Neumega

Oprelvekin is a protein that stimulates production of platelets in the blood. Platelets are important for proper clotting of the blood and for wound healing.

Oprelvekin is used to prevent platelets from becoming dangerously low in certain people receiving chemotherapy that can result in bone marrow suppression or the need for blood platelet transfusions.

Oprelvekin may also be used for purposes not listed in this medication guide.

Stop using oprelvekin and get emergency medical help if you have any of these signs of an allergic reaction: fever, rash, shortness of breath, chest pain, wheezing, confusion, fainting, hives, or swelling of your face, lips, tongue, or throat.

Once you have had an allergic reaction to oprelvekin, you must never use it again.

Other serious side effects of oprelvekin include swelling or rapid weight gain, chest pain, uneven heartbeats, sudden numbness or weakness, confusion, problems with speech or balance, and sudden vision loss or pain behind your eyes. Call your doctor at once if you have any of these side effects.

You should not use oprelvekin if you are allergic to it.

To make sure oprelvekin is safe for you, tell your doctor if you have:

• congestive heart failure;
• heart rhythm disorder;
• a buildup of fluid around your lungs (also called pleural effusion);
• a history of heart disease or stroke;
• a history of fluid around your liver or heart;
• a seizure disorder;
• kidney disease;
• low levels of potassium in your blood; or
• if you take a diuretic or "water pill."

FDA pregnancy category C. It is not known whether oprelvekin will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medicine.

It is not known whether oprelvekin passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Avoid making any changes in your diet while using this medication. Oprelvekin can cause fluid retention and swelling. Your doctor may recommend a low-salt diet to prevent this condition.

Other drugs may interact with oprelvekin, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

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 which includes human growth hormone, granulocyte colony-stimulating factor (G-CSF), and other growth factors.

Oprelvekin, the active ingredient in Neumega, 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 and differs from the 178 amino acid length of native IL-11 only in lacking the amino-terminal proline residue. This alteration has not resulted in measurable differences in bioactivity either in vitro or in vivo.

Neumega is formulated in single-use vials containing 5 mg of oprelvekin (specific activity approximately 8 x 106 Units/mg) as a sterile, lyophilized powder with 23 mg Glycine, USP, 1.6 mg Dibasic Sodium Phosphate Heptahydrate, USP, and 0.55 mg Monobasic Sodium Phosphate Monohydrate, USP. When reconstituted with 1 mL of Sterile Water for Injection, USP, the resulting solution has a pH of 7.0 and a concentration of 5 mg/mL.

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 (see WARNINGS, Fluid Retention and Cardiovascular Events). If an overdose of Neumega is administered, Neumega should be discontinued, and the patient should be closely observed for signs of toxicity (see WARNINGS and ADVERSE REACTIONS). Reinstitution of Neumega therapy should be based upon individual patient factors (eg, evidence of toxicity, continued need for therapy).

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 (see WARNINGS, Fluid Retention and WARNINGS, Cardiovascular Events). Selected adverse events that occurred in ≥ 10% of Neumega-treated patients are listed in Table 3.

TABLE 3 : SELECTED ADVERSE EVENTS

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 lifethreatening 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 (see WARNINGS, Cardiovascular Events).

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 (see WARNINGS, Allergic Reactions Including Anaphylaxis). 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 (see WARNINGS, Fluid Retention). 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.

Post-marketing Reports

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) (see BOXED WARNING, WARNINGS, and CONTRAINDICATIONS).

Read the entire FDA prescribing information for Neumega (Oprelvekin)

Neumega is part of the drug class:

• Interleukins

Chemotherapy-induced Thrombocytopenia

Prevention of severe thrombocytopenia in adults with nonmyeloid malignancies receiving myelosuppressive antineoplastic therapy;1 3 5 6 7 10 14 17 designated an orphan drug by FDA for this use.4

Reduces the need for platelet transfusions following myelosuppressive chemotherapy.1 5 7 10 14 15 18

Indicated for patients at high risk (as judged by the clinician)3 of developing severe chemotherapy-induced thrombocytopenia.1 3 17

Not indicated for use in patients undergoing myeloablative chemotherapy†.1 10 15 (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)†.1

Administration

Sub-Q Administration

Administer by sub-Q injection daily.1 2 3 Give dose at approximately the same time each day.2

Administer as a single injection into the abdomen, thigh, hip, or upper arm.1 2 3 Rotate injection sites.2

Do not rub injection sites.2

Initiate oprelvekin 6–24 hours following completion of chemotherapy.1 Safety and efficacy of administering immediately prior to or concurrently with chemotherapy, or at the time of the expected platelet nadir, not established.1

If a dose is missed, resume next scheduled dose at the appropriate time; do not double a dose.2

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.1

Consult manufacturer's labeling for specific instructions on reconstitution, dilution, and administration.1 2

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.1 2

During reconstitution, direct diluent towards side of vial.1 2 Gently swirl to dissolve powder; do not shake.1 2

Vials are for single use only; discard any unused solution after withdrawal of dose and do not re-enter or reuse vial.1 2

Administer as soon as possible or within 3 hours after reconstitution.1 2

Dosage

Adults

50 mcg/kg daily.1 3 Administer first dose 6–24 hours following completion of chemotherapy and continue until platelet counts ≥50,000/mm3.1 3 Do not exceed 21 days of treatment per chemotherapy cycle.1 3 17

Discontinue oprelvekin at least 2 days prior to next cycle of chemotherapy.1

Prescribing Limits

Adults

Limited experience with doses >50 mcg/kg; may be associated with increased risk of cardiovascular events.1 (See Cardiovascular Effects under Cautions.)

Recommended maximum duration of therapy for each course of treatment is 21 days.1

Safety and efficacy of >6 cycles of oprelvekin treatment following a chemotherapy cycle not established.1 3

Special Populations

Renal Impairment

Reduce dosage to 25 mcg/kg daily in patients with severe renal impairment (Clcr<30 mL/minute, as estimated from Scr).1 (See Absorption: Special Populations, under Pharmacokinetics.)

• A thrombopoietic growth factor structurally and functionally similar to endogenous human interleukin-11 (IL-11); lacks only amino-terminal proline residue of endogenous IL-11.1 8 9 10 No measurable difference in biologic activity in vivo or in vitro compared with endogenous IL-11.1 8 10

• Stimulates multiple stages of the hematopoietic pathway.5 6 10 16 Binds directly to IL-11 receptors on myeloid progenitor cell surfaces and stimulates production of erythrocytes, platelets, neutrophils, and macrophages within the bone marrow.5 6 10 16 18

• Principally affects megakaryocytopoiesis.1 3 10 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]).1 3 5 6 7 10 12 13 14 15 16 18

• 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.1 6 10 12 16

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Oprelvekin has caused joint and tendon problems in animals and there is a possibility it could also cause these effects in children receiving it. Discuss these possible effects with your doctor.

Geriatric

This medicine has been tested and has not been shown to cause different side effects or problems in older people than it does in younger adults.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Congestive heart failure—May be worsened because oprelvekin causes the body to retain water
• Atrial arrhythmias (heart rhythm problems)—This medicine may cause heart rhythm problems
• Fluid build-up in the abdomen or lungs—May be worsened by oprelvekin
• Myeloablative chemotherapy— May lead to serious side effects

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

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 which includes human growth hormone, granulocyte colony-stimulating factor (G-CSF), and other growth factors.

Oprelvekin, the active ingredient in Neumega, 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 and differs from the 178 amino acid length of native IL-11 only in lacking the amino-terminal proline residue. This alteration has not resulted in measurable differences in bioactivity either in vitro or in vivo.

Neumega is formulated in single-use vials containing 5 mg of oprelvekin (specific activity approximately 8 x 106 Units/mg) as a sterile, lyophilized powder with 23 mg Glycine, USP, 1.6 mg Dibasic Sodium Phosphate Heptahydrate, USP, and 0.55 mg Monobasic Sodium Phosphate Monohydrate, USP. When reconstituted with 1 mL of Sterile Water for Injection, USP, the resulting solution has a pH of 7.0 and a concentration of 5 mg/mL.

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.

Preclinical trials have shown that mature megakaryocytes which develop during in vivo treatment with Neumega are ultrastructurally normal. Platelets produced in response to Neumega were morphologically and functionally normal and possessed a normal life span.

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 (see PRECAUTIONS, Pediatric Use and PRECAUTIONS, Pregnancy Category C).

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)

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 (see PRECAUTIONS, Use in Patients with Renal Impairment and DOSAGE AND ADMINISTRATION). No dosage reduction is required for smaller changes in renal function.

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.

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 cycleseight 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.

Study in Patients Following Myeloablative Chemotherapy

In a randomized, double-blind, placebo-controlled, Phase 2 study conducted in 80 women with high-risk breast cancer who received 0 (n=26), 25 mcg/kg (n=28), or 50 mcg/kg (n=26) Neumega following myeloablative chemotherapy and autologous bone marrow transplantation, the incidence of platelet transfusions and time to neutrophil and platelet engraftment were similar in the Neumega and placebo-treated arms. The study showed a statistically significant increased incidence in edema, conjunctival bleeding, hypotension, and tachycardia in patients receiving Neumega as compared to placebo.

In long term follow-up of patients, the distribution of survival and progression-free survival times was similar between patients randomized to Neumega therapy and those randomized to receive placebo.

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. Efficacy was demonstrated in patients who had experienced severe thrombocytopenia following the previous chemotherapy cycle. Neumega is not indicated following myeloablative chemotherapy (see WARNINGS, Increased Toxicity Following Myeloablative Therapy). The safety and effectiveness of Neumega have not been established in pediatric patients.

Neumega is contraindicated in patients with a history of hypersensitivity to Neumega or any component of the product (see WARNINGS, Allergic Reactions Including Anaphylaxis).

General

Dosing with Neumega should begin 6 to 24 hours following the completion of chemotherapy dosing. The safety and efficacy of Neumega given immediately prior to or concurrently with cytotoxic chemotherapy or initiated at the time of expected nadir have not been established (see DOSAGE AND ADMINISTRATION).

The effectiveness of Neumega has not been evaluated in patients receiving chemotherapy regimens of greater than five days duration or regimens associated with delayed myelosuppression (eg, nitrosoureas, mitomycin-C).

Chronic Administration

Neumega has been administered safely using the recommended dosage schedule (see DOSAGE AND ADMINISTRATION) for up to six cycles following chemotherapy. The safety and efficacy of chronic administration of Neumega have not been established. Continuous dosage (two to 13 weeks) in nonhuman primates produced joint capsule and tendon fibrosis and periosteal hyperostosis (see PRECAUTIONS, Pediatric Use). The relevance of these findings to humans is unclear.

Information for Patients

Neumega should be used under the guidance and supervision of a health care professional. However, when the physician determines that Neumega may be used outside of the hospital or office setting, persons who will be administering Neumega should be instructed as to the proper dose, and the method for reconstituting and administering Neumega (see DOSAGE AND ADMINISTRATION). If home use is prescribed, patients should be instructed in the importance of proper disposal and cautioned against the reuse of needles, syringes, drug product, and diluent. A puncture resistant container should be used by the patient for the disposal of used needles.

Patients should be informed of the serious and most common adverse reactions associated with Neumega administration, including those symptoms related to allergic or hypersensitivity reactions (see BOXED WARNING). Patients should be advised to immediately seek medical attention if any of the following signs or symptoms develop: swelling of the face, tongue, or throat; difficulty breathing, swallowing or talking; shortness of breath; wheezing; chest pain; throat tightness; lightheadedness; loss of consciousness; confusion; drowsiness; rash; itching; hives; flushing and/or fever. Mild to moderate peripheral edema and shortness of breath on exertion can occur within the first week of treatment and may continue for the duration of administration of Neumega. Patients who have preexisting pleural or other effusions or a history of congestive heart failure should be advised to contact their physician for worsening of dyspnea (see ADVERSE REACTIONS and WARNINGS, Fluid Retention). Most patients who receive Neumega develop anemia. Patients should be advised to contact their physician if symptoms attributable to atrial arrhythmia develop. Female patients of childbearing potential should be advised of the possible risks to the fetus of Neumega (see PRECAUTIONS, Pregnancy Category C).

Laboratory Monitoring

A complete blood count should be obtained prior to chemotherapy and at regular intervals during Neumega therapy (see DOSAGE AND ADMINISTRATION). Platelet counts should be monitored during the time of the expected nadir and until adequate recovery has occurred (post-nadir counts ≥50,000/µL).

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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies have been performed to assess the carcinogenic potential of Neumega. In vitro, Neumega did not stimulate the growth of tumor colony-forming cells harvested from patients with a variety of human malignancies. Neumega has been shown to be non-genotoxic in in vitro studies. These data suggest that Neumega is not mutagenic. Although prolonged estrus cycles have been noted at two to 20 times the human dose, no effects on fertility have been observed in rats treated with Neumega at doses up to 1000 mcg/kg/day.

Pregnancy Category 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.

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 (see CLINICAL PHARMACOLOGY, Pharmacokinetics). Papilledema was dose-limiting and occurred in 16% of children (see WARNINGS, Papilledema).

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 (see ADVERSE REACTIONS).

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.

Geriatric 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).

Use in Patients with 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) (see DOSAGE AND ADMINISTRATION). 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 (see WARNINGS, Fluid Retention).

Applies to oprelvekin: subcutaneous powder for solution

Along with its needed effects, oprelvekin (the active ingredient contained in Neumega) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

The side effects listed below include only those that might be caused by oprelvekin. To find out about other side effects that may be caused by the cancer medicines you are also receiving, see the information about those medicines.

Check with your doctor as soon as possible if any of the following side effects occur while taking oprelvekin:

• Fast heartbeat
• fluid retention
• irregular heartbeat
• shortness of breath
• sore mouth or tongue
• swelling of feet or lower legs
• white patches in mouth and/or on tongue

• Bloody eye
• blurred vision
• severe redness and peeling of skin

• bleeding
• blistering
• bloody urine
• blurred vision
• burning
• change in ability to see colors, especially blue or yellow
• cloudy urine
• coldness
• cough
• decrease or increase in amount of urine
• difficulty swallowing
• discoloration of skin
• dizziness
• fainting or lightheadedness
• fast heartbeat
• feeling of pressure
• hives
• increased blood pressure
• increased thirst
• infection
• inflammation
• itching
• loss of appetite
• lower back/side pain
• lumps
• nausea
• numbness
• pain
• puffiness or swelling of the eyelids or around the eyes face, lips or tongue
• rash
• redness
• scarring
• shortness of breath
• skin rash
• soreness
• stinging
• stomach pain;
• swelling
• tenderness
• tightness in chest
• tingling
• troubled breathing
• ulceration
• unusual tiredness or weakness
• vomiting
• warmth at site
• weight gain
• wheezing

This medicine may also cause the following side effect that your doctor will watch for:

• Heart rhythm problems

Some side effects of oprelvekin may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Red eyes
• weakness

• Numbness or tingling of hands or feet
• skin discoloration
• skin rash at place of injection