Oprelvekin (Monograph)

Brand name: Neumega
Drug class: Hematopoietic Agents
VA class: BL400
Chemical name: 2-178-Interleukin 11 (human clone pXM/IL-11)
Molecular formula: C₈₅₄H₁₄₁₁N₂₅₃O₂₃₅S₂
CAS number: 145941-26-0

Introduction

Biosynthetic (recombinant DNA-derived) form of human interleukin-11 (IL-11); a thrombopoietic growth factor that principally affects megakaryocytopoiesis.

Uses for Oprelvekin

Chemotherapy-induced Thrombocytopenia

Prevention of severe thrombocytopenia in adults with nonmyeloid malignancies receiving myelosuppressive antineoplastic therapy; designated an orphan drug by FDA for this use.

Reduces the need for platelet transfusions following myelosuppressive chemotherapy.

Indicated for patients at high risk (as judged by the clinician) of developing severe chemotherapy-induced thrombocytopenia.

Not indicated for use in patients undergoing myeloablative chemotherapy^{† [off-label]}. (See Fluid Retention under Cautions.)

Efficacy not established in patients receiving chemotherapy regimens of >5 days duration or regimens associated with delayed myelosuppression (e.g., nitrosoureas, mitomycin-C)^{† [off-label]}.

Oprelvekin Dosage and Administration

Administration

Sub-Q Administration

Administer by sub-Q injection daily. Give dose at approximately the same time each day.

Administer as a single injection into the abdomen, thigh, hip, or upper arm. Rotate injection sites.

Do not rub injection sites.

Initiate oprelvekin 6–24 hours following completion of chemotherapy. Safety and efficacy of administering immediately prior to or concurrently with chemotherapy, or at the time of the expected platelet nadir, not established.

If a dose is missed, resume next scheduled dose at the appropriate time; do not double a dose.

Intended for use under the guidance and supervision of a clinician, but may be self-administered if clinician determines that patient and/or caregiver is competent to prepare and safely administer the drug.

Consult manufacturer's labeling for specific instructions on reconstitution, dilution, and administration.

Reconstitution

Reconstitute vial labeled as containing 5 mg of oprelvekin powder for injection with 1 mL of sterile water for injection to provide a solution containing oprelvekin 5 mg/mL.

During reconstitution, direct diluent towards side of vial. Gently swirl to dissolve powder; do not shake.

Vials are for single use only; discard any unused solution after withdrawal of dose and do not re-enter or reuse vial.

Administer as soon as possible or within 3 hours after reconstitution.

Dosage

Adults

Chemotherapy-induced Thrombocytopenia

Sub-Q

50 mcg/kg daily. Administer first dose 6–24 hours following completion of chemotherapy and continue until platelet counts ≥50,000/mm³. Do not exceed 21 days of treatment per chemotherapy cycle.

Discontinue oprelvekin at least 2 days prior to next cycle of chemotherapy.

Prescribing Limits

Adults

Chemotherapy-induced Thrombocytopenia

Sub-Q

Limited experience with doses >50 mcg/kg; may be associated with increased risk of cardiovascular events. (See Cardiovascular Effects under Cautions.)

Recommended maximum duration of therapy for each course of treatment is 21 days.

Safety and efficacy of >6 cycles of oprelvekin treatment following a chemotherapy cycle not established.

Special Populations

Renal Impairment

Chemotherapy-induced Thrombocytopenia

Sub-Q

Reduce dosage to 25 mcg/kg daily in patients with severe renal impairment (Cl_cr<30 mL/minute, as estimated from S_cr). (See Absorption: Special Populations, under Pharmacokinetics.)

Cautions for Oprelvekin

Contraindications

• Known hypersensitivity to oprelvekin or any ingredient in the formulation.

Warnings/Precautions

Warnings

Fluid Retention

Fluid retention, usually a result of increased sodium and water retention, reported. Clinical manifestations range from mild to moderate peripheral edema to more severe conditions (e.g., pulmonary edema, capillary leak syndrome, atrial arrhythmias, development or exacerbation of pleural or pericardial effusion). Fluid retention usually develops within first few weeks of therapy and may continue for the duration of therapy. In most cases, edema is self-limiting and resolves within several days after drug discontinuance.

Serious, sometimes fatal, cases of fluid retention reported in patients who received oprelvekin following bone marrow transplantation. Do not use oprelvekin in patients undergoing myeloablative chemotherapy.

Increased plasma volume may result in decreased concentrations of serum proteins (e.g., albumin, transferrin, gamma globulin) and serum calcium.

Use with caution in patients with CHF or who may be susceptible to developing CHF (e.g., history of heart failure even if well compensated and receiving appropriate medical management). Also use caution in those with other conditions or treatments that may precipitate or exacerbate fluid retention (e.g., pleural effusions, aggressive hydration, concomitant drugs known to cause edema). Closely monitor fluid status and initiate appropriate treatment if fluid imbalance occurs. Monitor preexisting fluid collections (e.g., pericardial effusions, ascites) and consider drainage if indicated.

Monitor fluid and electrolyte status carefully in patients receiving maintenance therapy with diuretics. Sudden death has occurred in at least 2 patients who developed severe hypokalemia (<3 mEq/L) while receiving diuretic therapy concomitantly with ifosfamide and oprelvekin.

Hematologic Effects

Moderate decreases in hemoglobin, hematocrit, and RBCs reported, principally because of fluid retention and hemodilution. (See Fluid Retention under Cautions.) Usually manifests within 3–5 days following initiation of therapy and reverses over approximately 1 week upon drug discontinuance. Monitor CBC prior to chemotherapy and periodically during therapy.

Reversible increases in plasma fibrinogen (e.g., twofold increase), haptoglobin, and other acute-phase reactants (e.g., C-reactive protein) observed. Increased concentrations of Von Willebrand factor (with normal multimer pattern) also reported in healthy individuals who received oprelvekin.

Cardiovascular Effects

Risk of cardiovascular events (e.g., arrhythmias, MI, stroke, cardiomegaly, pulmonary edema).

Atrial arrhythmias (fibrillation or flutter) reported in about 10–15% of patients, in some cases resulting in stroke. Such arrhythmias are usually transient and convert to normal sinus rhythm spontaneously or with rate-control therapy. Cardiac arrest also reported, but causal relationship to drug uncertain.

Ventricular arrhythmias, generally occurring within 2–7 days of initiation, reported during postmarketing experience.

Use with caution in patients with a history of cardiac arrhythmias, including atrial and ventricular arrhythmias. Carefully consider potential risks versus benefits of therapy. Doses >50 mcg/kg may increase risk of adverse cardiovascular effects.

Cerebrovascular Effects

Stroke reported in association with atrial arrhythmias. (See Cardiovascular Effects under Cautions.) Risk may be increased in those with a history of stroke or TIA.

Ocular Effects

Possible development or worsening of papilledema. Generally resolves upon drug discontinuance. Risk may increase with high dosages (e.g., >50 mcg/kg daily). Higher incidence of papilledema observed in children (16%) compared with adults (1%) in clinical trials. (See Pediatric Use under Cautions.) Use with caution in patients with preexisting papilledema or CNS tumors.

Other visual disturbances reported, including blurred vision, optic neuropathy, and blindness.

Renal Effects

Renal failure reported during postmarketing experience in patients who received oprelvekin following bone marrow transplantation. Do not use oprelvekin in patients undergoing myeloablative chemotherapy.

Sensitivity Reactions

Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylaxis and shock, reported during postmarketing experience. (See Boxed Warning.) Reported reactions include edema of the face, tongue, or larynx; dyspnea; wheezing; chest pain; hypotension (including shock); dysarthria; loss of consciousness; mental status changes; rash; urticaria; flushing; and fever. Such reactions can occur after initial administration or at any time during therapy. Take appropriate precautionary measures in case of hypersensitivity reactions (e.g., immediate availability of antihistamines, epinephrine, oxygen, corticosteroids).

Advise patient regarding potential manifestations of hypersensitivity for which they should seek immediate medical attention. (See Advice to Patients.) Permanently discontinue therapy if allergic or hypersensitivity-type reactions occur.

Antibody Formation

Development of antibodies to oprelvekin reported infrequently; clinical importance unknown.

General Precautions

Laboratory Monitoring

Perform CBC prior to chemotherapy and at regular intervals during therapy. (See Hematologic Effects under Cautions.)

Monitor platelet counts at time of expected nadir and continue monitoring until platelet counts recover to ≥50,000/mm³.

Monitor fluid status. (See Fluid Retention under Cautions.)

Monitor electrolytes in those receiving concomitant diuretic therapy. (See Fluid Retention under Cautions.)

Specific Populations

Pregnancy

Category C.

Lactation

Not known whether oprelvekin is distributed into milk. Discontinue nursing or the drug.

Pediatric Use

Safety and efficacy not established in children younger than 12 years of age. Restrict use to clinical trial settings in pediatric patients, especially in those <12 years of age.

Evaluated in a limited number of patients 8 months to 18 years of age. Pharmacokinetic studies suggest higher than recommended dosages may be necessary to achieve therapeutic effect in children and adolescents; however, dosages >50 mcg/kg daily have been associated with increased risk of adverse effects (i.e., papilledema, periosteal bone changes.) (See Absorption: Special Populations, under Pharmacokinetics.)

Tachycardia, conjunctival injection, cardiomegaly, periosteal changes, and papilledema reported more frequently in children than in adults. (See Ocular Effects under Cautions.)

Long-term effects of oprelvekin on bone growth and development in children not established. Limited data in animals suggest possible adverse effects on bone, joints, and tendons (e.g., thickening of femoral and tibial growth plates, joint and tendon fibrosis, periosteal hyperostosis).

Geriatric Use

Select dosage with caution because of greater frequency of decreased renal function in geriatric patients. (See Renal Impairment under Cautions.)

Renal Impairment

Possible increased serum concentrations and systemic exposure to oprelvekin. (See Absorption: Special Populations, under Pharmacokinetics.) Reduce dosage in patients with severe renal impairment (Cl_cr <30 mL/minute). (See Dosage in Renal Impairment under Dosage and Administration.)

A substantial decrease in hemoglobin observed on day 2 of oprelvekin therapy in patients with any degree of renal impairment. (See Hematologic Effects under Cautions.)

Effects of oprelvekin on fluid retention in patients with renal impairment not established; carefully monitor fluid balance in such patients. (See Fluid Retention under Cautions.)

Common Adverse Effects

Adverse effects reported in at least 10% of patients receiving oprelvekin in clinical trials and significantly more often than with placebo include edema, tachycardia, palpitations, atrial fibrillation/flutter, oral moniliasis, dyspnea, pleural effusions, and conjunctival injection.

Drug Interactions

Drug interactions with oprelvekin not fully elucidated; in vitro and nonclinical in vivo studies suggest that the drug is not metabolized by CYP enzymes.

Specific Drugs

Oprelvekin Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability >80% with sub-Q administration in healthy adults.

Relative bioavailability of a 50-mcg/kg sub-Q dose was 65% compared with same dose given IV.

Peak plasma concentrations attained within 2–3 hours following single sub-Q dose.

Onset

Platelet counts begin to increase in dose-dependent manner 5–9 days following daily sub-Q administration.

Duration

Platelet counts continue to increase for up to 7 days following drug discontinuance and return to normal within 14 days.

Special Populations

In patients with severe renal impairment (Cl_cr <30 mL/minute), mean AUC and peak plasma concentrations are approximately 2.6- and 2.2-fold higher, respectively, than in individuals with normal renal function. Clearance in severe renal impairment approximately 40% of that observed in individuals with normal renal function. No substantial change in pharmacokinetic parameters observed in patients with mild or moderate renal impairment compared with those with normal renal function.

In infants, children, and adolescents 8 months to 18 years of age receiving a 50 mcg/kg dose, mean AUC approximately half that observed in adults. Limited data suggest children <12 years of age may not achieve adequate plasma concentrations with recommended dosages (50 mcg/kg daily). (See Pediatric Use under Cautions.)

Distribution

Extent

Not known whether oprelvekin crosses the placenta or is distributed into milk.

May distribute through lymphatic system before entering systemic circulation. Rapidly distributes into highly perfused organs.

Elimination

Metabolism

Metabolic fate of oprelvekin not fully elucidated, but presumed to be extensively metabolized or degraded.

Elimination Route

Excreted principally in urine; only small amounts of parent drug recovered.

Half-life

Terminal half-life: Approximately 7 hours.

No evidence of drug accumulation following multiple sub-Q doses.

Special Populations

Clearance higher in infants and children 8 months to 11 years of age than in adolescents and adults ≥12 years of age. (See Pediatric Use under Cautions.)

Stability

Storage

Parenteral

Powder for Injection

Lyophilized powder: 2–8°C; do not freeze. Protect from light.

Reconstituted solution: 2–8°C or at room temperature (≤25°C); do not store in syringes. Use within 3 hours of reconstitution. Do not freeze or shake.

Discard unused portion immediately after withdrawal of intended dose from vial.

Actions

• A thrombopoietic growth factor structurally and functionally similar to endogenous human interleukin-11 (IL-11); lacks only amino-terminal proline residue of endogenous IL-11. No measurable difference in biologic activity in vivo or in vitro compared with endogenous IL-11.

• Stimulates multiple stages of the hematopoietic pathway. Binds directly to IL-11 receptors on myeloid progenitor cell surfaces and stimulates production of erythrocytes, platelets, neutrophils, and macrophages within the bone marrow.

• Principally affects megakaryocytopoiesis. Produces a dose-dependent increase in platelet counts by stimulating the proliferation and differentiation of megakaryocyte progenitor cells in synergy with other growth factors (e.g., interleukin-3 [IL-3], thrombopoietin [TPO], stem cell factor [SCF]).

• Non-hematologic effects include regulation of intestinal epithelium growth, inhibition of adipogenesis, stimulation of synthesis of acute phase reactants, modulation (e.g., inhibition) of pro-inflammatory cytokines, and stimulation of osteoclastogenesis and neurogenesis.

Advice to Patients

• Risk of cardiovascular effects; importance of immediately informing clinician if symptoms of atrial arrhythmia (e.g., rapid heart rate, palpitations) or stroke occur.

• Risk of fluid retention; importance of immediately informing clinician if swelling in hands or feet, rapid weight gain, shortness of breath, or difficulty breathing occurs; importance of informing clinician of preexisting heart failure or concurrent therapy with medications that can cause fluid retention.

• Importance of recognizing symptoms of allergic or hypersensitivity reactions (e.g., swelling of the face, tongue, or throat; tightness in throat; difficulty breathing, swallowing, or talking; shortness of breath; wheezing; chest pain; lightheadedness; loss of consciousness; confusion; drowsiness; rash; itching; hives; flushing; fever), and immediately informing clinician if any of these symptoms occur.

• Risk of papilledema; importance of patient and/or caregiver immediately informing clinician if headache or visual impairment (e.g., blurry vision, blindness) occurs.

• Importance of informing clinician if any swelling or bruising persists at injection site.

• Importance of providing copy of manufacturer's patient information if drug is being self-administered. Instruct patient and/or caregiver regarding proper dosage and administration of oprelvekin, including use of aseptic technique and safe disposal of needles and syringes (e.g., using puncture-resistant container).

• Importance of not taking a double dose to make up for a missed dose but instead taking the next scheduled dose at appropriate time.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing clinicians of existing or contemplated concomitant therapy (e.g., diuretics), including prescription and OTC drugs as well as any concomitant illnesses (e.g., CHF, renal impairment, papilledema).

• Importance of informing patients of other important precautionary information (e.g., likelihood of developing anemia). (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Reload page with references included

Medical Disclaimer