"Sabahaddin Akman, owner of the Istanbul, Turkey, firm Ozay Pharmaceuticals, has pleaded guilty to charges of smuggling misbranded and adulterated cancer treatment drugs into the United States.
Akman pleaded guilty in the U.S. District Court"...
Allergic Reactions Including Anaphylaxis
In the post-marketing setting, Neumega (oprelvekin) has caused allergic or hypersensitivity reactions, including anaphylaxis. The administration of Neumega (oprelvekin) 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 (see PRECAUTIONS, Information for Patients). 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 (oprelvekin) . Administration of Neumega (oprelvekin) should be permanently discontinued in any patient who develops an allergic or hypersensitivity reaction (see BOXED WARNING, CONTRAINDICATIONS, ADVERSE REACTIONS, and ADVERSE REACTIONS, Immunogenicity).
Increased Toxicity Following Myeloablative Therapy
Neumega (oprelvekin) is not indicated following myeloablative chemotherapy. In a randomized, placebocontrolled Phase 2 study, the effectiveness of Neumega (oprelvekin) was not demonstrated (see Clinical Studies, Study in Patients Following Myeloablative Chemotherapy). In this study, a statistically significant increased incidence in edema, conjunctival bleeding, hypotension, and tachycardia was observed in patients receiving Neumega (oprelvekin) as compared to placebo.
The following severe or fatal adverse reactions have been reported in post-marketing use in patients who received Neumega (oprelvekin) following bone marrow transplantation: fluid retention or overload (eg, facial edema, pulmonary edema), capillary leak syndrome, pleural and pericardial effusion, papilledema and renal failure.
Neumega (oprelvekin) 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 (oprelvekin) . Neumega (oprelvekin) is not indicated following myeloablative chemotherapy (see CLINICAL PHARMACOLOGY, Pharmacodynamics; WARNINGS, Increased Toxicity Following Myeloablative Therapy; WARNINGS, Cardiovascular Events; and WARNINGS, Dilutional Anemia). 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 (oprelvekin) . During dosing with Neumega (oprelvekin) , 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 (see ADVERSE REACTIONS).
Pre-existing fluid collections, including pericardial effusions or ascites, should be monitored. Drainage should be considered if medically indicated.
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 (oprelvekin) , and is reversible over approximately a week following discontinuation of Neumega (oprelvekin) (see WARNINGS, Fluid Retention).
Neumega (oprelvekin) use is associated with cardiovascular events including arrhythmias and pulmonary edema. Cardiac arrest has been reported, but the causal relationship to Neumega (oprelvekin) 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 (oprelvekin) at doses of 50 µg/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 (oprelvekin) .
The mechanism for induction of arrhythmias is not known. Neumega (oprelvekin) 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 (see WARNINGS, 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 (oprelvekin) (see WARNINGS, Cardiovascular Events). Patients with a history of stroke or transient ischemic attack may also be at increased risk for these events.
Papilledema has been reported in 2% (10/405) of patients receiving Neumega (oprelvekin) 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 (oprelvekin) at a dose of 1,000 µg/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 (oprelvekin) 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 (see ADVERSE REACTIONS). Changes in visual acuity and/or visual field defects ranging from blurred vision to blindness can occur in patients with papilledema taking Neumega (oprelvekin) .
Dosing with Neumega (oprelvekin) should begin 6 to 24 hours following the completion of chemotherapy dosing. The safety and efficacy of Neumega (oprelvekin) 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 (oprelvekin) 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).
Neumega (oprelvekin) 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 (oprelvekin) 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 (oprelvekin) should be used under the guidance and supervision of a health care professional. However, when the physician determines that Neumega (oprelvekin) may be used outside of the hospital or office setting, persons who will be administering Neumega (oprelvekin) 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 (oprelvekin) 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 (oprelvekin) . 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 (oprelvekin) 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 (oprelvekin) (see PRECAUTIONS, Pregnancy Category C).
Acomplete 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 (postnadir counts ≥ 50,000/µL).
Carcinogenesis, Mutagenesis, Impairment of Fertility
No studies have been performed to assess the carcinogenic potential of Neumega (oprelvekin) .
In vitro, Neumega (oprelvekin) did not stimulate the growth of tumor colony-forming cells harvested from patients with a variety of human malignancies. Neumega (oprelvekin) has been shown to be non-genotoxic in in vitro studies. These data suggest that Neumega (oprelvekin) 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 (oprelvekin) at doses up to 1000 µg/kg/day.
Pregnancy Category C
Neumega (oprelvekin) 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 (oprelvekin) in pregnant women. Neumega (oprelvekin) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Neumega (oprelvekin) 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 (oprelvekin) is given at doses of two to 20 times the human dose ( ≥ 100 µg/kg/day) in the rat and at 0.02 to 2.0 times the human dose ( ≥ 1 µg/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 µg/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 (oprelvekin) were observed in rabbits at doses up to 0.6 times the human dose (30 µg/kg/day).
Adverse effects in the first generation offspring of rats given Neumega (oprelvekin) at maternally toxic doses ≥ 2 times the human dose ( ≥ 100 µg/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 µg/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.
It is not known if Neumega (oprelvekin) 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 (oprelvekin) , a decision should be made whether to discontinue nursing or to discontinue Neumega (oprelvekin) , taking into account the importance of the drug to the mother.
A safe and effective dose of Neumega (oprelvekin) has not been established in children. In a Phase 1, single arm, dose-escalation study, 43 pediatric patients were treated with Neumega (oprelvekin) at doses ranging from 25 to 125 µg/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 µg/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 (oprelvekin) at a dose of 50 µg/kg in the randomized studies in adults receiving chemotherapy (see ADVERSE REACTIONS).
Studies in animals were predictive of the effect of Neumega (oprelvekin) on developing bone in children. In growing rodents treated with 100, 300, or 1000 µg/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 (oprelvekin) , animals treated for two to 13 weeks at doses of 10 to 1000 µg/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 (oprelvekin) treatment. The relationship of these findings to treatment with Neumega (oprelvekin) is unclear. No studies have been performed to assess the long-term effects of Neumega (oprelvekin) on growth and development.
Use in Patients with Renal Impairment
Neumega (oprelvekin) is eliminated primarily by the kidneys. The pharmacokinetics of Neumega (oprelvekin) 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 (oprelvekin) 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 (oprelvekin) treatment has not been studied in patients with renal impairment, but fluid balance should be carefully monitored in these patients (see WARNINGS, Fluid Retention).
Last reviewed on RxList: 10/21/2008
This monograph has been modified to include the generic and brand name in many instances.
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