotoxicity (early death of embryos and reduction of number of fetus, fetal malformations etc.). There is no sufficient human data available. Pregnant women should only be treated, if the benefit to the mother outweighs the potential risk to the unborn.

Lactation

No human data is available if the drug is distributed into human milk. Nursing women should either discontinue breast-feeding or Neumega®, the decision should take into account the importance of the drug to the mother.

Side-Effects

Neumega® has caused allergic reaction which at times have been very serious. Symptoms have been edema of the face and tongue, or larynx; shortness of breath; wheezing; chest pain; hypotension (including shock); dysarthria; loss of consciousness, rash, urticaria, flushing, and fever. These reaction can occur after the first dose or after any later application. Neumega® should be permanently discontinued in patients with any sign of allergy. Treatment is largely symptomatic.

Oprelvekin also has caused quite often fluid retention, ranging from peripheral edema (approximately 40% of patients) to dyspnea and full developed lung edema with or without cardiac decompensation (see contraindications and precautions). These symptoms have led to some deaths. Fluid retention my also lead to dilutional anemia (in 10 to 15% of patients). Hypokalema my also result. Symptoms of fluid retention have been observed more often in patients following myeloablative chemotherapy (see contraindications). Severe arrhythmias (atrial flutter and atrial fibrillation) as well as fatal cardiac arrest have also been seen which may or may be not attributed to fluid retention/increased volume. Isolated cases of stroke have been noted, those patients with previous transient ischemic attacks or partial/minor strokes may be at particular risk.

Papilledema of the eyes has been observed (2%) and may lead to disturbed visual acuity and even temporary or permanent blindness. Patients with preexisting papilledema or with involvement of the central nervous system may be at higher risk.

In postmarketing studies isolated cases of severe ventricular arrhythmias and renal failure have been seen.

Injection site reaction like have also been observed (dermatitis, pain, and discoloration), but are usually mild.

Interactions

The concomitant application of GM-CSFs such as filgrastim or Sargramostim showed no potential interactions. Additionally, no other interactions are known. Interactions with drugs undergoing P450 enzyme metabolism are not likely to occur.

Necessary Examinations during Treatment

Complete blood counts should be obtained before starting chemotherapy and in short intervals afterwards. Platelet counts should be done at the time of expected nadir (lowest number of platelets) and at least until remission starts (platelet counts greater than 50,000). The patients should be watched for signs of allergy, fluid retention and anemia during and after therapy with Neumega®. Preexisting ascites and pericardial effusions should be monitored closely for signs of worsening.

Dosage Regime

The dosage in patients without severe renal impairment is 50 µg/kg subcutaneously once a day either abdominal, in thigh, or hip. Most patients will be able to self-administer the drug after appropriate training.

Patients with severe renal impairment should receive only 25µg/kg daily.

The first dose should be given 6 to 24 hours after completion of chemotherapy. Dosing should be continued until platelet counts reach at least 50,000 cells. Usually, one course of Neumega® encompasses 10 to 21 days.

The drug should be discontinued at least 2 days before starting the next chemotherapy cycle.

Additional Information

Neumega® vials must be stored in a refrigerator at 2 to 8 C (36 to 46 F). Protect from light. Do not freeze.

Information for Patients/'non-specialized' people

This section provides information for patients treated with Neumega® or those people 'non-specialized' but interested in medicine/pharmacology:

You have been diagnosed having a cancer disease. This cancer is in your case treated with chemotherapy. The chemotherapy has caused or can cause severe depression of platelets. You need a normal level of platelets to maintain coagulation and prevent severe bleeding episodes. Neumega® is used to increase depressed platelet counts to a higher level to promote protection against bleeding episodes. The drug is injected once a day subcutaneously e.g., in your hip or thigh. Your clinician will show you the correct technique, so you can complete further courses of Neumega-therapy at home. One course of Neumega® usually starts 6 to 24 hours after completion of chemotherapy and is continued for 10 to 21 days at the discretion of the physician. Your doctors will ask you to undergo frequent blood cell counts to determine effects of therapy and the further course of treatment. Please adhere to his/her advices for reasons of your own safety.

Neumega® is a potent drug and can have certain, sometimes dangerous, side-effects. Most important are severe allergic reactions, which can occur at any time of Neumega-therapy. Inform you doctor immediately if you experience swollen face, tongue or larynx, shortness of breath, hypotension, shock, fever or skin reactions (urticaria, rash). Additionally, Neumega® can cause fluid retention in a high rate of patients. If you notice an unexplainable massive gain of weight, peripheral edemas (e.g. swollen ankles, arms or legs) that are more than mild to moderate, or if you experience shortness of breath without signs of allergy contact your doctor immediately or dial 911. You maybe suffer from lung edema and/or decompensated heart failure which must be treated immediately. The same is true, if you have an irregular heartbeat together with dizziness and vertigo, or sudden loss of consciousness.

If you should notice a decrease in visual acuity or even blindness call you doctor at once or dial 911, because you are in a situation of absolute emergency.

Reactions at the injection site are usually mild and consist of skin-reaction (dermatitis), pain or discoloration. They do not require termination of therapy. To prevent these side-effects you will be asked to change injection-sites regularly.

References

• http://www.rxlist.com/cgi/generic3/oprelvek.htm
• http://www.wyeth.com/products_hcp?product=/wyeth_html/home/products/prescription/Neumega®%20(oprelvekin)/Neumega®%20(oprelvekin)_overview.html (Drug Information provided by Wyeth)
• http://redpoll.pharmacy.ualberta.ca/drugbank/cgi-bin/getCard.cgi?CARD=BTD00021.txt (DrugBank entry)